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Cardiac stem cells: biology and clinical applications.

By Sykes24Tracey

SIGNIFICANCE:

Heart disease is the primary cause of death in the industrialized world. Cardiac failure is dictated by an uncompensated reduction in the number of viable and fully functional cardiomyocytes. While current pharmacological therapies alleviate the symptoms associated with cardiac deterioration, heart transplantation remains the only therapy for advanced heart failure. Therefore, there is a pressing need for novel therapeutic modalities. Cell-based therapies involving cardiac stem cells (CSCs) constitute a promising emerging approach for the replenishment of the lost tissue and the restoration of cardiac contractility.

CSCs reside in the adult heart and govern myocardial homeostasis and repair after injury by producing new cardiomyocytes and vascular structures. In the last decade, different classes of immature cells expressing distinct stem cell markers have been identified and characterized in terms of their growth properties, differentiation potential, and regenerative ability. Phase I clinical trials, employing autologous CSCs in patients with ischemic cardiomyopathy, are being completed with encouraging results.

Accumulating evidence concerning the role of CSCs in heart regeneration imposes a reconsideration of the mechanisms of cardiac aging and the etiology of heart failure. Deciphering the molecular pathways that prevent activation of CSCs in their environment and understanding the processes that affect CSC survival and regenerative function with cardiac pathologies, commonly accompanied by alterations in redox conditions, are of great clinical importance.

Further investigations of CSC biology may be translated into highly effective and novel therapeutic strategies aiming at the enhancement of the endogenous healing capacity of the diseased heart.

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Guidelines for Preventing Opportunistic Infections Among …

By Sykes24Tracey

Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Please note: An erratum has been published for this article. To view the erratum, please click here.

Clare A. Dykewicz, M.D., M.P.H. Harold W. Jaffe, M.D., Director Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention

Clare A. Dykewicz, M.D., M.P.H., Chair Harold W. Jaffe, M.D. Thomas J. Spira, M.D. Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D. Hospital Infections Program National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D. Division of HIV/AIDS Prevention---Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A. Beth Hibbs, R.N., M.P.H. Epidemiology and Surveillance Division National Immunization Program, CDC

Raleigh A. Bowden, M.D. Keith Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

David Emanuel, M.B.Ch.B. Indiana University Indianapolis, Indiana

David L. Longworth, M.D. Cleveland Clinic Foundation Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S. International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry Milwaukee, Wisconsin

Robert H. Rubin, M.D. Massachusetts General Hospital Boston, Massachusetts and Massachusetts Institute of Technology Cambridge, Massachusetts

Kent A. Sepkowitz, M.D. Memorial-Sloan Kettering Cancer Center New York, New York

John R. Wingard, M.D. University of Florida Gainesville, Florida

John F. Modlin, M.D. Dartmouth Medical School Hanover, New Hampshire

Donna M. Ambrosino, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Norman W. Baylor, Ph.D. Food and Drug Administration Rockville, Maryland

Albert D. Donnenberg, Ph.D. University of Pittsburgh Pittsburgh, Pennsylvania

Pierce Gardner, M.D. State University of New York at Stony Brook Stony Brook, New York

Roger H. Giller, M.D. University of Colorado Denver, Colorado

Neal A. Halsey, M.D. Johns Hopkins University Baltimore, Maryland

Chinh T. Le, M.D. Kaiser-Permanente Medical Center Santa Rosa, California

Deborah C. Molrine, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Keith M. Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)2, IgG4, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 106 leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

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Regenerative Medicine Conferences | Tissue Engineering …

By Sykes24Tracey

The 5th International Conference on Tissue Engineering & Regenerative Medicine which is going to be held during September 12-14, 2016 at Berlin, Germany will bring together world-class personalities working on stem cells, tissue engineering and regenerative medicine to discuss materials-related strategies for disease remediation and tissue repair.

Tissue Regeneration

In the field of biology, regeneration is the progression of renewal, regeneration and growth that makes it possible for genomes, cells, organ regeneration to natural changes or events that cause damage or disturbance.This study is carried out as craniofacial tissue engineering, in-situtissue regeneration, adipose-derived stem cells for regenerative medicine which is also a breakthrough in cell culture technology. The study is not stopped with the regeneration of tissue where it is further carried out in relation with cell signaling, morphogenetic proteins. Most of the neurological disorders occurred accidental having a scope of recovery by replacement or repair of intervertebral discs repair, spinal fusion and many more advancements. The global market for tissue engineering and regeneration products such as scaffolds, tissueimplants, biomimetic materials reached $55.9 billion in 2010 and it is expected to reach $89.7 billion by 2016 at a compounded annual growth rate (CAGR) of 8.4%. It grows to $135 billion by 2024.

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Designs for Tissue Engineering

The developing field of tissue engineering aims to regenerate damaged tissues by combining cells from the body withbioresorbablematerials, biodegradable hydrogel, biomimetic materials, nanostructures andnanomaterials, biomaterials and tissue implants which act as templates for tissue regeneration, to guide the growth of new tissue by using with the technologies. The global market for biomaterials, nanostructures and bioresorbable materials are estimated to reach $88.4 billion by 2017 from $44.0 billion in 2012 growing at a CAGR of 15%. Further the biomaterials market estimated to be worth more than 300 billion US Dollars and to be increasing 20% per year.

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Organ Engineering

This interdisciplinary engineering has attracted much attention as a new therapeutic means that may overcome the drawbacks involved in the current artificial organs and organtransplantationthat have been also aiming at replacing lost or severely damaged tissues or organs. Tissue engineering and regenerative medicine is an exciting research area that aims at regenerative alternatives to harvested tissues for organ transplantation with soft tissues. Although significant progress has been made in thetissue engineeringfield, many challenges remain and further development in this area will require ongoing interactions and collaborations among the scientists from multiple disciplines, and in partnership with the regulatory and the funding agencies. As a result of the medical and market potential, there is significant academic and corporate interest in this technology.

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Cancer Stem Cells

The characterization of cancer stem cell is done by identifying the cell within a tumor that possesses the capacity to self-renew and to cause theheterogeneous lineagesof cancer cells that comprise the tumor. This stem cell which acts as precursor for the cancer acts as a tool against it indulging the reconstruction of cancer stem cells, implies as the therapeutic implications and challenging the gaps globally. The global stem cell market will grow from about $5.6 billion in 2013 to nearly $10.6 billion in 2018, registering a compound annual growth rate (CAGR) of 3.6% from 2013 through 2018. The Americas is the largest region of globalstem cellmarket, with a market share of about $2.0 billion in 2013. The region is projected to increase to nearly $3.9 billion by 2018, with a CAGR of 13.9% for the period of 2013 to 2018. Europe is the second largest segment of the global stem cell market and is expected to grow at a CAGR of 13.4% reaching about $2.4 billion by 2018 from nearly $1.4 billion in 2013.

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Bone Tissue Engineering

Tissue engineering ofmusculoskeletal tissues, particularly bone and cartilage, is a rapidly advancing field. In bone, technology has centered on bone graft substitute materials and the development of biodegradable scaffolds. Recently, tissue engineering strategies have included cell and gene therapy. The availability of growth factors and the expanding knowledge base concerning the bone regeneration with modern techniques like recombinant signaling molecules, solid free form fabrication of scaffolds, synthetic cartilage, Electrochemical deposition,spinal fusionand ossification are new generated techniques for tissue-engineering applications. The worldwide market for bone and cartilage repairs strategies is estimated about $300 million. During the last 10/15 years, the scientific community witnessed and reported the appearance of several sources of stem cells with both osteo and chondrogenic potential.

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Scaffolds

Scaffolds are one of the three most important elements constituting the basic concept of regenerative medicine, and are included in the core technology of regenerative medicine. Every day thousands of surgical procedures are performed to replace or repair tissue that has been damaged through disease or trauma. The developing field of tissue engineering (TE) aims to regeneratedamaged tissuesby combining cells from the body with highly porous scaffold biomaterials, which act as templates for tissue regeneration, to guide the growth of new tissue. Scaffolds has a prominent role in tissue regeneration the designs, fabrication, 3D models, surface ligands and molecular architecture, nanoparticle-cell interactions and porous of thescaffoldsare been used in the field in attempts to regenerate different tissues and organs in the body. The world stem cell market was approximately 2.715 billion dollars in 2010, and with a growth rate of 16.8% annually, a market of 6.877 billion dollars will be formed in 2016. From 2017, the expected annual growth rate is 10.6%, which would expand the market to 11.38 billion dollars by 2021.

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Tissue Regeneration Technologies

Guided tissue regeneration is defined as procedures attempting to regenerate lost periodontal structures through differential tissue responses. Guidedbone regenerationtypically refers to ridge augmentation or bone regenerative procedures it typically refers to regeneration of periodontal therapy. The recent advancements and innovations in biomedical and regenerative tissue engineering techniques include the novel approach of guided tissue regeneration and combination ofnanotechnologyand regenerative medicine.

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Regeneration and Therapeutics

Regenerative medicinecan be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies. It deals with the different therapeutic uses like stem cells for tissue repair, tissue injury and healing process, cardiacstem cell therapyfor regeneration, functional regenerative recovery, effects of aging on tissuerepair/regeneration, corneal regeneration & degeneration. The global market is expected to reach $25.5 billion by 2011 and will further grow to $36.1 billion by 2016 at a CAGR of 7.2%. It is expected to reach $65 billion mark by 2024.

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Regenerative medicine

Regenerative medicine is a branch oftranslational researchin tissue engineering and molecular biology which deals with the process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function. The latest developments involve advances in cell and gene therapy and stem cell research, molecular therapy, dental and craniofacial regeneration.Regenerative medicineshave the unique ability to repair, replace and regenerate tissues and organs, affected due to some injury, disease or due to natural aging process. These medicines are capable of restoring the functionality of cells and tissues. The global regenerative medicine market will reach $ 67.6 billion by 2020 from $16.4 billion in 2013, registering a CAGR of 23.2% during forecast period (2014 - 2020). Small molecules and biologics segment holds prominent market share in the overall regenerative medicine technology market and is anticipated to grow at a CAGR of 18.9% during the forecast period.

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Applications of Tissue Engineering

The applications of tissue engineering and regenerative medicine are innumerable as they mark the replacement of medication andorgan replacement. The applications involve cell tracking andtissue imaging, cell therapy and regenerative medicine, organ harvesting, transport and transplant, the application of nanotechnology in tissue engineering and regenerative medicine and bio banking. Globally the research statistics are increasing at a vast scale and many universities and companies are conducting events on the subject regenerative medicine conference like tissue implants workshops, endodontics meetings, tissue biomarkers events, tissue repair meetings, regenerative medicine conferences, tissue engineering conference, regenerative medicine workshop, veterinary regenerative medicine, regenerative medicine symposiums, tissue regeneration conferences, regenerative medicine congress.

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Regenerative Medicine Market

There are strong pricing pressures from public healthcare payers globally as Governments try to reduce budget deficits. Regenerative medicine could potentially save public health bodies money by reducing the need for long-term care and reducing associated disorders, with potential benefits for the world economy as a whole.The global market fortissue engineeringand regeneration products reached $55.9 billion in 2010, is expected to reach $59.8 billion by 2011, and will further grow to $89.7 billion by 2016 at a compounded annual growth rate (CAGR) of 8.4%. It grows to $135 billion to 2024. The contribution of the European region was 43.3% of the market in 2010, a value of $24.2 billion. Themarketis expected to reach $25.5 billion by 2011 and will further grow to $36.1 billion by 2016 at a CAGR of 7.2%. It grows to $65 billion to 2024.

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Regenerative Medicine Europe

Leading EU nations with strong biotech sectors such as the UK and Germany are investing heavily in regenerative medicine, seeking competitive advantage in this emerging sector. The commercial regenerative medicine sector faces governance challenges that include a lack of proven business models, an immature science base and ethical controversy surrounding hESC research. The recent global downturn has exacerbated these difficulties: private finance has all but disappeared; leading companies are close to bankruptcy, and start-ups are struggling to raise funds. In the UK the government has responded by announcing 21.5M funding for the regenerative medicine industry and partners. But the present crisis extends considerably beyond regenerative medicine alone, affecting much of the European biotech sector. A 2009 European Commission (EC) report showed the extent to which the global recession has impacted on access to VC finance in Europe: 75% of biopharma companies in Europe need capital within the next two years if they are to continue their current range of activities.

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Embryonic Stem Cell

Embryonic stem cells are pluripotent, meaning they are able to grow (i.e. differentiate) into all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body as long as they are specified to do so. Embryonic stem cells are distinguished by two distinctive properties: their pluripotency, and their ability to replicate indefinitely. ES cells are pluripotent, that is, they are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult body. Pluripotency distinguishes embryonic stem cells from adult stem cells found in adults; while embryonic stem cells can generate all cell types in the body, adult stem cells are multipotent and can produce only a limited number of cell types. Additionally, under defined conditions, embryonic stem cells are capable of propagating themselves indefinitely. This allows embryonic stem cells to be employed as useful tools for both research and regenerative medicine, because they can produce limitless numbers of themselves for continued research or clinical use.

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Stem Cell Transplant

Stem cell transplantation is a procedure that is most often recommended as a treatment option for people with leukemia, multiple myeloma, and some types of lymphoma. It may also be used to treat some genetic diseases that involve the blood. During a stem cell transplant diseased bone marrow (the spongy, fatty tissue found inside larger bones) is destroyed with chemotherapy and/or radiation therapy and then replaced with highly specialized stem cells that develop into healthy bone marrow. Although this procedure used to be referred to as a bone marrow transplant, today it is more commonly called a stem cell transplant because it is stem cells in the blood that are typically being transplanted, not the actual bone marrow tissue.

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Market Analysis Report:

Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ. Regenerative medicine is not one discipline. It can be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies

Currently it has emerged as a rapidly diversifying field with the potential to address the worldwide organ shortage issue and comprises of tissue regeneration and organ replacement. Regenerative medicine could potentially save public health bodies money by reducing the need for long-term care and reducing associated disorders, with potential benefits for the world economy as a whole.The global tissue engineering and regeneration market reached $17 billion in 2013. This market is expected to grow to nearly $20.8 billion in 2014 and $56.9 billion in 2019, a compound annual growth rate (CAGR) of 22.3%. On the basis of geography, Europe holds the second place in the global market in the field of regenerative medicine & tissue engineering. In Europe countries like UK, France and Germany are possessing good market shares in the field of regenerative medicine and tissue engineering. Spain and Italy are the emerging market trends for tissue engineering in Europe.

Tissue engineering is "an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ. Currently it has emerged as a rapidly diversifying field with the potential to address the worldwide organ shortage issue and comprises of tissue regeneration and organ replacement. A novel set of tissue replacement parts and implementation strategies had shown a great revolution in this field. Cells placed on or within the tissue constructs is the most common methodology in tissue engineering.

Regenerative medicine is not one discipline. It can be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies

This field continues to evolve. In addition to medical applications, non-therapeutic applications include using tissues as biosensors to detect biological or chemical threat agents, and tissue chips that can be used to test the toxicity of an experimental medication. Tissue Engineering and Regenerative Medicine is the major field in Medicine, which is still under research and the advancements are maximizing day to day.

Regenerative Medicine-2015 is an engrossed a vicinity of cognizant discussions on novel subjects like Tissue Regeneration, Materials & Designs for Tissue Engineering, Stem CellTools to Battle Cancer, Bioreactors in Tissue Engineering, Regeneration & Therapeutics, Cord Blood & Regenerative Medicine and Clinical Medicine, to mention a few. The three days event implants a firm relation of upcoming strategies in the field of Tissue Science & Regenerative Medicine with the scientific community. The conceptual and applicable knowledge shared, will also foster organizational collaborations to nurture scientific accelerations.We bring together business, creative, and technology leaders from the tissue engineering, marketing, and research industry for the most current and relevant.

Berlin is one of the largest and most diverse science regions in Europe. Roughly 200,000 people from around the world teach, research, work and study here. Approximately 17 percent of all students come from abroad, most of them from China, Russia and the USA. Many cooperative programs link Berlins institutes of higher education with partner institutes around the world. Berlin is a city of science at the heart of Europe a city whose history of scientific excellence stems from its many important research institutions and its long track record of scientific breakthroughs. Berlin has numerous modern Technology Centers. Their science-oriented infrastructure makes them attractive locations for young, technology-oriented companies.

Germany places great emphasis on globally networked research cooperation. Many organizations support international researchers and academics: Today more than 32,000 are being supported with scholarships. Besides this, research funding in Germany has the goal of financing the development of new ideas and technologies. The range covers everything from basic research in natural sciences, new technologies to structural research funding at institutions of higher education. On the basis of geography, the regenerative medicine bone and joint market Europe hold the second place in the global market in the field of regenerative medicine & tissue engineering. The market growth is expected to reach $65 billion by 2024 in Europe. In Europe countries like UK, France, and Germany are possessing good market share in the field of regenerative medicine and tissue engineering. Spain and Italy are the emerging market trends for tissue engineering in Europe. As per the scope and emerging market for tissue engineering and regenerative medicine Berlin has been selected as Venue for the 5th International Conference on Tissue Science and Regenerative Medicine.

Meet Your Target MarketWith members from around the world focused on learning about Advertising and marketing, this is the single best opportunity to reach the largest assemblage of participants from the tissue engineering and regenerative medicine community. The meeting engrossed a vicinity of cognizant discussions on novel subjects like Tissue Regeneration, Materials & Designs for Tissue Engineering, Stem CellTools to Battle Cancer, Bioreactors in Tissue Engineering, Regeneration & Therapeutics, Cord Blood & Regenerative Medicine and Clinical Medicine, to mention a few. The three days event implants a firm relation of upcoming strategies in the field of Tissue Engineering & Regenerative Medicine with the scientific community. The conceptual and applicable knowledge shared, will also foster organizational collaborations to nurture scientific accelerations.Conduct demonstrations, distribute information, meet with current and potential customers, make a splash with a new product line, and receive name recognition.

International Stem Cell Forum (ISCF)

International Society for Stem Cell Research (ISSCR)

UK Medical Research Council (MRC)

Australian Stem Cell Center

Canadian Institutes of Health Research (CIHR)

Euro Stem Cell (ACR)

Center for Stem Cell Biology

Stem Cell Research Singapore

UK National Stem Cell Network

Spain Mobile Marketing Association

European Marketing Confederation (EMC)

European Letterbox Marketing Association(ELMA)

European Sales & Marketing Association (ESMA)

The Incentive Marketing Association (IMA Europe)

European Marketing Academy

Figure 1: Statistical Analysis of Societies and Associations

Source: Reference7

Presidents or Vice Presidents/ Directors of Associations and Societies, CEOs of the companies associated with regenerative medicine and tissue engineering Consumer Products. Retailers, Marketing, Advertising and Promotion Agency Executives, Solution Providers (digital and mobile technology, P-O-P design, retail design, and retail execution), Professors and Students from Academia in the study of Marketing and Advertising filed.

Industry 40%

Academia 50%

Others 10%

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Regenerative Medicine Conferences | Tissue Engineering ...

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Bone marrow transplant – NHS Choices

By Sykes24Tracey

Introduction

A bone marrow transplant, alsoknown as a haemopoietic stem cell transplant, replaces damaged bone marrow with healthy bone marrow stem cells.

Bone marrow is aspongytissue found in the hollow centres of some bones. It contains specialist stem cells, which produce the body's blood cells.

Stem cells in bone marrow produce three important types of blood cells:

Bone marrow transplants are often needed to treat conditions thatdamage bone marrow. If bone marrow is damaged, it is no longer able to produce normal blood cells. The new stem cells take over blood cellproduction.

Conditions that bone marrow transplants are used to treat include:

Read more about why a bone marrow transplantis needed.

A bone marrow transplant involves taking healthy stem cells from the bone marrow of one person and transferring them to the bone marrow of another person.

In some cases, it may be possible to take the bone marrow from your own body. This is known as an autologous transplantation. Before it is returned, the bone marrow is cleared of any damaged or diseased cells.

A bone marrowtransplant has five stages. These are:

Having a bone marrow transplant can be an intensive and challenging experience. Many people take up to a year to fully recover from the procedure.

Read more about what happens during a bone marrow transplant.

Bone marrow transplants are usually only recommended if:

Read more about who can have a bone marrow transplant.

Bone marrow transplants arecomplicated procedures with significant risks.

In some cases, the transplanted cells (graft cells) recognise the recipient's cells as "foreign"and try to attack them. This is known as graft versus host disease (GvHD).

The risk of infectionis alsoincreased because your immune system is weakened when you're conditioned (prepared) for the transplant.

Read more about the risks of having a bone marrow transplant.

It's nowpossible to harvest stem cells from sources other than bone marrow.

Peripheral blood stem cell donation involves injectinga medicine into the donor's blood thatcauses the stem cells to moveout of the bone marrow and into the bloodstream where theycan be harvested (collected).

The advantage of this type of stem cell donation is that the donor doesn't needa general anaesthetic.

Stem cells can also be collectedfrom the placenta and umbilical cord of a newborn baby and stored in a laboratory until they're needed.

Cord blood stem cells are very usefulbecause they don't need to be as closely matched as bone marrow or peripheral blood stem cells for a successful outcome.

Find out more about theNHS Cord Blood Bank(external link).

Page last reviewed: 18/02/2014

Next review due: 18/02/2016

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The Rockefeller University Stem Cells of the Skin and …

By Sykes24Tracey

We observed similar stem cell plasticity when we purified and tested the myoepithelial stem cells from sweat glands (Lu et al., 2012; Blanpain and Fuchs, 2014). Similar to myoepithelial stem cells of mammary glands, these stem cells normally act unipotently and only replenish dying myoepithelial cells of the gland. However, when purified by fluorescence activated cell sorting (FACS) and transplanted directly into a mammary fat pad, the stem cells can regenerate the complete bi-layered gland, and the new luminal cells secrete sweat. Moreover, when engrafted to the skin, these stem cells can make epidermis. An area of interest in my lab is to understand the environmental cues that dictate the fascinating plasticity of epithelial stem cells, and to elucidate the chromatin remodeling that leads to the changes in gene expression necessary to generate different tissues from a common progenitor.

To understand how a stem cell chooses its differentiation pathway, we have taken several approaches. An ongoing approach of the lab is to express different fluorescent proteins under the control of various skin promoters, active at different stages in stem cells and their lineages. Through FACS, we've purified cells at different time points along the lineages and generated a battery of lineage-specific profiles, enabling us to define at an mRNA (RNA-seq) and chromatin (ChIP-seq) level how stem cells change as they transition from quiescence to activation to lineage determination. Our global objective is to exploit this information to understand how stem cells receive signals, change their program of gene expression and select a lineage. We also want to understand the functional significance of these changes. The beauty of the hair follicle as a model is that it is currently the only system where sufficient quantities of stem cells can be isolated directly from their native niche in order to carry out whole-genome wide analyses in vivo. This eliminates the caveats arising from culturing cells, namely induction of a stress response and large-scale epigenetic changes in gene expression.

For the hair follicle, >150 mRNAs are selectively upregulated in the bulge stem cells relative to their short-lived progeny (Tumbar et al., 2004; Blanpain et al., 2004; Keyes et al., 2013). A number of these changes are in transcription factors and epigenetic regulators. Weve conducted in vivo chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) on chromatin from hair follicle stem cells (HFSCs) and their short-lived progeny. Bioinformatics reveals which genes bind these transcription factors, and how this changes as the stem cells progress to form transiently dividing cells that then terminally differentiate along one of the 7 distinct concentric cell layers that constitute the hair and its channel. By conducting high throughput RNA sequencing (RNA-seq) on HFSCs lacking each of these genes, weve learned which target genes depend upon binding these transcription factors. Finally, by engineering inducible-conditional knockouts to selectively remove these transcription factors in the stem cells, weve learned the physiological relevance of these factors.

Based upon these analyses, TCF3/TCF4, LHX2 and SOX9 are all essential for maintaining the hair follicle stem cells in their native niche (Nguyen et al., 2006; 2009; Rhee et al., 2006; Folgueras et al., 2013; Lien et al., 2011; 2014; Nowak et al., 2008; Kadaja et al., 2014). In addition, LHX2 represses sebaceous gland differentiation: following its loss, the stem cell niche soon becomes a sebaceous gland (Folgueras et al., 2013). SOX9 represses epidermal differentiation: following its loss, the niche becomes an epidermal cyst (Kadaja et al., 2014). TCF3 and TCF4 repress HF differentiation: following their loss, quiescent HFSCs precociously activate a new hair cycle (Lien et al., 2014). TCF3 and TCF4 can partner with -catenin, which is stabilized and becomes nuclear upon Wnt signaling: if -catenin is silenced in the quiescent HFSCs, they never reenter a new hair cycle. In their native niche, quiescent HFSCs express a transcriptional repressor TLE4 which binds to TCF3 and TCF4: our findings are consistent with the view that Wnt signaling functions by relieving TCF3/4/TLE4-mediated repression (Lien et al., 2014).

NFATc1 is required for maintaining HFSC quiescence, and in its absence, HFs cycle precociously (Horsley et al., 2008). Additionally, NFATc1 is downstream of BMP signaling, offering a potential explanation as to why BMP signaling must be lowered to activate hair cycling. A major feature of the aging HFSC signature is elevated NFATc1 target genes, and we can stimulate old follicles by inhibiting NFATc1 (Keyes et al., 2013). A major question still to be answered is whether HFSCs have an endless capacity for hair cycling and whether this same phenomenon operates in aging scalp hairs in humans. If so, these findings may open new doors for future therapeutics.

NFiB is a transcription factor which is specific to the HFSCs, but functions by repressing the expression of genes that are essential for the differentiation of the melanocyte stem cells, which reside within the same stem cell niche (Chang et al., 2013). These two stem cell populations must be activated at the same time so that differentiating melanocytes can transfer pigment to the differentiating hair cells to provide the natural coloring to our hair. Loss of NFiB uncouples this crosstalk and leads to the precocious activation of a key NFiB target gene that encodes a secreted melanocyte differentiation factor (Chang et al., 2013).

There are a number of additional transcription factors and epigenetic regulators which are enhanced in the complex milieu of HF stem cell chromatin, and there is still much to be learned. Of the epigenetic regulators, weve thus far examined only the role of polycomb chromatin repressor complexes, which weve shown function critically in controlling the fate switch from a stem cell to a committed, transit-amplifying state (Ezhkova et al., 2009; 2011; Lien et al., 2011). In coming years, we will continue to systematically work our way through the functional significance and mechanism of action of epigenetic and transcriptional controls on stem cells as they transit from a quiescent to activated to committed state. When coupled with our recent ability to efficiently knockdown genes in a few days using lentiviral-mediated shRNA delivery (Beronja et al., 2010), this now becomes a powerful tool for exploiting bioinformatics analyses to gain biological insights.

Our ultimate goal is to understand how external signals from the surrounding niche microenvironment impact chromatin dynamics to achieve tissue production. Equally important will be the expression of specific genes that enables them to remodel their cytoskeleton and adhesive contacts and either form a stratified epidermis or an epithelial bud that can then develop into a hair follicle (Perez-Moreno et al., 2003; Blanpain and Fuchs, 2009; Hsu et al., 2014). While our model is the skin, the problem is a general one of how a single epithelial stem cell gives rise to a spatially organized, functional tissue. It is also integrally linked to understanding the basis of cancer progression.

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Challenges in identifying the best source of stem cells …

By Sykes24Tracey

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Challenges in identifying the best source of stem cells ...

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Induced pluripotent stem cell – Wikipedia, the free …

By Sykes24Tracey

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.[1] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent." [2]

Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) [3] of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines.

Since iPSCs can be derived directly from adult tissues, they not only bypass the need for embryos, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific basis of disease.[citation needed]

Depending on the methods used, reprogramming of adult cells to obtain iPSCs may pose significant risks that could limit their use in humans. For example, if viruses are used to genomically alter the cells, the expression of oncogenes (cancer-causing genes) may potentially be triggered. In February 2008, scientists announced the discovery of a technique that could remove oncogenes after the induction of pluripotency, thereby increasing the potential use of iPS cells in human diseases.[4] In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency.[5] The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

iPSCs are typically derived by introducing a specific set of pluripotency-associated genes, or reprogramming factors, into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the genes Oct4 (Pou5f1), Sox2, cMyc, and Klf4. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.

iPSC derivation is typically a slow and inefficient process, taking 12 weeks for mouse cells and 34 weeks for human cells, with efficiencies around 0.01%0.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes.

Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University, Japan, in 2006.[1] Their hypothesis was that genes important to embryonic stem cell function might be able to induce an embryonic state in adult cells. They began by choosing twenty-four genes that were previously identified as important in embryonic stem cells, and used retroviruses to deliver these genes to fibroblasts from mice. The mouse fibroblasts were engineered so that any cells that reactivated the ESC-specific gene, Fbx15, could be isolated using antibiotic selection.

Upon delivery of all twenty-four factors, colonies emerged that had reactivated the Fbx15 reporter, resembled ESCs, and could propagate indefinitely. They then narrowed their candidates by removing one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which as a group were both necessary and sufficient to obtain ESC-like colonies under selection for reactivation of Fbx15.

Similar to ESCs, these first-generation iPSCs showed unlimited self-renewal and demonstrated pluripotency by contributing to lineages from all three germ layers in the context of embryoid bodies, teratomas, fetal chimeras. However, the molecular makeup of these cells, including gene expression and epigenetic marks, was somewhere between that of a fibroblast and an ESC, and the cells also failed to produce viable chimeras when injected into developing embryos.

In June 2007, the same group published a breakthrough study along with two other independent research groups from Harvard, MIT, and the University of California, Los Angeles, showing successful reprogramming of mouse fibroblasts into iPS cells. Unlike the first generation of iPS cells, these cells could produce viable chimeric mice and could contribute to the germline, the 'gold standard' for pluripotent stem cells. These cells were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4), but the researchers used a different marker to select for pluripotent cells. Instead of Fbx15, they used Nanog, a gene that is functionally important in ESCs. By using this different strategy, the researchers were able to create iPS cells that were more similar to ESCs than the first generation of iPS cells, and independently proved that it was possible to create iPS cells that are functionally identical to ESCs.[6][7][8][9]

Unfortunately, two of the four genes used (namely, c-Myc and KLF4) are oncogenic, and 20% of the chimeric mice developed cancer. In a later study, Yamanaka reported that one can create iPSCs even without c-Myc. The process takes longer and is not as efficient, but the resulting chimeras didn't develop cancer.[10]

Induced pluripotent cells have been made from adult stomach, liver, skin cells, blood cells, prostate cells and urinary tract cells.[11]

In November 2007, a milestone was achieved[12][13] by creating iPSCs from adult human cells; two independent research teams' studies were released one in Science by James Thomson at University of WisconsinMadison[14] and another in Cell by Shinya Yamanaka and colleagues at Kyoto University, Japan.[15] With the same principle used earlier in mouse models, Yamanaka had successfully transformed human fibroblasts into pluripotent stem cells using the same four pivotal genes: Oct3/4, Sox2, Klf4, and c-Myc with a retroviral system. Thomson and colleagues used OCT4, SOX2, NANOG, and a different gene LIN28 using a lentiviral system.

On 8 November 2012, researchers from Austria, Hong Kong and China presented a protocol for generating human iPSCs from exfoliated renal epithelial cells present in urine on Nature Protocols.[16] This method of acquiring donor cells is comparatively less invasive and simple. The team reported the induction procedure to take less time, around 2 weeks for the urinary cell culture and 3 to 4 weeks for the reprogramming; and higher yield, up to 4% using retroviral delivery of exogenous factors. Urinary iPSCs (UiPSCs) were found to show good differentiation potential, and thus represent an alternative choice for producing pluripotent cells from normal individuals or patients with genetic diseases, including those affecting the kidney.[16]

Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

The table at right summarizes the key strategies and techniques used to develop iPS cells over the past half-decade. Rows of similar colors represents studies that used similar strategies for reprogramming.

One of the main strategies for avoiding problems (1) and (2) has been to use small compounds that can mimic the effects of transcription factors. These molecule compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanakas traditional transcription factor method).[25] The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency.[26] Deng et al. of Beijing University reported on July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse somatic cells into stem cells which they called CiPS cells with the efficiency at 0.2% comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.[27][28]

Ding et al. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the MET (mesenchymal-epithelial transition) process in which fibroblasts are pushed to a stem-cell like state, Dings group identified two chemicals ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, Thiazovivin further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks. [29][30]

Another key strategy for avoiding problems such as tumor genesis and low throughput has been to use alternate forms of vectors: adenovirus, plasmids, and naked DNA and/or protein compounds.

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis.[31] In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells.[32] Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid.[33] The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed the other three factors (Oct4, Klf4, and Sox2). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the piggyBac transposon system. The lifecycle of this system is shown below. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving any footprint mutations in the host cell genome. As demonstrated in the figure, the piggyBac transposon system involves the re-excision of exogenous genes, which eliminates issues like insertional mutagenesis

In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency.[34]

In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted.[35] On 4 June 2014, the lead author, Obokata agreed to retract both the papers [36] after she was found to have committed research misconduct as concluded in an investigation by RIKEN on 1 April 2014.[37]

Studies by Blelloch et al. in 2009 demonstrated that expression of ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhances the efficiency of induced pluripotency by acting downstream of c-Myc .[38] More recently (in April 2011), Morrisey et al. demonstrated another method using microRNA that improved the efficiency of reprogramming to a rate similar to that demonstrated by Ding. MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Morriseys team worked on microRNAs in lung development, and hypothesized that their microRNAs perhaps blocked expression of repressors of Yamanakas four transcription factors. Possible mechanisms by which microRNAs can induce reprogramming even in the absence of added exogenous transcription factors, and how variations in microRNA expression of iPS cells can predict their differentiation potential discussed by Xichen Bao et al.[39]

[citation needed]

The generation of iPS cells is crucially dependent on the genes used for the induction.

Oct-3/4 and certain members of the Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog, and LIN28, have been identified to increase the induction efficiency.

Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem (ES) cells, in many aspects, such as the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still being assessed.[42]

Gene expression and genome-wide H3K4me3 and H3K27me3 were found to be extremely similar between ES and iPS cells.[43][citation needed] The generated iPSCs were remarkably similar to naturally isolated pluripotent stem cells (such as mouse and human embryonic stem cells, mESCs and hESCs, respectively) in the following respects, thus confirming the identity, authenticity, and pluripotency of iPSCs to naturally isolated pluripotent stem cells:

Recent achievements and future tasks for safe iPSC-based cell therapy are collected in the review of Okano et al.[55]

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells. The Wu group at Stanford University has made significant progress with this strategy.[56] Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound[57]

An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease.[58][59] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy patients, providing insight into the pathophysiology of the disease.[60] An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of disease. Managed by the University of Oxford, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment.[61]

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human liver buds (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocytes (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in fetal development. After growing in vitro for a few days, the liver buds were transplanted into mice where the liver quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors.[62][63] Using this method, cells from one mouse could be used to test 1,000 drug compounds to treat liver disease, and reduce animal use by up to 50,000.[64]

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146, researchers identified 'vascular progenitor', the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels.[65][66]

In a study conducted in China in 2013, Superparamagnetic iron oxide (SPIO) particles were used to label iPSCs-derived NSCs in vitro. Labeled NSCs were implanted into TBI rats and SCI monkeys 1 week after injury, and then imaged using gradient reflection echo (GRE) sequence by 3.0T magnetic resonance imaging (MRI) scanner. MRI analysis was performed at 1, 7, 14, 21, and 30 days, respectively, following cell transplantation. Pronounced hypointense signals were initially detected at the cell injection sites in rats and monkeys and were later found to extend progressively to the lesion regions, demonstrating that iPSCs-derived NSCs could migrate to the lesion area from the primary sites. The therapeutic efficacy of iPSCs-derived NSCs was examined concomitantly through functional recovery tests of the animals. In this study, we tracked iPSCs-derived NSCs migration in the CNS of TBI rats and SCI monkeys in vivo for the first time. Functional recovery tests showed obvious motor function improvement in transplanted animals. These data provide the necessary foundation for future clinical application of iPSCs for CNS injury.[67]

In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Each pint of blood contains about two trillion red blood cells, while some 107 million blood donations are collected globally every year. Human transfusions were not expected to begin until 2016.[68]

The first human clinical trial using autologous iPSCs is approved by the Japan Ministry Health and will be conducted in 2014 in Kobe. iPSCs derived from skin cells from six patients suffering from wet age-related macular degeneration will be reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet will be transplanted into the affected retina where the degenerated RPE tissue has been excised. Safety and vision restoration monitoring is expected to last one to three years.[69][70] The benefits of using autologous iPSCs are that there is theoretically no risk of rejection and it eliminates the need to use embryonic stem cells.[70]

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Historic turning point for IPS cell field in Japan …

By Sykes24Tracey

As many of you know, the pioneering, first of its kind IPSC clinical study in Japan has been suspended as I first blogged about here.

In the comments section of that blog post there has been a helpful overall discussion that has involved Dr. Masayo Takahashi, the leader of the trial. It is great that Dr. Takahashi has been participating in this discussion and I commend her for that openness.

This comment stream has been particularly important because the media have only minimally reported on this important development. There have been only a few articles in Japanese (several months ago) and as far as I know only one in English, which was posted in the last day or so in The New Scientist. Unfortunately The New Scientist article, as many have noted here, used an inflammatory title invoking a supposed cancer scare and some over-the-top language. Although that article had some bits of important info, the negative bias in the article made it overall not very helpful. Some readers of that article were likely confused by how it was written and the title.

The clinical study in question is for macular degeneration and involves the use of sheets of retinal pigmented epithelial cells (RPE) made from IPSC (e.g. see image above from RIKEN).Several of us have been discussing the suspension of this trial over on Twitter too including Dr. Takahashi (@masayomasayo). Some tweets by the community have been constructive. Others not so much.

Two main possible issues have come up in the discussion of the reasons for the trial stopping: (1) six mutations were detected in the 2nd patients IPSC and (2) significant regulatory changes are on the way in Japan that apparently in some way will delimit IPSC research there. Dr. Takahashi has indicated that the latter reason was the dominant factor in their decision to suspend the trial. The fact that the 2nd patients IPSC reportedly had six mutations that were not present in the original somatic cells warrantsfurther discussion too. For example, when and how did these mutations arise? To be clear, however, I do not see (based on the information available) that there was a cancer scare by any stretch of the imagination as The New Scientist article had indicated.

At some point a restarted version of this study will likely focus on allogeneic use of IPSC perhaps via an IPSC bank being developed by Dr. Shinya Yamanaka. For many years the consensus, most exciting aspect of IPSCs in the field was considered to be their potential for use as the basis for powerful patient-specific autologous therapies. The apparent planned shift to non-autologous clinical use of IPSC in this case raises the question of how it would be superior or substantially different to the use of hESC, other than that making IPSC does not involve the use of a leftover IVF embryo.

This development also raises a 2nd question as to whether there will be a domino effect now of other clinical studies or trials that are in the works using IPSC switching to allogeneic paths as well. In other words, is this a historic, turning point moment for the IPSC field in Japan overall away from an autologous path?Or is the switch here to allogeneic just a one time, one study decision? More info on the regulatory changes is needed to help clarify the answer to this question and the path forward as well.

Hopefully the regulatory body in Japan (Ministry of Education?) that has made or is making the relevant regulatory changes will announce them publicly in detail soon. If that information is already out there (e.g. in Japanese on the web) perhaps someone can find it and well post it here.

. Bookmark the

.

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JAMA | Comparison of Allogeneic vs Autologous Bone Marrow …

By Sykes24Tracey

Corresponding Author: Joshua M. Hare, MD, The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Biomedical Research Bldg/Room 908, PO Box 016960 (R-125), Miami, FL 33101 (jhare@med.miami.edu).

Published Online: November 6, 2012. doi:10.1001/jama.2012.25321

Author Contributions:Dr Hare had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hare, Gerstenblith, DiFede Velazquez, George, Mendizabal, McNiece, Heldman.

Acquisition of data: Hare, Fishman, Gerstenblith, DiFede Velazquez, Zambrano, Suncion, Tracy, Johnston, Brinker, Breton, Davis-Sproul, Byrnes, George, Lardo, Mendizabal, Lowery, Wong Po Foo, Ruiz, Amador, Da Silva, McNiece, Heldman.

Analysis and interpretation of data: Hare, Fishman, Zambrano, Suncion, Tracy, Ghersin, Lardo, Schulman, Mendizabal, Altman, Ruiz, Amador, Da Silva, McNiece, Heldman.

Drafting of the manuscript: Hare, Fishman, Ghersin, Mendizabal, Ruiz, Amador, Heldman.

Critical revision of the manuscript for important intellectual content: Hare, Fishman, Gerstenblith, DiFede Velazquez, Suncion, Tracy, Johnston, Brinker, Breton, Davis-Sproul, Schulman, Byrnes, Geroge, Lardo, Mendizabal, Lowery, Rouy, Altman, Wong Po Foo, Ruiz, Da Silva, McNiece, Heldman.

Statistical analysis: Hare, Mendizabal, McNiece, Heldman.

Obtained funding: Hare, Lardo.

Administrative, technical, or material support: Hare, DiFede Velazquez, Zambrano, Suncion, Ghersin, Johnston, Breton, Davis-Sproul, Schulman, Byrnes, Lowery, Rouy, Altman, Wong Po Foo, Da Silva, McNiece, Heldman.

Study supervision: Hare, Fishman, Gerstenblith, Tracy, George, Schulman, Altman, Da Silva, McNiece, Heldman.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hare reported having a patent for cardiac cell-based therapy, receiving research support from and being a board member of Biocardia, having equity interest in Vestion Inc, and being a consultant for Kardia. Dr George reported serving on the board of GE Healthcare, consulting for ICON Medical Imaging, and receiving trademark royalties for fluoroperfusion imaging. Mr Mendizabal is an employee of EMMES Corporation. Drs Rouy, Altman, and Wong Po Foo are employees of Biocardia Inc. Dr McNiece reported being a consultant and board member of Proteonomix Inc. Dr Heldman reported having a patent for cardiac cell-based therapy, receiving research support from and being a board member of Biocardia, and having equity interest in Vestion Inc. No other authors reported any financial disclosures.

Funding/Support: This study was funded by the US National Heart, Lung, and Blood Institute (NHLBI) as part of the Specialized Centers for Cell-Based Therapy U54 grant (U54HL081028-01). Dr Hare is also supported by National Institutes of Health (NIH) grants RO1 HL094849, P20 HL101443, RO1 HL084275, RO1 HL107110, RO1 HL110737, and UM1HL113460. The NHLBI provided oversight of the clinical trial through the independent Gene and Cell Therapy Data and Safety Monitoring Board (DSMB). Biocardia Inc provided the Helical Infusion Catheters for the conduct of POSEIDON.

Role of the Sponsors: The NHLBI, NIH, and Biocardia Inc had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank the NHLBI Gene and Cell Therapy DSMB, the patients who participated in this trial, the bone marrow donors, the staff of the cardiac catheterization laboratories at the University of Miami Hospital and The Johns Hopkins Hospital. Erica Anderson, MA (EMMES Corporation), provided data management and Hongwei Tang, MD (TeraRecon Inc), provided consultation regarding CT imaging analysis. Ms Anderson received compensation for her contribution via the Specialized Centers for Cell-Based Therapy grant. Dr Tang did not receive any compensation for his contribution.

This article was corrected for errors on July 19, 2013.

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Standards in Cell Therapy

By Sykes24Tracey

This is a sixth post of the series Not Lost in Translation.

If youre trying to develop a cellular product and just entering the field of cell therapy, you should be aware of existent standards. Why is it important? Knowing standards in your field allows to:

Even though, cell therapy filed relatively new, there are numerous related standards. Unfortunately, many professionals are unaware about organizations and standards in cell therapy field. The purpose of this post is to indicate few leadig organizations, providing standards and types of standards in cell products development. Significant part of this topic was summarized from the recent public FDA workshop Synergizing Efforts in Standards Development for Cellular Therapies and Regenerative Medicine Products.

Type of standards in cell therapy:

Standards-developing organizations and examples: ISO International Organization for Standardization Developing and providing international standards, including medical devices, laboratory testing and some, related to cell therapy and tissue engineered products. Examples: ISO/TC 194/SC 1 Tissue product safety ISO/TC 150/SC 7 Tissue-engineered medical products

ASTM International American Society for Testing and Materials ASTM leading international standards organization. ASTM has Subcommittee F04.43 for developing standards in cell therapy and tissue engineering. Examples: ASTM F2210 Standard Guide for Processing Cells, Tissues, and Organs for Use in Tissue Engineered Medical Products ASTM F2739 Standard Guide for Quantitating Cell Viability Within Biomaterial Scaffolds ASTM F2315 Standard Guide for Immobilization or Encapsulation of Living Cells or Tissue in Alginate Gels ASTM F2944 Standard Test Method for Automated Colony Forming Unit (CFU) Assays

USP U.S. Pharmacopeial Convention Provides standards for use ancillary and raw materials for cellular and tissue products. Examples: Chapter 1046 Cell and Gene Therapies Products Chapter 1047 Gene Therapy Products Chapter 1043 Ancillary Materials for Cell, Gene and Tissue-Engineered Products Chapter 92 Growth Factors and Cytokines Used in Cell Therapy Manufacturing Chapter 90 Fetal Bovine SerumQuality Attributes and Functionality Tests

GBSI Global Biological Standard Institute Developing standards for life sciences, including biomedical research.

ATCC American Type Culture Collection Manufactures and provides reference material (including cells), developing biological standards for basic and translational research. Examples: ATCC Certified reference material ATCC Standards Development Organization

BSI British Standards Institution Has a project for developing regenerative medicine definitions and guidelines for clinical cell products characterization. Examples: PAS 93:2011 Characterization of human cells for clinical applications. Guide PAS 84:2012 Cell therapy and regenerative medicine. Glossary

FACT Foundation for the Accreditation of Cellular Therapy Provides standards for collection and processing cellular products. Accredits clinical stem cell labs, cord blood banks and more than minimal manipulation cell therapy facilities. Examples: FACT-JACIE International Standards for Cellular Therapy Product Collection, Processing and Administration FACT-JACIE Cellular Therapy Accreditation Manual

AABB American Association of Blood Banks Center for Cellular Therapies In cell therapy field, AABB has very similar functions with FACT. Examples: Standards for Cellular Therapy Services

ICCBBA International Council for Commonality in Blood Bank Automation Management of the ISBT-128 Standard the terminology, identification, coding and labeling of medical products of human origin (including blood, cell, tissue, and organ products).

ISCT International Society for Cellular Therapy ISCT leverages expertise of cell therapy professionals to develop guidelines and recommendations for cellular products development, characterization, and quality. Examples: Minimal criteria for defining multipotent mesenchymal stromal cells Potency assay development for cellular therapy products Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells IFATS/ISCT statement

Coordination and harmonization As you can see, there are many organizations, involved in different aspects of cell therapy standardization. How can we make sure that there are no overlaps between them? How to coordinate and harmonize their activities? There are some good existent examples of such coordination:

*********************** This post is a part of Not Lost in Translation online community project. In this series we will try to bridge the translational gaps between scientific discovery in research labs and clinical cell applications for therapies. We will look at challenges in translation of cell product development and manufacturing in academic and industry settings. If you would like to contribute to this community project, please contact us!

Tagged as: cell therapy, reference material, standard, translation

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Stem Cell Treatment May Help Ease Osteoarthritis Pain …

By Sykes24Tracey

Last year, Patricia Beals was told she'd need a double knee replacement to repair her severely arthritic knees or she'd probably spend the rest of her life in a wheelchair.

Hoping to avoid surgery, Beals, 72, opted instead for an experimental treatment that involved harvesting bone marrow stem cells from her hip, concentrating the cells in a centrifuge and injecting them back into her damaged joints.

"Almost from the moment I got up from the table, I was able to throw away my cane," Beals says. "Now I'm biking and hiking like a 30-year-old."

A handful of doctors around the country are administering treatments like the one Beals received to stop or even reverse the ravages of osteoarthritis. Stem cells are the only cells in the body able to morph into other types of specialized cells. When the patient's own stem cells are injected into a damaged joint, they appear to transform into chondrocytes, the cells that go on to produce fresh cartilage. They also seem to amplify the body's own natural repair efforts by accelerating healing, reducing inflammation, and preventing scarring and loss of function.

Christopher J. Centeno, M.D., the rehab medicine specialist who performed Beals' procedure, says the results he sees from stem cell therapy are remarkable. Of the more-than-200 patients his Bloomfield, Colo., clinic treated over a two-year period, he says, "two thirds of them reported greater than 50 percent relief and about 40 percent reported more than 75 percent relief one to two years afterward."

According to Centeno, knees respond better to the treatment than hips. Only eight percent of his knee patients opted for a total knee replacement two years after receiving a stem cell injection. The complete results from his clinical observations will be published in a major orthopedic journal later this year.

The Pros and Cons

The biggest advantage stem cell injections seem to offer over more invasive arthritis remedies is a quicker, easier recovery. The procedure is done on an outpatient basis and the majority of patients are up and moving within 24 hours. Most wear a brace for several weeks but still can get around. Many are even able to do some gentle stationary cycling by the end of the first week.

There are also fewer complications. A friend who had knee replacement surgery the same day Beals had her treatment developed life-threatening blood clots and couldn't walk for weeks afterwards. Six months out, she still hasn't made a full recovery.

Most surgeries don't go so awry, but still: Beals just returned from a week-long cycling trip where she covered 20 to 40 miles per day without so much as a tweak of pain.

As for risks, Centeno maintains they are virtually nonexistent.

"Because the stem cells come from your own body, there's little chance of infection or rejection," he says.

Not all medical experts are quite so enthusiastic, however. Dr. Tom Einhorn, chairman of the department of orthopedic surgery at Boston University, conducts research with stem cells but does not use them to treat arthritic patients. He thinks the idea is interesting but the science is not there yet.

"We need to have animal studies and analyze what's really happening under the microscope. Then, and only then, can you start doing this with patients," he says.

The few studies completed to date have examined how stem cells heal traumatic injuries rather than degenerative conditions such as arthritis. Results have been promising but, as Einhorn points out, the required repair mechanisms in each circumstance are very different.

Another downside is cost: The injections aren't approved by the FDA, which means they aren't covered by insurance. At $4,000 a pop -- all out of pocket -- they certainly aren't cheap, and many patients require more than one shot.

Ironically, one thing driving up the price is FDA involvement. Two years ago, the agency stepped in and stopped physicians from intensifying stem cells in the lab for several days before putting them back into the patient. This means all procedures must be done on the same day, no stem cells may be preserved and many of the more expensive aspects of the treatment must be repeated each time.

Centeno says same day treatments often aren't as effective, either.

But despite the sky-high price tag and lack of evidence, patients like Beals believe the treatment is nothing short of a miracle. She advises anyone who is a candidate for joint replacement to consider stem cells first.

"Open your mind up and step into it," she says. "Do it. It's so effective. It's the future and it works."

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Renal cell carcinoma – Wikipedia, the free encyclopedia

By Sykes24Tracey

Renal cell carcinoma (RCC, also known as hypernephroma, Grawitz tumor, renal adenocarcinoma) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport waste molecules from the blood to the urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90-95% of cases.[1] Initial treatment is most commonly either partial or complete removal of the affected kidney(s) and remains the mainstay of curative treatment.[2] Where the cancer has not metastasised (spread to other organs) or burrowed deeper into the tissues of the kidney the 5-year survival rate is 65-90%,[3] but this is lowered considerably when the cancer has spread. It is relatively resistant to radiation therapy and chemotherapy, although some cases respond to targeted therapies such as sunitinib, temsirolimus, bevacizumab, interferon alfa and sorafenib which have improved the outlook for RCC.[4]

The body is remarkably good at hiding the symptoms and as a result people with RCC often have advanced disease by the time it is discovered.[5] The initial symptoms of RCC often include: blood in the urine (occurring in 40% of affected persons at the time they first seek medical attention), flank pain (40%), a mass in the abdomen or flank (25%), weight loss (33%), fever (20%), high blood pressure (20%), night sweats and generally feeling unwell.[1] RCC is also associated with a number of paraneoplastic syndromes (PNS) which are conditions caused by either the hormones produced by the tumour or by the body's attack on the tumour and are present in about 20% of those with RCC.[1] These syndromes most commonly affect tissues which have not been invaded by the cancer.[1] The most common PNSs seen in people with RCC are: anaemia (due to an underproduction of the hormone, erythropoietin), high blood calcium levels, polycythaemia (the opposite to anaemia, due to an overproduction of erythropoietin), thrombocytosis (too many platelets in the blood, leading to an increased tendency for blood clots and bleeds) and secondary amyloidosis.[6] When RCC metastasises it most commonly spreads to the lymph nodes, lungs, liver, adrenal glands, brain or bones.[6]

Historically, medical practitioners expected a person to present with three findings. This classic triad[7] is 1: haematuria, which is when there is blood present in the urine, 2: flank pain, which is pain on the side of the body between the hip and ribs, and 3: an abdominal mass, similar to bloating but larger. It is now known that this classic triad of symptoms only occurs in 10-15% of cases, and is usually indicative that the renal cell carcinoma (RCC) in an advanced stage.[7] Today, RCC is often asymptomatic (meaning little to no symptoms) and is generally detected incidentally when a person is being examined for other ailments.[8]

Other signs and symptom may include haematuria;[7] loin pain;[7] abdominal mass;[8]malaise, which is a general feeling of feeling unwell;[8] weight loss and/or loss of appetite;[9]anaemia resulting from depression of erythropoietin;[7]erythrocytosis (increased production of red blood cells) due to increased erythropoietin secretion;[7]varicocele, which is seen in males as an enlargement of the tissue at the testicle (more often the left testicle)[8]hypertension (high blood pressure) resulting from secretion of renin by the tumour;[10]hypercalcemia, which is elevation of calcium levels in the blood;[11] sleep disturbance or night sweats;[9] recurrent fevers;[9] and chronic fatigue.[12]

The greatest risk factors for RCC are lifestyle-related; smoking, obesity and hypertension (high blood pressure) have been estimated to account for up to 50% of cases.[13] Occupational exposure to some chemicals such as asbestos, cadmium, lead, chlorinated solvents, petrochemicals and PAH (polycyclic aromatic hydrocarbon) has been examined by multiple studies with inconclusive results.[14][15][16] Another suspected risk factor is the long term use of non-steroidal anti-inflammatory drugs (NSAIDS).[17]

Finally, studies have found that women who have had a hysterectomy are at more than double the risk of developing RCC than those who have not.[18] The reason for this remains unclear.

Hereditary factors have a minor impact on individual susceptibility with immediate relatives of people with RCC having a two to fourfold increased risk of developing the condition.[19] Other genetically linked conditions also increase the risk of RCC, including hereditary papillary renal carcinoma, hereditary leiomyomatosis, Birt-Hogg-Dube syndrome, hyperparathyroidism-jaw tumor syndrome, familial papillary thyroid carcinoma, von Hippel-Lindau disease[20] and sickle cell disease.[21]

The most significant disease affecting risk however is not genetically linked patients with acquired cystic disease of the kidney requiring dialysis are 30 times greater more likely than the general population to develop RCC.[22]

The tumour arises from the cells of the proximal renal tubular epithelium.[1] It is considered an adenocarcinoma.[6] There are two subtypes: sporadic (that is, non-hereditary) and hereditary.[1] Both such subtypes are associated with mutations in the short-arm of chromosome 3, with the implicated genes being either tumour suppressor genes (VHL and TSC) or oncogenes (like c-Met).[1]

The first steps taken to diagnose this condition are consideration of the signs and symptoms, and a medical history (the detailed medical review of past health state) to evaluate any risk factors. Based on the symptoms presented, a range of biochemical tests (using blood and/or urine samples) may also be considered as part of the screening process to provide sufficient quantitative analysis of any differences in electrolytes, renal and liver function, and blood clotting times.[21] Upon physical examination, palpation of the abdomen may reveal the presence of a mass or an organ enlargement.[23]

Although this disease lacks characterization in the early stages of tumor development, considerations based on diverse clinical manifestations, as well as resistance to radiation and chemotherapy are important. The main diagnostic tools for detecting renal cell carcinoma are ultrasound, computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the kidneys.[24]

Renal cell carcinoma (RCC) is not a single entity, but rather a collection of different types of tumours, each derived from the various parts of the nephron (epithelium or renal tubules) and possessing distinct genetic characteristics, histological features, and, to some extent, clinical phenotypes.[21]

Clear Cell Renal Cell Carcinoma (CCRCC)

Array-based karyotyping can be used to identify characteristic chromosomal aberrations in renal tumors with challenging morphology.[28][29] Array-based karyotyping performs well on paraffin embedded tumours[30] and is amenable to routine clinical use. See also Virtual Karyotype for CLIA certified laboratories offering array-based karyotyping of solid tumours.

The 2004 World Health Organization (WHO) classification of genitourinary tumours recognizes over 40 subtypes of renal neoplasms. Since the publication of the latest iteration of the WHO classification in 2004, several novel renal tumour subtypes have been described:[31]

Laboratory tests are generally conducted when the patient presents with signs and symptoms that may be characteristic of kidney impairment. They are not primarily used to diagnose kidney cancer, due to its asymptomatic nature and are generally found incidentally during tests for other illnesses such as gallbladder disease.[33] In other words, these cancers are not detected usually because they do not cause pain or discomfort when they are discovered. Laboratory analysis can provide an assessment on the overall health of the patient and can provide information in determining the staging and degree of metastasis to other parts of the body (if a renal lesion has been identified) before treatment is given.

The presence of blood in urine is a common presumptive sign of renal cell carcinoma. The haemoglobin of the blood causes the urine to be rusty, brown or red in colour. Alternatively, urinalysis can test for sugar, protein and bacteria which can also serve as indicators for cancer. A complete blood cell count can also provide additional information regarding the severity and spreading of the cancer.[34]

The CBC provides a quantified measure of the different cells in the whole blood sample from the patient. Such cells examined for in this test include red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). A common sign of renal cell carcinoma is anaemia whereby the patient exhibits deficiency in red blood cells.[35] CBC tests are vital as a screening tool for examination the health of patient prior to surgery. Inconsistencies with platelet counts are also common amongst these cancer patients and further coagulation tests, including Erythrocyte Sedimentation Rate (ESR), Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) should be considered.

Blood chemistry tests are conducted if renal cell carcinoma is suspected as cancer has the potential to elevate levels of particular chemicals in blood. For example, liver enzymes such as aspartate aminotransferase [AST] and alanine aminotransferase [ALT] are found to be at abnormally high levels.[36] The staging of the cancer can also be determined by abnormal elevated levels of calcium, which suggests that the cancer may have metastasised to the bones.[37] In this case, a doctor should be prompted for a CT scan. Blood chemistry tests also assess the overall function of the kidneys and can allow the doctor to decide upon further radiological tests.

The characteristic appearance of renal cell carcinoma (RCC) is a solid renal lesion which disturbs the renal contour. It will frequently have an irregular or lobulated margin and may be seen as a lump on the lower pelvic or abdomen region. Traditionally, 85 to 90% of solid renal masses will turn out to be RCC but cystic renal masses may also be due to RCC.[38] However, the advances of diagnostic modalities are able to incidentally diagnose a great proportion of patients with renal lesions that may appear to be small in size and of benign state. Ten percent of RCC will contain calcifications, and some contain macroscopic fat (likely due to invasion and encasement of the perirenal fat.[39] Deciding on the benign or malignant nature of the renal mass on the basis of its localized size is an issue as renal cell carcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, haemorrhagic renal cyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist to differentiate a benign cystic lesion from a malignant one.[40] The Bosniak classification system for cystic renal lesions classifies them into groups that are benign and those that need surgical resection, based on specific imaging features.[41]

The main imaging tests performed in order to identify renal cell carcinoma are pelvic and abdominal CT scans, ultrasound tests of the kidneys (ultrasonography), MRI scans, intravenous pyelogram (IVP) or renal angiography.[42] Among these main diagnostic tests, other radiologic tests such as excretory urography, positron-emission tomography (PET) scanning, ultrasonography, arteriography, venography, and bone scanning can also be used to aid in the evaluation of staging renal masses and to differentiate non-malignant tumours from malignant tumours.

Contrast-enhanced Computed tomography (CT) scanning is a routinely used imaging procedure in determining the stage of the renal cell carcinoma in the abdominal and pelvic regions of the patient. CT scans have the potential to distinguish solid masses from cystic masses and may provide information on the localization, stage or spread of the cancer to other organs of the patient. Key parts of the human body which are examined for metastatic involvement of renal cell carcinoma may include the renal vein, lymph node and the involvement of the inferior vena cava.[43] According to a study conducted by Sauk et al., multidetector CT imaging characteristics have applications in diagnosing patients with clear renal cell carcinoma by depicting the differences of these cells at the cytogenic level.[44]

Ultrasonographic examination can be useful in evaluating questionable asymptomatic kidney tumours and cystic renal lesions if Computed Tomography imaging is inconclusive. This safe and non-invasive radiologic procedure uses high frequency sound waves to generate an interior image of the body on a computer monitor. The image generated by the ultrasound can help diagnose renal cell carcinoma based on the differences of sound reflections on the surface of organs and the abnormal tissue masses. Essentially, ultrasound tests can determine whether the composition of the kidney mass is mainly solid or filled with fluid.[42]

A Percutaneous biopsy can be performed by a radiologist using ultrasound or computed tomography to guide sampling of the tumour for the purpose of diagnosis by pathology. However this is not routinely performed because when the typical imaging features of renal cell carcinoma are present, the possibility of an incorrectly negative result together with the risk of a medical complication to the patient may make it unfavourable from a risk-benefit perspective.[11] However, biopsy tests for molecular analysis to distinguish benign from malignant renal tumours is of investigative interest.[11]

Magnetic Resonance Imaging (MRI) scans provide an image of the soft tissues in the body using radio waves and strong magnets. MRI can be used instead of CT if the patient exhibits an allergy to the contrast media administered for the test.[45][46] Sometimes prior to the MRI scan, an intravenous injection of a contrasting material called gadolinium is given to allow for a more detailed image. Patients on dialysis or those who have renal insufficiency should avoid this contrasting material as it may induce a rare, yet severe, side effect known as nephrogenic systemic fibrosis.[47] A bone scan or brain imaging is not routinely performed unless signs or symptoms suggest potential metastatic involvement of these areas. MRI scans should also be considered to evaluate tumour extension which has grown in major blood vessels, including the vena cava, in the abdomen. MRI can be used to observe the possible spread of cancer to the brain or spinal cord should the patient present symptoms that suggest this might be the case.

Intravenous pyelogram (IVP) is a useful procedure in detecting the presence of abnormal renal mass in the urinary tract. This procedure involves the injection of a contrasting dye into the arm of the patient. The dye travels from the blood stream and into the kidneys which in time, passes into the kidneys and bladder. This test is not necessary if a CT or MRI scan has been conducted.[48]

Renal angiography uses the same principle as IVP, as this type of X-ray also uses a contrasting dye. This radiologic test is important in diagnosing renal cell carcinoma as an aid for examining blood vessels in the kidneys. This diagnostic test relies on the contrasting agent which is injected in the renal artery to be absorbed by the cancerous cells.[49] The contrasting dye provides a clearer outline of abnormally-oriented blood vessels believed to be involved with the tumour. This is imperative for surgeons as it allows the patients blood vessels to be mapped prior to operation.[43]

The staging of renal cell carcinoma is the most important factor in predicting its prognosis.[50] Staging can follow the TNM staging system, where the size and extent of the tumour (T), involvement of lymph nodes (N) and metastases (M) are classified separately. Also, it can use overall stage grouping into stage I-IV, with the 1997 revision of AJCC described below:[50]

At diagnosis, 30% of renal cell carcinomas have spread to the ipsilateral renal vein, and 5-10% have continued into the inferior vena cava.[51]

The gross and microscopic appearance of renal cell carcinomas is highly variable. The renal cell carcinoma may present reddened areas where blood vessels have bled, and cysts containing watery fluids.[52] The body of the tumour shows large blood vessels that have walls composed of cancerous cells. Gross examination often shows a yellowish, multilobulated tumor in the renal cortex, which frequently contains zones of necrosis, haemorrhage and scarring. In a microscopic context, there are four major histologic subtypes of renal cell cancer: clear cell (conventional RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Sarcomatoid changes (morphology and patterns of IHC that mimic sarcoma, spindle cells) can be observed within any RCC subtype and are associated with more aggressive clinical course and worse prognosis. Under light microscopy, these tumour cells can exhibit papillae, tubules or nests, and are quite large, atypical, and polygonal.

Recent studies have brought attention to the close association of the type of cancerous cells to the aggressiveness of the condition. Some studies suggest that these cancerous cells accumulate glycogen and lipids, their cytoplasm appear "clear", the nuclei remain in the middle of the cells, and the cellular membrane is evident.[53] Some cells may be smaller, with eosinophilic cytoplasm, resembling normal tubular cells. The stroma is reduced, but well vascularised. The tumour compresses the surrounding parenchyma, producing a pseudocapsule.[54]

The most common cell type exhibited by renal cell carcinoma is the clear cell, which is named by the dissolving of the cells' high lipid content in the cytoplasm. The clear cells are thought to be the least likely to spread and usually respond more favourably to treatment. However, most of the tumours contain a mixture of cells. The most aggressive stage of renal cancer is believed to be the one in which the tumour is mixed, containing both clear and granular cells.[55]

The recommended histologic grading schema for RCC is the Fuhrman system (1982), which is an assessment based on the microscopic morphology of a neoplasm with haematoxylin and eosin (H&E staining). This system categorises renal cell carcinoma with grades 1, 2, 3, 4 based on nuclear characteristics. The details of the Fuhrman grading system for RCC are shown below:[56]

Nuclear grade is believed to be one of the most imperative prognostic factors in patients with renal cell carcinoma.[21] However, a study by Delahunt et al. (2007) has shown that the Fuhrman grading is ideal for clear cell carcinoma but may not be appropriate for chromophobe renal cell carcinomas and that the staging of cancer (accomplished by CT scan) is a more favourable predictor of the prognosis of this disease.[57] In relation to renal cancer staging, the Heidelberg classification system of renal tumours was introduced in 1976 as a means of more completely correlating the histopathological features with the identified genetic defects.[58]

The type of treatment depends on multiple factors and the individual, some of which include:[7][59]

Every form of treatment has both risks and benefits; a health care professional will provide the best options that suit the individual circumstances.

Active surveillance or "watchful waiting" is becoming more common as small renal masses or tumours are being detected and also within the older generation when surgery is not always suitable.[60] Active surveillance involves completing various diagnostic procedures, tests and imaging to monitor the progression of the RCC before embarking on a more high risk treatment option like surgery.[60] In the elderly, patients with co-morbidities, and in poor surgical candidates, this is especially useful.

Different procedures may be most appropriate, depending on circumstances.

Radical nephrectomy is the removal of the entire affected kidney including Gerota's fascia, the adrenal gland which is on the same side as the affected kidney, and the regional lymph nodes, all at the same time.[7] This method, although severe, is effective. But it is not always appropriate, as it is a major surgery that contains the risk of complication both during and after the surgery and can have a longer recovery time.[61] It is important to note that the other kidney must be fully functional, and this technique is most often used when there is a large tumour present in only one kidney.

Nephron-sparing partial nephrectomy is used when the tumor is small (less than 4cm in diameter) or when the patient has other medical concerns such as diabetes or hypertension.[7] The partial nephrectomy involves the removal of the affected tissue only, sparing the rest of the kidney, Gerota's fascia and the regional lymph nodes. This allows for more renal preservation as compared to the radical nephrectomy, and this can have positive long term health benefits.[62] Larger and more complex tumors can also be treated with partial nephrectomy by surgeons with a lot of kidney surgery experience.[63]

Laparoscopic nephrectomy uses laparoscopic surgery, with minimally invasive surgical techniques. Commonly referred to as key hole surgery, this surgery does not have the large incisions seen in a classically performed radical or partial nephrectomy, but still successfully removes either all or part of the kidney. Laparoscopic surgery is associated with shorter stays in the hospital and quicker recovery time but there are still risks associated with the surgical procedure.

Surgery for metastatic disease: If metastatic disease is present surgical treatment may still a viable option. Radical and partial nephrectomy can still occur, and in some cases if the metastasis is small this can also be surgically removed.[7] This depends on what stage of growth and how far the disease has spread.

Targeted ablative therapies are also known as percutaneous ablative therapies. Although the use of laparoscopic surgical techniques for complete nephrectomies has reduced some of the risks associated with surgery,[64] surgery of any sort in some cases will still not be feasible. For example, the elderly, people already suffering from severe renal dysfunction, or people who have several comorbidities, surgery of any sort is not warranted.[65] Instead there are targeted therapies which do not involve the removal of any organs or serious surgery. Rather, these therapies involve the ablation of the tumor or the affected area. Ablative treatments use imaging such as computed tomography (CT) or magnetic resonance imaging (MRI) to identify the location of the tumors, which ideally are smaller than 3.5cm and to guide the treatment. However there are some cases where ablation can be used on tumors that are larger.[65]

The two main types of ablation techniques that are used for renal cell carcinoma are radio frequency ablation and cryoablation.[65]

Radio frequency ablation uses an electrode probe which is inserted into the affected tissue, to send radio frequencies to the tissue to generate heat through the friction of water molecules. The heat destroys the tumor tissue.[7] Cell death will generally occur within minutes of being exposed to temperatures above 50C.

Cryoablation also involves the insertion of a probe into the affected area,[7] however, cold is used to kill the tumor instead of heat. The probe is cooled with chemical fluids which are very cold. The freezing temperatures cause the tumor cells to die by causing osmotic dehydration, which pulls the water out of the cell destroying the enzyme, organelles, cell membrane and freezing the cytoplasm.[65]

Immunotherapy is a method that activates the person's immune system and uses it to their own advantage. It was developed after observing that in some cases there was spontaneous regression.[66] That is, the renal cell carcinoma improved with no other therapies. Immunotherapy capitalises on this phenomenon and aims to build up a person's immune response to cancer cells.[66] Other medications target things such as growth factors that have been shown to promote the growth and spread of tumours.[67] They inhibit the growth factor in order to prevent tumours from forming.[68] There have been many different medications developed and most have only been approved in the last seven or so years.[69]

Some of the most recently developed treatments are listed below:[70]

Each of the treatments listed above is slightly different; some only work for a little while and others need to be used in conjunction with other therapies. There are also different side effects and risks associated with different forms of medication. As always, the advice of a health care professional should be sought if considering any of the therapies mentioned.

Chemotherapy and radiotherapy are not as successful in the case of RCC. RCC is resistant in most cases but there is about a 4-5% success rate sometimes, but this is often short lived with more tumours and growths developing later.[7]

Cancer vaccines are being developed but so far have been found to be effective for only certain forms of the RCC.[7] The vaccines are being designed to "prime" the immune system to provide tumour specific immunity.[66] They are still being developed but the present another treatment possibility.

Adjuvant therapy, which refers to therapy given after a primary surgery, has not been found to be beneficial in renal cell cancer.[72] Conversely, neoadjuvant therapy is administered before the intended primary or main treatment. In some cases neoadjuvant therapy has been shown to decrease the size and stage of the RCC to then allow it to be surgically removed.[68] This is a new form of treatment and the effectiveness of this approach is still being assessed in clinical trials.

Metastatic renal cell carcinoma (mRCC) is the spread of the primary renal cell carcinoma from the kidney to other organs. 25-30% of people have this metastatic spread by the time they are diagnosed with renal cell carcinoma.[73] This high proportion is explained by the fact that clinical signs are generally mild until the disease progresses to a more severe state.[74] The most common sites for metastasis are the lymph nodes, lung, bones, liver and brain.[8] How this spread affects the staging of the disease and hence prognosis is discussed in the Diagnosis and Prognosis section.

MRCC has a poor prognosis compared to other cancers although average survival times have increased in the last few years due to treatment advances. Average survival time in 2008 for the metastatic form of the disease was under a year[75] and by 2013 this improved to an average of 22 months.[76] Despite this improvement the 5 year survival rate for mRCC remains under 10%[77] and 20-25% of suffers remain unresponsive to all treatments and in these cases, the disease has a rapid progression.[76]

The available treatments for RCC discussed in the Treatment section are also relevant for the metastatic form of the disease. Options include interleukin-2 which is a standard therapy for advanced renal cell carcinoma.[72] In the past six years, seven new treatments have been approved specifically for mRCC (sunitinib, temsirolimus, bevacizumab, sorafenib, everolimus, pazopanib and axitinib).[4] These new treatments are based on the fact that renal cell carcinomas are very vascular tumors they contain a large number of blood vessels. The drugs aim to inhibit the growth of new blood vessels in the tumors, hence slowing growth and in some cases reducing the size of the tumors.[78] Side effects unfortunately are quite common with these treatments and include:[79]

Radiotherapy and chemotherapy are more commonly used in the metastatic form of RCC to target the secondary tumors in the bones, liver, brain and other organs. While not curative, these treatments do provide relief for suffers from symptoms associated with the spread of tumors.[76] Other potential treatments are still being developed, including tumor vaccines and small molecule inhibitors.[73]

The prognosis for renal cell carcinoma is largely influenced by a variety of factors, including tumour size, degree of invasion and metastasis, histologic type, and nuclear grade.[21] For metastatic renal cell carcinoma, factors which may present a poor prognosis include a low Karnofsky performance-status score (a standard way of measuring functional impairment in patients with cancer), a low haemoglobin level, a high level of serum lactate dehydrogenase, and a high corrected level of serum calcium.[80][81] For non-metastatic cases, the Leibovich scoring algorithm may be used to predict post-operative disease progression.[82]

Renal cell carcinoma is one of the cancers most strongly associated with paraneoplastic syndromes, most often due to ectopic hormone production by the tumour. The treatment for these complications of RCC is generally limited beyond treating the underlying cancer.

For those that have tumour recurrence after surgery, the prognosis is generally poor. Renal cell carcinoma does not generally respond to chemotherapy or radiation. Immunotherapy, which attempts to induce the body to attack the remaining cancer cells, has shown promise. Recent trials are testing newer agents, though the current complete remission rate with these approaches is still low, around 12-20% in most series. Most recently, treatment with tyrosine kinase inhibitors including nexavar, pazopanib, and rapamycin have shown promise in improving the prognosis for advanced RCC.[83]

The incidence of the disease varies according to geographic, demographic and, to a lesser extent, hereditary factors. There are some known risk factors, however the significance of other potential risk factors remains more controversial. The incidence of the cancer has been increasing in frequency worldwide at a rate of approximately 2-3% per decade[75] until the last few years where the number of new cases has stabilised.[14]

The incidence of RCC varies between sexes, ages, races and geographic location around the world. Men have a higher incidence than women (approximately 1.6:1)[72] and the vast majority are diagnosed after 65 years of age.[72] Asians reportedly have a significantly lower incidence of RCC than whites and while African countries have the lowest reported incidences, African Americans have the highest incidence of the population in the United States.[14] Developed countries have a higher incidence than developing countries, with the highest rates found in North America, Europe and Australia / New Zealand[84]

Daniel Sennert made the first reference suggesting a tumour arising in the kidney in his text Practicae Medicinae, first published in 1613.[85]

Miril published the earliest unequivocal case of renal carcinoma in 1810.[86] He described the case of Franoise Levelly, a 35 year old woman, who presented to Brest Civic Hospital on April 6, 1809, supposedly in the late stages of pregnancy.[85]

Koenig published the first classification of renal tumours based on macroscopic morphology in 1826. Koenig divided the tumors into scirrhous, steatomatous, fungoid and medullary forms.[87]

Following the classification of the tumour, researchers attempted to identify the tissue of origin for renal carcinoma.

The pathogenesis of renal epithelial tumours was debated for decades. The debate was initiated by Paul Grawitz when in 1883, he published his observations on the morphology of small, yellow renal tumours. Grawitz concluded that only alveolar tumours were of adrenal origin, whereas papillary tumours were derived from renal tissue.[85]

In 1893, Paul Sudeck challenged the theory postulated by Grawitz by publishing descriptions of renal tumours in which he identified atypical features within renal tubules and noted a gradation of these atypical features between the tubules and neighboring malignant tumour. In 1894, Otto Lubarsch, who supported the theory postulated by Grawitz coined the term hypernephroid tumor, which was amended tohypernephroma by Felix Victor Birch-Hirschfeld to describe these tumours.[88]

Vigorous criticism of Grawitz was provided by Oskar Stoerk in 1908, who considered the adrenal origin of renal tumours to be unproved. Despite the compelling arguments against the theory postulated by Grawitz, the term hypernephroma, with its associated adrenal connotation, persisted in the literature.[85]

Foot and Humphreys, and Foote et al. introduced the term Renal Celled Carcinoma to emphasize a renal tubular origin for these tumours. Their designation was slightly altered by Fetter to the now widely accepted term Renal Cell Carcinoma.[89]

Convincing evidence to settle the debate was offered by Oberling et al. in 1959 who studied the ultrastructure of clear cells from eight renal carcinomas. They found that the tumour cell cytoplasm contained numerous mitochondria and deposits of glycogen and fat. They identified cytoplasmic membranes inserted perpendicularly onto basement membrane with occasional cells containing microvilli along the free borders. They concluded that these features indicated that the tumours arose from the epithelial cells of the renal convoluted tubule, thus finally settling one of the most debated issues in tumour pathology.[85][90]

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Spinal Cord Injury Treatment, Stem Cell Therapy For Spinal …

By Sykes24Tracey

Ankylosing Spondilytis, is a kind of inflammatory, autoimmune disorder of unknown etiology primarily affecting the spine, axial skeleton and large proximal joints of the body, this may inturn lead to eventual fusion of the spine.It can rage from mild to progressively degenerating diseases.

Although autoimmune, 90% of the patients suffering from the condition have proved to express the presence of HLA-B27 geneotype, confirming the genetic association of the disorder. Estimates may vary but it is observed that young men between the age group 20-40 are affected. The characterization of AS is done various symptoms, three of them occur most generally and they are pain, stiffness,excessive fatigue etc. Although the symptoms are very generalized there are some telltale conditions such as severe back pain.

The current treatments include severe physiotherapy, medication and other rehabilitation approach. However with these treatment regimen the pathophysiology of the disease is not reversed neither the further progression is stopped. On the contrary, the cutting edge stem cell treatment can offer the solution for the condition. Stem cells are the original, naive cells capable of forming any cells of the same or different lineage.

Ankylosing Spondilytis is a kind of arthritis mainly affecting the spine, but sometimes other organs are also involved.

Mentioned below is case analysis of a patient who had been suffering from Ankylosing Spondilytis. And at a young age of 25 years, he was unable to walk. Now after stem cells treatment he has started walking and his quality of life has improved.

Case Study

Name of the patient:- Rahul (name is changed for privacy reasons)

Disease: Ankylosing Spondilytis

Rahul was suffering from Ankylosing Spondilytis since past 14 years. Painful joints, restricted movements and stiffness in the body was his way of life. Although Rahul doesn't have any family history of joint diseases.

Rahul's symptoms started with sudden onset of the back pain, which went on to be severe with the whole body aches, upto the extent that he could hardly walk or if he could, he started walking like an old man. Although the initial X ray analysis showed nothing, may be because practically it take several years to show changes associated with the spine. Consequently Rahul had to visit rheumatologists, who confirmed after almost 3 years that he is suffering from AS. His treatment regimen involved diet plan, some oral medications and restricted sports activities.

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Adult Non-Hodgkin Lymphoma Treatment – National Cancer …

By Sykes24Tracey

General Information About Adult Non-Hodgkin Lymphoma (NHL)

The NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.[1]

Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.

Estimated new cases and deaths from NHL in the United States in 2015:[2]

NHL usually originates in lymphoid tissues.

Anatomy of the lymph system.

The NHLs can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas.

Indolent NHL types have a relatively good prognosis with a median survival as long as 20 years, but they usually are not curable in advanced clinical stages.[3] Early-stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology.

The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.

In general, with modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.[4]

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Haematopoietic stem cells and early lymphoid progenitors …

By Sykes24Tracey

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Haematopoietic stem cells and early lymphoid progenitors ...

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Sickle-cell disease – Wikipedia, the free encyclopedia

By Sykes24Tracey

Sickle-cell disease (SCD), also known as sickle-cell anaemia (SCA) and drepanocytosis, is a hereditary blood disorder, characterized by an abnormality in the oxygen-carrying haemoglobin molecule in red blood cells. This leads to a propensity for the cells to assume an abnormal, rigid, sickle-like shape under certain circumstances. Sickle-cell disease is associated with a number of acute and chronic health problems, such as severe infections, attacks of severe pain ("sickle-cell crisis"), and stroke, and there is an increased risk of death.

Sickle-cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. A person with a single abnormal copy does not experience symptoms and is said to have sickle-cell trait. Such people are also referred to as carriers.

The complications of sickle-cell disease can be prevented to a large extent with vaccination, preventive antibiotics, blood transfusion, and the drug hydroxyurea/hydroxycarbamide. A small proportion requires a transplant of bone marrow cells.

Almost 300,000 children are born with a form of sickle-cell disease every year, mostly in sub-Saharan Africa, but also in other parts of the world such as the West Indies and in people of African origin elsewhere in the world. In 2013 it resulted in 176,000 deaths up from 113,000 deaths in 1990.[1] The condition was first described in the medical literature by the American physician James B. Herrick in 1910, and in the 1940s and 1950s contributions by Nobel prize-winner Linus Pauling made it the first disease where the exact genetic and molecular defect was elucidated.

Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.[2]

The terms "sickle-cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD. SCD results in anemia and crises that could be of many types including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis, and others. Most episodes of sickle-cell crises last between five and seven days.[3] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."[4]

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in ischaemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood transfusion; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis[5] or lungs are considered an emergency and treated with red-blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.[6]

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected.[7] It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This spleen damage increases the risk of infection from encapsulated organisms;[8][9] preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.

Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in hemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 12 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 34 hours and may last for one day.[10]

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia.[11] It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with vaso-occlusive crises then they develop ACS.[12][13] Nevertheless, about 80% of patients have vaso-occlusive crises during ACS.

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Sickle-cell disease - Wikipedia, the free encyclopedia

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Bone marrow or stem cell transplants for AML | Cancer …

By Sykes24Tracey

Having someone elses marrow or stem cells is called a donor transplant, or an allogeneic transplant. This is pronounced al-lo-jen-ay-ik.

The donors bone marrow cells must match your own as closely as possible. The most suitable donor is usually a close relative, such as a brother or sister. It is sometimes possible to find a match in an unrelated donor. Doctors call this a matched unrelated donor (MUD). To find out if there is a suitable donor for you, your doctor will contact The Anthony Nolan Bone Marrow Register and other UK based and international bone marrow registers.

To make sure that your donors cells match, you and the donor will have blood tests. These are to see how many of the proteins on the surface of their blood cells match yours. This is called tissue typing or HLA matching. HLA stands for human leucocyte antigen.

Once you have a donor and are in remission, you have high dose chemotherapy either on its own or with radiotherapy. A week later the donor goes into hospital and their stem cells or marrow are collected. You then have the stem cells or bone marrow as a drip through your central line.

If you've had a transplant from a donor, there is a risk of graft versus host disease (GVHD). This happens because the transplanted stem cells or bone marrow contain cells from your donor's immune system. These cells can sometimes recognise your own tissues as being foreign and attack them. This can be an advantage because the immune cells may also attack any leukaemia cells left after your treatment.

Acute GVHD starts within 100 days of the transplant and can cause

If you develop GVHD after your transplant, your doctor will prescribe medicines to damp down this immune reaction. These are called immunosuppressants.

Chronic GVHD starts more than 100 days after the transplant and you may have

Your doctor is likely to suggest that you stay out of the sun because GVHD skin rashes can often get worse in the sun.

There is detailed information about graft versus host disease in the section about coping physically with cancer.

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Bone marrow or stem cell transplants for AML | Cancer ...

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iPSCTherapy.com: Induced Pluripotent Stem Cell therapy …

By Sykes24Tracey

There have been hundreds of science fiction stories and books written about growing organs in scientific laboratories as replacements for those that no longer function properly, or about injecting scientifically transmuted cells into ailing patients that can repair the broken cells within their bodies, bringing them back to robust health. In todays language what they were talking about was Induced Pluripotent Stem Cell (iPSC) Therapy.

Here, in the early 21st century, the gap between science fiction and science truth is closing at a record rate due to the rapid progress made in iPSC Therapy research, especially over the last three years.

After the virtual stop order placed on embryonic cell stem research in 2001, the race to find an alternative type of stem cell began in earnest, and in 2006 Shinya Yamanaka of Kyoto University in Japan announced his teams successful reprogramming of mouse cells into iPSCs. This was the breakthrough that made it possible for stem cell research to continue without the use of controversial embryonic stem cells.

The next major announcement came in 2007, again from Yamanaka in Japan, followed by one only a few weeks later by James A. Thompson from the University of Wisconsin, detailing the making of iPSC from adult human cells. Again, neither used embryos in their experiments.

From that time on the goal has been developing stem cell science that will eventually be safe iPS Cell Therapy modalities to be used in Regenerative or Reparative Medicine. What kinds of illnesses or diseases will iPSC Therapies be used to treat in the future? Only a partial list would include:

The world of iPSC Therapy research is wide open today and its on the move! This website is dedicated to bringing you first, the story of stem cell research, both embryonic and iPStem Cell, and the controversy surrounding them, as well as the most up to date information in the easiest to understand language about major milestone accomplishments in the field.

If you were to go back 100 years you would be amazed by how primitive medicine was. Even 60 years ago there were no organ transplants, no cystoscopic surgeries, and there was a massive polio outbreak in the United States that closed public swimming pools and beaches and other public gathering places across the country for the summer. Who can tell where medicine will be in 10 or 15 years? There is no predicting, but with the rapid advancement of the last few years and the bright promise shown so far, iPSC Therapy is sure to play a major role.

Continued here: iPSCTherapy.com: Induced Pluripotent Stem Cell therapy

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iPSCTherapy.com: Induced Pluripotent Stem Cell therapy ...

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Stem Cell Therapy in Mexico

By Sykes24Tracey

Stem Cell MX is dedicated to providing COPD and heart disease patients with information about stem cell therapy at Angeles Health International, Mexicos largest private hospital network.

Stem Cell Therapy is a fast growing area of medical research. Research into how stem cells can cure a number of conditions has been extensive over the past 3 decades and here at Stem Cell MX we are proud to be at the forefront of breakthrough discoveries and treatments. We dedicate ourselves to providing you with information about Stem Cells and what they can do for you.

At Stem Cell MX we can use Stem Cell therapy to treat 11 core treatable conditions including chronic obstructive pulmonary disease (COPD), heart conditions and joint conditions, such as osteoarthritis. We use two types of stem cell programs; autologous, meaning that we use your own stem cells, and allogeneic, where we use donated adult stem cells from one of the best labs in the world.

Stem cell research has had bad press over the years due to the misconception that Stem Cells can only come from embryos. This isnt true. Here at Stem Cell MX we only use Adult Stem Cells which have been harvested from either the donor or the patients themselves.

If you want to find out more about stem cell therapy with no obligation then contact us today. Our stem cell clinical trials are based on thirty years of research and clinical experience conducted by leading researchers and clinicians in Europe and the United States.

To find out the basics about stem cells read An Introduction to Stem Cells

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Stem Cell Therapy in Switzerland Life Cell Injections …

By Sykes24Tracey

Stem Cell Therapy Plus is also called Live Cell Therapy or Regenerative Medicine.

Anecdotal evidence shows that through the usage of Stem Cell Therapy Plus, improvements can be seen in the following cases of degenerative diseases:

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Stem cells are cells with the ability to divide for indefinite periods in culture and to give rise to specialized cells. Stem cells have the remarkable potential to develop into many different cell types. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells.

When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a nerve cell, or a brain cell.

Stem Cell Supplements are developed based on the merits of stem cells and they are applied for degenerative diseases treatments and to stimulate the formation of all the different tissues of the body: muscle, cartilage, tendon, ligament, bone, blood, nerve, organs, etc.

Stem Cell Supplements bring essential anti-ageing, health & beauty benefits by providing necessary elements to the body to improve cellular regeneration, organ rejuvenation and tissue healing.

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Stem Cell Therapy in Switzerland Life Cell Injections ...

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