Showing papers on "Transplantation published in 2008"
TL;DR: This study illustrates how combining comparative metagenomics with gnotobiotic mouse models and specific dietary manipulations can disclose the niches of previously uncharacterized members of the gut microbiota.
2,578 citations
TL;DR: Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD.
2,510 citations
TL;DR: Eight constructs decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent a cellular valves and intact chamber geometry that could generate pump function in a modified working heart preparation.
Abstract: About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22 million individuals are living with heart failure. A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Generating a bioartificial heart requires engineering of cardiac architecture, appropriate cellular constituents and pump function. We decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent acellular valves and intact chamber geometry. To mimic cardiac cell composition, we reseeded these constructs with cardiac or endothelial cells. To establish function, we maintained eight constructs for up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By day 4, we observed macroscopic contractions. By day 8, under physiological load and electrical stimulation, constructs could generate pump function (equivalent to about 2% of adult or 25% of 16-week fetal heart function) in a modified working heart preparation.
2,454 citations
TL;DR: Improved outcome of patients with myeloma in recent years is demonstrated, both in the relapsed setting as well as at diagnosis, both from time of diagnosis and the time of relapse.
2,077 citations
University of Alberta1, Harvard University2, Johns Hopkins University3, Mayo Clinic4, University of São Paulo5, University of Maryland, Baltimore6, Vanderbilt University7, University of Manitoba8, University of Paris9, Wake Forest University10, Katholieke Universiteit Leuven11, National Institutes of Health12, University of Basel13, Westmead Hospital14, University of North Carolina at Chapel Hill15, University of Pittsburgh16, University of Vienna17, University of Oxford18, University of Padua19
TL;DR: Emerging research data led to the establishment of collaborative working groups addressing issues like isolated ‘v’ lesion and incorporation of omics‐technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.
1,700 citations
TL;DR: Genes represented in the new stroma-derived prognostic predictor (SDPP) reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.
Abstract: Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.
1,571 citations
TL;DR: Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body–like inclusions that stained positively for α-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter.
Abstract: Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body–like inclusions that stained positively for α-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.
1,489 citations
TL;DR: Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD, and there was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttrans transplantation Cy.
1,420 citations
TL;DR: The results show that a cellular, tissue-engineered airway with mechanical properties that allow normal functioning, and which is free from the risks of rejection, is produced, suggesting that autologous cells combined with appropriate biomaterials might provide successful treatment for patients with serious clinical disorders.
1,355 citations
TL;DR: It is shown that iPS cells can be efficiently differentiated into neural precursor cells, giving rise to neuronal and glial cell types in culture and demonstrating the therapeutic potential of directly reprogrammed fibroblasts for neuronal cell replacement in the animal model.
Abstract: The long-term goal of nuclear transfer or alternative reprogramming approaches is to create patient-specific donor cells for transplantation therapy, avoiding immunorejection, a major complication in current transplantation medicine. It was recently shown that the four transcription factors Oct4, Sox2, Klf4, and c-Myc induce pluripotency in mouse fibroblasts. However, the therapeutic potential of induced pluripotent stem (iPS) cells for neural cell replacement strategies remained unexplored. Here, we show that iPS cells can be efficiently differentiated into neural precursor cells, giving rise to neuronal and glial cell types in culture. Upon transplantation into the fetal mouse brain, the cells migrate into various brain regions and differentiate into glia and neurons, including glutamatergic, GABAergic, and catecholaminergic subtypes. Electrophysiological recordings and morphological analysis demonstrated that the grafted neurons had mature neuronal activity and were functionally integrated in the host brain. Furthermore, iPS cells were induced to differentiate into dopamine neurons of midbrain character and were able to improve behavior in a rat model of Parkinson's disease upon transplantation into the adult brain. We minimized the risk of tumor formation from the grafted cells by separating contaminating pluripotent cells and committed neural cells using fluorescence-activated cell sorting. Our results demonstrate the therapeutic potential of directly reprogrammed fibroblasts for neuronal cell replacement in the animal model.
1,234 citations
TL;DR: A transparent adult zebrafish is created in which either hematopoietic stem/progenitor cells or tumor cells are transplanted, serving as the ideal combination of both sensitivity and resolution for in vivo stem cell analyses.
TL;DR: Current biomimetic materials approaches in tissue engineering include synthesis to achieve certain compositions or properties similar to those of the extracellular matrix, novel processing technologies to achieve structural features mimicking the ext racellular matrix on various levels, and biologic delivery strategies to recapitulate a signaling cascade or developmental/wound healing program.
TL;DR: The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.
Abstract: Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.
TL;DR: This population-wide study shows that the MELD score and the serum sodium concentration are important predictors of survival among candidates for liver transplantation.
Abstract: BACKGROUND Under the current liver-transplantation policy, donor organs are offered to patients with the highest risk of death. METHODS Using data derived from all adult candidates for primary liver transplantation who were registered with the Organ Procurement and Transplantation Network in 2005 and 2006, we developed and validated a multivariable survival model to predict mortality at 90 days after registration. The predictor variable was the Model for End-Stage Liver Disease (MELD) score with and without the addition of the serum sodium concentration. The MELD score (on a scale of 6 to 40, with higher values indicating more severe disease) is calculated on the basis of the serum bilirubin and creatinine concentrations and the international normalized ratio for the prothrombin time. RESULTS In 2005, there were 6769 registrants, including 1781 who underwent liver transplantation and 422 who died within 90 days after registration on the waiting list. Both the MELD score and the serum sodium concentration were significantly associated with mortality (hazard ratio for death, 1.21 per MELD point and 1.05 per 1-unit decrease in the serum sodium concentration for values between 125 and 140 mmol per liter; P<0.001 for both variables). Furthermore, a significant interaction was found between the MELD score and the serum sodium concentration, indicating that the effect of the serum sodium concentration was greater in patients with a low MELD score. When applied to the data from 2006, when 477 patients died within 3 months after registration on the waiting list, the combination of the MELD score and the serum sodium concentration was considerably higher than the MELD score alone in 32 patients who died (7%). Thus, assignment of priority according to the MELD score combined with the serum sodium concentration might have resulted in transplantation and prevented death. CONCLUSIONS This population-wide study shows that the MELD score and the serum sodium concentration are important predictors of survival among candidates for liver transplantation.
Journal Article•
TL;DR: A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing dacluzumab induction plus either low- doses of cyclosporine or low- dose sirolimus or with standard-dose cyclosporaine without induction.
TL;DR: In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups.
TL;DR: The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed.
Abstract: This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.
TL;DR: Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen, and it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation.
Abstract: Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA.
TL;DR: Myoblast injections combined with coronary surgery in patients with depressed LV function failed to improve echocardiographic heart function and the increased number of early postoperative arrhythmic events after myoblast transplantation warrants further investigation.
Abstract: Background— Phase I clinical studies have demonstrated the feasibility of implanting autologous skeletal myoblasts in postinfarction scars. However, they have failed to determine whether this procedure was functionally effective and arrhythmogenic. Methods and Results— This multicenter, randomized, placebo-controlled, double-blind study included patients with left ventricular (LV) dysfunction (ejection fraction ≤35%), myocardial infarction, and indication for coronary surgery. Each patient received either cells grown from a skeletal muscle biopsy or a placebo solution injected in and around the scar. All patients received an implantable cardioverter-defibrillator. The primary efficacy end points were the 6-month changes in global and regional LV function assessed by echocardiography. The safety end points comprised a composite index of major cardiac adverse events and ventricular arrhythmias. Ninety-seven patients received myoblasts (400 or 800 million; n=33 and n=34, respectively) or the placebo (n=30). ...
TL;DR: A consensus on a new definition, criteria for diagnosis and recommendations on HRS treatment was reached at the 56th Meeting of the American Association for the Study of Liver Diseases (AASLD) as mentioned in this paper.
Abstract: 34 and the only effective treatment is liver transplantation. During the 56th Meeting of the American Association for the Study of Liver Diseases, the International Ascites Club held a Focused Study Group (FSG) on HRS for the purpose of reporting the results of an international workshop and to reach a consensus on a new definition, criteria for diagnosis and recommendations on HRS treatment. A similar workshop was held in Chicago in 1994 in which standardised nomenclature and diagnostic criteria for refractory ascites and HRS were established. 5 The introduction of innovative treatments and improvements in our understanding of the pathogenesis of HRS during the previous decade led to an increasing need to undertake a new consensus meeting. This paper reports the scientific rationale behind the new definitions and recommendations.
TL;DR: In perioperative survivors of Fontan surgery, gradual attrition occurs predominantly from thromboembolic, heart failure–related, and sudden deaths.
Abstract: Background— To better define determinants of mortality in patients with univentricular physiology, a database registry was created of patients born in 1985 or earlier with Fontan surgery who were followed up at Children’s Hospital Boston. Methods and Results— A total of 261 patients, 121 of whom (46.4%) were women, had a first Fontan surgery at a median age of 7.9 years: right atrium–to–pulmonary artery connection in 135 (51.7%); right atrium to right ventricle in 25 (9.6%); and total cavopulmonary connection in 101 (38.7%). Over a median of 12.2 years, 76 (29.1%) died, 5 (1.9%) had cardiac transplantation, 5 (1.9%) had Fontan revision, and 21 (8.0%) had Fontan conversion. Perioperative mortality decreased steadily over time and accounted for 68.4% of all deaths. In early survivors, actuarial freedom from death or transplantation was 93.7%, 89.9%, 87.3%, and 82.6% at 5, 10, 15, and 20 years, respectively, with no significant difference between right atrium to pulmonary artery versus total cavopulmonary co...
TL;DR: It is shown that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells, and protected genetically susceptible mice against lethal Listeria monocytogenes infection.
TL;DR: It is shown that fibroblasts can be reprogrammed to a pluripotent state by Oct4, Sox2, and Klf4 in the absence of c-Myc.
TL;DR: The effects of preculturing human bone marrow‐derived MSC in hypoxic conditions (1%–3% oxygen) to elucidate the best conditions that enhance their tissue regenerative potential are examined, and it is demonstrated that MSC cultured in hypoxia activate the Akt signaling pathway while maintaining their viability and cell cycle rates.
Abstract: Mesenchymal stem cells (MSC) are adult multipotent cells found in bone marrow, adipose tissue, and other adult tissues. MSC have been shown to improve regeneration of injured tissues in vivo, but the mechanisms remain unclear. Typically, MSC are cultured under ambient, or normoxic, conditions (21% oxygen). However, the physiological niches for MSC in the bone marrow and other sites have much lower oxygen tension. When used as a therapeutic tool to repair tissue injuries, MSC cultured in standard conditions must adapt from 21% oxygen in culture to less than 1% oxygen in the ischemic tissue. We therefore examined the effects of preculturing human bone marrow-derived MSC in hypoxic conditions (1%–3% oxygen) to elucidate the best conditions that enhance their tissue regenerative potential. We demonstrated that MSC cultured in hypoxia activate the Akt signaling pathway while maintaining their viability and cell cycle rates. We also showed that MSC cultured in hypoxia induced expression of cMet, the major receptor for hepatocyte growth factor (HGF), and enhanced cMet signaling. MSC cultured in hypoxic conditions increased their migration rates. Since migration and HGF responsiveness are thought to be key mediators of MSC recruitment and/or activation in vivo, we next examined the tissue regenerative potential of MSC cultured under hypoxic conditions, using a murine hind limb ischemia model. We showed that local expression of HGF is increased in ischemic muscle in this model. Intra-arterial injection of MSC cultured in either normoxic or hypoxic conditions 24 hours after surgical induction of hind limb ischemia enhanced revascularization compared with saline controls. However, restoration of blood flow was observed significantly earlier in mice that had been injected with hypoxic preconditioned MSC. Collectively, these data suggest that preculturing MSC under hypoxic conditions prior to transplantation improves their tissue regenerative potential.
TL;DR: The results of this meta-analysis emphasize and quantify the long-term detrimental association between DGF and important graft outcomes like graft survival, acute rejection and renal function.
Abstract: Background Delayed graft function (DGF) is a common complication of renal transplantation. The short-term consequences of DGF are well known, but the long-term relationship between DGF and patient and graft survival is controversial in the published literature. We conducted a systematic review and meta-analysis to precisely estimate these relationships. Methods We performed a literature search for original studies published through March 2007 pertaining to long-term (>6 months) outcomes of DGF. The primary outcome was graft survival. Secondary outcomes were patient survival, acute rejection and kidney function. Results When compared to patients without DGF, patients with DGF had a 41% increased risk of graft loss (RR 1.41, 95% CI 1.27-1.56) at 3.2 years of follow-up. There was no significant relationship between DGF and patient survival at 5 years (RR 1.14, 95% CI 0.94-1.39). The mean creatinine in the non-DGF group was 1.6 mg/dl. Patients with DGF had a higher mean serum creatinine (0.66 mg/dl, 95% CI 0.57-0.74) compared to patients without DGF at 3.5 years of follow-up. DGF was associated with a 38% relative increase in the risk of acute rejection (RR 1.38, 95% CI 1.29-1.47). Conclusion The results of this meta-analysis emphasize and quantify the long-term detrimental association between DGF and important graft outcomes like graft survival, acute rejection and renal function. Efforts to prevent and treat DGF should be aggressively investigated in order to improve graft survival given the deficit in the number of kidney donors.
TL;DR: In vitro generation of putative rod and cone photoreceptors from mouse, monkey and human ES cells by stepwise treatments under defined culture conditions, in the absence of retinal tissues, may facilitate the development of human ES cell–based transplantation therapies for retinal diseases.
Abstract: We previously reported the differentiation of mouse embryonic stem (ES) cells into retinal progenitors. However, these progenitors rarely differentiate into photoreceptors unless they are cultured with embryonic retinal tissues. Here we show the in vitro generation of putative rod and cone photoreceptors from mouse, monkey and human ES cells by stepwise treatments under defined culture conditions, in the absence of retinal tissues. With mouse ES cells, Crx+ photoreceptor precursors were induced from Rx+ retinal progenitors by treatment with a Notch signal inhibitor. Further application of fibroblast growth factors, Shh, taurine and retinoic acid yielded a greater number of rhodopsin+ rod photoreceptors, in addition to default cone production. With monkey and human ES cells, feeder- and serum-free suspension culture combined with Wnt and Nodal inhibitors induced differentiation of Rx+ or Mitf+ retinal progenitors, which produced retinal pigment epithelial cells. Subsequent treatment with retinoic acid and taurine induced photoreceptor differentiation. These findings may facilitate the development of human ES cell–based transplantation therapies for retinal diseases.
TL;DR: It is suggested that SC fat is intrinsically different from VIS fat and produces substances that can act systemically to improve glucose metabolism.
TL;DR: Findings suggest that the combination of intravenous immune globulin and rituximab may prove effective as a desensitization regimen for patients awaiting a transplant from either a living donor or a deceased donor.
Abstract: Background Few options for transplantation currently exist for patients highly sensitized to HLA. This exploratory, open-label, phase 1–2, single-center study examined whether intravenous immune globulin plus rituximab could reduce anti-HLA antibody levels and improve transplantation rates. Methods Between September 2005 and May 2007, a total of 20 highly sensitized patients (with a mean [±SD] T-cell panel-reactive antibody level, determined by use of the complement-dependent cytotoxicity assay, of 77±19% or with donor-specific antibodies) were enrolled and received treatment with intravenous immune globulin and rituximab. We recorded rates of transplantation, panel-reactive antibody levels, cross-matching results at the time of transplantation, survival of patients and grafts, acute rejection episodes, serum creatinine values, adverse events and serious adverse events, and immunologic factors. Results The mean panel-reactive antibody level was 44±30% after the second infusion of intravenous immune globul...
TL;DR: Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure.
TL;DR: Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarction resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy.