News Article | May 10, 2017
MIAMI, Florida -- Scientists from the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine have produced the first clinical results demonstrating that pancreatic islet cells transplanted within a tissue-engineered platform can successfully engraft and achieve insulin independence in type 1 diabetes. The findings, published in the May 11 issue of the New England Journal of Medicine, are part of an ongoing clinical study to test this novel strategy as an important step toward offering this life-changing cell replacement therapy to millions living with the disease. Islet transplantation has demonstrated the ability to restore natural insulin production and eliminate severe hypoglycemia in people with type 1 diabetes. The insulin-producing cells have traditionally been implanted within the liver, but this transplant site poses some limitations for emerging applications, leading researchers to investigate other options. DRI scientists have focused on the omentum, an apron-like tissue covering abdominal organs, which is easily accessed with minimally invasive surgery and has the same blood supply and physiological drainage characteristics as the pancreas. "The objective of testing this novel tissue-engineered platform is to initially determine that insulin-producing cells can function in this new site, and subsequently introduce additional technologies towards our ultimate goal to replace the pancreatic endocrine function lost in type 1 diabetes without the need for anti-rejection drugs, what we call the DRI BioHub," explains Camillo Ricordi, M.D., director of the DRI and the Stacy Joy Goodman Professor of Surgery, Distinguished Professor of Medicine, Professor of Biomedical Engineering, Microbiology and Immunology at the University of Miami Miller School. Dr. Ricordi also serves as director of the DRI's Cell Transplant Center. This was the first successful tissue-engineered "mini pancreas" that has achieved long-term insulin independence in a patient with type 1 diabetes. The biological platform was made by combining donor islets with the patient's own (autologous) blood plasma, which was laparoscopically layered onto the omentum. Clinical-grade thrombin was then layered over the islet/plasma mixture. Together, these substances create a gel-like material that sticks to the omentum and holds the islets in place. Over time, the body will absorb the gel, leaving the islets intact. The technique has been designed to minimize the inflammatory reaction that is normally observed when islets are implanted in the liver or in other sites with immediate contact to blood. The DRI's clinical trial, an important first step toward developing the BioHub mini organ, includes the immunosuppressive regimen currently used for clinical islet transplantation studies. "The results thus far have shown that the omentum appears to be a viable site for islet implantation using this new platform technique," said lead author David Baidal, M.D., Assistant Professor of Medicine and member of the DRI's Clinical Cell Transplant team. "Data from our study and long-term follow up of additional omental islet transplants will determine the safety and feasibility of this strategy of islet transplantation, but we are quite excited about what we are seeing now." In type 1 diabetes, the insulin-producing cells of the pancreas have been mistakenly destroyed by the immune system, requiring patients to manage their blood sugar levels through a daily regimen of insulin therapy. Islet transplantation has allowed many patients to live without the need for insulin injections after receiving a transplant of donor cells. Some patients who have received islet transplants at the DRI have been insulin independent for more than a decade, as DRI researchers have published. The research projects that comprise the DRI BioHub receive philanthropic support from the Diabetes Research Institute Foundation. Funding for the DRI BioHub is also provided by other sources, including JDRF, The Leona M. and Harry B. Helmsley Charitable Trust, National Institutes of Health (NIH), NIH Small Business Innovation Research (SBIR), University of Miami, pharmaceutical companies, and additional corporate and philanthropic partners. For more information on the development of the BioHub, visit http://www. The Diabetes Research Institute at the University of Miami Miller School of Medicine leads the world in cure-focused research. As the largest and most comprehensive research center dedicated to curing diabetes, the DRI is aggressively working to develop a biological cure by restoring natural insulin production and normalizing blood sugar levels without imposing other risks. Researchers have already shown that transplanted islet cells allow patients to live without the need for insulin therapy. Some study participants have maintained insulin independence for more than 10 years. The DRI is now building upon these promising outcomes by developing the DRI BioHub, a bioengineered "mini organ" that mimics the native pancreas. While various BioHub platforms are being tested in preclinical and clinical studies, the DRI is also developing strategies to eliminate the need for anti-rejection drugs and reset the immune system to block autoimmunity. For more information, please visit DiabetesResearch.org, call 800-321-3437, or Tweet @Diabetes_DRI.
Folmes C.D.L.,Center for Regenerative Medicine |
Nelson T.J.,Center for Regenerative Medicine |
Nelson T.J.,Transplant Center |
Martinez-Fernandez A.,Center for Regenerative Medicine |
And 9 more authors.
Cell Metabolism | Year: 2011
The bioenergetics of somatic dedifferentiation into induced pluripotent stem cells remains largely unknown. Here, stemness factor-mediated nuclear reprogramming reverted mitochondrial networks into cristae-poor structures. Metabolomic footprinting and fingerprinting distinguished derived pluripotent progeny from parental fibroblasts according to elevated glucose utilization and production of glycolytic end products. Temporal sampling demonstrated glycolytic gene potentiation prior to induction of pluripotent markers. Functional metamorphosis of somatic oxidative phosphorylation into acquired pluripotent glycolytic metabolism conformed to an embryonic-like archetype. Stimulation of glycolysis promoted, while blockade of glycolytic enzyme activity blunted, reprogramming efficiency. Metaboproteomics resolved upregulated glycolytic enzymes and downregulated electron transport chain complex I subunits underlying cell fate determination. Thus, the energetic infrastructure of somatic cells transitions into a required glycolytic metabotype to fuel induction of pluripotency. © 2011 Elsevier Inc.
News Article | February 16, 2017
UC Davis physicians gave lifesaving kidney transplants to more than 400 people in 2016, making it the highest-volume kidney transplant program in the nation. In addition to the rapid growth — more than four-fold in the past decade — outcomes for UC Davis kidney transplant program patients have consistently exceeded the national average. Volume is an important factor transplant candidates consider when selecting centers for their care, because it is linked with experience and resources. It is also one of the reasons UC Davis was recognized in 2016 as a model hospital by the United Network for Organ Sharing (UNOS), the organization that manages the nation’s organ transplant system. The UC Davis Transplant Center has been within the top five programs in terms of kidney transplant volume since 2011, but this is the first time it has been in the top spot. Richard Perez, chief of transplant surgery, attributes the high numbers to UC Davis’ multidisciplinary team — from the transplant clinic to the operating room — that works closely with patients, donor families, hospital partners and organ-procurement organizations to make sure that transplants happen in Sacramento whenever possible. “We are working very hard to close the gap between the number of people who need kidney transplants and the number of kidneys available for transplant,” said Perez. “But it’s an ever-worsening health crisis. With our commitments to transplant science and compassionate, collaborative care, we hope to continue to close that gap even further.” Perez also credits the university’s transplant nephrology team, whose outreach clinics serve people on kidney transplant waitlists throughout central and northern California and northwestern Nevada. The result, according to Angelo De Mattos, chief of transplant nephrology, is the center’s statistically significant lower-than-expected waitlist and post-surgery mortality rates. “We have made a big difference in extending lifespans by bringing expert care to patients who otherwise would not have access to pre- and post-transplant specialists,” De Mattos said. De Mattos explained that all kidney transplant patients have end-stage renal disease (ESRD), which occurs when blood vessels in the kidneys become damaged. In the U.S., the condition is often a result of diabetes or hypertension. It eventually leads to organ failure and metabolic waste buildup in the bloodstream. Just two treatments prevent ESRD from being fatal. Regular dialysis helps purify the blood with waste-capturing chemicals. The more effective option, however, is transplanting an organ, ideally from a living donor or a carefully selected deceased donor, as it restores kidney function. Due to a shortage of available organs, surgery happens for less than a fifth of the 100,000 people on kidney transplant waitlists in the U.S. One reason for that gap is the number of deceased donor kidneys that are discarded, rather than transplanted. “It’s a tragedy, because we know a lot of those kidneys are usable,” Perez said. “Kidney donors have been enormously generous with their gift of life. We have an obligation to make sure that generosity is fulfilled whenever possible.” By leveraging its national network of relationships, UC Davis acquires many difficult-to-transplant kidneys that other centers lack the expertise to use. Comprehensive assessment processes, including onsite biopsies, the use of cold pulsatile perfusion technology and optimized donor-recipient matching, have increased the utilization of these organs. A high level of experience with complex surgeries, including those that involve kidneys from pediatric donors, has also contributed to the transplant program’s growth. Perez is currently developing next-generation perfusion technology. Called normothermic perfusion, it infuses kidneys with red blood cells, oxygen and nutrients at normal temperature, providing a more realistic assessment of post-surgical performance and restoring organs that at first may not seem usable. “We’re focused on moving this technology to the forefront, because we think it will be key to easing the nation’s organ shortage,” Perez said. “So far, it is leading us to believe that there are many more kidneys that can be used for transplant that are currently discarded.” More information about the UC Davis Transplant Center and how to become an organ donor is at http://www.ucdmc.ucdavis.edu/transplant/. Data on U.S. transplant centers and patients is available through the Scientific Registry of Transplant Recipients at http://www.srtr.org and UNOS at http://www.unos.org.
News Article | March 8, 2016
A 26-year-old woman who learned at age 16 that she would be unable to have children now has a chance to do so, thanks to the first uterus transplant in the U.S. The transplant provides hope for women who are unable to have babies due to uterus-related issues, said the doctors who completed the transplant. "This is an unbelievable event" and the patient is doing very well, said Dr. Andreas Tzakis, the program director of the Cleveland Clinic's Transplant Center, who led the surgery. A condition called uterine factor infertility — in which a woman is unable to get pregnant because she either does not have a uterus, or the uterus does not function properly — affects an estimated 50,000 women in the United States, according to the Cleveland Clinic. [Donated Uterus Transplanted Into Patient | Animation] A uterus transplant can enable a woman with uterine factor infertility to become pregnant and deliver a baby. The surgery took place February 2016, and required about 9 hours, said Dr. Toby Cosgrove, the CEO and president of the Cleveland Clinic, speaking at a news conference today (March 7). The team included eight surgeons and about 70 other caregivers, including fertility experts and bioethicists, he said. Tzakis and his team worked very closely with doctors in Sweden, who completed the world's first uterus transplant in 2015. In the Cleveland transplant, the uterus was taken from a deceased donor, Tzakis said. The surgeons used transplant techniques that have been well-established for other types of organ transplants. However, the surgery is a little more complex because the transplant site is deep within the pelvis and therefore more difficult to access, Tzakis said. Dr. Rebecca Flyckt, an OB/GYN surgeon who was part of the team, elaborated upon the surgery. The the most important of part of the transplant is to connect blood vessels, Flyckt said at the news conference. First, the uterine arteries and veins were connected to the recipient's blood vessels, she said. Once these were connected, the transplanted uterus started to turn pink, which indicated that blood is flowing, she said. [The 9 Most Interesting Transplants] Next, the surgeons connected the uterus to the vagina, as well as the connective tissue in the pelvis that helps anchor the uterus in place, she said. The transplanted uterus also included the cervix and the upper part of the vagina. The goal of the surgery is to allow the woman to have a baby, but the woman needs to wait at least a year before trying to get pregnant, Flyckt said. The team in Cleveland screened more than 250 women, and ultimately selected 10 who will receive transplants. All of the women were born with normal ovaries that produce healthy eggs, Flyckt said. But without a uterus, the eggs have nowhere to go, she said. Before the transplant, the women will undergo in vitro fertilization, Flyckt said. They will bank six to 10 embryos before they can be considered for the transplant, she said. After the transplant is completed, the women need to wait one full year before pregnancy is considered, Flyckt said. This is to make ensure that the woman is taking lower dosages of anti-rejection medications, which suppress the immune system, she said. Then, the doctors will begin to implant the embryos, Flyckt said. (Because the fallopian tubes were not transplanted, the patient cannot get pregnant through sex.) Dr. Uma Perni, an OB-GYN specializing in high-risk pregnancies, said the team plans to deliver babies via cesarean section on any women who have undergone uterus transplants, because there are many unknowns about vaginal delivery with a transplanted uterus. It isn't clear exactly how a transplanted uterus would respond to normal signs of labor, and it's possible that the complex connections that were made during the transplant could be disrupted during labor, Perni said. Ultimately, it isn't clear how the patient's body would tolerate a vaginal delivery, she said. Perni added that the risk of a preterm delivery is a little higher in women who have undergone a uterus transplant, compared with the average woman. Because of this, the team will be closely monitoring the patient in her third trimester, she said. Ultimately, they hope they can get very close to 37 weeks, which is considered full term, before delivering the baby, she said.
Hibi T.,University of Miami |
Nishida S.,University of Miami |
Levi D.M.,University of Miami |
Selvaggi G.,University of Miami |
And 5 more authors.
Annals of Surgery | Year: 2014
OBJECTIVE:: To identify complications associated with different techniques utilized to treat portal vein thrombosis (PVT) during primary liver transplantation and their impact on survival. BACKGROUND:: PVT remains an intricate problem in liver transplantation, and the long-term outcomes of patients with PVT who undergo transplantation are not well defined. METHODS:: We performed a retrospective cohort analysis of all consecutive adult patients who underwent primary isolated liver transplantation from 1998 to 2009 (median follow-up period, 89 months). The outcomes of patients with PVT were compared with those without PVT. RESULTS:: Among 1379 recipients, 174 (12.6%) had PVT at the time of transplantation [83 (48%) complete and 91 (52%) partial]. Among PVT patients with reestablished physiological portal inflow (PVT: physiological group; n = 149), 123 underwent thrombectomies, 16 received interpositional vein grafts, and 10 received mesoportal jump grafts. In 25 patients, physiological portomesenteric venous circulation was not reconstituted (PVT: nonphysiological group; 18 underwent cavoportal hemitranspositions, 6 renoportal anastomoses, and 1 arterialization). The PVT: nonphysiological group suffered a significantly increased incidence of rethrombosis of the portomesenteric veins and gastrointestinal bleeding, with a marginal 10-year overall survival rate of 42% (no PVT, 61%; P = 0.002 and PVT: physiological, 55%; P = 0.043). The PVT: physiological and no PVT groups exhibited comparable survival rates (P = 0.13). No significant differences in survival were observed between complete and partial PVT as long as physiological portal flow was reestablished. CONCLUSIONS:: The subset of PVT patients requiring nonphysiological portal vein reconstruction was associated with higher complication rates and suffered diminished long-term prognoses. For the most severe PVT cases, a comprehensive approach is critical to further improve outcomes. © 2013 by Lippincott Williams & Wilkins.
Gago M.,William von Liebig Transplant Center |
Gago M.,Mayo Medical School |
Cornell L.D.,Mayo Medical School |
Kremers W.K.,Mayo Medical School |
And 2 more authors.
American Journal of Transplantation | Year: 2012
This study assessed the development of allograft interstitial fibrosis and inflammation (GIF+"i"), a histologic pattern associated with reduced graft survival. Included are 795 adults, recipients of kidney allografts from 2000 to 2006. GIF+"i" was diagnosed in surveillance and clinical biopsies that had no transplant glomerulopathy. With time, posttransplant increasing number of grafts showed GIF+"i" and these patients had reduced death-censored graft survival (HR = 4.33 (2.49-7.53), p < 0.0001). Development of GIF+"i" was related to prior acute cellular rejection (ACR), BK nephropathy (PVAN), increasing number of HLA mismatches, retransplantation and DGF. However, 46.4% of GIF+"i" cases had no history of ACR or PVAN. Anti-HLA antibodies at transplant did not relate to GIF+"i" and these patients had no increased frequency of new antibody formation posttransplant. Post-ACR biopsies showed that GIF+"i" developed more commonly after clinically and/or histologically more severe ACR. Graft inflammation persisted in 38.7 and 29.6% of grafts 2 and 12 months post-ACR. Twelve months post-ACR, 27.1% of biopsies developed moderate-severe GIF and 51.8% showed GIF and inflammation. Persistent inflammation and progressive GIF is often subclinical but may lead to graft failure. GIF+"i" can be initiated by multiple etiologies but it is often postinfectious or due to persistent cellular immune-mediated injury. This study analyzes "graft interstitial fibrosis associated with inflammation" after kidney transplantation, the factors that relate to its development, and its implications for graft survival. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
Gali B.,Mayo Medical School |
Rosen C.B.,Transplant Center |
Plevak D.J.,Mayo Medical School
Journal of Intensive Care Medicine | Year: 2012
A perception that living donor liver transplantation can be accomplished with an acceptable donor complication rate and recipient survival rate has led to the acceptance of living donor liver transplantation as a viable alternative to decreased deceased donor transplantation. Careful candidate evaluation and selection has been crucial to the success of this procedure. Advancements in the understanding of the lobar nature of the liver and of liver regeneration have advanced the surgical technique. Initial attempts at adult-to-adult donation utilized the left hepatic lobe, but now have evolved into use of the right hepatic lobe. Size matching is very important to successful graft function in the recipient. There is great concern regarding morbidity and mortality in donors. Biliary complications and infections continue to be among the most highly reported complications, although rates vary among centers and countries. Reports of single center complications have ranged from 9% to 67%. A survey of centers in the United States in 2003 reported complications of 10%. A series from our institution reported complications arising in 13 (33%) of 39 patients. A review focused on documenting donor deaths found 33 living liver donor deaths worldwide. The much publicized immediate postoperative mishap of 2002 that resulted in a donor's death resulted in a drop in the utilization of living donor liver transplantation in the United States, from which this procedure has never fully recovered. The future development and expansion of living donor liver transplantation depends on open communication regarding donor complications and deaths. Close immediate postoperative monitoring and meticulous management will remain an essential aspect in limiting donor complications and deaths. © SAGE Publications 2012.
Thapa B.,Transplant Center |
Sayami P.,Transplant Center
Asian Pacific Journal of Cancer Prevention | Year: 2014
Background: Resection rates of lung cancer are low in general and especially in countries like Nepal. Advanced stage at presentation and poor general condition of the patient are the usual causes. Materials and Methods: In this prospective observational study, one hundred cases of lung cancer who presented at the Thoracic Surgery Unit between October 2011 and October 2012 were included. Results: Those aged in the 6th and 7th decades together accounted for 72/100 patients. The male to female ratio was 2:1. There was a mean-29.2±14.2 pack yrs smoking history with only five non-smokers. Seventy-six patients presented with locally advanced disease while 21 had metastases. Only three had local disease. The average time between onset of symptoms to first contact with a doctor was 2.3±5.3 months (range: 0-35.6 months). Average time between first contact to referral was 50.4±65.7 days (range-0-365). Only three patients were resected, one after neo-adjuvant chemotherapy. Advanced disease was the cause of unresectability in 95 cases. One of three patients with local disease had pulmonary functions allowing the warranted resection. N2 disease with T1-3 on CT scan was found in 47. Three of these patients underwent mediastinoscopy and all confirmed uninvolved N2. Conclusions: Lung resection rates in our center remain low. Late presentation leading to advanced disease and poor pulmonary reserves preclude resection in most cases. More liberal use of mediastinal staging and better assessment of pulmonary functions may allow us to improve resection rates.
Nelson T.J.,Transplant Center |
Terzic A.,Transplant Center
Clinical Pharmacology and Therapeutics | Year: 2011
Nuclear reprogramming generates induced pluripotent stem (iPS) cells endowed with the unlimited potential to reconstruct genetically identical tissues. This biomedical tool offers unprecedented opportunities to develop scalable yet personalized cell-based reagents. The emerging platform of regenerative theranostics provides a unique approach to expose mechanisms of disease etiology in the context of dysfunctional cell biology. Resolved molecular dynamics that define and regulate the regenerative capacity of individual stem cells will enable next-generation, patient-specific diagnostic and therapeutic applications. © 2011 american Society for Clinical Pharmacology and Therapeutics.
Russo M.W.,Transplant Center
Expert Review of Gastroenterology and Hepatology | Year: 2010
End-stage liver disease from hepatitis C is a leading cause of decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and liver-related deaths. The goals of antiviral therapy are to prevent these sequelae and prolong life. Clinical trials of α-interferons and ribavirin have used sustained viral response as an outcome because it is considered synonymous with cure and is assumed to be associated with decreasing complications caused by cirrhosis. However, it is only recently that data has emerged supporting this assumption. This study demonstrates that meaningful clinical end points are seen in patients who achieve a sustained virologic response (SVR) with a reduction in liver-related deaths, rates of hepatocellular carcinoma (HCC) and liver-related complications. None of the patients who achieved SVR developed variceal bleeding. The rates of HCC were significantly lower in the SVR group, but six cases of HCC occurred in the SVR group, underscoring the importance of continued surveillance in hepatitis C virus patients with SVR who have advanced fibrosis or cirrhosis. © 2010 Expert Reviews Ltd.