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Gautam S.,Beth Israel Deaconess Medical Center | Goldfarb-Rumyantzev A.S.,Transplant Institute | Goldfarb-Rumyantzev A.S.,Beth Israel Deaconess Medical Center | Pavlakis M.,Transplant Institute | And 6 more authors.
American Journal of Nephrology | Year: 2013

Background: Modern immunosuppression and rabbit antithymocyte globulin (rATG) have facilitated the success of early steroid withdrawal (ESW) protocols. Little data exist on optimal rATG dosing in ESW protocols. Methods: Rejection at 12 months in era 1 (four doses of rATG, 1.25 mg/kg) vs. era 2 (three doses of rATG, 1.25 mg/kg) was the primary endpoint. Secondary endpoints included patient and graft survival, renal function and infectious complications. Factors associated with rejection at 1 year were identified. Results: 199 patients received rATG induction and ESW: 102 in era 1 and 97 in era 2. Compared to era 1, era 2 was not associated with worse outcomes, including rejection, renal function, infection or graft survival. Rejection at 1 year and uncensored graft survival differed between the dosing groups. Rejection rates were significantly higher in the <4 mg/kg group compared to the 4-5.9-mg/kg and the ≥6-mg/kg groups, whereas uncensored graft survival was the lowest in the ≥6-mg/kg group. Factors associated with rejection at 12 months included: rATG dose received of 4-5.9 versus <4 mg/kg (OR 0.20, 95% CI 0.036-0.85, p = 0.026); recipient age (per year, OR 0.94, 95% CI 0.89-1.0, p = 0.038); panel reactive antibody 10-79.9 versus <10% (OR 5.4, 95% CI 1.2-25, p = 0.030) and rATG dose held (OR 4.0, 95% CI 1.0-15, p = 0.049). Conclusions: A comparison of rATG dosing based on era did not result in a significant difference in rejection, renal function, infection or graft survival. However, when evaluating the study population based on actual dose received there were notable differences in both rejection rates and uncensored graft survival. © 2013 S. Karger AG, Basel.


SAN DIEGO, CA--(Marketwired - October 24, 2016) - Targazyme Inc., a clinical stage biopharmaceutical company developing novel enzyme technologies and products to improve clinical efficacy and cost of care outcomes for a variety of cell therapies including stem cell transplantation, immunotherapy, gene therapy and regenerative medicine, announced today that the U.S. Food and Drug Administration (FDA) has granted IND Clearance to begin enrolling patients in a Phase II clinical study to evaluate the safety and efficacy of TZ101-fucosylated bone marrow stem cells from haplo-identical donors in cancer patients. The transplantation of blood-forming stem cells from bone marrow is an accepted treatment to restore the body's ability to make blood and immune cells and is a treatment for various cancers like leukemia, lymphoma and some types of anemia. Recent medical advances have made possible the use of a haploidentical donor who is usually a 50% match to the recipient. Targazyme's product (TZ101) has the potential to improve the outcomes of this lifesaving treatment by improving the ability of TZ101 treated stem cells to home, adhere and engraft into the bone marrow, accelerating hematopoietic recovery, reducing both opportunistic infections and ICU/hospital stay for cancer patients undergoing the haplo-identical transplants. "Enhancing bone marrow stem cell engraftment with a product like TZ101 will improve clinical outcomes for patients with serious, life-threatening cancers and other disorders for which hematopoietic stem cell transplant is prescribed," said Dr. Gheath Alatrash, Assistant Professor, Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. "This FDA IND clearance for a phase 2 TZ101 haplo-identical transplant study is an important clinical milestone to help us drive towards our initial target product label of accelerating hematopoietic recovery post hematopoietic stem cell transplantation" said Lynnet Koh, Chief Executive Officer of Targazyme. "This clinical study builds on available clinical data that TZ101 improves time to absolute neutrophil count and platelet recovery in patients undergoing hematopoietic stem cell transplants, and together, with our second product TZ102, provides proof of concept that our pipeline of products are enabling technologies for improving efficacy outcomes for various cells such as T cells, natural killer cells, and hematopoietic, cardiac and neural stem cells, that are used to prevent and treat a variety of different diseases for which there is a high unmet medical need." Targazyme Inc. is a San Diego-based, clinical-stage biopharmaceutical company developing novel enzyme-based platform technologies and products to improve clinical efficacy and cost of care outcomes for cell therapy, immunotherapies for autoimmune diseases and cancer, stem cell transplantation, gene therapy and regenerative medicine. The Company's clinical-grade fucosyltransferase enzymes and small molecule products (TZ101 and TZ102) are off-the-shelf biologic products used at the point-of-care to treat therapeutic cells immediately before infusion into the patient using a simple procedure that is easily incorporated into existing medical practice. The Company has received worldwide patents, multiple FDA orphan drug designations, has an open investigational new drug application (IND) with multiple ongoing clinical studies and a Phase 3 Special Protocol Assessment (SPA) with the FDA. Targazyme's fucosylation technology has received numerous medical and scientific awards from institutions such as NIH, NCI, US Treasury, CPRIT, ETF, OCAST, JDRF, Leukemia, Lymphoma Society. Targazyme has partnerships and collaborations with Kyowa Hakko Kirin and Florida Biologix, as well as various medical research institutions including The University of Texas M.D. Anderson Cancer Center, Oklahoma Medical Research Foundation, Texas Transplant Institute, Case Western/University Hospitals, Scripps Hospitals, Fred Hutchinson Cancer Research Center, University of California Los Angeles Medical Center, Stanford University Medical Center, University of Minnesota Medical Center, University of California San Diego Medical Center, Sanford-Burnham Medical Research Institute, Indiana University, Memorial Sloan Kettering Cancer Center, and New York Blood Center. Learn more at http://www.targazyme.com.


Toffanin S.,Mount Sinai Liver Cancer Program | Toffanin S.,Tisch Cancer Institute | Toffanin S.,Transplant Institute | Toffanin S.,Italian National Cancer Institute | And 12 more authors.
Hepatology | Year: 2012

Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation, and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in non-bone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease. © 2012 American Association for the Study of Liver Diseases.


Ben-Shabat I.,Institute of Clinical science | Ben-Shabat I.,Sahlgrenska University Hospital | Hansson C.,Institute of Clinical science | Hansson C.,Sahlgrenska University Hospital | And 12 more authors.
Journal of Visualized Experiments | Year: 2015

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation. In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma. © JoVE 2006-2015. All Rights Reserved.


Pavlakis M.,Transplant Institute | Khwaja K.,Lahey Clinic | Mandelbrot D.,Transplant Institute | Tang H.,Transplant Institute | And 7 more authors.
Transplantation | Year: 2010

BACKGROUND.: The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection. METHODS.: Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre-or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure. RESULTS.: Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year. CONCLUSIONS.: In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure. Copyright © 2010 by Lippincott Williams & Wilkins.


News Article | April 11, 2016
Site: motherboard.vice.com

The promise of immortality is core to many religions, but it’s rarely as literal as it is at The Church of Perpetual Life, a zealous house of worship in Hollywood, Florida whose members have decided they don’t want to die. "We are fighting against involuntary death, and view immortality as the ultimate solution to every problem mankind faces,” said Bill Faloon, one of the church’s founders. His parishioners call themselves “immortalists.” Other monikers include transhumanists, “longevity enthusiasts,” and “people who really are committed to the anti-aging concept.” Whatever they call themselves, they all share one thing in common: They believe that science and technology will find a way for humans to live forever on Earth. Motherboard’s Claire Evans visited the church and spent time with Faloon, who also cofounded the Life Extension Foundation Inc., which sells a variety of nutritional supplements that promise to do everything from protecting against eyesight degeneration to promoting cell regeneration. The Foundation says its primary goal is to fund research into anti-aging science. Forever Young, a short documentary produced by Evans, Jaimie Sanchez, and Motherboard, explores the psychology of the church’s members, the history of transhumanism and anti-aging, and the reaction of the mainstream medical community to some of these ideas. Gerontology expert Aubrey Grey, transhumanist and Sirius XM founder Martine Rothblatt, and Dr. Dinarine Maharaj of the South Florida Stem Cell Transplant Institute also make an appearance in the film. The people Evans spoke to, including Faloon, seem genuine in their quest for eternal life. However, it’s hard to overlook the fact that the church was formed after the Life Extension Foundation had its tax-exempt status revoked by the IRS. Is the Church of Perpetual Life a fellowship of purist transhumanist devotees, or a front for shilling vitamins? Is its promise of immortality a scam that draws in wishful thinkers, or is it actually possible that one day, humans might conquer death? "Sometimes it's very difficult to draw a line about what seems crazy and what doesn't seem crazy,” Evans said, “because crazier things have happened. We went to the Moon. Where do you draw the line and say, ‘oh that's really science fiction, that's never going to happen?’"


Moll H.P.,Transplant Institute | Lee A.,Transplant Institute | Minussi D.C.,Transplant Institute | Minussi D.C.,Beth Israel Deaconess Medical Center | And 6 more authors.
Journal of Biological Chemistry | Year: 2014

IFNγ signaling in endothelial (EC) and smooth muscle cells (SMC) is a key culprit of pathologic vascular remodeling. The impact of NFκB inhibitory protein A20 on IFNγ signaling in vascular cells remains unknown. In gain- and loss-of-function studies, A20 inversely regulated expression of IFNγ-induced atherogenic genes in human EC andSMCby modulating STAT1 transcription. In vivo, inadequate A20 expression in A20 heterozygote mice aggravated intimal hyperplasia following partial carotid artery ligation. This outcome uniquely associated with increased levels of Stat1 and super-induction of Ifnγ-dependent genes. Transcriptome analysis of the aortic media from A20 heterozygote versus wild-type mice revealed increased basal Ifnβ signaling as the likely cause for higher Stat1 transcription. We confirmed higher basal IFNβ levels in A20-silenced human SMC and showed that neutralization or knockdown of IFNβ abrogates heightened STAT1 levels in these cells. Upstream of IFNβ A20-silenced EC and SMC demonstrated higher levels of phosphorylated/activated TANK-binding kinase-1 (TBK1), a regulator of IFNβ transcription. This suggested that A20 knockdown increased STAT1 transcription by enhancing TBK1 activation and subsequently basal IFNβ levels. Altogether, these results uncover A20 as a key physiologic regulator of atherogenic IFNγ/STAT1 signaling. This novel function of A20 added to its ability to inhibit nuclear factor-κB (NFκB) activation solidifies its promise as an ideal therapeutic candidate for treatment and prevention of vascular diseases. In light of recently discovered A20/TNFAIP3 (TNFα-induced protein 3) single nucleotide polymorphisms that impart lower A20 expression or function, these results also qualify A20 as a reliable clinical biomarker for vascular risk assessment. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.


Tamimi T.I.A.-R.,Digestive Disease Institute | Elgouhari H.M.,Transplant Institute | Alkhouri N.,Cleveland Clinic | Yerian L.M.,Cleveland Clinic | And 5 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: The extrinsic death receptor-mediated pathway of apoptosis is involved in nonalcoholic steatohepatitis (NASH) development. Our aims were to create and validate a noninvasive prediction model for NASH diagnosis based on specific circulating markers of apoptosis. Methods: Our initial cohort consisted of 95 consecutive patients undergoing a liver biopsy for clinically suspected NASH. Blood was obtained from each patient at the time of liver biopsy. Plasma caspase 3 generated cytokeratin-18 fragments (CK-18), soluble Fas (sFas), and soluble Fas ligand (sFasL) were measured. Histology was assessed by an experienced hepatopathologist. The validation cohort consisted of 82 consecutive patients that underwent liver biopsy at the time of bariatric surgery. Results: Patients with NASH had significantly higher levels of CK-18 and sFas than patients in the "not NASH" group [median (25th, 75th percentile): 508 (280, 846) U/L versus 176 (131, 224) U/L (p <0.001), and 11.8 (7.8, 12.5) ng/ml versus 5.9 (4.8, 8.3) ng/ml (p <0.001), respectively]. A significant positive correlation was revealed between the apoptosis markers and liver histopathology independent of other metabolic factors. A prediction model was generated including CK-18 fragments and sFas levels that showed an AUC of 0.93 and 0.79 in the initial and validation cohorts, respectively. A cutoff value using this model predicted NASH with a sensitivity and specificity of 88% and 89%, respectively. Conclusions: Quantification of circulating levels of two apoptotic markers accurately predicts the presence of NASH, supporting the potential usefulness of these markers in clinical practice for noninvasive diagnosis of NASH. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Hardinger K.L.,University of Missouri | Hutcherson T.,University of Missouri | Preston D.,University of Missouri | Murillo D.,Transplant Institute
Pharmacotherapy | Year: 2012

Study Objective. To determine the influence of pill burden and drug cost on outcomes after renal transplantation. Design. Retrospective medical record review. Setting. Kidney and pancreas transplantation center. Patients. Sixty-eight adults who underwent kidney or kidney-pancreas transplantation during 2007. Measurements and Main Results. The median pretransplantation pill burden was 15 pills/day, which increased to 25 pills/day at 1 month after transplantation and returned to 16 pills/day by 1 year after transplantation. Pretransplantation pill burden was lower than the burden at 1, 3, 6, 12, and 24 months after transplantation (p<0.05). The mean pretransplantation drug cost of $1918/month was lower than the cost at 1 month after transplantation ($2564/mo, p=0.04) but was similar thereafter. Higher pretransplantation pill burden was associated with increased serum creatinine concentration at 6 months after transplantation (r=0.288, p=0.017). Higher pill burdens at 1 month (r=0.364, p=0.002), 3 months (r=0.332, p=0.006), and 6 months (r=0.374, p=0.002) were associated with increased 3-month serum creatinine concentration. Higher drug costs were associated with increased serum creatinine concentrations throughout the study. Conclusion. Higher pretransplantation pill burden and higher drug cost may be associated with poor renal function after transplantation. Further study addressing factors associated with nonadherence is needed. Copyright © 1999-2012 John Wiley & Sons, Inc.


Singhal A.,Transplant Institute | Kanagala R.,Transplant Institute | Jalil S.,Transplant Institute | Wright H.I.,Transplant Institute | Kohli V.,Transplant Institute
Annals of Hepatology | Year: 2011

Chronic HBV infection is a dynamic state of interaction between HBV, hepatocytes, and the immune system of the host. A series of reactivation flares and remissions may occur due to multiple causes. Among them, spontaneous reactivation and immunosuppressive drugs including steroids or cancer chemotherapy are well known. This is due to immune-mediated destruction of HBV-expressing cells following withdrawal of immunosuppressive effect. Few cases have been reported in females during postpartum period. We report a case of fulminant hepatic failure during pregnancy in a previously unrecognized hepatitis B positive female requiring emergent liver transplantation.

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