Center for Cell Signaling in Gastroenterology

Rochester, MN, United States

Center for Cell Signaling in Gastroenterology

Rochester, MN, United States
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NEW YORK, Dec. 13, 2016 (GLOBE NEWSWIRE) -- Tyme Technologies, Inc. (“Tyme” or “the Company”) (OTCQB:TYMI), a clinical-stage pharmaceutical company focused on developing highly targeted cancer therapeutics for a broad range of oncology indications, today announced the launch of a Pancreatic Research Program with the Mayo Clinic led by Dr. Martin Fernandez-Zapico. Dr. Martin E. Fernandez-Zapico, Associate Professor of Medicine and Pharmacology at the Mayo Clinic, is an international expert in the field of pancreatic cancer, a disease predicted to be the second leading cause of cancer in 2030. Dr. Fernandez-Zapico's programs are affiliated with the Mayo Clinic Cancer Center, Department of Oncology, Division of Gastroenterology and Hepatology, and the Center for Cell Signaling in Gastroenterology. His research is supported by the National Institutes of Health (NIH), the NIH-funded Mayo Clinic Pancreatic Cancer Specialized Program of Research Excellence (SPORE), the NIH-funded Mayo Clinic Center for Cell Signaling in Gastroenterology, and the Leukemia and Lymphoma Foundation. His work has been seminal for the understanding of mechanisms driving this malignancy and serves as a foundation for multiple National Cancer Institute sponsored clinical trials. "Tyme is extremely pleased to be working with Dr. Fernandez-Zapico of the Mayo Clinic in an effort to potentially discover the future cure of pancreatic cancer.  I believe the pancreatic research experiments planned by Dr. Fernandez-Zapico, using our proprietary discoveries and supported by Tyme, could lead to significant progress in battling this devastating form of cancer.  We look forward to continuing our clinical development program in pancreatic and other cancers, based on collaborations with Mayo and other leading institutions," said Dr. Del Priore, Chief Medical Officer of Tyme. Our research and development efforts are based on patented technologies and our patent pending proprietary platform technology, for which we retain global IP and commercial rights.  Our lead program is SM-88, a proprietary combination drug product.  We believe SM-88 is a first-in-class oncology therapy that increases the power of the body’s innate defenses to utilize oxidative stress to kill cancer cells.  SM-88 is designed to penetrate only living cancer cells without toxic effects and without involving healthy body tissue.  We believe that SM-88’s therapeutic potential is based on its ability to increase the availability of free radicals and promote their entry into cancer cells by stripping the cancer cells of their normal barriers to these toxic electrons.  SM-88 is a combination of a proprietary novel molecule with three currently-marketed drugs that are generally considered safe for their already approved indications, which are in areas other than cancer treatment. In addition to historical information, this press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, Section 27A of the U.S. Securities Act of 1933, and Section 21E of the U.S. Securities Exchange Act of 1934.  Such forward-looking statements may include projections regarding Tyme’s future performance, and readers can identify forward-looking statements by sentences or passages involving the use of terms such as "anticipates," "believes," “designed,” "could," "estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "would" and similar expressions intended to identify forward-looking statements.  The forward-looking statements contained in this press release are based on management's current expectations, which are subject to uncertainty, risks and changes in circumstances that are difficult to predict and many of which are outside of Tyme’s control.  Forward-looking statements within this press release include, without limitation, statements regarding our drug development strategies, the therapeutic mechanisms of our drug candidates and our completed and planned clinical trials.  These statements involve known and unknown risks, uncertainties and other factors which may cause the Company's actual results, performance or achievements to be materially different from any historical results and future results, performances or achievements expressed or implied by the forward-looking statements.  These risks and uncertainties include, but are not limited to, the factors described in the section captioned "Risk Factors" of Tyme's Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission on March 30, 2016 (available at

De Assuncao T.M.,Mayo Clinic and Foundation | De Assuncao T.M.,Gastroenterology Research Unit | Sun Y.,Mayo Clinic and Foundation | Sun Y.,Gastroenterology Research Unit | And 20 more authors.
Laboratory Investigation | Year: 2015

Cholangiocytes are the target of a heterogeneous group of liver diseases known as the cholangiopathies. An evolving understanding of the mechanisms driving biliary development provides the theoretical underpinnings for rational development of induced pluripotent stem cell (iPSC)-derived cholangiocytes (iDCs). Therefore, the aims of this study were to develop an approach to generate iDCs and to fully characterize the cells in vitro and in vivo. Human iPSC lines were generated by forced expression of the Yamanaka pluripotency factors. We then pursued a stepwise differentiation strategy toward iDCs, using precise temporal exposure to key biliary morphogens, and we characterized the cells, using a variety of morphologic, molecular, cell biologic, functional, and in vivo approaches. Morphology shows a stepwise phenotypic change toward an epithelial monolayer. Molecular analysis during differentiation shows appropriate enrichment in markers of iPSC, definitive endoderm, hepatic specification, hepatic progenitors, and ultimately cholangiocytes. Immunostaining, western blotting, and flow cytometry demonstrate enrichment of multiple functionally relevant biliary proteins. RNA sequencing reveals that the transcriptome moves progressively toward that of human cholangiocytes. iDCs generate intracellular calcium signaling in response to ATP, form intact primary cilia, and self-assemble into duct-like structures in three-dimensional culture. In vivo, the cells engraft within mouse liver, following retrograde intrabiliary infusion. In summary, we have developed a novel approach to generate mature cholangiocytes from iPSCs. In addition to providing a model of biliary differentiation, iDCs represent a platform for in vitro disease modeling, pharmacologic testing, and individualized, cell-based, regenerative therapies for the cholangiopathies. © 2015 USCAP, Inc.

Norgan A.P.,Mayo Medical School | Lee J.R.E.,Mayo Medical School | Lee J.R.E.,University of Utah | Oestreich A.J.,Mayo Medical School | And 4 more authors.
PLoS ONE | Year: 2012

Heterologous expression of HIV-1 Gag in a variety of host cells results in its packaging into virus-like particles (VLPs) that are subsequently released into the extracellular milieu. This phenomenon represents a useful tool for probing cellular factors required for viral budding and has contributed to the discovery of roles for ubiquitin ligases and the endosomal sorting complexes required for transport (ESCRTs) in viral budding. These factors are highly conserved throughout eukaryotes and have been studied extensively in the yeast Saccharomyces cerevisiae, a model eukaryote previously utilized as a host for the production of VLPs. We used heterologous expression of HIV Gag in yeast spheroplasts to examine the role of ESCRTs and associated factors (Rsp5, a HECT ubiquitin ligase of the Nedd4 family; Bro1, a homolog of Alix; and Vps4, the AAA-ATPase required for ESCRT function in all contexts/organisms investigated) in the generation of VLPs. Our data reveal: 1) characterized Gag-ESCRT interaction motifs (late domains) are not required for VLP budding, 2) loss of function alleles of the essential HECT ubiquitin ligase Rsp5 do not display defects in VLP formation, and 3) ESCRT function is not required for VLP formation from spheroplasts. These results suggest that the egress of HIV Gag from yeast cells is distinct from the most commonly described mode of exit from mammalian cells, instead mimicking ESCRT-independent VLP formation observed in a subset of mammalian cells. As such, budding of Gag from yeast cells appears to represent ESCRT-independent budding relevant to viral replication in at least some situations. Thus the myriad of genetic and biochemical tools available in the yeast system may be of utility in the study of this aspect of viral budding. © 2012 Norgan et al.

Tabibian J.H.,Mayo Medical School | Tabibian J.H.,Center for Cell Signaling in Gastroenterology | MacUra S.I.,Mayo Medical School | O'Hara S.P.,Mayo Medical School | And 15 more authors.
Laboratory Investigation | Year: 2013

The cholangiopathies are a diverse group of biliary tract disorders, many of which lack effective treatment. Murine models are an important tool for studying their pathogenesis, but existing noninvasive methods for assessing biliary disease in vivo are not optimal. Here we report our experience with using micro-computed tomography (microCT) and nuclear magnetic resonance (MR) imaging to develop a technique for live-mouse cholangiography. Using mdr2 knockout (mdr2KO, a model for primary sclerosing cholangitis (PSC)), bile duct-ligated (BDL), and normal mice, we performed in vivo: (1) microCT on a Siemens Inveon PET/CT scanner and (2) MR on a Bruker Avance 16.4 T spectrometer, using Turbo Rapid Acquisition with Relaxation Enhancement, IntraGate Fast Low Angle Shot, and Half-Fourier Acquisition Single-shot Turbo Spin Echo methods. Anesthesia was with 1.5-2.5% isoflurane. Scans were performed with and without contrast agents (iodipamide meglumine (microCT), gadoxetate disodium (MR)). Dissection and liver histology were performed for validation. With microCT, only the gallbladder and extrahepatic bile ducts were visualized despite attempts to optimize timing, route, and dose of contrast. With MR, the gallbladder, extra-, and intrahepatic bile ducts were well-visualized in mdr2KO mice; the cholangiographic appearance was similar to that of PSC (eg, multifocal strictures) and could be improved with contrast administration. In BDL mice, MR revealed cholangiographically distinct progressive dilation of the biliary tree without ductal irregularity. In normal mice, MR allowed visualization of the gallbladder and extrahepatic ducts, but only marginal visualization of the diminutive intrahepatic ducts. One mouse died during microCT and MR imaging, respectively. Both microCT and MR scans could be obtained in ≤20 min. We, therefore, demonstrate that MR cholangiography can be a useful tool for longitudinal studies of the biliary tree in live mice, whereas microCT yields suboptimal duct visualization despite requiring contrast administration. These findings support further development and application of MR cholangiography to the study of mouse models of PSC and other cholangiopathies. © 2013 USCAP, Inc All rights reserved.

Tabibian J.H.,Mayo Medical School | Tabibian J.H.,Center for Cell Signaling in Gastroenterology | O'Hara S.P.,Mayo Medical School | O'Hara S.P.,Center for Cell Signaling in Gastroenterology | And 10 more authors.
Hepatology | Year: 2016

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested the hypothesis that germ-free (GF) mutltidrug resistance 2 knockout (mdr2-/-) mice develop a distinct PSC phenotype, compared to conventionally housed (CV) mdr2-/- mice. Mdr2-/- mice (n=12) were rederived as GF by embryo transfer, maintained in isolators, and sacrificed at 60 days in parallel with age-matched CV mdr2-/- mice. Serum biochemistries, gallbladder bile acids, and liver sections were examined. Histological findings were validated morphometrically, biochemically, and by immunofluorescence microscopy (IFM). Cholangiocyte senescence was assessed by p16INK4a in situ hybridization in liver tissue and by senescence-associated β-galactosidase staining in a culture-based model of insult-induced senescence. Serum biochemistries, including alkaline phosphatase, aspartate aminotransferase, and bilirubin, were significantly higher in GF mdr2-/- (P<0.01) Primary bile acids were similar, whereas secondary bile acids were absent, in GF mdr2-/- mice. Fibrosis, ductular reaction, and ductopenia were significantly more severe histopathologically in GF mdr2-/- mice (P<0.01) and were confirmed by hepatic morphometry, hydroxyproline assay, and IFM. Cholangiocyte senescence was significantly increased in GF mdr2-/- mice and abrogated in vitro by ursodeoxycholic acid (UDCA) treatment. Conclusions: GF mdr2-/- mice exhibit exacerbated biochemical and histological features of PSC and increased cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease. UDCA, a commensal microbial metabolite, abrogates senescence in vitro. These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and suggest avenues for future studies of biomarkers and therapeutic interventions in PSC. © 2016 by the American Association for the Study of Liver Diseases.

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