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Landmark molecular profiling efforts have identified multiple targetable alterations in cholangiocarcinoma. Among the molecular-driven subsets of cholangiocarcinoma, targeting the fibroblast growth factor receptor (FGFR) has shown promise and represents the first targeted therapy to be approved in treatment-refractory, advanced cholangiocarcinoma. In this review, we provide an up-to-date overview of the clinical development of FGFR inhibitors in advanced cholangiocarcinoma. We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma.

Manufacture of thermoplastic foams with a fine cellular structure (a higher expansion ratio, a higher cell density, and smaller cell sizes) is challenging work due to the weak viscoelastic behavior and the unsuitable crystallization behavior of common thermoplastic materials. In this work, a novel method of making microcellular foams with micro-/nano-fibrillar reinforced polymeric composites (M/NFC) is introduced, which shows various advantages compared to conventional foams. The M/NFC foams have improved cellular structures, excellent mechanical properties, and enhanced thermal insulation properties, which make them popular candidates for structural applications and insulative products. Various methods to manufacture of M/NFC foam are summarized. To understand the fundamental mechanisms of the foaming enhancement by incorporating micro-/nano-size fibrils, the rheological and crystallization behavior of the M/NFC are analyzed. It is shown that the micro-/nano-fibrils can strengthen the melt strength, induce faster crystallization, and increase the number of crystals. Due to the improvement of the cell morphology and the stiffness of the cell walls, the reinforced foams have superior mechanical properties. A hierarchically porous structure in high expansion ratio reinforced foams has also been developed. It is believed that the nano-size holes in the cell walls can further reduce the thermal conductivity of the foams. KEYWORDS composites, foams, nanofibers, polymer nanofiber, 1 | INTRODUCTION Foams are materials containing small bubbles inside liquids or solids. First impressions of the foam are usually lightweight, energy-saving, and low cost. In fact, the capability of [...]

Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism.

Pluripotent stem cells offer great therapeutic promise for personalized treatment platforms for numerous injuries, disorders, and diseases. Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene maintaining pluripotency and self-renewal of mammalian cells. With site-specific integration for gene correction in cellular therapeutics, use of the OCT4 promoter may have advantages when expressing a suicide gene if pluripotency remains. However, the human OCT4 promoter region is 4 kb in size, limiting the capacity of therapeutic genes and other regulatory components for viral vectors, and decreasing the efficiency of homologous recombination. The purpose of this investigation was to characterize the functionality of a novel 967bp OCT4-short response element during pluripotency and to examine the OCT4 titer-dependent response during differentiation to human derivatives not expressing OCT4. Our findings demonstrate that the OCT4-short response element is active in pluripotency and this activity is in high correlation with transgene expression in vitro, and the OCT4-short response element is inactivated when pluripotent cells differentiate. These studies demonstrate that this shortened OCT4 regulatory element is functional and may be useful as part of an optimized safety component in a site-specific gene transferring system that could be used as an efficient and clinically applicable safety platform for gene transfer in cellular therapeutics.

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC., Introduction The therapeutic landscape of cancer treatment has been transformed by potent immunotherapeutic agents such as checkpoint blockade inhibitors. Despite their promise, the majority of cancer patients demonstrate an inadequate [...]

Data suggest that clinical applications of human induced pluripotent stem cells (hiPSCs) will be realized. Nonetheless, clinical applications will require hiPSCs that are free of exogenous DNA and that can be manufactured through Good Manufacturing Practice (GMP). Optimally, derivation of hiPSCs should be rapid and efficient in order to minimize manipulations, reduce potential for accumulation of mutations and minimize financial costs. Previous studies reported the use of modified synthetic mRNAs to reprogram fibroblasts to a pluripotent state. Here, we provide an optimized, fully chemically defined and feeder-free protocol for the derivation of hiPSCs using synthetic mRNAs. The protocol results in derivation of fully reprogrammed hiPSC lines from adult dermal fibroblasts in less than two weeks. The hiPSC lines were successfully tested for their identity, purity, stability and safety at a GMP facility and cryopreserved. To our knowledge, as a proof of principle, these are the first integration-free iPSCs lines that were reproducibly generated through synthetic mRNA reprogramming that could be putatively used for clinical purposes.