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Acute hemorrhage related to gastric varices (GV) is more severe and often more difficult to immediately treat upon detection, leading to a poorer patient prognosis, as compared to esophageal variceal bleeding. Currently, the recommended treatment of bleeding GV is endoscopic cyanoacrylate injection and transjugular intrahepatic portosystemic shunt placement for endoscopic failures. Newer endoscopic (e.g. hemospray) and endosonographic (e.g. coil injection, glue obliteration, or combined coil and glue injection) techniques have been developed to offer an alternative treatment and improve patient outcome. The present article serves to review the endoscopic, endosonographic, and interventional radiological techniques used to treat GV and their clinical applications.

Hepatic stellate cells (HSCs) generate matrix, which in turn may also regulate HSCs function during liver fibrosis. We hypothesized that HSCs may endocytose matrix proteins to sense and respond to changes in microenvironment. Primary human HSCs, LX2, or mouse embryonic fibroblasts (MEFs) [wild-type; c-abl−/−; or Yes, Src, and Fyn knockout mice (YSF−/−)] were incubated with fluorescent-labeled collagen or gelatin. Fluorescence-activated cell sorting analysis and confocal microscopy were used for measuring cellular internalization of matrix proteins. Targeted PCR array and quantitative real-time PCR were used to evaluate gene expression changes. HSCs and LX2 cells endocytose collagens in a concentration- and time-dependent manner. Endocytosed collagen colocalized with Dextran 10K, a marker of macropinocytosis, and 5-ethylisopropyl amiloride, an inhibitor of macropinocytosis, reduced collagen internalization by 46%. Cytochalasin D and ML7 blocked collagen internalization by 47% and 45%, respectively, indicating that actin and myosin are critical for collagen endocytosis. Wortmannin and AKT inhibitor blocked collagen internalization by 70% and 89%, respectively, indicating that matrix macropinocytosis requires phosphoinositide-3-kinase (PI3K)/AKT signaling. Overexpression of dominant-negative dynamin-2 K44A blocked matrix internalization by 77%, indicating a role for dynamin-2 in matrix macropinocytosis. Whereas c-abl−/− MEF showed impaired matrix endocytosis, YSF−/− MEF surprisingly showed increased matrix endocytosis. It was also associated with complex gene regulations that related with matrix dynamics, including increased matrix metalloproteinase 9 (MMP-9) mRNA levels and zymographic activity. HSCs endocytose matrix proteins through macropinocytosis that requires a signaling network composed of PI3K/AKT, dynamin-2, and c-abl. Interaction with extracellular matrix regulates matrix dynamics through modulating multiple gene expressions including MMP-9.

Background—Nuclear reprogramming inculcates pluripotent capacity by which de novo tissue differentiation is enabled. Yet, introduction of ectopic reprogramming factors may desynchronize natural developmental schedules. This study aims to evaluate the effect of imposed transgene load on the cardiogenic competency of induced pluripotent stem (iPS) cells.Methods and Results—Targeted inclusion and exclusion of reprogramming transgenes (c-MYC,KLF4,OCT4, andSOX2) was achieved using a drug-inducible and removable cassette according to the piggyBac transposon/transposase system. Pulsed transgene overexpression, before iPS cell differentiation, hindered cardiogenic outcomes. Delayed in counterparts with maintained integrated transgenes, transgene removal enabled proficient differentiation of iPS cells into functional cardiac tissue. Transgene-free iPS cells generated reproducible beating activity with robust expression of cardiac α-actinin, connexin 43, myosin light chain 2a, α/β-myosin heavy chain, and troponin I. Although operational excitation–contraction coupling was demonstrable in the presence or absence of transgenes, factor-free derivatives exhibited an expedited maturing phenotype with canonical responsiveness to adrenergic stimulation.Conclusions—A disproportionate stemness load, caused by integrated transgenes, affects the cardiogenic competency of iPS cells. Offload of transgenes in engineered iPS cells ensures integrity of cardiac developmental programs, underscoring the value of nonintegrative nuclear reprogramming for derivation of competent cardiogenic regenerative biologics.

Background Recent studies evaluated short-term efficacy and safety of peripheral nerve stimulation (PNS) of the occipital nerves for managing chronic migraine. We present 52-week safety and efficacy results from an open-label extension of a randomized, sham-controlled trial. Methods In this institutional review board-approved, randomized, multicenter, double-blinded study, patients were implanted with a neurostimulation system, randomized to an active or control group for 12 weeks, and received open-label treatment for an additional 40 weeks. Outcomes collected included number of headache days, pain intensity, migraine disability assessment (MIDAS), Zung Pain and Distress (PAD), direct patient reports of headache pain relief, quality of life, satisfaction and adverse events. Statistical tests assessed change from baseline to 52 weeks using paired t-tests. Intent-to-treat (ITT) analyses of all patients ( N = 157) and analyses of only patients who met criteria for intractable chronic migraine (ICM; N = 125) were performed. Results Headache days were significantly reduced by 6.7 (±8.4) days in the ITT population ( p < 0.001) and by 7.7 (±8.7) days in the ICM population ( p < 0.001). The percentages of patients who achieved a 30% and 50% reduction in headache days and/or pain intensity were 59.5% and 47.8%, respectively. MIDAS and Zung PAD scores were significantly reduced for both populations. Excellent or good headache relief was reported by 65.4% of the ITT population and 67.9% of the ICM population. More than half the patients in both cohorts were satisfied with the headache relief provided by the device. A total of 183 device/procedure-related adverse events occurred during the study, of which 18 (8.6%) required hospitalization and 85 (40.7%) required surgical intervention; 70% of patients experienced an adverse event. Conclusion Our results support the 12-month efficacy of PNS of the occipital nerves for headache pain and disability associated with chronic migraine. More emphasis on adverse event mitigation is needed in future research. Trial registration: Clinical trials.gov (NCT00615342).

ABSTRACTMitotic bookmarking is an epigenetic control mechanism that sustains gene expression in progeny cells; it is often found in genes related to the maintenance of cellular phenotype and growth control. RUNX transcription factors regulate a broad spectrum of RNA Polymerase (Pol II) transcribed genes important for lineage commitment but also regulate RNA Polymerase I (Pol I) driven ribosomal gene expression, thus coordinating control of cellular identity and proliferation. In this study, using fluorescence microscopy and biochemical approaches we show that the principal RUNX co‐factor, CBFβ, associates with nucleolar organizing regions (NORs) during mitosis to negatively regulate RUNX‐dependent ribosomal gene expression. Of clinical relevance, we establish for the first time that the leukemogenic fusion protein CBFβ‐SMMHC (smooth muscle myosin heavy chain) also associates with ribosomal genes in interphase chromatin and mitotic chromosomes to promote and epigenetically sustain regulation of ribosomal genes through RUNX factor interactions. Our results demonstrate that CBFβ contributes to the transcriptional regulation of ribosomal gene expression and provide further understanding of the epigenetic role of CBFβ‐SMMHC in proliferation and maintenance of the leukemic phenotype. J. Cell. Biochem. 115: 2155–2164, 2014. © 2014 Wiley Periodicals, Inc.

AbstractEndocrine regulation of uterine biology is critical for embryo receptivity and human reproduction. Uterine endometrium depends on extrinsic sex steroid input and hence likely has mechanisms that enable adaptation to hormonal variation. Emerging evidence suggests that sex steroid bioavailability in the endometrium is determined by adjusting their metabolic rate and fate via regulation of cytochrome (CYP) p450 enzymes. The CYP enzymes are targeted by ubiquitously expressed Sp/Krüppel-like (Sp/KLF) transcription factors. Specifically, KLF11 is highly expressed in reproductive tissues, regulates an array of endocrine/metabolic pathways via epigenetic histone-based mechanisms and, when aberrantly expressed, is associated with diabetes and reproductive tract diseases, such as leiomyoma and endometriosis. Using KLF11 as a model to investigate epigenetic regulation of endometrial first-pass metabolism, we evaluated the expression of a comprehensive array of metabolic enzymes in Ishikawa cells. KLF11 repressed most endometrial CYP enzymes. To characterize KLF11-recruited epigenetic regulatory mechanisms, we focused on the estrogen-metabolizing enzyme CYP3A4. KLF11 expression declined in secretory phase endometrial epithelium associated with increased CYP3A4 expression. Additionally, KLF11 bound to CYP3A4 promoter GC elements and thereby repressed promoter, message, protein as well as enzymatic function. This repression was epigenetically mediated, because KLF11 colocalized with and recruited the corepressor SIN3A/histone deacetylase resulting in selective deacetylation of the CYP3A4 promoter. Repression was reversed by a mutation in KLF11 that abrogated cofactor recruitment and binding. This repression was also pharmacologically reversible with an histone deacetylase inhibitor. Pharmacological alteration of endometrial metabolism could have long-term translational implications on human reproduction and uterine disease.

Purpose The purpose of this study was to determine failure rates, functional outcomes, and risk factors for failure after revision anterior shoulder stabilization surgery in high‐risk adolescent athletes. Methods Adolescent athletes who underwent primary anterior shoulder stabilization were reviewed. Patients undergoing subsequent revision stabilization surgery were identified and analyzed. Failure rates after revision surgery were assessed by Kaplan‐Meier analysis. Failure was defined as recurrent instability requiring reoperation. Functional outcomes included the Marx activity score; American Shoulder and Elbow Surgeons score; and University of California, Los Angeles score. The characteristics of patients who required reoperation for recurrent instability after revision surgery were compared with those of patients who required only a single revision to identify potential risk factors for failure. Results Of 90 patients who underwent primary anterior stabilization surgery, 15 (17%) had failure and underwent revision surgery (mean age, 16.6 years; age range, 14 to 18 years). The mean follow‐up period was 5.5 years (range, 2 to 12 years). Of the 15 revision patients, 5 (33%) had recurrent dislocations and required repeat revision stabilization surgery at a mean of 50 months (range, 22 to 102 months) after initial revision. No risk factors for failure were identified. The Kaplan‐Meier reoperation‐free estimates were 86% (95% confidence interval, 67% to 100%) at 24 months and 78% (95% confidence interval, 56% to 100%) at 48 months after revision surgery. The mean final Marx activity score was 14.8 (range, 5 to 20); American Shoulder and Elbow Surgeons score, 82.1 (range, 33 to 100); and University of California, Los Angeles score, 30.8 (range, 16 to 35). Conclusions At 5.5 years' follow‐up, adolescent athletes had a high failure rate of revision stabilization surgery and modest functional outcomes. We were unable to convincingly identify specific risk factors for failure of revision surgery. Level of Evidence Level IV, retrospective therapeutic case series.