Cellular growth inhibition by TGF-β1 involves IRS proteins

AbstractIn Mv1Lu cells, insulin partially reverses transforming growth factor-β1 (TGF-β1) growth inhibition in the presence of α5β1 integrin antagonists. TGF-β1 appears to induce phosphorylation of IRS-2 in these cells; this is inhibited by a TGF-β antagonist known to reverse TGF-β growth inhibition. Stable transfection of 32D myeloid cells (which lack endogenous IRS proteins and are insensitive to growth inhibition by TGF-β1) with IRS-1 or IRS-2 cDNA confers sensitivity to growth inhibition by TGF-β1; this IRS-mediated growth inhibition can be partially reversed by insulin in 32D cells stably expressing IRS-2 and the insulin receptor (IR). These results suggest that growth inhibition by TGF-β1 involves IRS proteins

Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype

Abstract Background Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disease characterized by the combination of glomerulopathy with early-onset nephrotic syndrome and microcephaly with central nervous system anomalies. Given its clinical heterogeneity, GAMOS is believed to be a genetically heterogenous group of disorders. Recently, it has been reported that mutations in KEOPS-encoding genes, including the OSGEP gene, were responsible for GAMOS. Results Overall, 6 patients from 5 different Taiwanese families were included in our study; the patients had an identical OSGEP gene mutation (c.740G > A transition) and all exhibited a uniform clinical phenotype with early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism, primary microcephaly with pachygyria, and death before 2 years of age. We reviewed their clinical manifestations, the prenatal and postnatal presentations and ultrasound findings, results of imaging studies, associated anomalies, and outcome on follow-up. All individuals were found to have an “aged face” comprising peculiar facial dysmorphisms. Arachnodactyly or camptodactyly were noted in all patients. Neurological findings consisted of microcephaly, hypotonia, developmental delay, and seizures. Brain imaging studies all showed pachygyria and hypomyelination. All patients developed early-onset nephrotic syndrome. The proteinuria was steroid-resistant and eventually resulted in renal function impairment. Prenatal ultrasound findings included microcephaly, intrauterine growth restriction, and oligohydramnios. Fetal MRI in 2 patients confirmed the gyral and myelin abnormalities. Conclusions Our study suggests that a careful review of the facial features can provide useful clues for an early and accurate diagnosis. Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation analysis may be useful for an early prenatal diagnosis

Inhibitors of clathrin-dependent endocytosis enhance TGFβ signaling and responses

Clathrin-dependent endocytosis is believed to be involved in TGFβ-stimulated cellular responses, but the subcellular locus at which TGFβ induces signaling remains unclear. Here, we demonstrate that inhibitors of clathrin-dependent endocytosis, which are known to arrest the progression of endocytosis at coated-pit stages, inhibit internalization of cell-surface-bound TGFβ and promote colocalization and accumulation of TβR-I and SARA at the plasma membrane. These inhibitors enhance TGFβ-induced signaling and cellular responses (Smad2 phosphorylation/nuclear localization and expression of PAI-1). Dynasore, a newly identified inhibitor of dynamin GTPase activity, is one of the most potent inhibitors among those tested and, furthermore, is a potent enhancer of TGFβ. Dynasore ameliorates atherosclerosis in the aortic endothelium of hypercholesterolemic ApoE-null mice by counteracting the suppressed TGFβ responsiveness caused by the hypercholesterolemia, presumably acting through its effect on TGFβ endocytosis and signaling in vascular cells

Prevalence of BRAF and NRAS mutations in cutaneous melanoma patients in Taiwan

BRAF and NRAS mutations have been described in melanomas among Caucasians and some Asian populations. However, few large-scale studies have investigated the status and clinical significance of BRAF and NRAS mutations in a Taiwanese population. Methods: Melanoma samples (n = 119) were analyzed for mutations in exons 11 and 15 of the BRAF gene, and in exons 1 and 2 of the NRAS gene. The samples were studied in genomic DNA, using polymerase chain reaction amplification and Sanger sequencing. Mutations of the BRAF and NRAS genes were then correlated with clinicopathological features and patients' prognosis. Results: The incidence of somatic mutations within the BRAF and NRAS genes was 14.3% (17/119 patients) and 10.1% (12/119 patients), respectively. Among the 17 patients with BRAF mutations, 15 (88.2%) had V600E mutations. BRAF mutation was frequently detected in younger patients (p = 0.0035), in thin melanomas (p = 0.0181), and in melanomas with less ulceration (p = 0.0089). NRAS mutation was more often seen in patients with lymph node metastasis (p = 0.0332). Both BRAF and NRAS mutations were not significantly correlated with overall survival and disease-free survival. Conclusion: As BRAF and NRAS mutations are rare in Taiwan, BRAF- or NRAS-targeted therapies may be effective only for selected Taiwanese melanoma patients

Emergency department utilization and resuscitation rate among patients receiving maintenance hemodialysis

[[abstract]]Background End-stage renal disease (ESRD) is a growing global health concern with increased disease burden and high medical costs. Utilization of the emergency department (ED) among dialyzed patients and the associated risk factors remain unknown. Methods Participants of this study, selected from the National Health Insurance Database in Taiwan, were aged 19–90 years and received maintenance hemodialysis from January 1, 2010, to December 31, 2010. A control group consisting of individuals who did not receive dialysis, selected from the same data source, were matched for age, sex, and the Charlson Comorbidity Index (CCI). Subgroup analysis with hemodialysis frequency was also performed. ED utilization among enrolled individuals was assessed in 2012. Generalized estimating equations with multiple variable adjustments were used to identify risk factors associated with resuscitation during ED visits. Results One group of 2985 individuals who received maintenance hemodialysis, and another group of 2985 patients that did not receive hemodialysis, between January 1, 2010, and December 31, 2010, were included in this study. There were 4822 ED visits in the hemodialysis group, and 1755 ED visits in the non-dialysis group between January 1, 2012, and December 31, 2012. Analysis of multivariable generalized estimating equations identified the risk associated with resuscitation during ED visits to be greater in individuals who were receiving maintenance hemodialysis, aged older than 55 years, hospitalized in the past year, and assigned first and second degree of triage. Conclusion Patients receiving maintenance hemodialysis had higher ED utilization and a significantly higher risk of resuscitation during ED visits than those without hemodialysis

Emergency department utilization and resuscitation rate among patients receiving maintenance hemodialysis

[[abstract]]Background: End-stage renal disease (ESRD) is a growing global health concern with increased disease burden and high medical costs. Utilization of the emergency department (ED) among dialyzed patients and the associated risk factors remain unknown. Methods: Participants of this study, selected from the National Health Insurance Database in Taiwan, were aged 19-90 years and received maintenance hemodialysis from January 1, 2010, to December 31, 2010. A control group consisting of individuals who did not receive dialysis, selected from the same data source, were matched for age, sex, and the Charlson Comorbidity Index (CCI). Subgroup analysis with hemodialysis frequency was also performed. ED utilization among enrolled individuals was assessed in 2012. Generalized estimating equations with multiple variable adjustments were used to identify risk factors associated with resuscitation during ED visits. Results: One group of 2985 individuals who received maintenance hemodialysis, and another group of 2985 patients that did not receive hemodialysis, between January 1, 2010, and December 31, 2010, were included in this study. There were 4822 ED visits in the hemodialysis group, and 1755 ED visits in the non-dialysis group between January 1, 2012, and December 31, 2012. Analysis of multivariable generalized estimating equations identified the risk associated with resuscitation during ED visits to be greater in individuals who were receiving maintenance hemodialysis, aged older than 55 years, hospitalized in the past year, and assigned first and second degree of triage. Conclusion: Patients receiving maintenance hemodialysis had higher ED utilization and a significantly higher risk of resuscitation during ED visits than those without hemodialysis

Advances in Image-Guided Radiotherapy in the Treatment of Oral Cavity Cancer

Image-guided radiotherapy (IGRT) is an advanced auxiliary radiotherapy technique. During cancer treatment, patients with oral cavity cancer (OCC) experience not only disease but also adverse effects due to RT. IGRT provides the relevant advantages of RT by precisely delivering tumoricidal doses via real-time knowledge of the target volume location and achieves maximal tumor control with minimal complications as recommended for cancer treatment. Additionally, studies have shown that IGRT can improve clinical outcomes in terms of not only treatment side effects but also survival benefits for cancer patients. IGRT can be performed alongside various imaging methods, including computed tomography and magnetic resonance imaging, and at different times during the radiotherapy regimen. This article reviews the literature to discuss the effects and importance of IGRT for patients with OCC, examines the rationale underlying the advantages of IGRT, discusses the limitations of IGRT with respect to different techniques, and summarizes the strategies and future prospects of IGRT in the treatment of OCC