The Fer tyrosine kinase regulates interactions of Rho GDP-Dissociation Inhibitor α with the small GTPase Rac

<p>Abstract</p> <p>Background</p> <p>RhoGDI proteins are important regulators of the small GTPase Rac, because they shuttle Rac from the cytoplasm to membranes and also protect Rac from activation, deactivation and degradation. How the binding and release of Rac from RhoGDI is regulated is not precisely understood.</p> <p>Results</p> <p>We report that the non-receptor tyrosine kinase Fer is able to phosphorylate RhoGDIα and form a direct protein complex with it. This interaction is mediated by the C-terminal end of RhoGDIα. Activation of Fer by reactive oxygen species caused increased phosphorylation of RhoGDIα and pervanadate treatment further augmented this. Tyrosine phosphorylation of RhoGDIα by Fer prevented subsequent binding of Rac to RhoGDIα, but once a RhoGDIα-Rac complex was formed, the Fer kinase was not able to cause Rac release through tyrosine phosphorylation of preformed RhoGDIα-Rac complexes.</p> <p>Conclusions</p> <p>These results identify tyrosine phosphorylation of RhoGDIα by Fer as a mechanism to regulate binding of RhoGDIα to Rac.</p

BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition.

Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones

A Survey of Diabetic Educators and Patients for the Revision of Korean Food Exchange Lists

BackgroundFood exchange lists are one of the main methods of nutritional education. However, Korean food exchange lists have not been revised since 1994. Therefore, we surveyed the opinions of diabetes educators and patients with diabetes regarding the need for revision of the current food exchange lists.MethodsFor two weeks beginning on 10 March 2008, a 12-item questionnaire regarding the opinion and need for revision of the current food exchange lists was e-mailed to diabetes educators nationwide. Another 15-question survey was administered to patients with diabetes in 13 hospitals located in the Seoul and Gyeonggi regions of Korea.ResultsWe obtained survey responses from 101 diabetes educators and 209 patients; 65 (64.3%) of the educators answered that the current food exchange lists should be revised. The items that needed revision were the glycemic index, addition of new foods and reaffirmation of exchange standard amounts. The patients demanded specific education about choosing appropriate foods, a balanced meal plan, proper snacks, and dining intake.ConclusionOur survey results demonstrate the need to revise the Korean food exchange lists. This process should focus on glycemic index, the addition of new foods and reconfirmation of one exchange reference unit

Heterozygous Midnolin Knockout Attenuates Severity of Nonalcoholic Fatty Liver Disease in Mice Fed a Western-Style Diet High in Fat, Cholesterol, and Fructose

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology

Effect of Chongkukjang on histamine-induced skin wheal response: A randomized, double-blind, placebo-controlled trial

AbstractBackgroundStudies in animals have demonstrated the antiallergenic properties of Chongkukjang (CKJ), a traditional Korean food made by fermentation of soybean with Bacillus subtilis. CKJ might therefore be used as an ingredient in a functional food designed to suppress allergies. The purpose of this study was to investigate the effect of CKJ on histamine-induced skin wheal response in healthy participants.MethodsA randomized, double-blind, placebo-controlled trial was conducted. Sixty participants (48 women and 12 men) were randomly assigned to one of two groups: One group received 35 g CKJ daily for 12 weeks, and the other received a placebo at the same dosing frequency. A skin prick test with histamine (10 mg/mL) was conducted on the ventral forearm 10 cm from the elbow, and assessed 15 minutes later. Outcomes included measurement of efficacy [skin wheal response, immunoglobulin E (IgE), histamine, interferon-gamma, interleukin-4, eosinophil, and eosinophil cationic protein (ECP)], and safety (adverse events, laboratory test results, electrocardiogram, anthropometric values, and vital signs).ResultsFifty-five participants (28 in the CKJ group and 27 in the placebo group) completed the study. After 12 weeks of supplementation, participants in the CKJ group showed a significant reduction in histamine-induced skin wheal areas compared with placebo group (p < 0.05). At 12 weeks, the CKJ group showed a significant improvement in percentage change from baseline in histamine-induced wheal area, compared with the placebo group (p < 0.05). CKJ did not influence blood levels of IgE, histamine, interferon-gamma, interleukin-4, eosinophil, or ECP.ConclusionOral administration of CKJ for 12 weeks resulted in a reduction of the skin wheal response to histamine, with no apparent adverse effects. Trial registration: ClinicalTrials.gov: NCT01402141

BCL6 is critical for the development of a diverse primary B cell repertoire

BCL6 protects germinal center (GC) B cells against DNA damage–induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7–dependent B cell precursors, we report that IL-7Rα–Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a μ heavy chain, however, activation of pre–B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Rα–Stat5 signaling is attenuated. At the transition from IL-7–dependent to –independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre–B cells from DNA damage–induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre–B cell self-renewal and the formation of a diverse polyclonal B cell repertoire

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Abstract: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Abstract: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women

Processing Constraints on Relative Clauses in Korean as a Foreign Language

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