Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Potential improvement of tumor control probability by induction chemotherapy for advanced nasopharyngeal carcinoma

Purpose: To assess the reduction of tumor bulk and improvement of tumor control probability (TCP) by using induction chemotherapy for advanced nasopharyngeal carcinoma (NPC). Materials and methods: From February to December 2005, 20 patients with Stage III-IVB NPC were treated with induction-concurrent chemotherapy and intensity-modulated radiotherapy with accelerated fractionation. Combination of cisplatin and 5-fluorouracil was used in the induction phase and single agent Cisplatin in the concurrent phase. All patients were irradiated at 2 Gy per fraction, 6 daily fractions per week, to a total dose of 70 Gy. Results: Nineteen (95%) patients completed all 3 cycles of induction chemotherapy and 90% had ≥2 cycles of concurrent chemotherapy. Induction chemotherapy achieved significant down-staging of T-category in 35% of patients (p = 0.016) and reduction of gross tumor volume (GTV_P) from 55.6 to 22.9 cc (mean 61.4%, p < 0.001). Although the mean radiation dose did not show any substantial change, the volume within GTV_P that failed to reach 70 Gy was reduced from 10.2% to 3.8% (p = 0.017). The estimated local TCP increased from 0.83 to 0.89 (p = 0.002). Conclusions: Induction chemotherapy using cisplatin-5-fluorouracil could significantly reduce tumor bulk leading to potential improvement in tumor control. © 2008 Elsevier Ireland Ltd. All rights reserved.Link_to_subscribed_fulltex

Experience from Asian centers in a named-patient-use program for afatinib in patients with advanced non-small-cell lung cancer who had progressed following prior therapies, including patients with uncommon EGFR mutations

10.1007/s10147-021-01869-0INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY265841-85

Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians

Systemic lupus erythematosus (SLE) has a complex etiology and is affected by both genetic and environmental factors. Althoughmorethan 40 loci haveshownrobust association withSLE, the details of these loci,suchas the independent contributors and the genes involved, are still unclear. In this study, we performed meta-analysis of two existing genome-wide association studies (GWASs) on Chinese Han populations from Hong Kong and Anhui, China, and followed the findings by further replication on three additional Chinese and Thailand cohorts with a total of 4254 cases and 6262 controls matched geographically and ethnically. We discovered multiple susceptibility variants for SLE in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023, P_combined 5 1.25E208, OR 5 1.20), DDX6 (rs638893, P_combined 5 5.19E207, OR 5 1.22) and CXCR5 (rs10892301, P_combined 5 2.51E208, OR 5 0.85). Genetic contributions from the newly identified variants were all independent of SNP rs4639966, whose association was reported from the previous GWAS. In addition, the three newly identified variants all showed independent association with the disease through modeling by both stepwise and conditional logistic regression. The presence of multiple independent variants in this region emphasizes its role in SLE susceptibility, and also hints the possibility that distinct biological mechanisms might be involved in the disease involving this genomic region. © The Author 2013. Published by Oxford University Press. All rights reserved.Link_to_subscribed_fulltex

Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus

© The Author 2014. Published by Oxford University Press. All rights reserved. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.Link_to_subscribed_fulltex

Search for direct top squark pair production in final states with two leptons in s=13\sqrt{s} = 13 TeV pppp collisions with the ATLAS detector

International audienceThe results of a search for direct pair production of top squarks in events with two opposite-charge leptons (electrons or muons) are reported, using $36.1~\hbox {fb}^{-1}$ of integrated luminosity from proton–proton collisions at $\sqrt{s}=13$ TeV collected by the ATLAS detector at the Large Hadron Collider. To cover a range of mass differences between the top squark $\tilde{t}$ and lighter supersymmetric particles, four possible decay modes of the top squark are targeted with dedicated selections: the decay $\tilde{t} \rightarrow b \tilde{\chi }_{1}^{\pm }$ into a b-quark and the lightest chargino with $\tilde{\chi }_{1}^{\pm } \rightarrow W \tilde{\chi }_{1}^{0}$ , the decay $\tilde{t} \rightarrow t \tilde{\chi }_{1}^{0}$ into an on-shell top quark and the lightest neutralino, the three-body decay $\tilde{t} \rightarrow b W \tilde{\chi }_{1}^{0}$ and the four-body decay $\tilde{t} \rightarrow b \ell \nu \tilde{\chi }_{1}^{0}$ . No significant excess of events is observed above the Standard Model background for any selection, and limits on top squarks are set as a function of the $\tilde{t}$ and $\tilde{\chi }_{1}^{0}$ masses. The results exclude at 95% confidence level $\tilde{t}$ masses up to about 720 GeV, extending the exclusion region of supersymmetric parameter space covered by previous searches