A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations

Correlates of Attitudes Toward Homosexuality and Intention to Care for Homosexual People Among Psychiatric Nurses in Southern Taiwan

This study examined the association between attitudes toward homosexual individuals and intention to provide care and demographic and occupational factors, sexual orientation, knowledge about homosexuality, and experiences of contact with homosexual people among psychiatric nurses in southern Taiwan. In total, 133 psychiatric nurses from a medical center, three regional teaching hospitals, and one psychiatric hospital in southern Taiwan were recruited into this study. Their attitudes toward homosexual people as recorded on the Attitudes Toward Homosexuality Questionnaire, intention to provide care to homosexual individuals, and related factors were examined. The results revealed that psychiatric nurses who had a bachelor's or master's degree, higher level of knowledge about homosexuality, and friends or relatives with a homosexual orientation had a more positive attitude toward homosexuality. These psychiatric nurses, with more positive attitudes, and who worked in the medical center or regional teaching hospitals had a higher intention to care for homosexual people. The factors related to attitudes toward homosexuality and intention to care for homosexual people identified in this study should be taken into consideration when intervening in psychiatric nurses' attitudes toward homosexuality and intention to care for homosexual people

Internal ribosome entry segment activity of ATXN8 opposite strand RNA.

Spinocerebellar ataxia type 8 (SCA8) involves the expansion of CTG/CAG repeats from the overlapping ataxin 8 opposite strand (ATXN8OS) and ataxin 8 (ATXN8) genes located on chromosome 13q21. Although being transcribed, spliced and polyadenylated in the CTG orientation, ATXN8OS does not itself appear to be protein coding, as only small open reading frames (ORFs) were noted. In the present study we investigated the translation of a novel 102 amino acids containing-ORF in the ATXN8OS RNA. Expression of chimeric construct with an in-frame ORF-EGFP gene demonstrated that ATXN8OS RNA is translatable. Using antiserum raised against ORF, ATXN8OS ORF expression was detected in various human cells including lymphoblastoid, embryonic kidney 293, neuroblastoma IMR-32, SK-N-SH, SH-SY5Y cells and human muscle tissue. The biological role of the ATXN8OS ORF and its connection to SCA8 remains to be determined

Transient expression of <i>ATXN8OS</i> ORF-EGFP constructs in HEK-293 cells.

<p>(A) ORF-EGFP constructs. A 752-bp cDNA fragment containing exon D, C2 and portion of C1 was inserted into pEGFP-N1 MCS so that <i>ATXN8OS</i> ORF was fused in-frame with the EGFP gene to generate pCMV/+801. A +1∼+800 <i>ATXN8OS</i> fragment was inserted between CMV promoter and exon D of pCMV/+801 to generate pCMV/+1. In pATXN8OS/−114 and/−481, 114 and 481-bp <i>ATXN8OS</i> promoter fragments was used to replace the CMV promoter in pCMV/+1. (B) Real-time PCR quantification of ORF-EGFP RNA level relative to endogenous <i>HPRT1</i> RNA. To normalize, expression level in pATXN8OS/−481 transfected cells is set as 1.0. (C) FACS analysis of EGFP fluorescence. Levels of EGFP were expressed as percentages of pIRES2-EGFP, which was set at 100%. Each value is the mean ± SD of three independent experiments each performed in duplicate.</p

Protein expression of <i>ATXN8OS</i> ORF-EGFP fusion protein in HEK-293 cells.

<p>(A) Confocal images of cells expressing EGFP and ORF-EGFP. Cells were transfected with pIRES2-EGFP, pCMV/+801, pCMV/+1 and pATXN8OS/−114 for two days. After counterstained nuclei with DAPI, cells were examined using a confocal microscope for GFP (green) and DAPI (blue) dual fluorescent imaging. (B) Western blot analysis of cells expressing ORF-EGFP and EGFP proteins. Cells were transfected with pCMV/+801, pEGFP-N1, or mock-transfected. After two days, cell lysates were prepared and proteins analyzed with anti-GFP antibody or anti-ORF antiserum.</p

ORF protein identification.

<p>(A) 2D PAGE image and 2D immunoblot. Proteins from urea lysis buffer-insoluble pellets were separated using 2D gels for SYPRO Ruby staining (left, 2D PAGE) and ORF antiserum or actin antibody staining (right, 2D immunoblot). The 2D PAGE map was compared to the 2D immunoblot to obtain ORF-specific spots (red arrow). (B) <i>ATXN8OS</i> ORF amino acid sequences initiated from GUG⁺⁹⁵³. The ORF-specific spots were analyzed and MS/MS data were searched in a database containing theoretical trypsinized fragments of 23-kDa ORF protein initiated at GUG⁺⁹⁵³ codon. Six matched peptides determined by LC-MS/MS were marked in boldface.</p

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma

Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months’ follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512</p