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The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide (APOBEC) family is composed of nucleic acid editors with roles ranging from antibody diversification to RNA editing. APOBEC2, a member of this family with an evolutionarily conserved nucleic acid-binding cytidine deaminase domain, has neither an established substrate nor function. Using a cellular model of muscle differentiation where APOBEC2 is inducibly expressed, we confirmed that APOBEC2 does not have the attributed molecular functions of the APOBEC family, such as RNA editing, DNA demethylation, and DNA mutation. Instead, we found that during muscle differentiation APOBEC2 occupied a specific motif within promoter regions; its removal from those regions resulted in transcriptional changes. Mechanistically, these changes reflect the direct interaction of APOBEC2 with histone deacetylase (HDAC) transcriptional corepressor complexes. We also found that APOBEC2 could bind DNA directly, in a sequence-specific fashion, suggesting that it functions as a recruiter of HDAC to specific genes whose promoters it occupies. These genes are normally suppressed during muscle cell differentiation, and their suppression may contribute to the safeguarding of muscle cell fate. Altogether, our results reveal a unique role for APOBEC2 within the APOBEC family., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial., Patients and Methods: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive., Results: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies., Conclusions: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC., Competing Interests: Role of the funder AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data and in the writing, reviewing, and approval of the manuscript. All authors had access to all relevant data and participated in writing, review, and approval of this manuscript, with editorial assistance funded by the study funder. No honoraria or payments were made for authorship. Disclosure CEG received travel funding from Genentech, Roche, Daiichi Sankyo, and AstraZeneca; has received writing support from Roche and AbbVie; has been on uncompensated advisory boards for Genentech, Roche, Daiichi Sankyo, and Seattle Genetics; has been on compensated advisory boards for Exact Sciences; has an uncompensated consulting role for Daiichi Sankyo; and has a compensated consulting role for Athenex. WMS is an unpaid member of the Steering Committee for AbbVie. JH received research funding from Celgene, Hexal, and Novartis; received honoraria from AbbVie, AstraZeneca, Celgene, Eisai, Gilead, Lilly, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, and Seagen; has a consulting and advisory role for AbbVie, AstraZeneca, Celgene, Lilly, Hexal, MSD, Novartis, and Roche; reports travel expenses from Celgene, Daiichi, Novartis, Pfizer, and Roche. HSR received research support for clinical trials through the University of California from AstraZeneca, Boehringer Ingelheim, Daiichi, Genentech, Immunomedics, Lilly, Macrogenics, Merck, Novartis, Odonate, Pfizer, Polyphor, Seattle Genetics, and Sermonix; received honoraria from Mylan, Puma, and Samsung. JO received honoraria for consulting and/or advisory boards from AbbVie, Agendia, and Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol Myers Squibb (BMS), Celgene Corporation, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Prime Oncology, Puma Biotechnology, Roche, Samsung Bioepis, Sanofi, Seagen, Syndax Pharmaceuticals, Taiho Oncology, Takeda, and Synthon. DM and MD are AbbVie employees and may hold stock or options. MU is on lectures and advisory boards for AbbVie, Agendia, Amgen, AstraZeneca, BioNTech, BMS, Celgene, Daiichi Sankyo, Eisai, GlaxoSmithKline (GSK), Jansen Cilag, Johnson & Johnson, Lilly, Molecular Health, MSD, Mundipharma, Myriad, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen; has a consulting role for AbbVie. MG is an unpaid member of the Steering Committee for AbbVie. JPL received honoraria for consulting and/or advisory boards from Novartis, Pfizer, AstraZeneca, Lilly, and Roche. OM received consulting fee from AbbVie and G1 Therapeutics; received research funding from AbbVie, Genentech, Pfizer, and Roche; reports travel expenses from AbbVie and Grupo Oncoclinicas; is uncompensated co-chair of advisory board for Pfizer. WFS holds founder shares from Delphi Diagnostics; has intellectual property from Delphi Diagnostics; holds public company shares from Eiger Biopharmaceuticals and IONIS Pharmaceuticals; is on compensated advisory board for Merck; is on uncompensated advisory boards for Delphi Diagnostics and Roche. PR reports unpaid advisory boards, travel, and accommodations from Genentech/Roche; reports travel and accommodations from Lilly and AstraZeneca. JHS received research funding from MSD, Roche, Novartis, AstraZeneca, Lilly, Pfizer, GSK, Daiichi Sankyo, Sanofi, and Boehringer Ingelheim. RY is on Speakers bureau for Genentech. GSW received grants or contracts from AbbVie, Astellas, AstraZeneca, Roche, Innocrine Pharm, H3BioMedicine Inc., G1 Therapeutics, Daiichi Sankyo, Sermonix Pharm, Taiho Oncology, Seattle Genetics, Inc., Immunogen, Incyte, Genentech, Novartis, Lilly, Janssen, Celgene, Bristol Myers Squibb, Boehringer Ingelheim, Medivation, Macrogenics, Merrimack, Tesaro, and Pfizer. DY has a consulting or advisory role for Novartis, Biotheranostics, Bristol Myers Squibb, G1 Therapeutics, Athenex, Immunomedics, Sanofi/Aventis, R-Pharm, Lilly; is on speakers bureau for Novartis and Genentech/Roche; received research funding from Genentech/Roche, Novartis, MedImmune, Lilly, Medivation, Pfizer, Tesaro, Macrogenics, AbbVie, Merck, Clovis Oncology, Amgen, Biomarin, Biothera, Dana Farber Cancer Hospital, Incyte, Innocrin Pharma, Nektar, NSABP Foundation, Odonate Therapeutics, Polyphor; reports travel expenses from Novartis and Genentech/Roche. SL reports grant paid to from AbbVie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Immunomedics/Gilead, Novartis, Pfizer, Roche, and Vifor; received honorarium for advisory boards paid to institute: AbbVie, Amgen, AstraZeneca, Bayer, BMS, Celgene, Daiichi Sankyo, Eirgenix, GSK, Lilly, Merck KG, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Puma, Roche, and Seagen; is on lectures paid to institute for Chugai (personal), Daiichi Sankyo, Novartis, Pfizer, Pierre Fabre, PriME/Medscape, Roche, and Samsung; has a medical writing role for AbbVie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Novartis, Pfizer, and Roche. All other authors have declared no conflicts of interest. Data sharing AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis datasets), as well as other information (e.g. protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: To update previous guidance of the Asia Pacific League of Associations for Rheumatology (APLAR) on the management of patients with rheumatic and musculoskeletal diseases (RMD) during the coronavirus disease 2019 (COVID-19) pandemic., Methods: Research questions were formulated focusing on diagnosis and treatment of adult patients with RMD within the context of the pandemic, including the management of RMD in patients who developed COVID-19. MEDLINE was searched for eligible studies to address the questions, and the APLAR COVID-19 task force convened 2 meetings through video conferencing to discuss its findings and integrate best available evidence with expert opinion. Consensus statements were finalized using the modified Delphi process., Results: Agreement was obtained around key aspects of screening for or diagnosis of COVID-19; management of patients with RMD without confirmed COVID-19; and management of patients with RMD with confirmed COVID-19. The task force achieved consensus on 25 statements covering the potential risk of acquiring COVID-19 in RMD patients, advice on RMD medication adjustment and continuation, the roles of telemedicine and vaccination, and the impact of the pandemic on quality of life and on treatment adherence., Conclusions: Available evidence primarily from descriptive research supported new recommendations for aspects of RMD care not covered in the previous document, particularly with regard to risk factors for complicated COVID-19 in RMD patients, modifications to RMD treatment regimens in the context of the pandemic, and COVID-19 vaccination in patients with RMD., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: A loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis, so changes in the control of ribosome synthesis are potential contributors to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR-424-5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD)., Methods: Targets of miR-424-5p were identified by Argonaute2 pull down, and the effects of the miRNA on RNA and protein expression were determined by quantitative polymerase chain reaction and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over-expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by quantitative polymerase chain reaction in patients with COPD and intensive care unit (ICU)-acquired weakness and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study., Results: Pull-down assays showed that miR-424-5p bound to messenger RNAs encoding proteins associated with muscle protein synthesis. The most highly enriched messenger RNAs encoded proteins required for the Pol I RNA pre-initiation complex required for ribosomal RNA (rRNA) transcription, (PolR1A and upstream binding transcription factor). In vitro, miR-424-5p reduced the expression of these RNAs, reduced rRNA levels, and inhibited protein synthesis. In mice, over-expression of miR-322 (rodent miR-424 orthologue) caused fibre atrophy and reduced upstream binding transcription factor expression and rRNA levels. In humans, elevated miR-424-5p associated with markers of disease severity in COPD (FEV 1 %), in patients undergoing aortic surgery (LVEF%), and in patients with ICU-acquired weakness (days in ICU). In patients undergoing aortic surgery, preoperative miR-424-5p expression in skeletal muscle was associated with muscle loss over the following 7 days., Conclusions: These data suggest that miR-424-5p regulates rRNA synthesis by inhibiting Pol I pre-initiation complex formation. Increased miR-424-5p expression in patients with conditions associated with muscle wasting is likely to contribute to the inhibition of protein synthesis and loss of muscle mass., (© 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Concurrent joint infection with Mycobacterium tuberculosis (TB) and demonstration of intraarticular monosodium urate (MSU) crystals has not previously been reported. We describe a patient with chronic tophaceous gout from whose joints both TB and MSU crystals were isolated. We propose a mechanism to explain this condition.

Low-loss waveguiding at lambda = 1.3 microm has been observed in a partially strained, 10-microm-thick, single-crystal layer of Ge(0.1)Si(0.9) grown by chemical-vapor deposition upon an intrinsic (100) silicon substrate. The TM-mode propagation loss in the multimode planar guide was 1.9 dB/cm.