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Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation. CONCLUSION In our cohort, ICI-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium. © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email journals.permissions@oup.com.In addition to the classical pathway of secretion, some transmembrane proteins reach the plasma membrane through alternative routes. Several proteins transit through endosomes and are exported in a Rab8-, Rab10-, and/or Rab11-dependent manner. GRAFs are membrane-binding proteins associated with tubules and vesicles. We found extensive colocalization of GRAF1b/2 with Rab8a/b and partial with Rab10. We identified MICAL1 and WDR44 as direct GRAF-binding partners. MICAL1 links GRAF1b/2 to Rab8a/b and Rab10, and WDR44 binds Rab11. Endogenous WDR44 labels a subset of tubular endosomes, which are closely aligned with the ER via binding to VAPA/B. With its BAR domain, GRAF2 can tubulate membranes, and in its absence WDR44 tubules are not observed. Endocrinology agonist We show that GRAF2 and WDR44 are essential for the export of neosynthesized E-cadherin, MMP14, and CFTR ΔF508, three proteins whose exocytosis is sensitive to ER stress. Overexpression of dominant negative mutants of GRAF1/2, WDR44, and MICAL1 also interferes with it, facilitating future studies of Rab8/10/11-dependent exocytic pathways of central importance in biology. © 2020 MRC Laboratory of Molecular Biology.Hematopoietic stem cells (HSCs) are regulated by signals from the bone marrow (BM) niche, which tune hematopoiesis at steady state and in hematologic disorders. To understand the HSC-niche interactions in altered non-malignant homeostasis, we elected as a paradigm β-thalassemia, a hemoglobin disorder. In this severe congenital anemia, secondary alterations to the primary hemoglobin defect have a potential impact on HSC-niche crosstalk. Here we report that HSCs in thalassemic mice (th3) have an impaired function, caused by the interaction with an altered BM niche. The HSC self-renewal defect is rescued upon transplantation into a normal microenvironment, thus proving the active role of BM stroma. Consistently with the common finding of osteoporosis in patients, we found reduced bone deposition with decreased levels of parathyroid hormone (PTH), which is a key regulator of bone metabolism but also of HSC activity. In vivo activation of PTH signaling through the reestablished Jagged1 and osteopontin levels correlates with the rescue of the functional pool of th3 HSCs by correcting HSC-niche crosstalk. Reduced HSC quiescence is confirmed in thalassemic patients, along with altered features of the BM stromal niche. Our findings uncover a defect of HSCs in β-thalassemia induced by an altered BM microenvironment and provide new relevant insight for improving transplantation and gene therapy approaches. Copyright © 2020 American Society of Hematology.Feathered leg is a trait in domestic chickens that has undergone intense selection by fancy breeders. Previous studies have shown that two major loci controlling feathered leg are located on chromosomes 13 and 15. Here we present genetic evidence for the identification of candidate causal mutations at these loci. This was accomplished by combining classical linkage mapping using an experimental cross segregating for feathered leg and high-resolution identical-by-descent mapping using whole genome sequence data from 167 samples of chicken with or without feathered legs. The first predicted causal mutation is a single base change located 25 kb upstream of the gene for the forelimb-specific transcription factor TBX5 on chromosome 15. The second is a 17.7 kb deletion located about 200 kb upstream of the gene for the hindlimb-specific transcription factor PITX1 on chromosome 13. These mutations are predicted to activate TBX5 and repress PITX1 expression, respectively. The study reveals a remarkable convergence in the evolution of the feathered leg phenotype in domestic chickens and domestic pigeons as this phenotype is caused by non-coding mutations upstream of the same two genes. Furthermore, the PITX1 causal variants are large overlapping deletions, 17.7 kb in chicken and 44 kb in pigeons. The results of the present study are consistent with the previously proposed model for pigeon, that feathered leg is caused by reduced PITX1 expression and ectopic expression of TBX5 in hindlimb buds resulting in a shift of limb identity from hindlimb to more forelimb-like identity. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.AIMS The aim of this study is to assess risk factors for alcohol misuse among older New York City residents and examine the effect of local public health efforts to address alcohol misuse. METHODS The Community Health Survey, a cross-sectional telephone survey of 8500 randomly selected adult New Yorkers, records the frequency of alcohol use. We examine these results among 65 and older subjects by sociodemographic status using logistic regression modeling and compare trends in smoking and alcohol consumption between 2002 and 2016. RESULTS Those with unhealthy drinking habits, combining binge drinking and excessive consumption, constituted 5.7% of 65 plus population and were more likely to be White, US born, healthy, better educated and wealthier. The percentage of older smokers in New York City has decreased while unhealthy drinking is nearly flat since 2002. CONCLUSIONS Our findings reinforce the importance of screening geriatric populations for alcohol use disorders and support the development of new public health efforts to address alcohol misuse if the city is to achieve results similar to those obtained in decreasing tobacco consumption.