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mous cell carcinoma cscc by analyzing international pharmacovigilance data and conducting a large cohort study we next demonstrated the causal link between ruxolitinib treatment and cscc development using in vitro and in vivo models mechanistically we revealed that ruxolitinib induces transformation of premalignant keratinocytes by activating the mapk pathway this effect is mostly driven by jak2 inhibition suggesting a pharmacological class effect to unravel the mechanistic underpinnings of ruxolitinib induced mapk activation we then applied a phosphoproteomic approach alternative mapk signaling downstream of the kinase cot was pinpointed as the main activator of the pathway in this context the central role of cot was functionally validated using chemical inhibition genetic impairment and inactivated cot mutant expression indeed impairment of cot rescued the pro oncogenic effect of ruxolitinib finally we determined using a combination of epidemiological in vitro and in vivo studies that ruxolitinib mediated oncogenic effects also result in an increased risk of melanoma suggesting that the uncovered cellular signaling mechanism might be extrapolated to other cancers with a high dependency on the mapk pathway authors hélène pasquer antoine forget maxime battistella raphael marie léa provent barouyr baroudjian emmanuelle latour cécile culeux blandine roux khansa saadallah amandine gouverneur maxime demourgues fanélie jouenne jérôme lambert bérangère lombard damarys loew sophie tartare deckert lionel adès emmanuel raffoux bruno cassinat juliette soret dulphy pernelle noize samia mourah camille lobry jean jacques kiladjian alexandre puissant céleste lebbé lina benajiba tarbp2 facilitates renal cell carcinoma immune escape by suppressing 53bp1 phase separation to upregulate b7 h3 minyu chen mingjie lin jiangquan zhu kezhi liu guannan shu zhuting tong mi zhou liangmin fu taowei yang yihui pan xinwei zhou jinchen luo wuyuan liao qihao li lican liao hansen lin kangbo huang lizhen zhang wei chen junhang luo jiaxing zhang minyu chen mingjie lin jiangquan zhu kezhi liu guannan shu zhuting tong mi zhou liangmin fu taowei yang yihui pan xinwei zhou jinchen luo wuyuan liao qihao li lican liao hansen lin kangbo huang lizhen zhang wei chen junhang luo jiaxing zhang view text pdf tarbp2 facilitates renal cell carcinoma immune escape by suppressing 53bp1 phase separation to upregulate b7 h3 text pdf abstract renal cell carcinoma rcc harbors an immunosuppressive tumor microenvironment that facilitates immune evasion and resistance to immune checkpoint blockade icb however the factors driving immune escape in rcc remain incompletely understood in this study transactivation response rna binding protein 2 tarbp2 was identified as a critical regulator of the immune checkpoint molecule b7 h3 elevated tarbp2 expression was associated with poor prognosis and icb resistance in patients with rcc functionally tarbp2 in rcc cells suppressed the intratumoral accumulation and cytotoxicity of t cells particularly nk cells thereby promoting immune escape mechanistically nuclear tarbp2 interacted with p53 binding protein 1 53bp1 inhibiting 53bp1 phase separation and subsequent p53 activation thereby augmenting b7 h3 transcription furthermore tarbp2 inhibition significantly enhanced icb efficacy when combined with adoptive nk cell therapy collectively these findings establish tarbp2 as a key mediator of immune evasion in rcc and a promising therapeutic target for overcoming icb resistance authors minyu chen mingjie lin jiangquan zhu kezhi liu guannan shu zhuting tong mi zhou liangmin fu taowei yang yihui pan xinwei zhou jinchen luo wuyuan liao qihao li lican liao hansen lin kangbo huang lizhen zhang wei chen junhang luo jiaxing zhang a single liver sparing myotropic aav ameliorates muscular dystrophy in humanized mice by base editing yu chung pien hui li gabrielle bulliard huachun liu mateusz z durbacz zhisheng xu andreas c chai francesco chemello efrain sanchez ortiz nerea zabaleta luk h vandenberghe ning liu eric n olson yu chung pien hui li gabrielle bulliard huachun liu mateusz z durbacz zhisheng xu andreas c chai francesco chemello efrain sanchez ortiz nerea zabaleta luk h vandenberghe ning liu eric n olson view text pdf a single liver sparing myotropic aav ameliorates muscular dystrophy in humanized mice by base editing text pdf abstract duchenne muscular dystrophy dmd is caused by mutations in the dmd gene most of which are large exon deletions that result in loss of dystrophin protein adenine base editing abe enables permanent gene correction by modifying splice sites to cause exon skipping and restoration of the dmd open reading frame we previously demonstrated that adeno associated virus 9 mediated aav9 mediated delivery of adenine base editors allows efficient gene editing in mouse models of dmd however conventional aav based gene delivery approaches are complicated by their limited packaging capacity and high dose related toxicity here we describe a single aav vector encoding a compact adenine base editor slugabe8e and a single guide rna which enable efficient editing in a humanized dmd mouse model at a lower dose using the muscle tropic myoaav4 capsid systemic myoaav4a delivery in juvenile dmd mice efficiently restored dystrophin expression in the heart and skeletal muscles this molecular rescue was accompanied by reduced serum creatine kinase activity and diminished muscle pathology a liver detargeted myoaav4e off capsid eliminated viral entry and editing in the liver we also explored a high fidelity base editor slughf abe8e v106w which showed similar on target and off target editing to slugabe8e together these findings establish an all in one aav strategy that efficiently mitigates dmd disease progression authors yu chung pien hui li gabrielle bulliard huachun liu mateusz z durbacz zhisheng xu andreas c chai francesco chemello efrain sanchez ortiz nerea zabaleta luk h vandenberghe ning liu eric n olson immune cell specific smn expression and sustained immune alterations in treated spinal muscular atrophy ines tapken katharina rahmel stein christine ehlers federica cieri nora t detering tobias schüning bogdan bjelica charlotte mindermann svenja neuhoff linda isabell schmitt markus leo tim hagenacker sabine illsinger elia di schiavi theresa graalmann susanne petri ulrich kalinke peter claus ines tapken katharina rahmel stein christine ehlers federica cieri nora t detering tobias schüning bogdan bjelica charlotte mindermann svenja neuhoff linda isabell schmitt markus leo tim hagenacker sabine illsinger elia di schiavi theresa graalmann susanne petri ulrich kalinke peter claus view text pdf immune cell specific smn expression and sustained immune alterations in treated spinal muscular atrophy text pdf abstract mutations in the survival of motor neuron 1 smn1 can reduce functional smn protein levels which causes spinal muscular atrophy sma a disease affecting the nervous system and peripheral tissues including the immune system yet smn expression across immune cell subsets and the effect of smn modulating therapies on the immune system remain underexplored we found that in neonatal mouse spleens smn expression was highest in b cells and was massively reduced in sma mice in human pbmcs from adults dcs and monocytes expressed the highest smn levels whereas patients with sma showed reduced dc frequencies and increased b cell frequencies patients receiving systemic versus cns restricted therapy showed similar differences in immune cell composition and smn expression levels similarly an exploratory cohort including untreated patients did not show a substantial treatment specific effect relative to controls to assess the effect of differentiation on smn we analyzed pma treated thp 1 cells and found enhanced aberrant smn splicing and increased smn cajal bodies smn levels varied across immune cell types and reduced smn levels were associated with altered immune cell composition immune alterations and decreased smn levels were observed in both treated and untreated patients with sma and may have contributed to dysfunctions of the immune system authors ines tapken katharina rahmel stein christine ehlers federica cieri nora t detering tobias schüning bogdan bjelica charlotte mindermann svenja neuhoff linda isabell schmitt markus leo tim hagenacker sabine illsinger elia di schiavi theresa graalmann susanne petri ulrich kalinke peter claus conserved neuronal like and secretory programs define the spatial architecture of gastroenteropancreatic neuroendocrine tumors julie karam samantha e hoffman amanda garza dan gui hannah i hoffman breanna m titchen yutaro tanaka erica pimenta theodora pappa laura valderrabano kevin bi riaz gillani lauren brais erin shannon jason l hornick jihye park jennifer chan eliezer m van allen julie karam samantha e hoffman amanda garza dan gui hannah i hoffman breanna m titchen yutaro tanaka erica pimenta theodora pappa laura valderrabano kevin bi riaz gillani lauren brais erin shannon jason l hornick jihye park jennifer chan eliezer m van allen view text pdf conserved neuronal like and secretory programs define the spatial architecture of gastroenteropancreatic neuroendocrine tumors text pdf abstract gastroenteropancreatic neuroendocrine tumors gep nets are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood here we integrated single nucleus multiomic and spatial transcriptomic profiling across 38 well differentiated pancreatic pannet and small intestinal sinet tumors to define conserved malignant programs their regulatory circuits and spatial niches we observed 2 conserved malignant cell programs spanning a continuous transcriptional spectrum a neuronal like program and a secretory neuroendocrine program matched chromatin accessibility profiles uncovered distinct tissue specific regulatory networks including max myc and mitf transcription factor binding motifs in sinets versus isl1 and tfap4 in pannets indicating organ specific epigenetic control spatial transcriptomic analyses revealed that neuronal like high regions localized to densely cellular tumor areas with relative depletion of stromal infiltration whereas secretory neuroendocrine high regions occupied fibrovascular and stromal niches enriched for endothelial fibroblast and myeloid populations and associated with tgfb1 itgb1 vegfa flt1 and lama2 itga1 signaling across both tumor types the cnmf2 program was enriched in metastatic lesions and was enriched for profibrotic and proangiogenic gene signatures thus gep nets are organized along a conserved neuronal to secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches this framework unifies net heterogeneity across organ sites and identifies pathway specific microenvironment linked vulnerabilities for therapeutic targeting authors julie karam samantha e hoffman amanda garza dan gui hannah i hoffman breanna m titchen yutaro tanaka erica pimenta theodora pappa laura valderrabano kevin bi riaz gillani lauren brais erin shannon jason l hornick jihye park jennifer chan eliezer m van allen dapagliflozin attenuates progression from prefrailty to frailty in patients with hypertension and chronic kidney disease pasquale mone davide viggiano antonella pansini maria virginia soldovieri giada sabatelli valeria visco gaetano macina eugenio boccalone michele ciccarelli giuseppe martinelli marco di mauro carmine vecchione maria morgante fahimeh varzideh germano guerra gaetano santulli pasquale mone davide viggiano antonella pansini maria virginia soldovieri giada sabatelli valeria visco gaetano macina eugenio boccalone michele ciccarelli giuseppe martinelli marco di mauro carmine vecchione maria morgante fahimeh varzideh germano guerra gaetano santulli view text pdf clinical research and public health dapagliflozin attenuates progression from prefrailty to frailty in patients with hypertension and chronic kidney disease text pdf abstract background chronic kidney disease ckd and hypertension share common pathophysiological pathways contributing to vascular damage endothelial dysfunction and physical decline particularly in older adults with prefrailty to evaluate the relationship among renal injury physical performance and frailty progression in hypertensive older adults with ckd and assess whether dapagliflozin associates with reduced frailty progression we designed the study dapa fortress dapagliflozin and frailty progression in hypertension and chronic kidney disease methods we enrolled 135 prefrail hypertensive patients with ckd aged 65 years and followed them for 1 year after coarsened exact matching our balanced cohort had 105 patients 52 dapagliflozin associations between albuminuria estimated glomerular filtration rate egfr and physical performance were analyzed using correlation and regression models effect of dapagliflozin on frailty progression was evaluated using multivariable logistic regression results a significant inverse association between gait speed and albuminuria r2 0 48 p 0 0001 and significant positive linear association between gait speed and egfr r2 0 18 p 0 0001 were observed patients with egfr 60 ml min 1 73 m2 exhibited significantly worse physical performance than those with higher egfr p 0 0003 in adjusted analyses receiving dapagliflozin was independently associated with lower odds of progressing to frailty at 1 year or 0 130 ci 0 045 0 381 p 0 001 conclusion in older hypertensive patients with ckd greater renal injury is associated with worse physical performance while dapagliflozin use reduces the risk of frailty progression these findings indicate a potential protective role of sodium glucose cotransporter 2 inhibition in mitigating functional decline in this high risk population funding nih national heart lung and blood institute r01 hl146691 national institute of diabetes and digestive and kidney diseases r01 dk123259 american heart association aha 24ipa1268813 aha 22 915561 aha 24 1195524 authors pasquale mone davide viggiano antonella pansini maria virginia soldovieri giada sabatelli valeria visco gaetano macina eugenio boccalone michele ciccarelli giuseppe martinelli marco di mauro carmine vecchione maria morgante fahimeh varzideh germano guerra gaetano santulli nuclear cgas governs transcription to control lipid metabolism tumor growth and therapy response yu deng matthew j niederhuber zhichuan zhu austin j hepperla le yu quentin hahn joshua hartsell tooba rashid piotr a mieczkowski hemant kelkar jeremy m simon yanqiong zhang alessandra livraghi butrico meredith j zeller joseph g c kennedy jazmin f depriest jiong li yan zhang xing qiu h ümit kaniskan jian jin corbin d jones laura e herring douglas h phanstiel xiaojing liu jesse r raab brian d strahl pengda liu yu deng matthew j niederhuber zhichuan zhu austin j hepperla le yu quentin hahn joshua hartsell tooba rashid piotr a mi...
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