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n tune h pers randy j seeley martin g myers jr weiwei qiu view text pdf a single dorsal vagal complex circuit mediates the aversive and anorectic responses to glp1r agonists text pdf abstract glucagon like peptide 1 glp 1 receptor agonists glp1ras effectively reduce feeding to treat obesity although nausea and other aversive side effects of these drugs can limit their use brainstem circuits that promote satiation and mediate the physiological control of body weight can be distinguished from those that cause aversion it remains unclear however whether brainstem glp1r neurons contribute to the normal regulation of energy balance and whether glp1ras control appetite via circuits distinct from those that mediate aversive responses here we silenced glp1r neurons in the nucleus of the solitary tract nts or area postrema ap ntsglp1r or apglp1r neurons respectively or restored their glp1r signaling on an otherwise glp1r deficient background to determine physiological and pharmacological roles for each neuron population although ntsglp1r neurons contributed to the normal restraint of food intake and body weight they failed to mediate glp1ra dependent weight loss in contrast while we detected no role for apglp1r neurons in physiological feeding they mediated both the weight lowering and aversive effects of glp1ras therefore while nonaversive ntsglp1r neurons controlled physiologic satiation they did not contribute to weight loss during glp1ra treatment rather apglp1r neurons mediated both the weight lowering and aversive effects of glp1ras preventing the separation of their nauseating and weight loss effects at a circuit level authors warren t yacawych yi wang guoxiang zhou shad hassan cagri bodur elisabeth walters john g santinga frederike sass martin devaux stace kernodle iris wu jenny m brown dylan belmont rausch alan c rupp abigail j tomlinson zitian lin emma vantongeren anna secher kirsten raun tune h pers randy j seeley martin g myers jr weiwei qiu cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular brain axis satoshi okawa yinan shi somanshu banerjee yi yin tai jamal nabhanizadeh stefan guenther anisha n shah siyi jiang timothy kim yassmin al aaraj caroline pidro metin aytekin omolara fatukasi nishita kalepalli joseph mettenburg timothy d girard james t becker kathiravan kaliyappan shanshan song sandra breuils bonnet steeve provencher sébastien bonnet theodore huppert lloyd d harvey seyed mehdi nouraie rajkumar savai dandan sun soban umar soni s pullamsetti stephen y chan satoshi okawa yinan shi somanshu banerjee yi yin tai jamal nabhanizadeh stefan guenther anisha n shah siyi jiang timothy kim yassmin al aaraj caroline pidro metin aytekin omolara fatukasi nishita kalepalli joseph mettenburg timothy d girard james t becker kathiravan kaliyappan shanshan song sandra breuils bonnet steeve provencher sébastien bonnet theodore huppert lloyd d harvey seyed mehdi nouraie rajkumar savai dandan sun soban umar soni s pullamsetti stephen y chan view text pdf cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular brain axis text pdf abstract connections between vascular and neurocognitive diseases are emerging but remain poorly defined cognitive impairment is increasingly recognized in pulmonary hypertension ph a disease traditionally viewed as limited to the heart and lungs given that inflammation is shared by ph and neurodegenerative diseases we investigated its role in driving brain and cognitive deficits in ph using structural and functional mri data from uk biobank n 248 ph and a prospective validation cohort we identified reduced cerebellar white matter volume thinner frontal gyri and weakened cerebellar frontal connectivity in patients with ph but not in other heart or lung diseases these changes were accompanied by worsened executive function and processing speed olink proteomics and targeted genomics linked inflammatory plasma proteins and a ph associated nuclear receptor coactivator 7 ncoa7 single nucleotide polymorphism rs11154337 to these deficits ph cerebellum showed increased microglial activation and white matter derangement in ph mice ncoa7 deficiency worsened cerebellar inflammation and atrophy microglial functional assays cerebellar single nucleus rna sequencing and spatial transcriptomic analyses further implicated ncoa7 dependent lysosomal inflammatory and cell specific mechanisms of cerebellar pathobiology these findings identify ncoa7 linked inflammatory dysfunction in the cerebellar frontal axis in ph redefining this disease with neurologic consequences and thus offering neural targets for diagnostic prognostic and therapeutic development authors satoshi okawa yinan shi somanshu banerjee yi yin tai jamal nabhanizadeh stefan guenther anisha n shah siyi jiang timothy kim yassmin al aaraj caroline pidro metin aytekin omolara fatukasi nishita kalepalli joseph mettenburg timothy d girard james t becker kathiravan kaliyappan shanshan song sandra breuils bonnet steeve provencher sébastien bonnet theodore huppert lloyd d harvey seyed mehdi nouraie rajkumar savai dandan sun soban umar soni s pullamsetti stephen y chan neoadjuvant pd l1 tgf β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients caroline hoffmann jan timon werle philémon sirven mamy andrianteranagna jocelyn gal wiem lassoued jerzy klijanienko jeremy mesple benjamin demaille abdenour abbas valentine gauthier kyra j e borgman isabelle puisieux serena janho dit hreich olivier choussy gregoire marret sonia lameiras nathalie badois antoine dubray vautrin gilles dolivet lionnel geoffrois renaud leclère wail zeitouni noemie robil jane merlevede altynbek zhubanchaliyev maud kamal ivan bieche laure monard clotilde simon delphine louis clint t allen arun rajan james l gulley maude guillot delost christophe le tourneau hélène salmon caroline hoffmann jan timon werle philémon sirven mamy andrianteranagna jocelyn gal wiem lassoued jerzy klijanienko jeremy mesple benjamin demaille abdenour abbas valentine gauthier kyra j e borgman isabelle puisieux serena janho dit hreich olivier choussy gregoire marret sonia lameiras nathalie badois antoine dubray vautrin gilles dolivet lionnel geoffrois renaud leclère wail zeitouni noemie robil jane merlevede altynbek zhubanchaliyev maud kamal ivan bieche laure monard clotilde simon delphine louis clint t allen arun rajan james l gulley maude guillot delost christophe le tourneau hélène salmon view text pdf clinical research and public health neoadjuvant pd l1 tgf β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients text pdf abstract background tgf β drives fibroblast activation in cancer and is a resistance biomarker to pd 1 pd l1 blockade methods focusing on the tumor stroma we characterized the impact of neoadjuvant treatment with bintrafusp alfa ba a dual pd l1 and tgf β inhibitor in a window of opportunity study with 6 patients with head and neck squamous cell carcinoma hnscc tumor biopsies before treatment and 3 weeks after therapy were analyzed using scrna seq imaging and spatial transcriptomics results after treatment we observed significantly decreased levels of activated lrrc15 cancer associated fibroblasts cafs remodeled stromal architecture with reduced collagen i and xii content and increased cd8 t cell infiltration in immune excluded tumors these changes were independently confirmed in an additional neoadjuvant ba treated cohort of 6 patients with hnscc the drastic caf and stromal compartment reduction observed indicated a fibroblast depletion rather than a fibroblast polarization shift conclusion while our final clinical cohort does not allow assessment of the treatment effect this study demonstrated that targeting tgf β in patients can disrupt the tumor stroma within a short time frame further trials and novel biomarkers are now needed to select patients who could benefit trial registration clinicaltrials gov nct04428047 funding merck kgaa arc emerging leaders in oncology anr 10 idex 0001 02 psl centre d investigation clinique igr curie 1428 site de recherche intégrée sur le cancer inca dgos inserm itmo cancer_18000 french government investissements d avenir program france 2030 program fondation pour la recherche médicale marie skłodowska curie grant agreement 847718 cooperative research and development agreement with emd serono and nih zia bc 010666 authors caroline hoffmann jan timon werle philémon sirven mamy andrianteranagna jocelyn gal wiem lassoued jerzy klijanienko jeremy mesple benjamin demaille abdenour abbas valentine gauthier kyra j e borgman isabelle puisieux serena janho dit hreich olivier choussy gregoire marret sonia lameiras nathalie badois antoine dubray vautrin gilles dolivet lionnel geoffrois renaud leclère wail zeitouni noemie robil jane merlevede altynbek zhubanchaliyev maud kamal ivan bieche laure monard clotilde simon delphine louis clint t allen arun rajan james l gulley maude guillot delost christophe le tourneau hélène salmon jak1 2 inhibition promotes aggressive cutaneous carcinogenesis through cot kinase mediated alternative mapk pathway activation 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 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 view text pdf jak1 2 inhibition promotes aggressive cutaneous carcinogenesis through cot kinase mediated alternative mapk pathway activation text pdf abstract secondary malignancies are the most feared adverse effects of cancer therapies in this study we explored the cutaneous oncogenic effects of the jak inhibitor ruxolitinib first we demonstrated an epidemiological association between ruxolitinib exposure and development of aggressive cutaneous squamous 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 dm...
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