Overall Survival by Response to First-line Induction Treatment with Atezolizumab plus Platinum-based Chemotherapy or Placebo plus Platinum-based Chemotherapy for Metastatic Urothelial Carcinoma

Standard-of-care first-line treatment for metastatic urothelial carcinoma (mUC) is platinum-based chemotherapy (CTx). Maintenance immunotherapy is a treatment option for patients without progressive disease (PD) after induction CTx. IMvigor130 was a randomised, phase 3 study evaluating atezolizumab plus platinum-based CTx (arm A), atezolizumab monotherapy (arm B), or placebo plus platinum-based CTx (arm C) as first-line treatment for mUC. The primary progression-free survival (PFS) analysis showed a statistically significant PFS benefit favouring arm A versus arm C, which did not translate into overall survival (OS) benefit at the final OS analysis. We report exploratory analyses based on response to combination induction treatment (arm A vs arm C) using final OS data. Post-induction OS was analysed for patients without PD during induction (4-6 CTx cycles) who received at least one dose of single-agent atezolizumab/placebo maintenance treatment. Post-progression OS was analysed for patients with PD during induction CTx. Addition of atezolizumab to CTx did not impact OS outcomes, regardless of response to induction CTx, with hazard ratios of 0.84 (95% confidence interval [CI] 0.63-1.10) for patients without PD and 0.75 (95% CI 0.54-1.05) for those with PD during induction CTx. Treatment effects appeared to be greatest for patients treated with cisplatin and for those with PD-L1-high tumours. Patient summary: The IMvigor130 trial showed that addition of atezolizumab to chemotherapy (CTx) did not improve survival over CTx alone in patients with bladder cancer. Overall, patients whose cancer did not progress during initial treatment tended to live longer than patients whose cancer did progress, but addition of atezolizumab to CTx did not help either group live longer in comparison to CTx alone. However, the results suggest that patients who received a certain CTx drug (cisplatin) or who had high levels of a marker called PD-L1 in their tumour may get the most improvement from addition of atezolizumab to CTx. The IMvigor130 trial is registered on ClinicalTrials.gov as NCT02807636. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Acid Adaptation Promotes TRPC1 Plasma Membrane Localization Leading to Pancreatic Ductal Adenocarcinoma Cell Proliferation and Migration through Ca(2+) Entry and Interaction with PI3K/CaM.

International audiencePancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a low overall survival rate of less than 10% and limited therapeutic options. Fluctuations in tumor microenvironment pH are a hallmark of PDAC development and progression. Many ion channels are bona fide cellular sensors of changes in pH. Yet, the interplay between the acidic tumor microenvironment and ion channel regulation in PDAC is poorly understood. In this study, we show that acid adaption increases PANC-1 cell migration but attenuates proliferation and spheroid growth, which are restored upon recovery. Moreover, acid adaptation and recovery conditions favor the plasma membrane localization of the pH-sensitive calcium (Ca(2+)) channel transient receptor potential C1 (TRPC1), TRPC1-mediated Ca(2+) influx, channel interaction with the PI3K p85α subunit and calmodulin (CaM), and AKT and ERK1/2 activation. Knockdown (KD) of TRPC1 suppresses cell migration, proliferation, and spheroid growth, notably in acid-recovered cells. KD of TRPC1 causes the accumulation of cells in G0/G1 and G2/M phases, along with reduced expression of CDK6, -2, and -1, and cyclin A, and increased expression of p21(CIP1). TRPC1 silencing decreases the basal Ca(2+) influx in acid-adapted and -recovered cells, but not in normal pH conditions, and Ca(2+) chelation reduces cell migration and proliferation solely in acid adaptation and recovery conditions. In conclusion, acid adaptation and recovery reinforce the involvement of TRPC1 in migration, proliferation, and cell cycle progression by permitting Ca(2+) entry and forming a complex with the PI3K p85α subunit and CaM

Acid Adaptation Promotes TRPC1 Plasma Membrane Localization Leading to Pancreatic Ductal Adenocarcinoma Cell Proliferation and Migration through Ca(2+) Entry and Interaction with PI3K/CaM.

International audiencePancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a low overall survival rate of less than 10% and limited therapeutic options. Fluctuations in tumor microenvironment pH are a hallmark of PDAC development and progression. Many ion channels are bona fide cellular sensors of changes in pH. Yet, the interplay between the acidic tumor microenvironment and ion channel regulation in PDAC is poorly understood. In this study, we show that acid adaption increases PANC-1 cell migration but attenuates proliferation and spheroid growth, which are restored upon recovery. Moreover, acid adaptation and recovery conditions favor the plasma membrane localization of the pH-sensitive calcium (Ca(2+)) channel transient receptor potential C1 (TRPC1), TRPC1-mediated Ca(2+) influx, channel interaction with the PI3K p85α subunit and calmodulin (CaM), and AKT and ERK1/2 activation. Knockdown (KD) of TRPC1 suppresses cell migration, proliferation, and spheroid growth, notably in acid-recovered cells. KD of TRPC1 causes the accumulation of cells in G0/G1 and G2/M phases, along with reduced expression of CDK6, -2, and -1, and cyclin A, and increased expression of p21(CIP1). TRPC1 silencing decreases the basal Ca(2+) influx in acid-adapted and -recovered cells, but not in normal pH conditions, and Ca(2+) chelation reduces cell migration and proliferation solely in acid adaptation and recovery conditions. In conclusion, acid adaptation and recovery reinforce the involvement of TRPC1 in migration, proliferation, and cell cycle progression by permitting Ca(2+) entry and forming a complex with the PI3K p85α subunit and CaM

Assembly of a TRPC1/PI3K/CaM complex regulates proliferation in acid adapted pancreatic ductal adenocarcinoma cells

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The TRPC1 Channel Forms a PI3K/CaM Complex and Regulates Pancreatic Ductal Adenocarcinoma Cell Proliferation in a Ca(2+)-Independent Manner.

International audienceDysregulation of the transient receptor canonical ion channel (TRPC1) has been found in several cancer types, yet the underlying molecular mechanisms through which TRPC1 impacts pancreatic ductal adenocarcinoma (PDAC) cell proliferation are incompletely understood. Here, we found that TRPC1 is upregulated in human PDAC tissue compared to adjacent pancreatic tissue and this higher expression correlates with low overall survival. TRPC1 is, as well, upregulated in the aggressive PDAC cell line PANC-1, compared to a duct-like cell line, and its knockdown (KD) reduced cell proliferation along with PANC-1 3D spheroid growth by arresting cells in the G1/S phase whilst decreasing cyclin A, CDK2, CDK6, and increasing p21(CIP1) expression. In addition, the KD of TRPC1 neither affected Ca(2+) influx nor store-operated Ca(2+) entry (SOCE) and reduced cell proliferation independently of extracellular calcium. Interestingly, TRPC1 interacted with the PI3K-p85α subunit and calmodulin (CaM); both the CaM protein level and AKT phosphorylation were reduced upon TRPC1 KD. In conclusion, our results show that TRPC1 regulates PDAC cell proliferation and cell cycle progression by interacting with PI3K-p85α and CaM through a Ca(2+)-independent pathway

Enfermements. Volume I

Dès le Moyen Âge, le claustrum et le carcer, le cloître et la prison, ont été associés. Exaltant l’ascèse monastique, Bernard de Clairvaux, pour ne citer que lui, comparait déjà le monastère à une prison ouverte, où seule la crainte de Dieu retenait les moines. Aujourd’hui, les liens entre cloître et prison sont encore perceptibles dans le site exceptionnel de Clairvaux, ancienne abbaye cistercienne fondée au xiie siècle et transformée en centre pénitentiaire au xixe siècle. Dans les années 1960-1970, penseurs des institutions répressives et historiens du monachisme ont âprement polémiqué sur l’analogie entre cloître et prison. Afin de dépasser les apories de ces controverses et de renouer les fils du dialogue interrompu entre historiens du cloître et historiens de la prison, cet ouvrage propose une histoire commune des deux enfermements. Il explore les conceptions et les valeurs associées à l’enfermement, les particularités de la vie en milieu clos, la sociologie des groupes exposés à l’enfermement, dans l’ensemble de l’Europe, de l’Espagne à la Saxe et de l’Angleterre à l’Italie, entre le vie et le xviiie siècle. Faisant appel aux meilleurs spécialistes internationaux de ces questions, il privilégie les vues synthétiques plutôt que les études de cas. Il dessine enfin les renouvellements historiographiques intervenus depuis quatre décennies dans les domaines de l’histoire du droit, de l’histoire sociale et de l’histoire religieuse