Systematic model behavior of adsorption on flat surfaces

A low density film on a flat surface is described by an expansion involving the first four virial coefficients. The first coefficient (alone) yields the Henry's law regime, while the next three correct for the effects of interactions. The results permit exploration of the idea of universal adsorption behavior, which is compared with experimental data for a number of systems

Prevalence of human herpesviruses in biliary fluid and their association with biliary complications after liver transplantation

Background: Beta-herpesviruses are common opportunistic pathogens that cause morbidity after liver transplantation (LT). Methods: Objective of the study was to evaluate the prevalence and correlation of herpesviruses in bile, blood and liver tissue and to investigate their association with biliary complications and retransplantation (re-LT) free survival after LT. The study design is a single-center case-control study. We performed quantative polymerase chain reaction (qPCR) for herpesvirus 1–8 DNA in bile, blood and liver tissue of 73 patients after first LT and analyzed their clinical courses retrospectively. Results: The median follow-up was 48 months (range 2–102), during which a total of 16 patients underwent re-LT and 11 patients died. Of the patients, 46.5% received valganciclovir prophylaxis at the time of bile sample acquisition. Cytomegalovirus (CMV) (18.3%), human herpesvirus 6 (HHV-6) (34.2%), human herpesvirus 7 (HHV-7) (20.5%) and Epstein-Barr virus (EBV) (16.4%) were highly prevalent in bile after LT, while herpes simpex virus 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV) and human herpesvirus 8 (HHV-8) were not or rarely detected in bile. Valganciclovir prophylaxis did not reduce the prevalence of HHV-6 and HHV-7 in bile, but it did reduce the presence of CMV and EBV. The presence of HHV-6 in bile was associated with non-anastomotic biliary strictures (NAS) and acute cellular rejection (ACR). Conclusions: CMV, EBV, HHV-6 and HHV-7 are more prevalent in biliary fluid than in liver biopsy or blood serum after LT. HHV-6 and HHV-7 might be associated with biliary complications after LT. Biliary fluids might be an attractive target for routine herpesvirus detection

Nox2-deficient Tregs improve heart transplant outcomes via their increased graft recruitment and enhanced potency.

Nox2 is a ROS-generating enzyme, deficiency of which increases suppression by Tregs in vitro and in an in vivo model of cardiac remodelling. Since Tregs have emerged as a candidate therapy in autoimmunity and transplantation, we hypothesised that Nox2 deficiency in Tregs in recipient mice may improve outcomes in a heart transplant model. A novel B6129 mouse model with Treg-targeted Nox2 deletion (Nox2fl/flFoxP3Cre+) was generated and transplanted with hearts from CB6F1 donors. As compared to littermate controls, Nox2fl/flFoxP3Cre+ mice had lower plasma levels of alloantibodies and troponin-I, reduced levels of IFN-γ in heart allograft homogenates and diminished cardiomyocyte necrosis and allograft fibrosis. Single cell analyses of allografts revealed higher absolute numbers of Tregs and lower CD8+ T cell infiltration in Nox2-deficient recipients compared to Nox2-replete mice. Mechanistically, in addition to a greater suppression of CD8+CD25- T effector cell proliferation and IFN-γ production, Nox2-deficient Tregs expressed higher levels of CCR4 and CCR8, driving cell migration to allografts; this was associated with increased expression of miR214-3p. These data indicate that Nox2 deletion in Tregs enhances their suppressive ability and migration to heart allografts. Therefore, Nox2 inhibition in Tregs may be a useful approach to improve their therapeutic efficacy

The 2015 Plains Elevated Convection at Night Field Project

The central Great Plains region in North America has a nocturnal maximum in warm-season precipitation. Much of this precipitation comes from organized mesoscale convective systems (MCSs). This nocturnal maximum is counterintuitive in the sense that convective activity over the Great Plains is out of phase with the local generation of CAPE by solar heating of the surface. The lower troposphere in this nocturnal environment is typically characterized by a low-level jet (LLJ) just above a stable boundary layer (SBL), and convective available potential energy (CAPE) values that peak above the SBL, resulting in convection that may be elevated, with source air decoupled from the surface. Nocturnal MCS-induced cold pools often trigger undular bores and solitary waves within the SBL. A full understanding of the nocturnal precipitation maximum remains elusive, although it appears that bore-induced lifting and the LLJ may be instrumental to convection initiation and the maintenance of MCSs at night. To gain insight into nocturnal MCSs, their essential ingredients, and paths toward improving the relatively poor predictive skill of nocturnal convection in weather and climate models, a large, multiagency field campaign called Plains Elevated Convection At Night (PECAN) was conducted in 2015. PECAN employed three research aircraft, an unprecedented coordinated array of nine mobile scanning radars, a fixed S-band radar, a unique mesoscale network of lower-tropospheric profiling systems called the PECAN Integrated Sounding Array (PISA), and numerous mobile-mesonet surface weather stations. The rich PECAN dataset is expected to improve our understanding and prediction of continental nocturnal warm-season precipitation. This article provides a summary of the PECAN field experiment and preliminary findings

Etude sur le rôle de l'axe MAdCAM-alpha4beta7 intestinal dans l'immunosurveillance tumorale pendant l'inhibition de PD-1

Les antibiotiques (ATB) inhibent l'efficacité anti-tumorale du blocage de PD1, mais les mécanismes sous-jacents à leurs effets immunosuppresseurs demeurent inconnus. Nous montrons ici que les ATB favorisent l'accumulation des cellules T FoxP3+ et RORct+ a4b7hi dans les ganglions lymphatiques et les lésions tumorales. Les ATB induisent la perte de l'adressine MadCAM-1 iléale provoquant la recirculation des lymphocytes T régulateurs et TH17 α4β7hi de l’iléon vers le microenvironnement tumoral (TME). Cette migration a été visualisée grâce à 2 méthodes, la première consiste en l’ injection directe de carboxyfluoresceine succinimidyl ester (CFSE) dans les ganglions lymphatiques mésentériques des souris porteuses de tumeurs, l’autre utilise des souris transgéniques Kaede contenant une protéine flurorescente photoconvertible. Les hétérodimères d'adressine MAdCAM-1 et d'intégrine α4β7 sont indispensables pour l'efficacité anti-tumorale et dans l'immuno-surveillance induite par les anticorps anti-PD1. L’utilisation de modèles knock-out de MadCAM-1 ou d’ anticorps bloquant son ligand α4β7, compromettent l’efficacité anticancéreuse du blocage du PD1 ceci en mobilisant les cellules entérotropes α4β7hi Treg et TH17 vers le TME et inversement, en réduisant le retour du Treg du TME vers l'intestin. L’inhibition de la voie MadCAM-1 au niveau iléal réduit simultanément les lymphocytes CCR5+ effecteurs et mémoires dans le tissu tumoral. Ces résultats démontrent l’existence d’un lien mécanistique entre la dysbiose intestinale et l'efficacité du traitement anti- tumoral, l’importance de l'axe intestin-tumeur dans l’ immunosurveillance du cancer et ouvre des perspectives d’application clinique pour cibler la voie MAdCAM-1 α4β7+ .Antibiotics (ATB) inhibit the anticancer efficacy of PD1 blockade but the mechanisms underlying their immunosuppressive effects remains unknown. Here we show that ATB promote the accumulation of enterotropic, ileum egressing FoxP3+ and RORct+ α4β7 hi T cells into tumor draining lymph nodes and tumor lesions. ATB induce the loss of ileal MadCAM-1 adressin provoking the recirculation of α4β7 hi ileal Treg and TH17 cells to the tumor microenvironment (TME), as visualized using direct injection of carboxyfluorescein succinimidyl ester in mesenteric lymph nodes of tumor bearers as well as Kaede transgenic mice harboring a photoconvertible flurorescent protein. MAdCAM-1 addressin and α4β7 integrin heterodimers are indispensable for the anticancer efficacy and the immuno-surveillanc elicited by anti-PD1 antibodies. Gene defects in MadCAM-1 as well as antibodies blocking its ligand α4β7, severely compromise the anticancer effects of PD1 blockade by mobilizing enterotropic α4β7hi Treg and TH17 cells towards the TME and conversely reducing Treg homing from the TME to the gut, concomitantly reducing CCR5+ effector memory tumor infiltrating lymphocytes. These findings demonstrate a mechanistic link between gut dysbiosis and tumor treatment efficacy and unveil the potential clinical relevance of the MAdCAM-1 α4β7+ and the gut-tumor axis in cancer immunosurveillance

The 2015 Plains Elevated Convection At Night field project

The article of record as published may be found at http://dx.doi.org/10.1175/BAMS-D-15-00257.1The PECAN field campaign assembled a rich array of observations from lower-tropospheric profiling systems, mobile radars and mesonets, and aircraft over the Great Plains during June–July 2015 to better understand nocturnal mesoscale convective systems and their relationship with the stable boundary layer, the low-level jet, and atmospheric bores.National Science Foundation (NSF)AGS-1327695 (NSF)AGS-1359726 (NSF)AGS-1359645 (NSF)AGS-1359606 (NSF)AGS-1359098 (NSF)AGS-1359771 (NSF)AGS-1442054 (NSF)ATM-1359703 (NSF)AGS-1359720 (NSF)AGS-1359698 (NSF)AGS-136237 (NSF)AGS-1237404 (NSF)AGS-1359723 (NSF

Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.

International audienc

Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients

International audienceBackground: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC.Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients.Design, setting, and participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVO-REN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed.Outcome measurements and statistical analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/ fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors.Results and limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae).Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers.Patient summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy. (c) 2020 Published by Elsevier B.V. on behalf of European Association of Urology

Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer

Background Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT.Methods Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens.Results In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so.Conclusions These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients