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Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored. Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC. Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment. Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC. Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology. journal article research support, non-u.s. gov't 2023 Feb 2022 10 27 imported

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.

BACKGROUND/OBJECTIVES: Several scoring systems have been specifically developed for risk stratification in COVID-19 patients. DESIGN: We compared, in a cohort of confirmed COVID-19 older patients, three specifically developed scores with a previously established early warning score. Main endpoint was all causes in-hospital death. SETTING: This is a single-center, retrospective observational study, conducted in the Emergency Department (ED) of an urban teaching hospital, referral center for COVID-19. PARTICIPANTS: We reviewed the clinical records of the confirmed COVID-19 patients aged 60 years or more consecutively admitted to our ED over a 6-week period (March 1st to April 15th, 2020). A total of 210 patients, aged between 60 and 98 years were included in the study cohort. MEASUREMENTS: International Severe Acute Respiratory Infection Consortium Clinical Characterization Protocol-Coronavirus Clinical Characterization Consortium (ISARIC-4C) score, COVID-GRAM Critical Illness Risk Score (COVID-GRAM), quick COVID-19 Severity Index (qCSI), National Early Warning Score (NEWS). RESULTS: Median age was 74 (67-82) and 133 (63.3%) were males. Globally, 42 patients (20.0%) deceased. All the score evaluated showed a fairly good predictive value with respect to in-hospital death. The ISARIC-4C score had the highest area under ROC curve (AUROC) 0.799 (0.738-0.851), followed by the COVID-GRAM 0.785 (0.723-0.838), NEWS 0.764 (0.700-0.819), and qCSI 0.749 (0.685-0.806). However, these differences were not statistical significant. CONCLUSION: Among the evaluated scores, the ISARIC-4C and the COVID-GRAM, calculated at ED admission, had the best performance, although the qCSI had similar efficacy by evaluating only three items. However, the NEWS, already widely validated in clinical practice, had a similar performance and could be appropriate for older patients with COVID-19.

Background and aims The COVID‐19 pandemic represents a source of stress and potential burnout for many physicians. This single‐site survey aimed at assessing perceived stress and risk to develop burnout syndrome among physicians operating in COVID wards. Methods This longitudinal survey evaluated stress and burnout in 51 physicians operating in the COVID team of Gemelli Hospital, Italy. Participants were asked to complete the Maslach Burnout Inventory (MBI) and the Perceived Stress Questionnaire on a short run (PSQs) (referring to the past 7 days) at baseline (T0) and then for four weeks (T1‐T4). Perceived Stress Questionnaire on a long run (PSQl) (referring to the past 2 years) was completed only at T0. Results Compared with physicians board‐certified in internal medicine, those board‐certified in other disciplines showed higher scores for the Emotional Exhaustion (EE) score of the MBI scale (P

Background The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has a tropism for the gastrointestinal tract and several studies have shown an alteration of the gut microbiota in hospitalized infected patients. However, long-term data on microbiota changes after recovery are lacking. Methods We enrolled 30 patients hospitalized for SARS‑CoV‑2-related pneumonia. Their gut microbiota was analyzed within 48 h from the admission and compared with (1) that of other patients admitted for suspected bacterial pneumonia (control group) (2) that obtained from the same subject 6 months after nasopharyngeal swab negativization. Results Gut microbiota alpha-diversity increased 6 months after the resolution of SARS-CoV-2 infection. Bacteroidetes relative abundance was higher (≈ 36.8%) in patients with SARS-CoV-2, and declined to 18.7% when SARS-CoV-2 infection resolved (p = 0.004). Conversely, Firmicutes were prevalent (≈ 75%) in controls and in samples collected after SARS-CoV-2 infection resolution (p = 0.001). Ruminococcaceae, Lachnospiraceae and Blautia increased after SARS-CoV-2 infection resolution, rebalancing the gut microbiota composition. Conclusion SARS-CoV-2 infection is associated with changes in the gut microbiome, which tend to be reversed in long-term period.

SUMMARY Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is frequently associated with liver tests abnormalities. Aims To describe the evolution of liver involvement during SARS‐CoV‐2 infection and its effect on clinical course and mortality. Methods Data of 515 SARS‐CoV‐2 positive patients were collected at baseline and during follow‐up, last evaluation or death. Stratification based on need for hospitalization, severe disease and admission to intensive care unit (ICU) was performed. The association between liver tests abnormalities (baseline and peak values) and ICU admission or death was also explored. Results Liver tests abnormalities were found in 161 (31.3%) patients. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were increased in 20.4%, 19% and 13.6% of patients, respectively. Baseline liver tests abnormalities were associated with increased risk of ICU admission (OR 2.19 [95%CI 1.24‐3.89], p=0.007) but not with mortality (OR 0.84 [95%CI 0.49‐1.41], p=0.51). Conversely, ALP peak values were correlated with the risk of death (OR 1.007 [95%CI 1.002‐1.01], p=0.005) along with age, multiple comorbidities, acute respiratory distress syndrome (ARDS), ICU admission, and C‐reactive protein. Alterations of liver tests worsened within 15 days after hospitalization; however, in patients with the longest median follow‐up, the prevalence of liver tests alterations decreased over time, returning similar to that of baseline. Conclusions In SARS‐CoV‐2 positive patients without pre‐existing severe chronic liver disease, baseline liver tests abnormalities are associated with the risk of ICU admission and tend to normalize over time. ALP peak value seems to be predictive of a worse prognosis.

Introduction: Hepatocellular carcinoma (HCC) is the fastest rising and fourth leading cause of cancer death worldwide. While new therapeutic modalities have been recently approved, treatment response and survival in patients remain poor. Claudin-1 (CLDN1) is a cell membrane protein mediating cell-cell adhesion, fate and differentiation. While the function of CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 in HCC remains unexplored. Aim and methods: Using humanized monoclonal antibodies (mAbs) targeting specifically the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as therapeutic target for treatment of HCC. Results: Targeting non-junctional CLDN1 robustly suppressed tumor growth in a large series of patient-derived model systems, including multicellular tumorspheres and patient-derived xenograft (PDX) mouse models. In vivo and ex vivo studies further suggested synergistic efficacy in combination with sorafenib. Mechanistic studies revealed that CLDN1 mAbs suppressed tumor cell proliferation, invasion and stemness by interfering with Src, Wnt-β-catenin and STAT3 signaling. Treatment with humanized anti-CLDN1 mAbs is considered to be safe, as administration in non-human primates and mouse models did not reveal any major toxicity even when high doses largely exceeding the therapeutic need were repeatedly applied. Conclusion: Our results provide robust pre-clinical proof-of-concept for humanized CLDN1-specific mAbs for treatment of HCC. The unique and differentiated mechanism of action has the potential to break the plateau of limited response and survival offered by currently approved therapies. Citation Format: Natascha Roehlen, Marion Muller, Sara Cherradi, Frank Juehling, Francois H.T. Duong, Nuno Almeida, Fabio Del Zompo, Mirian Fernandez, Tobias Riedl, Hussein El Saghire, Antonio Saviano, Sarah Durand, Clara Ponsolles, Marine Oudot, Emanuele Felli, Patrick Pessaux, Irwin Davidson, Emilie Crouchet, Patrick Laquerriere, Mathias Heikenwälder, Roberto Iacone, Markus Meyer, Greg Elson, Tamas Schweighoffer, Catherine Schuster, Laurent Mailly, Joachim Lupberger, Thomas F Baumert. Claudin-1 is a therapeutic target for hepatocellular carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P153.

The prevalence of cardiometabolic disorders (obesity, type 2 diabetes and cardiovascular disorders) is increasing globally and is a leading cause of mortality worldwide. Both genetics and environmental factors are involved in the pathogenesis of these disorders. Recent studies have shown that a state of dysbiosis may be implicated in body weight control, insulin resistance and cardio-metabolic risk factors, but the underlying mechanisms remain to be fully understood. Here we describe the possible role of the gut microbiota in cardiovascular diseases.

Microparticles (MPs) are submicron vesicles shed from various cell types upon activation, stimulation, and death. Activated platelets are an important source of circulating MPs in subjects with inflammatory diseases, including Crohn&rsquo, s disease (CD). Angiogenesis is a hallmark of inflammation in CD and plays an active role in sustaining disease progression, while targeting angiogenesis may be an effective approach to block colitis. In this study, we analyzed the angiogenic content of the MPs produced by activated platelets in subjects with CD. We also evaluated whether the angiogenic signal carried by these MPs was functionally active, or able to induce angiogenesis. We found that, in subjects with CD, MPs produced by activated platelets contain significantly higher levels of angiogenic mRNAs, such as epidermal growth factor (EGF), platelet-derived growth factor-&alpha, (PDGF&alpha, ), fibroblast growth factor (FGF-2), and angiopoietin-1 (ANGPT1), compared to MPs isolated from control subjects. They also contain significantly higher levels of prototypical angiogenic proteins, including vascular endothelial growth factor (VEGF), angiopoietin-1, endoglin, endothelin-1, pentraxin 3, platelet factor-4, plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinases-1 (TIMP-1), and thrombospondin 1. The protein content of these MPs is functionally active, since it has the ability to induce a robust angiogenic process in an endothelial cell/interstitial cell co-culture in vitro assay. Our results reveal a potential novel mechanism through which the angiogenic signal is delivered in subjects with CD, with potentially important clinical and therapeutic implications.

Inflammatory bowel diseases are chronic diseases affecting the gastrointestinal tract, whose major forms are represented by Crohn’s disease (CD) and ulcerative colitis (UC). Their etiology is still unclear, although several factors have been identified as major determinants for induction or relapses. Among these, the role of the “forgotten organ”, gut microbiota, has become more appreciated in recent years. The delicate symbiotic relationship between the gut microbiota and the host appears to be lost in IBD. In this perspective, several studies have been conducted to assess the role of prebiotics and probiotics in gut microbiota modulation. This is a minireview aimed to address in an easy format (simple questions-simple answers) some common issues about the theme. An update on the role of selected constituents of gut microbiota in the pathogenesis of IBD is presented together with the analysis of the efficacy of gut microbiota modulation by prebiotics and probiotics administration in the management of IBD.