Novel Approaches to Inhibition of Gastric Acid Secretion

The gastric H,K-adenosine triphosphatase (ATPase) is the primary target for treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pKa of about 4.0 that allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pKa of about 1.0. Protonation of this benzimidazole activates these prodrugs, converting them to sulfenic acids and/or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. The maximal pharmacodynamic effect of PPIs as a group relies on cyclic adenosine monophosphate–driven H,K-ATPase translocation from the cytoplasm to the canalicular membrane of the parietal cell. At present, this effect can only be achieved with protein meal stimulation. Because of covalent binding, inhibitory effects last much longer than their plasma half-life. However, the short dwell-time of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. All PPIs give excellent healing of peptic ulcer and produce good, but less than satisfactory, results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori, but success has fallen to less than 80%. Longer dwell-time PPIs promise to improve acid suppression and hence clinical outcome. Potassium-competitive acid blockers (P-CABs) are another class of ATPase inhibitors, and at least one is in development. The P-CAB under development has a long duration of action even though its binding is not covalent. PPIs with a longer dwell time or P-CABs with long duration promise to address unmet clinical needs arising from an inability to inhibit nighttime acid secretion, with continued symptoms, delayed healing, and growth suppression of H. pylori reducing susceptibility to clarithromycin and amoxicillin. Thus, novel and more effective suppression of acid secretion would benefit those who suffer from acid-related morbidity, continuing esophageal damage and pain, nonsteroidal anti-inflammatory drug–induced ulcers, and nonresponders to H. pylori eradication

Mitochondria and Energetic Depression in Cell Pathophysiology

Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell’s ability to do work and control the intracellular Ca2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis

Are the 7C psychological antecedents associated with COVID-19 vaccine behaviours beyond intentions? A cross-sectional study on at-least-one-dose and up-to-date vaccination status, and uptake speed among adults in France

International audienceBackgroundWidely documented psychological antecedents of vaccination are confidence in vaccines, complacency, convenience, calculation, collective responsibility (5C model) with the recent addition of confidence in the wider system and social conformism. While the capacity of these seven antecedents (7C) to explain variance in COVID-19 vaccine intentions has been previously documented, we study whether these factors also are associated with vaccine behaviours, beyond intentions.MethodsFrom February to June 2022, we recruited a sample of adults in France, including persons with notified recent SARS-CoV-2 infection, along with relatives and randomly selected non-infected persons. Participants completed self-administered questionnaires assessing COVID-19 vaccination history and the 7C antecedents. We defined vaccination behaviours as three outcomes: at-least-one-dose vaccine status by 2022 (N = 49,019), up-to-date vaccination status (N = 46,566), and uptake speed of first dose (N = 25,998). We conducted multivariable logistic regressions and Cox models.ResultsAmong the 49,019 participants, 95.0% reported receipt of at least one dose and 89.8% were up to date with recommendations. All 7C antecedents were significantly associated with the outcomes, although effects were weaker for up-to-date vaccination status and uptake speed. The strongest effects (most vs. least vaccine-favourable attitude level, at-least-one-dose vaccination status) were observed for collective responsibility (OR: 14.44; 95%CI: 10.72–19.45), calculation (OR: 10.29; 95%CI: 7.53–14.05), and confidence in the wider system (OR: 8.94; 95%CI: 6.51–12.27).ConclusionThis study demonstrates that the 7C not only explain vaccine intention, but also vaccine behaviours, and underpins the importance of developing vaccine promotion strategies considering the 7C antecedents

Superposition for Lambda-Free Higher-Order Logic

We designed a superposition calculus for a clausal fragment of extensional polymorphic higher-order logic that includes anonymous functions but excludes Booleans. The inference rules work on βη-equivalence classes of λ-terms and rely on higher-order unification to achieve refutational completeness. We implemented the calculus in the Zipperposition prover and evaluated it on TPTP and Isabelle benchmarks. The results suggest that superposition is a suitable basis for higher-order reasoning

A pan-cancer analysis of the human tumor coagulome and its link to the tumor immune microenvironment

International audienceObjective Solid tumors often establish a procoagulable state that can lead to venous thromboembolism (VTE). Although some of the key genes involved in this process are known, no previous study has compared the ``coagulome'', i.e., the expression of coagulation/fibrinolysis genes, across different primary tumor types. It is also unclear whether the coagulome is associated with specific characteristics of the tumor microenvironment (TME). We aimed to address this question. Methods We analyzed the expression of the genesF3, PLAU, PLAT, PLAUR, SERPINB2,andSERPINE1in 32 cancer types using data from The Cancer Genome Atlas (TCGA) and other freely available resources. Results We identified specific expression patterns of procoagulant and fibrinolytic genes. The expression of the Tissue Factor (F3) was found to be tumor type dependent, with the highest expression in glioblastoma (GBM), a highly procoagulable tumor type. Conversely, high expression of the fibrinolysis gene clusterPLAU, PLAUR, SERPINE1was consistently linked to the characteristics of the TME (monocytic infiltration) and high expression of important checkpoints of the immune response, such as PD-L2 and CD276/B7-H3. Conclusion These tumor-specific patterns of expression might partially explain the differences in VTE risk among tumor types. We propose that biomarkers of coagulation fibrinolysis might provide valuable information about the TME in cancer patients

Immunological and clinical efficacy of COVID-19 vaccines in immunocompromised populations: a systematic review

International audienceBackground: Available data show that COVID-19 vaccines may be less effective in immunocompromised populations, who are at increased risk of severe COVID-19.Objectives: We conducted a systematic review of literature to assess immunogenicity, efficacy and effectiveness of COVID-19 vaccines in immunocompromised populations.Data sources: We searched Medline and Embase databases.Study eligibility criteria, patients, interventions: We included studies of COVID-19 vaccines after complete vaccination in immunocompromised patients until 31 August 2021. Studies with <10 patients, safety data only and case series of breakthrough infections were excluded.Methods: Risk of bias was assessed via the tool developed by the National Institutes of Health on interventional and observational studies. Immunogenicity was assessed through non-response rate defined as no anti-SARS-CoV-2 spike protein antibodies, efficacy and effectiveness by the relative reduction in risk of SARS-CoV-2 infection or COVID-19. We collected factors associated with the risk of non-response. We presented collected data by immunosuppression type.Results: We screened 5917 results, included 162 studies. There were 157 on immunogenicity in 25 209 participants, including 7835 cancer or haematological malignancy patients (31.1%), 6302 patients on dialysis (25.0%), 5974 solid organ transplant recipients (23.7%) and 4680 immune-mediated disease patients (18.6%). Proportion of non-responders seemed higher among solid organ transplant recipients (range 18-100%) and patients with haematological malignancy (range 14-61%), and lower in patients with cancer (range 2-36%) and patients on dialysis (range 2-30%). Risk factors for non-response included older age, use of corticosteroids, immunosuppressive or anti-CD20 agent. Ten studies evaluated immunogenicity of an additional dose. Five studies evaluated vaccine efficacy or effectiveness: three on SARS-CoV-2 infection (range 71-81%), one on COVID-19-related hospitalization (62.9%), one had a too small sample size.Conclusions: This systematic review highlights the risk of low immunogenicity of COVID-19 vaccines in immunocompromised populations, especially solid organ transplant recipients and patients with haematological malignancy. Despite lack of vaccine effectiveness data, enhanced vaccine regimens may be necessary

Source of SARS-CoV-2 infection: results from a series of 584,846 cases in France from October 2020 to August 2022

Abstract Background We aimed to study the source of infection for recently SARS-CoV-2-infected individuals from October 2020 to August 2022 in France. Methods Participants from the nationwide ComCor case–control study who reported recent SARS-CoV-2 infection were asked to document the source and circumstances of their infection through an online questionnaire. Multivariable logistic regression was used to identify the factors associated with not identifying any source of infection. Results Among 584,846 adults with a recent SARS-CoV-2 infection in France, 46.9% identified the source of infection and an additional 22.6% suspected an event during which they might have become infected. Known and suspected sources of infection were household members (30.8%), extended family (15.6%), work colleagues (15.0%), friends (11.0%), and possibly multiple/other sources (27.6%). When the source of infection was known, was not a household member, and involved a unique contact (n = 69,788), characteristics associated with transmission events were indoors settings (91.6%), prolonged (> 15 min) encounters (50.5%), symptomatic source case (64.9%), and neither the source of infection nor the participant wearing a mask (82.2%). Male gender, older age, lower education, living alone, using public transportation, attending places of public recreation (bars, restaurants, nightclubs), public gatherings, and cultural events, and practicing indoor sports were all independently associated with not knowing the source of infection. Conclusion Two-thirds of infections were attributed to interactions with close relatives, friends, or work colleagues. Extra-household indoor encounters without masks were commonly reported and represented avoidable circumstances of infection. Trial registration ClinicalTrials.gov registration number: NCT04607941

The coagulome of Head and Neck Squamous Cell Carcinoma

International audienc