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ABSTRACTCD73 is a cell surface 5’nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P= 1.6 × 10−6; IFNAR2, P= 9.8 × 10−11and IL-10RB, P= 2.3 × 10−14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RBand IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Ultralight axion-like particles are well-motivated dark matter candidates introduced by theories beyond the standard model of particle physics. However, directly constraining their parameter space with laboratory experiments usually yields weaker limits than indirect approaches relying on astrophysical observations. Here we report the search for axion-like particles with a quantum sensor in the mass range of 8.3–744.0 feV. The sensor makes use of hyperpolarized long-lived nuclear spins as a pre-amplifier that effectively enhances a coherently oscillating axion-like dark matter field by a factor of more than 100. Using these spin-based amplifiers, we achieve an ultrahigh magnetic sensitivity of 18 fT Hz–(1/2), which exceeds the performance of state-of-the-art nuclear spin magnetometers. Our experiment constrains the parameter space describing the coupling of axion-like particles to nucleons over the aforementioned mass range, namely, at 67.5 feV reaching 2.9 × 10−9GeV−1, improving on previous laboratory constraints by at least five orders of magnitude. Our measurements also constrain the quadratic interaction between axion-like particles and nucleons as well as interactions between dark photons and nucleons, exceeding bounds from astrophysical observations.

La démarche engagée depuis plusieurs années par la communauté des hydromètres pour quantifier les incertitudes associées au processus d'élaboration des données de débit mériterait de trouver des applications opérationnelles. La présente étude incite notamment les gestionnaires des stations hydrométriques à mieux valoriser les jaugeages effectués en systématisant la démarche de précision du modèle de courbe de tarage. Les auteurs proposent ensuite une démarche simplifiée de quantification de l'incertitude associée à une valeur de débit prédite par une courbe de tarage à partir du calcul de l'écart type des écarts en pour cent des jaugeages à la courbe de tarage et d'une tabulation en fonction des quantiles de débits observés. Elle s'appuie sur une démarche classique d'identification des sources d'incertitude et de leur propagation. Cette méthode permet de proposer une estimation de l'incertitude observée en moyenne sur les stations françaises pour la médiane des débits observés. On propose la formulation suivante : pour 45 à 55 % des stations françaises, la valeur la plus probable de l'incertitude au seuil de confiance de 95 % pour le quantile 50 % des débits observés en France est inférieure à 22 %.

Lors des crises (sécheresses ou crues) les données hydrométriques participent directement aux processus de décision pour la gestion en temps réel de la ressource en eau et des risques mais également à l'analyse a posteriori pour le règlement des litiges. Pour pouvoir prendre des décisions cohérentes, il est essentiel de connaître l'incertitude associée aux données de débit. Si les techniques hydrométriques se sont nettement améliorées au cours des dernières décennies, l'estimation des incertitudes reste un défi pour la communauté de l'hydrométrie en l'absence d'étalon de débit en milieu naturel. Cette étude, portant sur la quantification des incertitudes des jaugeages au courantomètre, s'inscrit dans une suite de travaux récents dont la perspective vise la mise à jour potentielle de la norme ISO 748. Une méthode de propagation analytique des incertitudes, nommée Flaure, est exposée dans cet article. Elle permet de pallier les inconvénients des méthodes existantes et vise l'objectivation des différentes sources d'incertitude. Une attention particulière est portée au terme prépondérant u'm d'incertitude due à l'intégration latérale des profils de vitesse et de profondeur. Grâce à l'étude de jaugeages de référence à haute résolution latérale, un lien a été établi entre les erreurs d'interpolation latérale et un indice de qualité d'échantillonnage calculable pour tout jaugeage réalisé au courantomètre.

La démarche engagée depuis plusieurs années par la communauté des hydromètres pour quantifier les incertitudes associées au processus d'élaboration des données de débit mériterait de trouver des applications opérationnelles. La présente étude incite notamment les gestionnaires des stations hydrométriques à mieux valoriser les jaugeages effectués en systématisant la démarche de précision du modèle de courbe de tarage. Les auteurs proposent ensuite une démarche simplifiée de quantification de l'incertitude associée à une valeur de débit prédite par une courbe de tarage à partir du calcul de l'écart type des écarts en pour cent des jaugeages à la courbe de tarage et d'une tabulation en fonction des quantiles de débits observés. Elle s'appuie sur une démarche classique d'identification des sources d'incertitude et de leur propagation. Cette méthode permet de proposer une estimation de l'incertitude observée en moyenne sur les stations françaises pour la médiane des débits observés. On propose la formulation suivante : pour 45 à 55 % des stations françaises, la valeur la plus probable de l'incertitude au seuil de confiance de 95 % pour le quantile 50 % des débits observés en France est inférieure à 22 %.

Le progrès conduit à allonger la durée de vie de la maladie cancéreuse métastatique, qui demeure le plus souvent une maladie évolutive et mortelle. Les soins se réalisent pendant une durée croissante au-delà des preuves fournies par les études cliniques, donc dans la complexité et l’incertitude sur les rapports bénéfice/risque. Respecter le cadre éthique, renforcé par la loi Claeys-Leonetti de février 2016, pour une maladie évolutive potentiellement mortelle, conduit à informer le patient de manière réaliste, évoquer le pronostic, développer les discussions anticipées, recueillir et respecter ses préférences. Ces évolutions conduisent à passer d’une médecine du consentement éclairé à une médecine du respect de la volonté, avec toute la complexité que suppose la détermination de cette dernière. Tandis que s’est structurée la pluridisciplinarité au diagnostic par l’association des expertises diagnostiques et thérapeutiques vis-à-vis de la maladie tumorale, émerge ainsi un besoin de structuration d’une autre pluridisciplinarité, interrogeant le sens pour la personne, la proportionnalité du soin, la trajectoire personnelle et la sécurisation du parcours de soins. Pour atteindre cet objectif, la précocité de l’alliance des expertises complémentaires est décisive. Ceci a conduit à des recommandations de la Société américaine d’oncologie clinique (ASCO). L’introduction de l’équipe de soins palliatifs est un temps essentiel et la qualité de la concertation onco-palliative est déterminante. Nous décrivons notre préconisation pour mettre en pratique une réunion de concertation (RCP) onco-palliative, véritable pivot d’un changement d’organisation du soin en situation d’incurabilité.

Lors des crises (sécheresses ou crues) les données hydrométriques participent directement aux processus de décision pour la gestion en temps réel de la ressource en eau et des risques mais également à l'analyse a posteriori pour le règlement des litiges. Pour pouvoir prendre des décisions cohérentes, il est essentiel de connaître l'incertitude associée aux données de débit. Si les techniques hydrométriques se sont nettement améliorées au cours des dernières décennies, l'estimation des incertitudes reste un défi pour la communauté de l'hydrométrie en l'absence d'étalon de débit en milieu naturel. Cette étude, portant sur la quantification des incertitudes des jaugeages au courantomètre, s'inscrit dans une suite de travaux récents dont la perspective vise la mise à jour potentielle de la norme ISO 748. Une méthode de propagation analytique des incertitudes, nommée Flaure, est exposée dans cet article. Elle permet de pallier les inconvénients des méthodes existantes et vise l'objectivation des différentes sources d'incertitude. Une attention particulière est portée au terme prépondérant u'm d'incertitude due à l'intégration latérale des profils de vitesse et de profondeur. Grâce à l'étude de jaugeages de référence à haute résolution latérale, un lien a été établi entre les erreurs d'interpolation latérale et un indice de qualité d'échantillonnage calculable pour tout jaugeage réalisé au courantomètre.

Because genetic background plays a pivotal role in humans and in various experimental models, we carefully monitored its impact on glomerular pathological characteristics during experimental anti-glomerular basement membrane glomerulonephritis (anti–GBM-GN), using two leading mouse strains, 129S2/SvPas (129Sv) and C57bl/6J (B6J). These mice exhibited different severities of renal failure, hypertension, and glomerular lesions, according to their genetic background. In addition to the classic glomerular proliferative lesions, glomerular thrombotic microangiopathy (TMA) was found as a common genetic background–dependent histopathological hallmark of anti–GBM-GN, combined with hemolytic anemia and thrombocytopenia. Glomerular expression profiling, using microarrays and Western blot analysis in B6J TMA-resistant and 129Sv TMA-prone mice, demonstrated major differences in vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) 2 pathways, despite similar Vegfa expression levels. Further analysis revealed a lower basal glomerular endothelial Vegfr2 expression level in 129Sv TMA-prone mice compared with B6J TMA-resistant mice. This difference was even more pronounced during anti–GBM-GN, explaining why an exogenous VEGFA supply failed to rescue any 129Sv TMA lesions. Conversely, the systemic blocking of Vegfr2 amplified TMA lesions only in B6J mice. Herein, we specified the role that genetic background plays in determining, in particular, the level of Vegfr2 expression. We also demonstrated that glomerular Vegfr2-dependent TMA lesions are an underevaluated common hallmark of anti–GBM-GN in mice.

New vaccine technology has led to vaccines containing highly purified antigens with improved safety profiles, but increased antigen purity often results in weakened immunogenicity. A better understanding of innate and adaptive immunity and their interaction at the molecular level has led to the use of innovative adjuvants combined with careful antigen selection. Adjuvants can be used to amplify the immune response, and the combination of antigens with more than one adjuvant, the Adjuvant System approach, allows the development of vaccines which generate specific and effective immune responses adapted to both the pathogen and the target population. One of those Adjuvant Systems is AS04, a combination of the TLR4 agonist MPL (3-O-desacyl-4-monophosphoryl lipid A) and aluminum salt. The added value of MPL in AS04-based formulation above Aluminium was evidenced for a prophylactic human papillomavirus (HPV)-16/18 vaccine by higher vaccine-elicited antibody responses, as well as the induction of higher levels of memory B-cells. This review focuses on the role of AS04 for development of Cervarix™, a vaccine for the prevention of cervical cancer.

Introduction:Hypertension is the most important modifiable risk factor for recurrent stroke. However, it remains poorly controlled after stroke, especially among Black and Hispanic patients. Black and Hispanics have a higher prevalence of uncontrolled BP and limited access to care. Interventions that promote equitable access are needed to improve outcomes.Aim:We tested whether a randomized trial of post-acute stroke care that integrates nurse-supported home BP telemonitoring, tailored infographics, and video visits with a multidisciplinary team including pharmacy (Telehealth After Stroke Care (TASC intervention) was feasible.Methods:Acute stroke patients with hypertension were randomized prior to discharge to usual care or TASC. Usual care patients received a video visit with primary care at 1-2 weeks and stroke specialist at 6 and 12 weeks after discharge. TASC patients received a tablet that wirelessly transmits BP data to the electronic health record, supported by remote telehealth nurse monitoring along with BP infographics, developed through community participatory design, at first visit and pharmacist visits. Outcomes included recruitment feasibility, visit adherence, and retention. Generalized linear modeling was used to evaluate within-patient home BP change.Results:Of 67 eligible patients, 6 were discharged before recruitment, 8 refused and 3 engaged in other studies. Fifty enrolled patients included 44% Hispanic, 32% Black and 36% women with mean age 64.3 (±14.0) yrs. About half had ≤ a high school education and 30% had commercial insurance. Baseline SBP was similar in TASC (140 ± 19 mmHg) vs. usual care (142 ± 19 mmHg). Retention rate was higher in TASC vs. usual care (84% vs 64%, p=0.11). Adherence to video visits was also higher in TASC (91% vs 75%, p=0.14). SBP control was better in TASC (76% vs. 25%, p<0.01). At 12 weeks, home SBP declined by 16 ± 19 mmHg from baseline in TASC vs increased by 3 ± 24 mmHg (p<0.01) in usual care. SBP control in Black patients improved from 40% at baseline to 100% in TASC vs from 14% to 29% in usual care.Conclusion:Enhancing post-acute stroke care with home BP telemonitoring is a promising approach to improving hypertension control in an underserved setting that should be tested in a definitive randomized trial.

We present the results of measurements of 1.04 GeV proton elastic and inelastic scattering on the 144,150,152Sm isotopes. The use of HFB p- and n-densities gives a quite good description of the elastic scattering data. Neutron transition strengths are deduced for the 21+and 31−levels in 144Sm. The channel coupling in the fairly well deformed 152Sm nucleus is shown to be important. It can be well accounted for in a microscopic way in the Glauber model.

The design of an adjuvant for eliciting a thymus-dependent response to LPS, a well-defined thymus-independent antigen, is presented. Hybrid liposomes containing LPS and HA2 peptide from the hemagglutinin protein of influenza virus within the liposome bilayer were prepared (LPS/HA2 liposomes). The HA2 polypeptide contains epitopes recognized by T-helper lymphocytes and T-cytotoxic lymphocytes. Outbred mice immunized with LPS/HA2 liposomes produced anti-LPS-specific IgG responses. IgG subclass analysis indicated that IgG1, IgG2, and IgG3 antibodies were produced by these animals. LPS liposomes (liposomes without HA2) stimulated a T-independent response only. This was demonstrated by the detection of IgG3 but not IgG1 or IgG2 in serum of mice immunized with LPS liposomes. These results support the concept that the simultaneous incorporation into liposomes of a polypeptide with T-cell recognition sites along with a T-independent antigen can lead to the generation of cognate T-cell help for the T-independent antigen. The synthesis and characterization of a neo-lipopolysaccharide T-independent antigen for incorporation in hybrid HA2 liposomes are also presented. Findings are discussed relative to the liposome model used and implications for development of vaccines for use in humans.

A rhodamine dye tracer study was conducted over eight tidal cycles to investigate mixing and tidal exchange processes in Perch Pond, a Cape Cod embayment subject to recurrent blooms of the toxic dinoflagellate, Gonyaulax tamarensis. Dye injected at the inlet to Perch Pond during flood tide became well-mixed within the pond in one day and was removed at an effective first order rate of 0.36 d−1, equivalent to a 70% utilization of the maximum possible tidal exchange. This relatively high flushing efficiency can be attributed to a density-driven circulation within the pond, consisting of a subsurface inflow of high salinity dense water on the flood tide followed by removal of lighter surface layers through the shallow inlet during ebb tide. The formation of a frontal convergence near the inlet on flood tide is consistent with the observed distribution of G. tamarensiscysts and shelifish toxicity. It is also clear that phytoplankton like G. tamarensis, whose maximum growth rates approximate the rate of tidal flushing, can only bloom within the embayment by avoiding the outflowing surface waters. Mixing within the pond is probably less efficient and population losses greater during dry periods when the pond salinity is higher and the stratification weaker.

Systemically administered CsA has not consistently suppressed the pulmonary immunoreactivity that leads to rejection in lung transplant patients. Pulmonary T cells from patients given CsA systemically still retain their immunoreactivity, which can be suppressed with added CsA. Direct application of CsA by aerosol to the respiratory epithelium should achieve high lung concentrations with minimum systemic effects. In the present study, CsA was most efficiently incorporated into liposomes composed of egg yolk phosphatidylcholine at a molar ratio of CsA to egg yolk phosphatidylcholine of 1:20. These CsA liposomes retained their biological activity and were as effective as free CsA in the suppression of anti-CD3-stimulated [3H]thymidine incorporation by mouse spleen cells. The generation of a small-particle aerosol of CsA liposomes had no effect on this biological activity. CsA liposome aerosol particles have a mass median aerodynamic diameter of 2 μm, which allows for distribution of drug throughout the respiratory tract. Quantitation of CsA in the lungs and blood of mice exposed to CsA liposome aerosols for 4 days showed that as little as 15 min daily (0.11 mg/kg/day) was sufficient to achieve an estimated concentration of CsA in respiratory secretions of 6 μg/ml without detectable blood levels. Thus, CsA liposomes can be produced and aerosolized that achieve pulmonary concentrations with sufficient immunosuppressive activity to be effective in the treatment of lung diseases.

1The contributions of neurotransmitters and neuromodulators to the responses of the respiratory network to acute hypoxia were analysed in anaesthetized cats.2Samples of extracellular fluid were collected at 1–1.5 min time intervals by microdialysis in the medullary region of ventral respiratory group neurones and analysed for their content of glutamate, γ‐aminobutyric acid (GABA), serotonin and adenosine by high performance liquid chromatography. Phrenic nerve activity was correlated with these measurements.3Levels of glutamate and GABA increased transiently during early periods of hypoxia, coinciding with augmented phrenic nerve activity and then fell below control during central apnoea. Serotonin and adenosine increased slowly and steadily with onset of hypoxic depression of phrenic nerve activity.4The possibility that serotonin contributes to hypoxic respiratory depression was tested by microinjecting the 5‐HT‐1A receptor agonist 8‐OH‐DPAT into the medullary region that is important for rhythmogenesis. Hypoxic activation of respiratory neurones and phrenic nerve activity were suppressed. Microinjections of NAN‐190, a 5‐HT‐1A receptor blocker, enhanced hypoxic augmentation resulting in apneustic prolongation of inspiratory bursts.5The results reveal a temporal sequence in the release of neurotransmitters and neuromodulators and suggest a specific role for each of them in the sequential development of hypoxic respiratory disturbances.

Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40) were of Ashkenazi Jewish descent. Seven patients (70) received platinum agents, two (20) received mitomycin-C, one (10) received a PARP inhibitor, and seven (70) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future.

The article presents an essay that explores the possibility that humanity has already been eliminated. It provides an overview of the original inhabitants of the world and examines their struggles to survive in the era of civilization. Various definitions of civilization are offered, emphasizing the notion that civilization is global with one economic system which is capitalism. It also discusses civilization's impact on humanity and how humanity has been extinguished by the civilization.

Les luxations et fractures luxations périlunaires du carpe sont des traumatismes graves avec des séquelles fonctionnelles fréquentes et sévères. Le but de cette étude était d’évaluer le devenir radio-clinique à long terme de ces patients et de mettre en évidence les facteurs pronostiques.

No relevant conflicts of interest to declare.

Introduction

Le but de cette étude était d’évaluer à moyen et long termes la désaxation du carpe après résection arthroplastique avec interposition tendineuse dans l’arthrose scapho-trapézo-trapézoïdienne (STT) isolée et ses conséquences cliniques.