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Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain- or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC ₅₀, 3–21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells as well as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management.

Context In France, 2300 adolescents and young adults (AYAs, 15–25 years old) are diagnosed with cancer each year. As soon as the disease is diagnosed, a number of physical, psychological and social needs may arise. The aim of this study is to develop a tool to measure unmet needs that will allow the specificities of AYAs to be understood while allowing health care staff to mobilise the necessary actors to resolve them. Methods We developed the Questionnaire nEEd Cancer AYAs (QUEEC-AYAs questionnaire), from two existing questionnaires: the Cancer Needs Questionnaire Young People and the Needs Assessment & Service Bridge. A main sample of 103 AYAs then received and completed the questionnaire in order to conduct an exploratory factor analysis. Results The final structure of the QUEEC-AYAs is composed of 7 dimensions and 48 items: information (8 items), cancer care team (6 items), Physical health (4 items), Emotional health (14 items), Sexual & reproductive health (6 items), Health behaviors & wellness (4 items), Daily life (6 items). The questionnaire has a good acceptability and all domains have a Cronbach’s alphas value above 0.80. Conclusion The QUEEC-AYAs is the first measure of the psychosocial needs of AYAs available in French. Its systematic use in health care services should improve the coordination of care required by AYAs during and after treatment. Trial registration This study was approved by the ethics committee of the Paoli-Calmettes Institute (IRB # IPC 2021-041, 2021 May 20).

The recent introduction of the “precision medicine” concept in oncology pushed cancer research to focus on dynamic measurable biomarkers able to predict responses to novel anticancer therapies in order to improve clinical outcomes. Recently, the involvement of extracellular vesicles (EVs) in cancer pathophysiology has been described, and given their release from all cell types under specific stimuli, EVs have also been proposed as potential biomarkers in cancer. Among the techniques used to study EVs, flow cytometry has a high clinical potential. Here, we have applied a recently developed and simplified flow cytometry method for circulating EV enumeration, subtyping, and isolation from a large cohort of metastatic and locally advanced nonhaematological cancer patients (N = 106); samples from gender- and age-matched healthy volunteers were also analysed. A large spectrum of cancer-related markers was used to analyse differences in terms of peripheral blood circulating EV phenotypes between patients and healthy volunteers, as well as their correlation to clinical outcomes. Finally, EVs from patients and controls were isolated by fluorescence-activated cell sorting, and their protein cargoes were analysed by proteomics. Results demonstrated that EV counts were significantly higher in cancer patients than in healthy volunteers, as previously reported. More interestingly, results also demonstrated that cancer patients presented higher concentrations of circulating CD31+ endothelial-derived and tumour cancer stem cell-derived CD133 + CD326- EVs, when compared to healthy volunteers. Furthermore, higher levels of CD133 + CD326− EVs showed a significant correlation with a poor overall survival. Additionally, proteomics analysis of EV cargoes demonstrated disparities in terms of protein content and function between circulating EVs in cancer patients and healthy controls. Overall, our data strongly suggest that blood circulating cancer stem cell-derived EVs may have a role as a diagnostic and prognostic biomarker in cancer.

Single-cell profiling methods have had a profound impact on the understanding of cellular heterogeneity. While genomes and transcriptomes can be explored at the single-cell level, single-cell profiling of proteomes is not yet established. Here we describe new single-molecule protein sequencing and identification technologies alongside innovations in mass spectrometry that will eventually enable broad sequence coverage in single-cell profiling. These technologies will in turn facilitate biological discovery and open new avenues for ultrasensitive disease diagnostics.This Perspective describes new single-molecule protein sequencing and identification technologies alongside innovations in mass spectrometry that will eventually enable broad sequence coverage in single-cell proteomics.

Protein therapeutics have numerous critical quality attributes (CQA) that must be evaluated to ensure safety and efficacy, including the requirement to adopt and retain the correct three-dimensional fold without forming unintended aggregates. Therefore, the ability to monitor protein higher order structure (HOS) can be valuable throughout the lifecycle of a protein therapeutic, from development to manufacture. 2D NMR has been introduced as a robust and precise tool to assess the HOS of a protein biotherapeutic. A common use case is to decide whether two groups of spectra are substantially different, as an indicator of difference in HOS. We demonstrate a quantitative use of principal component analysis (PCA) scores to perform this decision-making, and demonstrate the effect of acquisition and processing details on class separation using samples of NISTmAb monoclonal antibody Reference Material subjected to two different oxidative stress protocols. The work introduces an approach to computing similarity from PCA scores based upon the technique of histogram intersection, a method originally developed for retrieval of images from large databases. Results show that class separation can be robust with respect to random noise, reconstruction method, and analysis region selection. By contrast, details such as baseline distortion can have a pronounced effect, and so must be controlled carefully. Since the classification approach can be performed without the need to identify peaks, results suggest that it is possible to use even more efficient measurement strategies that do not produce spectra that can be analyzed visually, but nevertheless allow useful decision-making that is objective and automated.

Approximately one-third of the human population is estimated to be chronically infected with the obligate intracellular parasite Toxoplasma gondii . Humans are accidental hosts that are infected with T. gondii after consumption of undercooked meat or contaminated water. Toxoplasmosis affects one-third of the human population worldwide. Humans are accidental hosts and are infected after consumption of undercooked meat and water contaminated with Toxoplasma gondii cysts and oocysts, respectively. Neutrophils have been shown to participate in the control of T. gondii infection in mice through a variety of effector mechanisms, such as reactive oxygen species (ROS) and neutrophil extracellular trap (NET) formation. However, few studies have demonstrated the role of neutrophils in individuals naturally infected with T. gondii . In the current study, we evaluated the activation status of neutrophils in individuals with acute or chronic toxoplasmosis and determined the role of T. gondii -induced NET formation in the amplification of the innate and adaptive immune responses. We observed that neutrophils are highly activated during acute infection through increased expression of CD66b. Moreover, neutrophils from healthy donors (HDs) cocultured with tachyzoites produced ROS and formed NETs, with the latter being dependent on glycolysis, succinate dehydrogenase, gasdermin D, and neutrophil elastase. Furthermore, we observed elevated levels of the chemokines (CXC motif) CXCL8 and (CC motif) CCL4 ligands in plasma from patients with acute toxoplasmosis and production by neutrophils from HDs exposed to T. gondii . Finally, we showed that T. gondii -induced NETs activate neutrophils and promote the recruitment of autologous CD4 + T cells and the production of interferon gamma (IFN-γ), tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-17, and IL-10 by peripheral blood mononuclear cells. In conclusion, we demonstrated that T. gondii activates neutrophils and promotes the release of NETs, which amplify human innate and adaptive immune responses. IMPORTANCE Approximately one-third of the human population is estimated to be chronically infected with the obligate intracellular parasite Toxoplasma gondii . Humans are accidental hosts that are infected with T. gondii after consumption of undercooked meat or contaminated water. Neutrophils have been shown to control T. gondii growth by different mechanisms, including neutrophil extracellular traps (NETs). In the current study, we observed that neutrophils are highly activated during acute toxoplasmosis. We also determined that T. gondii -induced NETs are dependent on the energetic profile of neutrophils as well as the production of ROS and gasdermin D (GSDMD) cleavage. In addition, we showed that T. gondii -induced NETs activate neutrophils, promote the recruitment of autologous CD4 + T cells, and induce the production of cytokines by peripheral blood mononuclear cells, amplifying the innate and adaptive immune responses.

Background:Even though time-to-treatment has been shown to be a determinant of mortality in primary angioplasty, the potential benefits from early pharmacological reperfusion by glycoprotein (Gp) IIb–IIIa inhibitors are still unclear. The aim of this meta-analysis was to combine individual data from all randomised trials conducted on facilitated primary angioplasty by the use of early Gp IIb–IIIa inhibitors.Methods and results:The literature was scanned by formal searches of electronic databases (MEDLINE, EMBASE) from January 1990 to October 2007. All randomised trials on facilitation by the early administration of Gp IIb–IIIa inhibitors in ST-segment elevation myocardial infarction (STEMI) were examined. No language restrictions were enforced. Individual patient data were obtained from 11 out of 13 trials, including 1662 patients (840 patients (50.5%) randomly assigned to early and 822 patients (49.5%) to late Gp IIb–IIIa inhibitor administration). Preprocedural Thrombolysis in Myocardial Infarction Study (TIMI) grade 3 flow was more frequent with early Gp IIb–IIIa inhibitors. Postprocedural TIMI 3 flow and myocardial blush grade 3 were higher with early Gp IIb–IIIa inhibitors but did not reach statistical significance except for abciximab, whereas the rate of complete ST-segment resolution was significantly higher with early Gp IIb–IIIa inhibitors. Mortality was not significantly different between groups, although early abciximab demonstrated improved survival compared with late administration, even after adjustment for clinical and angiographic confounding factors.Conclusions:This meta-analysis shows that pharmacological facilitation with the early administration of Gp IIb–IIIa inhibitors in patients undergoing primary angioplasty for STEMI is associated with significant benefits in terms of preprocedural epicardial recanalisation and ST-segment resolution, which translated into non-significant mortality benefits except for abciximab.

Near-record warmth over much of the United States during March 2007 promoted early growth of crops and vegetation. A widespread arctic air outbreak followed in early April, resulting in extensive agricultural losses over much of the south-central and southeastern US. This ‘false spring’ event also resulted in widespread damage to newly grown tissues of native deciduous forest species, shown by previous researchers to have had measurable effects on the terrestrial carbon cycle. The current study reconstructed the historical occurrence of false springs over most of the southeastern quarter of the conterminous US (32–39°N; 75–98°W) from 1901 to 2007 using daily maximum and minimum temperature records from 176 stations in the Global Historical Climatology Network database, and enhanced vegetation index (EVI) data derived from Moderate Resolution Imaging Spectroradiometer (MODIS) satellite observations. A false spring index was derived that examined the timing of the start of the growing season (SGS), or leaf emergence, relative to the timing of a potentially damaging last hard freeze (minimum temperature ≤ − 2.2 °C). SGS was modeled for the domain by combining EVI data with ground-based temperature ‘degree day’ calculations reflecting the rate of springtime warming. No significant area-wide, long-term SGS trend was found; however, over much of a contiguous region stretching from Mississippi eastward to the Carolinas, the timing of the last hard freeze was found to occur significantly later, this change occurring along with increased frequency of false springs. Earlier last hard freeze dates and decreased frequency of false springs were found over much of the northwestern part of the study region, including Arkansas and southern Missouri.

Background Ovarian cancer is the most lethal of all gynecological cancers. Cancer Antigen 125 (CA125) is the best‐performing ovarian cancer biomarker which however is still not effective as a screening test in the general population. Recent literature reports additional biomarkers with the potential to improve on CA125 for early detection when using longitudinal multimarker models. Methods Our data comprised 180 controls and 44 cases with serum samples sourced from the multimodal arm of UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Our models were based on Bayesian change‐point detection and recurrent neural networks. Results We obtained a significantly higher performance for CA125–HE4 model using both methodologies (AUC 0.971, sensitivity 96.7% and AUC 0.987, sensitivity 96.7%) with respect to CA125 (AUC 0.949, sensitivity 90.8% and AUC 0.953, sensitivity 92.1%) for Bayesian change‐point model (BCP) and recurrent neural networks (RNN) approaches, respectively. One year before diagnosis, the CA125–HE4 model also ranked as the best, whereas at 2 years before diagnosis no multimarker model outperformed CA125. Conclusions Our study identified and tested different combination of biomarkers using longitudinal multivariable models that outperformed CA125 alone. We showed the potential of multivariable models and candidate biomarkers to increase the detection rate of ovarian cancer. Using the data from largest prospective ovarian cancer clinical trial, we assessed, for the first time, the performance of deep and statistical learning approaches in evaluating of the panel longitudinal biomarkers. Our results demonstrate that these models outperform CA125, the single best ovarian cancer biomarker. These findings underscore the potential of multimarker models in improving the detection rate of ovarian cancer and have significant implications for the field of cancer screening and early detection.