The presence of senescent peripheral T-cells is negatively correlated to COVID-19 vaccine-induced immunity in cancer patients under 70 years of age

PurposeCancer patients are at risk of severe COVID-19 infection, and vaccination is recommended. Nevertheless, we observe a failure of COVID-19 vaccines in this vulnerable population. We hypothesize that senescent peripheral T-cells alter COVID-19 vaccine-induced immunity.MethodsWe performed a monocentric prospective study and enrolled cancer patients and healthy donors before the COVID-19 vaccination. The primary objective was to assess the association of peripheral senescent T-cells (CD28-CD57+KLRG1+) with COVID-19 vaccine-induced immunity.ResultsEighty cancer patients have been included, with serological and specific T-cell responses evaluated before and at 3 months post-vaccination. Age ≥ 70 years was the principal clinical factor negatively influencing the serological (p=0.035) and specific SARS-CoV-2 T-cell responses (p=0.047). The presence of senescent T-cells was correlated to lower serological (p=0.049) and specific T-cell responses (p=0.009). Our results sustained the definition of a specific cut-off for senescence immune phenotype (SIP) (≥ 5% of CD4 and ≥ 39.5% of CD8 T-cells), which was correlated to a lower serological response induced by COVID-19 vaccination for CD4 and CD8 SIPhigh (p=0.039 and p=0.049 respectively). While CD4 SIP level had no impact on COVID-19 vaccine efficacy in elderly patients, our results unraveled a possible predictive role for CD4 SIPhigh T-cell levels in younger cancer patients.ConclusionsElderly cancer patients have a poor serological response to vaccination; specific strategies are needed in this population. Also, the presence of a CD4 SIPhigh affects the serological response in younger patients and seems to be a potential biomarker of no vaccinal response

Toward standardization of BK virus monitoring: evaluation of the BK virus R-gene kit for quantification of BK viral load in urine, whole-blood, and plasma specimens.

Screening of BK virus (BKV) replication is recommended to identify patients at increased risk of BKV-associated diseases. However, the heterogeneity of molecular techniques hinders the establishment of universal guidelines for BKV monitoring. Here we aimed to compare the performance of the CE-marked BK virus R-gene kit (R-gene) to the performance of our in-house assay for quantification of BKV DNA loads (BKVL). A 12-specimen panel from the Quality Control for Molecular Diagnostics (QCMD) organization, 163 urine samples, and 88 paired specimens of plasma and whole blood (WB) from transplant recipients were tested. Both the R-gene and in-house assays showed a good correlation within the QCMD panel (r = 0.995 and r = 0.989, respectively). BKVL were highly correlated between assays, although positive biases were observed with the in-house assay in analysis of urine (0.72 ± 0.83 log10 copies/ml), plasma (1.17 ± 0.63 log10 copies/ml), and WB (1.28 ± 0.37 log10 copies/ml). Recalibration with a common calibrator significantly reduced the bias in comparisons between assays. In contrast, BKVL was underestimated with the in-house PCR in eight samples containing BKV genotype II, presenting point mutations at primer-annealing sites. Using the R-gene assay, plasma and WB specimens were found to be equally suitable for quantification of BKVL, as indicated by the high correlation coefficient (r = 0.965, P < 0.0001). In conclusion, the R-gene assay demonstrated reliable performance and higher accuracy than the in-house assay for quantification of BKVL in urine and blood specimens. Screening of BKV replication by a well-validated commercial kit may enable clinical laboratories to assess viral loads with greater reproducibility and precision.comparative studyevaluation studiesjournal articleresearch support, non-u.s. gov't2014 Dec2014 10 08importe

Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells

Background: Constitutive activation of signal transducer and activator of transcription signalling 3 (STAT3) has been linked with survival, proliferation and angiogenesis in a wide variety of malignancies including hepatocellular carcinoma (HCC). Methods: We evaluated the effect of lupeol on STAT3 signalling cascade and its regulated functional responses in HCC cells. Results: Lupeol suppressed constitutive activation of STAT3 phosphorylation at tyrosine 705 residue effectively in a dose- and time-dependent manner. The phosphorylation of Janus-activated kinases (JAKs) 1 and 2 and Src was also suppressed by lupeol. Pervanadate treatment reversed the downregulation of phospho-STAT3 induced by lupeol, thereby indicating the involvement of a phosphatase. Indeed, we observed that treatment with lupeol increased the protein and mRNA levels of SHP-2, and silencing of SHP-2 abolished the inhibitory effects of lupeol on STAT3 activation. Treatment with lupeol also downregulated the expression of diverse STAT3-regulated genes and decreased the binding of STAT3 to VEGF promoter. Moreover, the proliferation of various HCC cells was significantly suppressed by lupeol, being associated with substantial induction of apoptosis. Depletion of SHP-2 reversed the observed antiproliferative and pro-apoptotic effects of lupeol. Conclusions: Lupeol exhibited its potential anticancer effects in HCC through the downregulation of STAT3-induced pro-survival signalling cascade

Mycobacteria counteract a TLR-mediated nitrosative defense mechanism in a zebrafish infection model.

Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments

Syndrome cytokinique lié à HHV8 mimant un choc septique

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Predictive factors of poor outcomes in the COVID-19 epidemic: Consider the inflammatory response

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Does type of immunosupression influence the course of Covid-19 infection?

International audienceCoronavirus disease 19 (Covid-19) is a new emerging virus responsible for pandemic and death. High blood pressure, diabetes, obesity have been described as poor prognosis factors. Few data have been reported in patient with immunocompromised status (solid tumor, hematological malignancy, rheumatoid conditions or organ transplant). We evaluated the characteristics of patients, including the outcome, with immunodepression hospitalized in Besancon University hospital (East of France). We wanted to identify if a type of immunosupression influences the course of Covid-19. In a cohort of 80 patients with immunosupression (42 solid tumors, 20 hematological malignancy and 18 non neoplastic immunosupression), poor outcomes (Intensive care unit hospitalization and or deaths) was frequent (38%) and tended to be more frequent in patients with hematological malignancy

Repurposing the Hybrid Capture 2 (HC2) screening test for whole-genome sequencing of human papillomaviruses

International audienceSimple and standardized approaches for genome analysis of human papillomavirus (HPV) by next-generation sequencing are needed. The aim of the study was to develop a protocol for direct deep sequencing of high-risk (hr) HPV strains, based on the widely used commercial Hybrid Capture 2 (QIAGEN) test, without any additional probe design. This protocol was applied to 15 HPV-positive and two HPV-negative cervical samples or cell lines and validated at the genotype level by comparing the sequencing results to those obtained using a commercial genotyping kit. The performance of our protocol, presented in this proof-of-principle study, supports its use for accurate characterization of genetic variants of hrHPV

Clinical relevance of herpes simplex virus viremia in Intensive Care Unit patients

International audienceOBJECTIVES:To determine the clinical relevance of herpes simplex virus (HSV) viremia episodes in critically ill adult patients.METHODS:1556 blood samples obtained for HSV PCR analysis in Intensive Care Unit (ICU) patients over 4 years were retrospectively analyzed, focusing on the comprehensive analysis of 88 HSV-viremic patients.RESULTS:HSV DNA was detected in 11.8% of samples from the ICU. HSV viral loads remained below 5×10(2) copies/ml in 68.2% of patients and exceeded 10(4) copies/ml in 7.9%. Episodes of HSV-viremia correlated with immunosuppressed status and mechanical ventilation in 79.5% and 65.9% of patients, respectively. Only a subset of patients exhibited HSV-related organ damage, including pneumonia and hepatitis (10.2% and 2.3%, respectively). The mortality rate in HSV-viremic patients was not significantly increased compared to the overall mortality rate in the ICU (27.3% vs. 22.9%, p = 0.33). Only patients with high HSV viral loads tended to have a higher, though non-significant, death rate (57.1%, p = 0.14).CONCLUSIONS:Our results suggest HSV viremia is common in ICU patients, potentially favored by immunocompromised status and mechanical ventilation. The global impact of HSV-viremia on mortality in the ICU was low. Quantifying HSV DNA may help identifying patients at-risk of severe HSV-induced symptoms

Electrostatic wipes as simple and reliable methods for influenza virus airborne detection

International audienceThe performance of an in-house protocol for virus detection on commercialized electrostatic wipes (EWs) was assessed experimentally by impregnating them with suspensions of cytomegalovirus, adenovirus, and influenza virus, and by determining the recovery efficiency, repeatability, and detection limit of the protocol. The protocol was sensitive enough to detect 4 log10 gene copies of virus. At room temperature, influenza RNA was stable on EWs for at least four days. When EWs were placed high in 32 influenza-infected patients' rooms, influenza RNA was detectable in 75% (N = 24) of EWs, suggesting that EWs are simple and reliable methods for influenza virus airborne detection