Perkinsus-marinus (Apicomplexa) As A Potential Source Of Oyster Crassostrea-virginica Mortality In Coastal Lagoons Of Tabasco, Mexico

Poorly documented, but apparently sporadic oyster Crassostrea virginica mortality in the coastal lagoons Carmen, Machona and Mecoacan at the southern extreme of the Gulf of Mexico in Tabasco, Mexico, has been attributed by local oystermen to pollution resulting from oil refinery operations. In September 1992 we sampled oysters in these lagoons to investigate the potential for disease-induced mortality from the oyster pathogen Perkinsus marinus. Prevalence of P. marinus was 100% at Lodazal, a high salinity (31 ppt) site in Carmen lagoon and 60% at Rio San Felipe, a low salinity (15 ppt) site. At Los Jimenez, a high salinity (32 ppt) site in Machona lagoon with previous high mortality, prevalence of P. marinus was 90% and weighted prevalence, a measure of intensity, was 3.1, a high value associated with heavy infections and mortality. Samples collected at the Buena Vista aquaculture facility in Mecoacan lagoon revealed 60 to 100% prevalence of P. marinus, although most infections were low intensity. P. marinus is a potential source of oyster mortality in these coastal lagoons; more intensive sampling is necessary to determine the mortality attributable to P. marinus

Aberrant innate immune sensing leads to the rapid progression of idiopathic pulmonary fibrosis

Novel approaches are needed to define subgroups of patients with Idiopathic pulmonary fibrosis (IPF) at risk for acute exacerbations and/or accelerated progression of this generally fatal disease. Progression of disease is an integral component of IPF with a median survival of 3 to 5 years. Conversely, a high degree of variability in disease progression has been reported among series. The characteristics of patients at risk of earlier death predominantly rely on baseline HRCT appearance, but this concept that has been challenged. Disparate physiological approaches have also been taken to identify patients at risk of mortality, with varying results. We hypothesized that the rapid decline in lung function in IPF may be a consequence of an abnormal host response to pathogen-associated molecular patterns (PAMPs), leading to aberrant activation in fibroblasts and fibrosis. Analysis of upper and lower lobe surgical lung biopsies (SLBs) indicated that TLR9, a hypomethylated CpG DNA receptor, is prominently expressed at the transcript and protein level, most notably in biopsies from rapidly progressive IPF patients. Surprisingly, fibroblasts appeared to be a major cellular source of TLR9 expression in IPF biopsies from this group of progressors. Further, CpG DNA promoted profibrotic cytokine and chemokine synthesis in isolated human IPF fibroblasts, most markedly again in cells from patients with the rapidly progressive IPF phenotype, in a TLR9-dependent manner. Finally, CpG DNA exacerbated fibrosis in an in vivo model initiated by the adoptive transfer of primary fibroblasts derived from patients who exhibited rapidly progressing fibrosis. Together, these data suggested that TLR9 activation via hypomethylated DNA might be an important mechanism in promoting fibrosis particularly in patients prone to rapidly progressing IPF

Relevance of Fc Gamma Receptor Polymorphisms in Cancer Therapy With Monoclonal Antibodies

Therapeutic monoclonal antibodies (mAbs), including immune checkpoint inhibitors (ICIs), are an important breakthrough for the treatment of cancer and have dramatically changed clinical outcomes in a wide variety of tumours. However, clinical response varies among patients receiving mAb-based treatment, so it is necessary to search for predictive biomarkers of response to identify the patients who will derive the greatest therapeutic benefit. The interaction of mAbs with Fc gamma receptors (Fc gamma R) expressed by innate immune cells is essential for antibody-dependent cellular cytotoxicity (ADCC) and this binding is often critical for their in vivo efficacy. Fc gamma RIIa (H131R) and Fc gamma RIIIa (V158F) polymorphisms have been reported to correlate with response to therapeutic mAbs. These polymorphisms play a major role in the affinity of mAb receptors and, therefore, can exert a profound impact on antitumor response in these therapies. Furthermore, recent reports have revealed potential mechanisms of ICIs to modulate myeloid subset composition within the tumour microenvironment through Fc gamma R-binding, optimizing their anti-tumour activity. The purpose of this review is to highlight the clinical contribution of Fc gamma R polymorphisms to predict response to mAbs in cancer patients

Durable Response After Tisagenlecleucel in Adults With Relapsed/Refractory Follicular Lymphoma: ELARA Trial Update

Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the ≥3rd-line setting. The primary analysis (median follow-up: 17 months) of the Phase II ELARA trial (ClinicalTrials.gov identifier: NCT03568461) reported high response rates and excellent safety profile in extensively pretreated patients with r/r FL. Here we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after a median follow-up of 29 months. As of March 29, 2022, 97 patients with r/r FL (grades 1-3A) after ≥2 lines of therapy or who relapsed after autologous stem cell transplant received tisagenlecleucel infusion (0.6-6×108 CAR+ viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment (TME), blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached after 29 months median follow-up (IQR, 22.2-37.7). Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% CI, 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2). Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T-cells and higher baseline levels of naïve CD8+ T-cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA

TESTING A SUBTYPE-SPECIFIC GP41 AMPLIFICATION METHOD FOR GENOTYPING INDIVIDUALS INFECTED BY HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 IN THE BRAZILIAN POPULATION OF ITAJAI, SOUTH BRAZIL

The method used by YAGYU et al. for the subtype-specific polymerase chain reaction (PCR) amplification of the gp41 transmembrane region of the human immunodeficiency virus type-1 (HIV-1) env gene, was tested. HIV-1 proviral DNA from 100 infected individuals in Itajaí, South Brazil was used to analyze this method. Seventy individuals were determined according to this method as having PCR products at the expected size for subtypes B, C, D and F. Of these individuals, 26 (37.1%) were observed as having the expected amplification for subtype C, and 42 (60%) were observed as having the expected products for subtypes B and D. Of the subtype B and D amplicons, 16 (22.9%) were classified as subtype D, and 26 (37.1%) were classified as subtype B. Two individuals (2.9%) had amplicons that were observed after subtype F-specific amplification was performed. Sequencing and comparing the patient sequences to reference sequences confirmed the classification of sequences of subtypes C and B. However, sequences that were falsely determined as being D and F in the PCR assay were determined as being subtypes C and B, respectively, by sequence analysis. For those individuals from whom no amplified products were obtained, a low viral load that was indicated in their patient history may explain the difficulty in subtyping by PCR methods. This issue was demonstrated by the results of ANOVA when testing the effect of viral load on the success of PCR amplification. The alignment of the obtained sequences with HIV-1 reference sequences demonstrated that there is high intra-subtype diversity. This indicates that the subtype-specific primer binding sites were not conserved or representative of the subtypes that are observed in the Brazilian populations, and that they did not allow the correct classification of HIV-1 subtypes. Therefore, the proposed method by YAGYU et al. is not applicable for the classification of Brazilian HIV-1 subtypes

Capacidade para o trabalho e saúde: o que pensam as trabalhadoras da indústria de vestuário

Este estudo objetivou conhecer como as mulheres que atuam na indústria do vestuário em Divinópolis, Minas Gerais, entendem e relacionam os constructos capacidade para o trabalho e saúde. Utilizou-se metodologia qualitativa com análise dos depoimentos ancorada na teoria das representações sociais. Os resultados apontaram que a capacidade para o trabalho depende de fatores como capacitação, suporte social, exercício da profissão a domicilio, satisfação com o trabalho, saúde e envelhecimento. Além disso, ela sofre muitas influências externas ao trabalhador, que, por sua vez, precisa constantemente se adaptar às mudanças ocorridas. Os resultados evidenciaram a necessidade de reflexão sobre o papel das condições de trabalho e emprego, da rigidez organizacional e da perda de controle sobre o trabalho, na saúde e na capacidade para o trabalho das mulheres atuantes na indústria do vestuário

Telomere Length Shows No Association with BRCA1 and BRCA2 Mutation Status

This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrolment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrolment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1.

Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue. In human endothelial cells, TSP1 promoted senescence and attenuated cell cycle progression and proliferation. At the molecular level, TSP1 increased Nox1-dependent generation of reactive oxygen species (ROS), leading to the increased abundance of the transcription factor p53. p53 mediated a DNA damage response that led to senescence through Rb and p21cip, both of which inhibit cell cycle progression. Nox1 inhibition blocked the ability of TSP1 to increase p53 nuclear localization and p21cip abundance and its ability to promote senescence. Mice lacking TSP1 showed decreases in ROS production, p21cip expression, p53 activity, and aging-induced senescence. Conversely, lung tissue from aging humans displayed increases in the abundance of vascular TSP1, Nox1, p53, and p21cip Finally, genetic ablation or pharmacological blockade of Nox1 in human endothelial cells attenuated TSP1-mediated ROS generation, restored cell cycle progression, and protected against senescence. Together, our results provide insights into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence and suggest potential targets for controlling the aging process at the molecular level