Qualidade dos frutos de variedades de videira do Banco Ativo de Germoplasma da Embrapa Semiárido.

O objetivo deste trabalho foi caracterizar a qualidade de uvas tintas para consumo in natura e para processamento, conservadas no Banco Ativo de Germoplasma (BAG) de videira da Embrapa Semiárido

Cathepsin S Levels and Survival Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are at high residual risk for long-term cardiovascular (CV) mortality. Cathepsin S (CTSS) is a lysosomal cysteine protease with elastolytic and collagenolytic activity that has been involved in atherosclerotic plaque rupture.; The purpose of this study was to determine the following: 1) the prognostic value of circulating CTSS measured at patient admission for long-term mortality in NSTE-ACS; and 2) its additive value over the GRACE (Global Registry of Acute Coronary Events) risk score.; This was a single-center cohort study, consecutively recruiting patients with adjudicated NSTE-ACS (n = 1,112) from the emergency department of an academic hospital. CTSS was measured in serum using enzyme-linked immunosorbent assay. All-cause mortality at 8 years was the primary endpoint. CV death was the secondary endpoint.; In total, 367 (33.0%) deaths were recorded. CTSS was associated with increased risk of all-cause mortality (HR for highest vs lowest quarter of CTSS: 1.89; 95% CI: 1.34-2.66; P < 0.001) and CV death (HR: 2.58; 95% CI: 1.15-5.77; P = 0.021) after adjusting for traditional CV risk factors, high-sensitivity C-reactive protein, left ventricular ejection fraction, high-sensitivity troponin-T, revascularization and index diagnosis (unstable angina/ non-ST-segment elevation myocardial infarction). When CTSS was added to the GRACE score, it conferred significant discrimination and reclassification value for all-cause mortality (Delta Harrell's C: 0.03; 95% CI: 0.012-0.047; P = 0.001; and net reclassification improvement = 0.202; P = 0.003) and CV death (AUC: 0.056; 95% CI: 0.017-0.095; P = 0.005; and net reclassification improvement = 0.390; P = 0.001) even after additionally considering high-sensitivity troponin-T and left ventricular ejection fraction.; Circulating CTSS is a predictor of long-term mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score

Estimated pulse wave velocity improves risk stratification for all-cause mortality in patients with COVID-19

Accurate risk stratification in COVID-19 patients consists a major clinical need to guide therapeutic strategies. We sought to evaluate the prognostic role of estimated pulse wave velocity (ePWV), a marker of arterial stiffness which reflects overall arterial integrity and aging, in risk stratification of hospitalized patients with COVID-19. This retrospective, longitudinal cohort study, analyzed a total population of 1671 subjects consisting of 737 hospitalized COVID-19 patients consecutively recruited from two tertiary centers (Newcastle cohort: n = 471 and Pisa cohort: n = 266) and a non-COVID control cohort (n = 934). Arterial stiffness was calculated using validated formulae for ePWV. ePWV progressively increased across the control group, COVID-19 survivors and deceased patients (adjusted mean increase per group 1.89 m/s, P &lt; 0.001). Using a machine learning approach, ePWV provided incremental prognostic value and improved reclassification for mortality over the core model including age, sex and comorbidities [AUC (core model + ePWV vs. core model) = 0.864 vs. 0.755]. ePWV provided similar prognostic value when pulse pressure or hs-Troponin were added to the core model or over its components including age and mean blood pressure (p &lt; 0.05 for all). The optimal prognostic ePWV value was 13.0 m/s. ePWV conferred additive discrimination (AUC: 0.817 versus 0.779, P &lt; 0.001) and reclassification value (NRI = 0.381, P &lt; 0.001) over the 4C Mortality score, a validated score for predicting mortality in COVID-19 and the Charlson comorbidity index. We suggest that calculation of ePWV, a readily applicable estimation of arterial stiffness, may serve as an additional clinical tool to refine risk stratification of hospitalized patients with COVID-19 beyond established risk factors and scores

MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma

Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors

Modulation of biliary cancer chemo-resistance through microRNA-mediated rewiring of the expansion of CD133+ cells

Changes in single microRNA (MIR) expression have been associated with chemo-resistance in Biliary Tract Cancer (BTC). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy. APPROACH AND RESULTS: high-throughput-screening of 997 LNA-MIR-inhibitors was performed in 6 CCA cell lines treated with Cisplatin-Gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with miRvana probes. MIR and gene expression was assessed by TaqMan-assay, RNA-sequencing and in-situ-hybridization in 4 indepedent cohorts of human BTC. Knock-out of microRNA was achieved by CRISPR-CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in-vitro and in-vivo. High-throughput-screening revealed that MIR1249-inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTC. In validation experiments, MIR1249-inhibition did not alter cell viability in untreated or DMSO-treated cells; however it did increase CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem niche of human BTC, as well as in CD133+ chemo-resistant CCLP cells. MIR1249 modulated the chemotherapy-induced enrichment of CD133+ cells by controlling their clonal expansion via the Wnt-regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of Cancer-Stem-Cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumour shrinkage after exposure to weekly CG, while WT models showed only stable disease over treatment

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Funder: FP7 People: Marie-Curie Actions; FundRef: http://dx.doi.org/10.13039/100011264; Grant(s): CIG 334261OBJECTIVE: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785). DESIGN: EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients. RESULTS: EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA. CONCLUSION: EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials

Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.

Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer

Chloramphenicol Derivatives as Antibacterial and Anticancer Agents: Historic Problems and Current Solutions

Chloramphenicol (CAM) is the D-threo isomer of a small molecule, consisting of a p-nitrobenzene ring connected to a dichloroacetyl tail through a 2-amino-1,3-propanediol moiety. CAM displays a broad-spectrum bacteriostatic activity by specifically inhibiting the bacterial protein synthesis. In certain but important cases, it also exhibits bactericidal activity, namely against the three most common causes of meningitis, Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. Resistance to CAM has been frequently reported and ascribed to a variety of mechanisms. However, the most important concerns that limit its clinical utility relate to side effects such as neurotoxicity and hematologic disorders. In this review, we present previous and current efforts to synthesize CAM derivatives with improved pharmacological properties. In addition, we highlight potentially broader roles of these derivatives in investigating the plasticity of the ribosomal catalytic center, the main target of CAM

A Simple Prognostic Score for Critical COVID-19 Derived from Patients without Comorbidities Performs Well in Unselected Patients

We aimed to search for laboratory predictors of critical COVID-19 in consecutive adults admitted in an academic center between 16 September 2020–20 December 2021. Patients were uniformly treated with low-molecular-weight heparin, and dexamethasone plus remdesivir when SpO2 n = 241, 49 year-old median, 71% males), 22 (9.1%) developed critical disease and 2 died (0.8%). White-blood-cell counts, neutrophils, neutrophil-to-lymphocyte ratio, CRP, fibrinogen, ferritin, LDH and γ-GT at admission were each univariably associated with critical disease. ROC-defined cutoffs revealed that CRP > 61.8 mg/L, fibrinogen > 616.5 mg/dL and LDH > 380.5 U/L were each associated with critical disease development, independently of age, sex and days from symptom-onset. A score combining higher-than-cutoff CRP (0/2), LDH (0/1) and fibrinogen (0/1) predicted critical disease (AUC: 0.873, 95% CI: 0.820–0.926). This score performed well in an unselected patient cohort (n = 1228, 100% unvaccinated) predominantly infected by the alpha variant (AUC: 0.718, 95% CI: 0.683–0.753), as well as in a mixed cohort (n = 527, 65% unvaccinated) predominantly infected by the delta variant (AUC: 0.708, 95% CI: 0.656–0.760). Therefore, we propose that a combination of standard biomarkers of acute inflammatory response, cell death and hypercoagulability reflects the severity of COVID-19 per se independently of comorbidities, age and sex, being of value for risk stratification in unselected patients