Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host

Purpose: In patients with colorectal cancer (CRC), a high-density local inflammatory infiltrate response is associated with improved survival, whereas elevated systemic inflammatory responses are associated with poor survival. One potential unifying mechanism is the IL-6/JAK/STAT3 pathway. The present study examines the relationship between tumour total STAT3 and phosphorylated STAT3Tyr705 (pSTAT3) expression, host inflammatory responses and survival in patients undergoing resection of stage I-III CRC. Experimental Design: Immunohistochemical assessment of STAT3/pSTAT3 expression was performed using a tissue microarray and tumour cell expression divided into tertiles using the weighted histoscore. The relationship between STAT3/pSTAT3 expression and local inflammatory (CD3+, CD8+, CD45R0+, FOXP3+ T-cell density and Klintrup-Mäkinen grade) and systemic inflammatory responses and cancer-specific survival were examined. Results: 196 patients were included in the analysis. Cytoplasmic and nuclear STAT3 expression strongly correlated (r=0.363, P<0.001); nuclear STAT3 and pSTAT3 expression weakly correlated (r=0.130, P=0.068). Cytoplasmic STAT3 was inversely associated with the density of CD3+ (P=0.012), CD8+ (P=0.003) and FOXP3+ T-lymphocytes (P=0.002) within the cancer cell nests and was associated with an elevated systemic inflammatory response as measured by modified Glasgow Prognostic Score (mGPS2: 19% vs. 4%, P=0.004). The combination of nuclear STAT3/pSTAT3 stratified five-year survival from 81% to 62% (P=0.012), however was not associated with survival independent of venous invasion, tumour perforation or tumour budding. Conclusion In patients undergoing CRC resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Up-regulation of tumour STAT3 may be an important mechanism whereby the tumour deregulates local and systemic inflammatory responses

Anti-bacterial, free radical scavenging activity and cytotoxicity of acetone extracts of Grewia flava .

Background: Bacterial infections of the gastrointestinal tract (GIT) cause vomiting, diarrhoea and even systemic disease. There is a need for the development of natural products into alternative and safer medicines. Objectives: This study evaluated the anti-microbial activity of extracts prepared from berries, leaves,bark and roots of the edible plant Grewia flava. Methods: The anti-bacterial activity was evaluated by the broth microdilution method. Anti-oxidant activity of the most active extracts was performed by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. The cytotoxicity of the extracts was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: The acetone extracts of the leaves and roots showed the best activity with MIC values as low as 0.03 mg/mL against Staphylococcus aureus and Salmonella typhimurium and 0.07 mg/mL against Bacillus cereus , Escherichia coli and Staphylococcus aureus. Quantitative analysis of the scavenging ability showed that acetone extracts exhibited good free radical scavenging activity in a dose-dependent manner. The berries extract had the highest LC50 (lowest toxicity) of 551.68 68 \ub5g/mL. Conclusion: Acetone extract of leaves and roots of Grewia flava contain anti-microbial and anti-oxidant compounds and could therefore be used as a natural product with little toxicity to host cells

Anti-bacterial, free radical scavenging activity and cytotoxicity of acetone extracts of Grewia flava

BACKGROUND : Bacterial infections of the gastrointestinal tract (GIT) cause vomiting, diarrhoea and even systemic disease. There is a need for the development of natural products into alternative and safer medicines. OBJECTIVES : This study evaluated the anti-microbial activity of extracts prepared from berries, leaves,bark and roots of the edible plant Grewia flava. METHODS : The anti-bacterial activity was evaluated by the broth microdilution method. Anti-oxidant activity of the most active extracts was performed by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. The cytotoxicity of the extracts was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS : The acetone extracts of the leaves and roots showed the best activity with MIC values as low as 0.03 mg/mL against Staphylococcus aureus and Salmonella typhimurium and 0.07 mg/mL against Bacillus cereus, Escherichia coli and Staphylococcus aureus. Quantitative analysis of the scavenging ability showed that acetone extracts exhibited good free radical scavenging activity in a dose-dependent manner. The berries extract had the highest LC50 (lowest toxicity) of 551.68 68 μg/mL. CONCLUSION : Acetone extract of leaves and roots of Grewia flava contain anti-microbial and anti-oxidant compounds and could therefore be used as a natural product with little toxicity to host cells.https://www.ajol.info/index.php/ahshttp://www.bioline.org.br/hsam2017Community DentistryParaclinical Science

Changes in Inflammatory and Atherogenesis Biomarkers With the 2-Drug Regimen Dolutegravir Plus Lamivudine in Antiretroviral Therapy-Experienced, Virologically Suppressed People With HIV-1: A Systematic Literature Review

Background: The 2-drug regimen dolutegravir plus lamivudine has demonstrated long-term noninferior efficacy vs 3-/4-drug regimens (3/4DRs) in phase 3 trials. This systematic literature review summarizes clinical trial and real-world evidence evaluating impact of dolutegravir plus lamivudine on inflammatory and atherogenesis biomarkers in people with human immunodeficiency virus type 1 (PWH). Methods: Using Ovid MEDLINE, Embase, PubMed, and Cochrane library databases and conference proceedings, we searched for studies published from 1 January 2013 to 14 July 2021, reporting changes in inflammatory and atherogenesis biomarkers with dolutegravir plus lamivudine in antiretroviral therapy-experienced, virologically suppressed PWH aged 6518 years. Results: Four records representing 2 randomized controlled trials (RCTs) and 6 records of real-world evidence met eligibility criteria. All real-world studies evaluated CD4+/CD8+\u2005ratio, while only 1 assessed inflammatory biomarkers. Across both RCTs, no consistent pattern of change in biomarkers was observed between dolutegravir/lamivudine and 3/4DR comparators. There were significant changes in soluble CD14 favoring dolutegravir/lamivudine in TANGO at weeks 48 and 144 and SALSA at week 48, and in interleukin-6 favoring the control group in TANGO at weeks 48 and 144. In the real-world study evaluating inflammatory biomarkers, median soluble CD14 significantly decreased 48 weeks postswitch to dolutegravir plus lamivudine (P\u2005<\u2005.001), while other biomarkers remained stable. In all 6 real-world studies, increases in CD4+/CD8+\u2005ratio were reported after switch to dolutegravir plus lamivudine (follow-up, 12-60 months). Conclusions: Results show that dolutegravir plus lamivudine has a comparable impact on inflammatory and atherogenesis biomarkers vs 3/4DRs, with no consistent pattern of change after switch in virologically suppressed PWH

Antiretroviral resistance after first-line antiretroviral therapy failure in diverse HIV-1 subtypes in the SECOND-LINE study

We investigate mutations and correlates according to HIV-1 subtype after virological failure (VF) of standard first-line antiretroviral therapy (ART) (non-nucleoside/nucleotide reverse transcriptase inhibitor [NNRTI] +2 nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI]). SECOND-LINE study participants were assessed at baseline for HIV-1 subtype, demographics, HIV-1 history, ART exposure, viral load (VL), CD4(+) count, and genotypic ART resistance. We used backward stepwise multivariate regression (MVR) to assess associations between baseline variables and presence of ≥3 N(t)RTI mutations, ≥1 NNRTI mutation, ≥3 thymidine analog-N(t)RTI [ta-N(t)RTI] mutations (TAMs), the K65/K70 mutation, and predicted etravirine (ETV)/rilpivirine (RPV) activity. The inclusion p-value for MVR was p  .05. Of 541 participants, 491 (91%) had successfully characterized baseline viral isolates. Subtype distribution: B (n = 123, 25%), C (n = 202, 41%), CRF01_AE (n = 109, 22%), G (n = 25, 5%), and CRF02_AG (n = 27, 5%). Baseline CD4(+) 200-394 cells/mm(3) were associated with <3 N(t)RTI mutations (OR = 0.47; 95% CI 0.29-0.77; p = .003), absence of the K65/K70 mutation (OR = 0.43; 95% CI 0.26-0.73; p = .002), and higher ETV sensitivity (OR = 0.52; 95% CI 0.35-0.78; p = .002). Recent tenofovir (TDF) use was associated with K65/K70 mutations (OR = 8.91; 95% CI 5.00-15.85; p < .001). Subtype CRF01_AE was associated with ≥3 N(t)RTI mutations (OR = 2.34; 95% CI 1.31-4.17; p = .004) and higher RPV resistance (OR = 2.13; 95% CI 1.30-3.49; p = .003), and subtype C was associated with <3 TAMs (OR = 0.45; 95% CI 0.21-0.99; p = .015). Subtypes CRF01_AE (OR = 2.46; 95% CI 1.26-4.78; p = .008) and G (OR = 4.77; 95% CI 1.44-15.76; p = .01) were associated with K65/K70 mutations. Higher VL at confirmed first-line VF was associated with ≥3 N(t)RTI mutations (OR = 1.39; 95% CI 1.07-1.78; p = .013) and ≥3 TAMs (OR = 1.62; 95% CI 1.15-2.29; p = .006). The associations of first-line resistance mutations across the HIV-1 subtypes in this study are consistent with knowledge derived from subtype B, with some exceptions. Patterns of resistance after failure of a first-line ta-N(t)RTI regimen support using TDF in N(t)RTI-containing second-line regimens, or using N(t)RTI-sparing regimens.Edward P. Lam, Cecilia L. Moore, Eduardo Gotuzzo, Chidi Nwizu, Adeeba Kamarulzaman, Ploenchan Chetchotisakd, Jean van Wyk, Hedy Teppler, Nagalingeswaran Kumarasamy, Jean-Michel Molina, Sean Emery, David A. Cooper, and Mark A. Boyd, for the SECOND-LINE study grou

Screening for neurocognitive impairment, depression, and anxiety in HIV-infected patients in Western Europe and Canada

CRANIum, a cross-sectional epidemiology study in Western Europe and Canada, was conducted to describe and compare the prevalence of a positive screen for neurocognitive impairment (NCI), depressive symptoms, and anxiety in an HIV-positive population either receiving combination antiretroviral therapy (cART) or who were naive to antiretroviral therapy (ART). HIV-positive patients ≥18 years of age attending a routine medical follow-up visit and able to complete the designated screening tools were eligible for study inclusion. The Brief Neurocognitive Screen was used to assess NCI; depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale. The evaluable patient population (N = 2863) included 1766 men (61.7%) and 1096 (38.3%) women. A total of 1969 patients were cART-experienced (68.8%), and 894 were ART-naive (31.2%). A positive screen for NCI was found in 41.5% of patients (cART-experienced, 42.5%; ART-naive, 39.4%; p = 0.12). A positive screen for depressive symptoms was found in 15.7% of patients (cART-experienced, 16.8%; ART-naive, 13.3%; p = 0.01), whereas 33.3% of patients screened positive for anxiety (cART-experienced, 33.5%; ART-naive, 32.8%; p = 0.71). A greater percentage of women compared with men screened positive for NCI (51.78% vs. 35.1%; p < 0.0001) and depressive symptoms (17.9% vs. 14.3%; p = 0.01). These data suggest that neurocognitive and mood disorders remain highly prevalent in HIV-infected patients. Regular mental health screening in this population is warranted

Spatially resolved transcriptomics deconvolutes prognostic histological subgroups in patients with colorectal cancer and synchronous liver metastases

Background: Patients demonstrating strong immune responses to primary colorectal cancer (CRC) have a survival benefit following surgery, while those with predominantly stromal microenvironments do poorly. Biomarkers to identify patients with colorectal cancer liver metastases (CRLM) who have good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary CRC and CRLM, and to interrogate the underlying functional biology that drives disease progression. Methods: Patients undergoing synchronous resection of primary CRC and CRLM underwent detailed histological assessment, panel genomic and bulk transcriptomic assessment, immunohistochemistry (IHC) and GeoMx Spatial Transcriptomics (ST) analysis. Integration with genomic features, pathway enrichment analysis and immune deconvolution were performed. Results: High-immune metastases were associated with improved cancer specific survival (HR, 0.36, P=0.01). Bulk transcriptomic analysis was confounded by stromal content but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for Type II Interferon signalling (NES=-2.05 P.Adj&lt;0.005) and MHC-Class II Antigen Presentation (NES=-2.09 P.Adj&lt;0.005). In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T-cells and neutrophils with enrichment of Notch (NES=2.2 P.Adj=0.022) and TGF-β (NES=2.2 P.Adj=0.02) signalling pathways at the metastatic tumor centre. Conclusions: Histological assessment stratifies outcome in patients undergoing synchronous resection of CRLM. ST analysis reveals significant intra-tumoral and inter-lesional heterogeneity with underlying transcriptomic programmes identified in driving each phenotype

Computerized clinical decision support systems for drug prescribing and management: A decision-maker-researcher partnership systematic review

<p>Abstract</p> <p>Background</p> <p>Computerized clinical decision support systems (CCDSSs) for drug therapy management are designed to promote safe and effective medication use. Evidence documenting the effectiveness of CCDSSs for improving drug therapy is necessary for informed adoption decisions. The objective of this review was to systematically review randomized controlled trials assessing the effects of CCDSSs for drug therapy management on process of care and patient outcomes. We also sought to identify system and study characteristics that predicted benefit.</p> <p>Methods</p> <p>We conducted a decision-maker-researcher partnership systematic review. We updated our earlier reviews (1998, 2005) by searching MEDLINE, EMBASE, EBM Reviews, Inspec, and other databases, and consulting reference lists through January 2010. Authors of 82% of included studies confirmed or supplemented extracted data. We included only randomized controlled trials that evaluated the effect on process of care or patient outcomes of a CCDSS for drug therapy management compared to care provided without a CCDSS. A study was considered to have a positive effect (<it>i.e.</it>, CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive.</p> <p>Results</p> <p>Sixty-five studies met our inclusion criteria, including 41 new studies since our previous review. Methodological quality was generally high and unchanged with time. CCDSSs improved process of care performance in 37 of the 59 studies assessing this type of outcome (64%, 57% of all studies). Twenty-nine trials assessed patient outcomes, of which six trials (21%, 9% of all trials) reported improvements.</p> <p>Conclusions</p> <p>CCDSSs inconsistently improved process of care measures and seldomly improved patient outcomes. Lack of clear patient benefit and lack of data on harms and costs preclude a recommendation to adopt CCDSSs for drug therapy management.</p