Comparative Analysis of Clinical Practice Guidelines for the Pharmacological Treatment of Type 2 Diabetes Mellitus in Latin America.

PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2DM) is one of the leading causes of death and disability in the world. The majority of diabetes deaths (> 80%) occur in low- and middle-income countries, which are predominant in Latin America. Therefore, the purpose of this article is to compare the clinical practice guideline (CPG) for the pharmacological management of T2DM in Latin America (LA) with international reference guidelines. RECENT FINDINGS: Several LA countries have recently developed CPGs. However, the quality of these guidelines is unknown according to the AGREE II tool and taking as reference three CPGs of international impact: American Diabetes Association (ADA), European Diabetes Association (EASD), and Latin American Diabetes Association (ALAD). Ten CPGs were selected for analysis. The ADA scored > 80% on the AGREE II domains and was selected as the main comparator. Eighty percent of LA CPGs were developed before 2018. Only one was not recommended (all domains < 60%). The CPGs in LA have good quality but are outdated. They have significant gaps compared to the reference. There is a need for improvement, as proposing updates every three years to maintain the best available clinical evidence in all guidelines.

Nicotiana tabacum Leaf Waste: Morphological Characterization and Chemical-Functional Analysis of Extracts Obtained from Powder Leaves by Using Green Solvents.

Tobacco cultivation and industrialization are characterized by the production of trillions of pre-harvest and post-harvest waste biomasses each year with the resulting negative effects on the environment. The leaves of blunt, pre-harvest waste, could be further used to obtain bioactive metabolites, i.e., polyphenols and alkaloids, for its potential cosmetic use. This study was conducted to obtain bio-compounds from pre-harvest tobacco leaf waste (var. Virginia) by applying conventional and green solvents (NaDES). Leaves and ground leaf waste were characterized based on their microscopic features. Conventional solvents, such as water, acetone, ethanol, and non-conventional solvents, such as Natural Deep Eutectic Solvents (NaDES), i.e., sucrose:lactic acid (LAS), frutose:glucose:sucrose (FGS), lactic acid:sucrose:water (SALA), choline chloride:urea (CU), and citric acid: propylene glycol (CAP) were used for bioactive extraction from tobacco waste powder. CU, FGS, and acetone/ethanol had similar behavior for the best extraction of alkaloids (6.37-11.23 mg ACE/g tobacco powder). LAS, FGS, SALA, and CU were more effective in phenolic compound extraction than conventional solvents (18.13-21.98 mg AGE/g tobacco powder). Because of this, LAS and SALA could be used to obtain phenolic-enriched extracts with lower alkaloid content rather than CU and FGS. Extracts of the powder obtained with conventional solvent or CU showed a high level of sugars (47 mg/g tobacco powder) The ABTS antioxidant capacity of tobacco leaf powder was higher in the extracts obtained with CU, FGS, and acetone (SC50 1.6-5 µg GAE/mL) while H2O2 scavenging activity was better in the extracts obtained with LAS, CAP and SALA (SC50 3.8-8.7 µg GAE/mL). Due to the biocompatibility of the NaDES with the components of tobacco leaf waste, the opportunity to apply these extracts directly in antioxidant formulations, such as cosmetics, phytotherapic, and other formulations of topic use seems promising. Furthermore, NaDES constituents, i.e., urea and organic acid can also have beneficial effects on the skin.

Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures.

OBJECTIVE: Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA). DESIGN: A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay. RESULTS: An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut. CONCLUSION: Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.

Methylation changes in the peripheral blood of Filipinos with type 2 diabetes suggest spurious transcription initiation at TXNIP.

While much work has been done in associating differentially methylated positions (DMPs) to type 2 diabetes (T2D) across different populations, not much attention has been placed on identifying its possible functional consequences. We explored methylation changes in the peripheral blood of Filipinos with T2D and identified 177 associated DMPs. Most of these DMPs were associated with genes involved in metabolism, inflammation and the cell cycle. Three of these DMPs map to the TXNIP gene body, replicating previous findings from epigenome-wide association studies (EWAS) of T2D. The TXNIP downmethylation coincided with increased transcription at the 3' UTR, H3K36me3 histone markings and Sp1 binding, suggesting spurious transcription initiation at the TXNIP 3' UTR as a functional consequence of T2D methylation changes. We also explored potential epigenetic determinants to increased incidence of T2D in Filipino immigrants in the USA and found three DMPs associated with the interaction of T2D and immigration. Two of these DMPs were located near MAP2K7 and PRMT1, which may point towards dysregulated stress response and inflammation as a contributing factor to T2D among Filipino immigrants.

[Serrated polyps and their association with synchronous advanced colorectal neoplasia]. / Pólipos serrados y su asociación con neoplasia avanzada de colon.

INTRODUCTION: Large serrated polyps (SP), proximal SP, SP with dysplasia and the presence of multiple sessile serrated adenomas/polyps (SSA/P), which we refer to as SP with increased risk of metachronous lesions (SPIRML), have been associated with an increased risk of advanced colon lesions on follow-up. It is unclear, however, whether SPIRML are also associated with an increased risk of synchronous advanced colorectal neoplasia (ACN). AIM: The aim of this study was to estimate the prevalence of SPIRML and to evaluate the association between SPIRML and synchronous ACN. METHODS: A cross-sectional population-based study in all patients (1,538) with histological diagnosis of SP obtained from colonoscopies, sigmoidoscopies and colonic surgery performed in Navarra Health Service hospitals (Spain) in 2011. Demographic parameters and synchronous colonic lesions (adenomas, advanced adenomas [AA] and ACN) were analyzed. RESULTS: One fourth of the sample (384 patients) presented SPIRML. These were older patients, with a slight predominance of women, and with no differences in body mass index (BMI) compared to patients without SPIRML. In the univariate analysis, patients with SPIRML showed an increased risk of adenoma, AA and ACN. In the multivariate analysis, the SPIRML group had a higher risk of synchronous AA and ACN (odds ratio [OR]: 2.38 [1.77-3.21] and OR: 2.29 [1.72-3.05], respectively); in the case of ACN, this risk was statistically significant in both locations (proximal or distal), with OR slightly higher for the proximal location. Different subtypes of SPIRML had a higher risk of AA and synchronous NA. CONCLUSION: SPIRML were common in patients with SP, and their presence was associated with an increased risk of synchronous ACN.

[Prevalence of altered mismatch repair protein nuclear expression detected by immunohistochemistry on adenomas with high-grade dysplasia and features associated with this risk in a population-based study]. / Prevalencia de alteración de expresión nuclear de proteínas reparadoras con inmunohistoquímica sobre adenomas con displasia de alto grado y características asociadas a dicho riesgo en un estudio de base poblacional.

INTRODUCTION: Alteration of mismatch repair system protein expression detected by immunohistochemistry (IHQ) in tumoural tissue is a useful technique for Lynch Syndrome (LS) screening. A recent review proposes LS screening through immunohistochemical study not only in all diagnosed cases of colorectal cancer (CRC) but also in advanced adenomas, especially in young patients. OBJECTIVE: To assess the prevalence of altered IHQ carried out in all adenomas with high-grade dysplasia (HGD) diagnosed in our community in 2011, as well as the variables associated with this alteration. METHODS: We included all the cases of adenomatous polyps with HGD diagnosed in the three public pathology laboratories of Navarre during 2011 and performed a statistical study to assess the association between different patient and lesion characteristics and altered IHQ results. RESULTS: A total of 213 colonic adenomas with HGD were diagnosed, and 26 (12.2%) cases were excluded from the final analysis (2 known LS, 22 without IHQ study and 2 with inconclusive IHQ studies). The final number of adenomas included was 187. Pathologic results were found in 10 cases (5.35%)-6 cases in MLH1 and PMS2, 2 cases in PMS2, 1 case in MSH6 and 1 case in MSH2 and MSH6. The factors showing a statistically significant association with the presence of abnormal proteins were the synchronous presence of CRC, the presence of only one advanced adenoma, proximal location of HGD and age <50 years. CONCLUSIONS: The percentage of pathologic nuclear expression found in IHQ is high. Consequently, screening of all diagnosed HGD could be indicated, especially in young patients, with a single AA and proximal HGD.

Virgin Coconut Oil as Adjunctive Therapy for Hospitalized COVID-19 Patients in a Tertiary Referral Hospital: A Randomized Controlled Trial.

Background: Virgin coconut oil (VCO) has anti-viral and anti-inflammatory properties, making it a potential therapeutic candidate against COVID-19 infection. Objective: To determine the efficacy and safety of VCO as adjunctive therapy for hospitalized patients with COVID-19. Methods: We conducted a randomized, open-label controlled trial involving laboratory-confirmed COVID-19 patients admitted at the Philippine General Hospital. The study participants were randomized to the intervention group who received virgin coconut oil with local standard of care, or to the control group who received local standard of care alone. Results: We enrolled 39 participants into the VCO group and 38 participants into the control group. Significantly fewer participants in the VCO group had abnormal CRP levels at the end of treatment compared to control. (relative risk [RR] 0.75, 95% confidence interval [CI] 0.58 to 0.95; p=0.02) No significant difference was found in the duration of hospital stay (mean 9.33 days for VCO vs. 10.29 days for control; p=0.45) and time to symptom resolution (mean 6.8 days for VCO, vs. 6.74 days for control; p=0.91). Although the proportion of patients who developed the secondary outcomes of mortality, need for ICU admission, need for invasive ventilation, and negative viral conversion was lower in the VCO group, results did not reach statistical significance. The VCO group had larger reduction in the inflammatory markers ferritin, lactate dehydrogenase, TNF-alpha, IP-10 and IL-6, but results did not reach statistical significance. Adverse events were significantly higher in the VCO group (RR 4.87, 95% CI 1.14 to 20.79; p=0.03). Conclusion: This clinical trial on hospitalized patients showed significant benefit in CRP levels of participants given VCO compared to control. There was no significant benefit in the use of VCO as adjunctive therapy in reducing duration of hospital stay. Larger studies are needed to conclusively demonstrate the effect of VCO on other clinical outcomes and inflammatory markers.

Morphological Characterization of Nicotiana tabacum Inflorescences and Chemical-Functional Analysis of Extracts Obtained from Its Powder by Using Green Solvents (NaDESs).

The production of smokeable tobacco for use in cigarettes is characterized by the production of pre-harvest and post-harvest waste, with ensuing undesirable effects on the environment. The inflorescences of tobacco after blunting, deflowering, or topping are considered pre-harvest waste and left in the field. Using green and ecofriendly solvents such as Natural deep eutectic solvents (NaDESs), these wastes could be used to obtain antioxidant molecules of interest in cosmetics. Taking into account its potential as plant matrix to obtain metabolites of commercial interest, tobacco inflorescences and inflorescence powders of different particle sizes were characterized by optic and electronic microscopy. Thus, the powdered inflorescences were extracted with four conventional solvents, i.e., distilled water (DW), acetone: distilled water (AW), ethanol 70° (EW), methanol (Me), and five NaDESs, i.e., lactic acid: sucrose (LAS), lactic acid: sucrose: distilled water (SALA), fructose: glucose: sucrose: distilled water (FGS), choline chloride: urea: distilled water (CU), and citric acid: propylene glycol (CAP). Among the tested NADESs, SALA was the most promising solvent; higher extraction yields of total phenolic compound (3420.0 ± 9.4 µg GAE/mL) than conventional solvents were attained and it was the only selective solvent to phenolics. CU was the best solvent for flavonoids and alkaloids extraction (215.3 ± 3.2 µg QE/mL and 392.3 ± 8.0 µg ACE/mL, respectively). All extracts showed antioxidant activity. A heatmap with dendrogram and main component analysis showed that acid-based NaDESs are grouped together, this group being the one with the best performance in H2O2 scavenging. The extracts obtained with green solvents could be used directly in cosmetic formulations as antioxidant ingredients because both tobacco flower oil and flower extracts are listed in the cosmetic ingredients database as non-toxic products. Additionally, the demand for sustainable ecological cosmetics is growing. In this sense, NaDESs represent an opportunity to develop innovative extracts with unique phytochemical fingerprints and biological activities.

Gochnatia glutinosa (D.Don) D.Don ex Hook. & Arn.: A plant with medicinal value against inflammatory disorders and infections.

Gochnatia glutinosa is a shrub that grown in the Argentinean semiarid region (Monte region) used in the ancestral medicine as an antiseptic and anti-inflammatory agent. This study was aimed to examine the morpho-anatomical characteristics of G. glutinosa aerial parts, identify the chemical composition of traditionally used preparations to assess its pharmacobotanical characterization and evaluate its activity as antiseptic and anti-inflammatory to give scientific support to its traditional uses. G. glutinosa morpho-anatomical description was performed following standard histological techniques. Tincture and infusion of its aerial parts were prepared and were subjected to phytochemical analysis. Xanthine oxidase (XOD) and lipoxygenase (LOX) inhibition experiments, as well as ABTS•+, superoxide radical, and hydrogen peroxide scavenging activity, were carried out. The growth inhibition of methicillin-resistant Staphylococcus aureus (MRSA) strains was also determined. The morpho-anatomical traits of G. glutinosa leaves and stems were reported for the first time. The medicinal preparations exhibited a large amount of phenolic chemicals mainly flavonoids such as rhamnetin, arcapillin, rhamnacin, hesperetin, isorhamnetin, centaureidin, europetin 7-O-mehylmyricetin, cirsiliol, sakuranetin, genkwanin and eupatorine and also phenolic acids and diterpenoid derivatives. Both preparations had free radical scavenging activity and were able to reduce both XOD and LOX activity, indicating their anti-inflammatory properties. Besides, tincture was effective against all MRSA strains (MIC values ranging from 60 to 240 g DW/mL). The results obtained in this work scientifically support the medicinal popular use of G. glutinosa as an antiseptic and anti-inflammatory. The identification of bioactive compounds and their morpho-anatomical description contribute to the quality control of this medicinal plant from Argentine Calchaquí Valley.

Effect of receiving a customizable brochure on breast cancer patients' knowledge about their diagnosis and treatment: A randomized clinical trial.

BACKGROUND: Patients' lack of knowledge about their own disease may function as a barrier to shared decision-making and well-being. This study aimed to evaluate the impact of written educational materials on breast cancer patients. METHODS: This multicenter, parallel, unblinded, randomized trial included Latin American women aged ≥18 years with a recent breast cancer diagnosis yet to start systemic therapy. Participants underwent randomization in a 1:1 ratio to receive a customizable or standard educational brochure. The primary objective was accurate identification of molecular subtype. Secondary objectives included identification of clinical stage, treatment options, participation in decision-making, perceived quality of information received, and illness uncertainty. Follow-up occurred at 7-21 and 30-51 days post-randomization. CLINICALTRIALS: gov identifier: NCT05798312. RESULTS: One hundred sixty-five breast cancer patients with a median age of 53 years and 61 days from diagnosis were included (customizable: 82; standard: 83). At first available assessment, 52%, 48%, and 30% identified their molecular subtype, disease stage, and guideline-endorsed systemic treatment strategy, respectively. Accurate molecular subtype and stage identification were similar between groups. Per multivariate analysis, customizable brochure recipients were more likely to identify their guideline-recommended treatment modalities (OR: 4.20,p = 0.001). There were no differences between groups in the perceived quality of information received or illness uncertainty. Customizable brochure recipients reported increased participation in decision-making (p = 0.042). CONCLUSIONS: Over one third of recently diagnosed breast cancer patients are incognizant of their disease characteristics and treatment options. This study demonstrates a need to improve patient education and shows that customizable educational materials increase patients' understanding of recommended systemic therapies according to individual breast cancer characteristics.

Utility of laboratory and immune biomarkers in predicting disease progression and mortality among patients with moderate to severe COVID-19 disease at a Philippine tertiary hospital.

Purpose: This study was performed to determine the clinical biomarkers and cytokines that may be associated with disease progression and in-hospital mortality in a cohort of hospitalized patients with RT-PCR confirmed moderate to severe COVID-19 infection from October 2020 to September 2021, during the first wave of COVID-19 pandemic before the advent of vaccination. Patients and methods: Clinical profile was obtained from the medical records. Laboratory parameters (complete blood count [CBC], albumin, LDH, CRP, ferritin, D-dimer, and procalcitonin) and serum concentrations of cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-γ, IP-10, TNF-α) were measured on Days 0-3, 4-10, 11-14 and beyond Day 14 from the onset of illness. Regression analysis was done to determine the association of the clinical laboratory biomarkers and cytokines with the primary outcomes of disease progression and mortality. ROC curves were generated to determine the predictive performance of the cytokines. Results: We included 400 hospitalized patients with COVID-19 infection, 69% had severe to critical COVID-19 on admission. Disease progression occurred in 139 (35%) patients, while 18% of the total cohort died (73 out of 400). High D-dimer >1 µg/mL (RR 3.5 95%CI 1.83-6.69), elevated LDH >359.5 U/L (RR 1.85 95%CI 1.05-3.25), lymphopenia (RR 1.91 95%CI 1.14-3.19), and hypoalbuminemia (RR 2.67, 95%CI 1.05-6.78) were significantly associated with disease progression. High D-dimer (RR 3.95, 95%CI 1.62-9.61) and high LDH (RR 5.43, 95%CI 2.39-12.37) were also significantly associated with increased risk of in-hospital mortality. Nonsurvivors had significantly higher IP-10 levels at 0 to 3, 4 to 10, and 11 to 14 days from illness onset (p<0.01), IL-6 levels at 0 to 3 days of illness (p=0.03) and IL-18 levels at days 11-14 of illness (p<0.001) compared to survivors. IP-10 had the best predictive performance for disease progression at days 0-3 (AUC 0.81, 95%CI: 0.68-0.95), followed by IL-6 at 11-14 days of illness (AUC 0.67, 95%CI: 0.61-0.73). IP-10 predicted mortality at 11-14 days of illness (AUC 0.77, 95%CI: 0.70-0.84), and IL-6 beyond 14 days of illness (AUC 0.75, 95%CI: 0.68-0.82). Conclusion: Elevated D-dimer, elevated LDH, lymphopenia and hypoalbuminemia are prognostic markers of disease progression. High IP-10 and IL-6 within the 14 days of illness herald disease progression. Additionally, elevated D-dimer and LDH, high IP-10, IL-6 and IL-18 were also associated with mortality. Timely utilization of these biomarkers can guide clinical monitoring and management decisions for COVID-19 patients in the Philippines.

Pleomorphic carcinoma of the breast with expression of macrophage markers: report of two cases.

Pleomorphic ductal carcinoma of the breast is a rare variant included in the morphological group of infiltrating ductal carcinoma. The pleomorphic carcinoma is composed predominantly of epithelial and multinucleated tumor giant cells. We report here two cases presenting a lesion composed microscopically of a proliferation of large pleomorphic cells with a predominance of multinucleated giant cells. These lesions were negative for estrogen receptor, progesterone receptor and Her2-neu (triple-negative phenotype). Basal markers (cytokeratin 5/6, cytokeratin 17 and epidermal growth factor receptor [EGFR]) were present, accompanied by the presence of histiocyte marker CD163 in most neoplastic giant cells. High-grade pleomorphic breast carcinomas with the triple-negative phenotype and expression of basal markers might be included in the basal subtype. This is the first report about the co-expression of macrophage marker CD163, with tumor (P53) or epithelial markers (CAM5.2), as indicated by double immunohistochemistry in pleomorphic ductal carcinoma of the breast.

Screening of neurodevelopmental delays in four communities of Mexico and Cuba.

OBJECTIVE: Nursing personnel applied a computerized evaluation instrument, Neuropediatric Development (NPED), and compared the prevalence of deviations from normal neurodevelopment in four communities of two Latin American countries, Mexico and Cuba. At the same time the feasibility of introducing this tool into Mexican local health centers was assessed. DESIGN AND SAMPLE: The NPED screening tool was applied to 400 children 1-60 months old from two suburban and one urban communities of Mexico and one urban community of Cuba. MEASURES: The NPED instrument was developed at the Neurosciences Centre of Cuba (Santos, & Pérez-Ábalo, 2011; Santos, Pérez-Abalo, & Álvarez, 2007), and explores three neurodevelopmental areas: language/communication, psychomotor, and sensory maturation (hearing/vision). RESULTS: Global (21.5%), language (16.5%), psychomotor (5.8%), and sensory (vision/audition; 2.3%/7%) failures were observed. Among Mexican communities, apart from the hearing test in which the urban community showed a significantly higher percentage of failures (p < .001), there were no other significant differences. When compared, the Cuban community showed a significantly higher proportion of audition failures in relation to the Mexican communities. CONCLUSIONS: The prevalence of deviations from normal neurodevelopment was highly similar between both countries, and the NPED system fulfils the necessary requisites for mass screening to be applied by nursing staff at a primary care level.

Clinical characteristics of patients with asymptomatic and symptomatic COVID-19 admitted to a tertiary referral centre in the Philippines.

Objectives: To describe the clinical profile and outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) across the spectrum of disease severity. Methods: This retrospective study included adult patients with confirmed COVID-19 infection admitted to a referral hospital. Descriptive statistics, tests for trend, Kaplan-Meier curve and log-rank test were used to compare characteristics and outcomes across disease severity categories. Results: Of 1500 patients with COVID-19, 14.8% were asymptomatic, 13.5% had mild disease, 36.6% had moderate disease, 12.3% had severe disease and 22.7% had critical disease. Asymptomatic patients were admitted for a concurrent condition or for isolation. Patients aged >60 years, male gender and with co-morbidities had more severe disease. Fever, cough, shortness of breath, malaise, gastrointestinal symptoms and decreased sensorium were more common in patients with severe disease. Bilateral pulmonary infiltrates were common (51.1%), with sicker patients having more abnormal findings. The overall mortality rate was 15.1%. Adopting a symptom-based strategy reduced the length of hospitalization from a median of 13 [interquartile range (IQR) 7-21] days to 9 (IQR 5-14) days. Conclusion: The clinical profile and outcomes for this cohort of patients with COVID-19 was consistent with published reports. Asymptomatic infection was common, and universal testing may be a valuable strategy in the correct context, given the implications for infection control. A symptom-based strategy was found to reduce the length of hospitalization considerably.

Predictors of mortality among inpatients with COVID-19 infection in a tertiary referral center in the Philippines.

Objectives: The aim of this study was to determine the predictors of mortality and describe laboratory trends among adults with confirmed COVID-19. Methods: The medical records of adult patients admitted to a referral hospital with COVID-19 were retrospectively reviewed. Demographic and clinical characteristics, and laboratory parameters, were compared between survivors and non-survivors. Predictors of mortality were determined by multivariate analysis. Mean laboratory values were plotted across illness duration. Results: Of 1215 patients, 203 (16.7%) had mild, 488 (40.2%) moderate, 183 (15.1%) severe, and 341 (28.1%) critical COVID-19 on admission. In-hospital mortality was 18.2% (0% mild, 6.1% moderate, 15.8% severe, 47.5% critical). Predictors of mortality were age ≥ 60 years, COPD, qSOFA score ≥ 2, WBC > 10 × 109/L, absolute lymphocyte count < 1000, neutrophil ≥ 70%, PaO2/FiO2 ratio ≤ 200, eGFR < 90 mL/min/1.73 m2, LDH > 600 U/L, and CRP > 12 mg/L. Non-survivors exhibited an increase in LDH and decreases in PaO2/FiO2 ratio and eGFR during the 2nd-3rd week of illness. Conclusion: The overall mortality rate was high. Predictors of mortality were similar to those of other reports globally. Marked inflammation and worsening pulmonary and renal function were evident among non-survivors by the 2nd-3rd week of illness.

Dual STAT­3 and IL­6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL­6/IL­6R/STAT­3 axis.

Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT­3, IL­6 receptor (R) and IL­6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT­3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE­1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU­145 (metastatic, castration­resistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT­3, phosphorylated STAT­3 (In­Cell Western), IL­6R, vimentin and epithelial (E­) cadherin (Western Blot). The effect of inhibition of STAT­3 (expressed constitutively in DU­145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and E­cadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL­6, C­X­C chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased E­cadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU­145 cells; addition of IL­6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL­6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT­3 inhibitor, with Tcz, an antibody against IL­6R, to target tumor cells.

Flourensia fiebrigii S.F. blake: A medicinal plant from the Argentinean highlands with potential use as anti-rheumatic and anti-inflammatory.

ETHNOPHARMACOLOGICAL RELEVANCE: Flourensia fiebrigii is a plant used in traditional medicine in the Argentine Calchaquí Valley as purgative, expectorant, anti-rheumatic and anti-inflammatory. AIM OF THE STUDY: The aim of this study was to analyze the macroscopic and microscopic characteristics of F. fiebrigii leaf and stem, the phytochemical composition of leaves ethanolic extracts and to validate its traditional use as anti-rheumatic and anti-inflammatory. MATERIALS AND METHODS: The macroscopic and microscopic description of F. fiebrigii leaf and stem was carried out. Two extracts (immersions and tinctures) from leaves were obtained. The phytochemical analysis and UHPLC-OT-MS metabolome fingerprinting of both extracts were performed. The anti-rheumatic and anti-inflammatory activities of both extracts were determined using enzymatic inhibition assays of xanthine-oxidase (XOD), secretory phospholipase A2 (sPLA2) and lipoxygenase (LOX). RESULTS: The macroscopic and micrographic characters of F. fiebrigii were described to allow the botanical characterization of the plant species. The leaves extracts showed a high level of phenolic compounds with similar chromatographic patterns. Forty-five compounds were identified based on UHPLC-OT-MS including several sesquiterpenes, chalcones, flavonoids, isoflavonoids, a lignan and phenylpropanoids phenolic acids that have been identified for the first time in this plant species. F. fiebrigii extracts were able to inhibit the XOD activity and, consequently, the formation of uric acid and reactive oxygen species, primary cause of diseases, such as gouty arthritis (IC50 values of 1.10-2.12 µg/mL). Pro-inflammatory enzymes like sPLA2 and LOX were also inhibited by F. fiebrigii extracts (IC50 values of 22.00-2.20 µg/mL) decreasing the production of inflammation mediators. CONCLUSIONS: The present work validates the traditional medicinal use of F. fiebrigii as anti-rheumatic and anti-inflammatory through the use of enzymatic assays. The presence of several chemical compounds with demonstrated anti-rheumatic and anti-inflammatory properties also supports the bioactivity of the F. fiebrigii.

A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma.

Molecular characterization of colorectal cancer has helped us understand better the biology of the disease. However, previous efforts have yet to provide significant clinical value in order to be integrated into clinical practice for patients with early-stage colon cancer (CC). The purpose of this study was to assess PD-L1, GLUT-1, e-cadherin, MUC2, CDX2, and microsatellite instability (dMMR) and to propose a risk-panel with prognostic capabilities. Biomarkers were immunohistochemically assessed through tissue microarrays in a cohort of 144 patients with stage II/III colon cancer. A biomarker panel consisting of PD-L1, GLUT-1, dMMR, and potentially CDX2 was constructed that divided patients into low, medium, and high risk of overall survival or disease-free survival (DFS) in equally sized groups. Compared with low-risk patients, medium-risk patients have almost twice the risk of death (HR = 2.10 (0.99-4.46), p = 0.054), while high-risk patients have almost four times the risk (HR = 3.79 (1.77-8.11), p = 0.001). The multivariate goodness of fit was 0.756 and was correlated with Kaplan-Meier curves (p = 0.002). Consistent results were found for DFS. This study provides a critical basis for the future development of an immunohistochemical assessment capable of discerning early-stage CC patients as a function of their prognosis. This tool may aid with treatment personalization in daily clinical practice and improve survival outcomes.

PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification.

BACKGROUND: There is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting. METHODS: Tissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: PD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26-0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001). CONCLUSIONS: Our study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.