Evaluation of the Abdala Vaccine: Antibody and Cellular Response to the RBD Domain of SARS-CoV-2.

Abdala is a recently released RBD protein subunit vaccine against SARS-CoV-2. A few countries, including Mexico, have adopted Abdala as a booster dose in their COVID-19 vaccination schemes. Despite that, most of the Mexican population has received full-scheme vaccination with platforms other than Abdala; little is known regarding Abdala's immunological features, such as its antibody production and T- and B-cell-specific response induction. This work aimed to study antibody production and the adaptive cellular response in the Mexican population that received the Abdala vaccine as a booster. We recruited 25 volunteers and evaluated their RBD-specific antibody production, T- and B-cell-activating profiles, and cytokine production. Our results showed that the Abdala vaccine increases the concentration of RBD IgG-specific antibodies. Regarding the cellular response, after challenging peripheral blood cultures with RBD, the plasmablast (CD19+CD27+CD38High) and transitional B-cell (CD19+CD21+CD38High) percentages increased significantly, while T cells showed an increased activated phenotype (CD3+CD4+CD25+CD69+ and CD3+CD4+CD25+HLA-DR+). Also, IL-2 and IFN-γ increased significantly in the supernatant of the RBD-stimulated cells. Our results suggest that Abdala vaccination, used as a booster, evokes antibody production and the activation of previously generated memory against the SARS-CoV-2 RBD domain.

Exogenous CFH Modulates Levels of Pro-Inflammatory Mediators to Prevent Oxidative Damage of Retinal Pigment Epithelial Cells with the At-Risk CFH Y402H Variant.

Age-related macular degeneration (AMD) is a complex, progressive degenerative retinal disease. Retinal pigment epithelial (RPE) cells play an important role in the immune defense of the eye and their dysfunction leads to the progressive irreversible degeneration of photoreceptors. Genetic factors, chronic inflammation, and oxidative stress have been implicated in AMD pathogenesis. Oxidative stress causes RPE injury, resulting in a chronic inflammatory response and cell death. The Y402H polymorphism in the complement factor H (CFH) protein is an important risk factor for AMD. However, the functional significance of CFH Y402H polymorphism remains unclear. In the present study, we investigated the role of CFH in the pro-inflammatory response using an in vitro model of oxidative stress in the RPE with the at-risk CFH Y402H variant. ARPE-19 cells with the at-risk CFH Y402H variant were highly susceptible to damage caused by oxidative stress, with increased levels of inflammatory mediators and pro-apoptotic factors that lead to cell death. Pretreatment of the ARPE-19 cell cultures with exogenous CFH prior to the induction of oxidative stress prevented damage and cell death. This protective effect may be related to the negative regulation of pro-inflammatory cytokines. CFH contributes to cell homeostasis and is required to modulate the pro-inflammatory cytokine response under oxidative stress in the ARPE-19 cells with the at-risk CFH Y402H variant.

Transcriptomic analyses of ovarian clear-cell carcinoma with concurrent endometriosis.

Introduction: Endometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are considered the precursor lesion for ovarian clear-cell carcinoma (OCCC). Methods: To explore this transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n = 4) were compared to benign endometriomas (n = 4) by bulk RNA and small-RNA sequencing. Results: Analysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P< 0.05, log2 fold-change > |1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of pathways involved in cell cycle regulation and DNA replication and downregulation of pathways involved in cytokine receptor signaling and matrisome. Comparison of pathway activation scores between the clinical samples and publicly-available datasets for OCCC cell lines revealed significant molecular similarities between OCCC with concurrent endometriosis and OVTOKO, OVISE, RMG1, OVMANA, TOV21G, IGROV1, and JHOC5 cell lines. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P< 0.05, log2 fold-change > |1|). MiR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2fold change = 4.37, P = 2.43e-18; QPCR: 8.1-fold change, P< 0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2 = 0.93). MiR-10a overexpression in vitro resulted in a significant decrease in proliferation (n = 6; P< 0.05) compared to transfection with a non-targeting control miRNA. Similarly, the cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 (n = 6; P< 0.0001). Bioinformatic analysis predicted that miR-10a-5p target genes that were downregulated in OCCC with endometriosis were involved in receptor signaling pathways, proliferation, and cell cycle progression. MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival including [SERPINE1 (3-fold downregulated; P< 0.05), CDK6 (2.4-fold downregulated; P< 0.05), and RAP2A (2-3-fold downregulated; P< 0.05)]. Discussion: These studies in OCCC suggest that miR-10a-5p is an impactful, potentially oncogenic molecule, which warrants further studies.

[Validation of a symptom scale for COVID-19 patients in ambulatory care]. / Validación de una escala de síntomas para evaluación ambulatoria en pacientes COVID-19.

Background: A symptom scale can be useful for the standardization of clinical evaluations and follow-up of COVID-19 patients in ambultaroy care. Scale development should be accompanied by an assessment of its reliablility and validity. Objective: To develop and measure the psychometric characteristics of a COVID-19 symptom scale to be answered by either healthcare personnel or adult patients in ambulatory care. Material and methods: The scale was developed by an expert panel using the Delphi method. We evaluated inter-rater reliability, where we defined a good correlation if Spearman's Rho was ≥ 0.8; test-retest, where we defined a good correlation if Spearman's Rho was ≥ 0.7; factor analysis using principal component methodology; and discriminant validity using Mann-Whitney's U test. A p < 0.05 was considered statistically significant. Results: We obtained an 8 symptom scale, each symptom is scored from 0-4, with a total minimum score of 0 and a maximum of 32 points. Inter-rater reliability was 0.995 (n = 31), test-retest showed correlation of 0.88 (n = 22), factor analysis detected 4 factors (n = 40) and discriminant capacity of healthy versus sick adults was significant (p < 0.0001, n = 60). Conclusions: We obtained a reliable and valid Spanish (from Mexico) symptom scale for COVID-19 ambulatory care, answerable by patients and health care staff.

Introducción: una escala de síntomas puede estandarizar la evaluación clínica y el seguimiento de sujetos con COVID-19 durante el cuidado ambulatorio. El desarrollo de una escala nueva debe incluir la determinación de su fiabilidad y validez. Objetivo: desarrollar y analizar las características psicométricas de una escala de síntomas de COVID-19 para ser contestada por personal de salud y por pacientes adultos en el ambiente ambulatorio. Material y métodos: la escala fue desarrollada por un panel de especialistas con el método Delphi. Se evaluó armonía entre jueces, en la cual se definió buena correlación cuando la prueba Rho de Spearman fuese ≥ 0.8; test-retest, en la cual se definió buena correlación cuando la prueba Rho de Spearman fuese ≥ 0.7; análisis factorial por el método de componentes principales, y validez discriminante mediante la prueba U de Mann-Whitney. Una p < 0.05 se consideró estadísticamente significativa. Resultados: se desarrolló una escala que evalúa 8 síntomas que se califican de 0 hasta 4, con calificación mínima total de 0 y máxima de 32 puntos. La armonía entre jueces fue de 0.995 (n = 31), el test-retest mostró una correlación de 0.88 (n = 22), se detectaron 4 factores en el análisis factorial (n = 40) y la capacidad para discriminar entre sanos y enfermos fue significativa (p < 0.0001, n = 60). Conclusiones: se desarrolló una escala de síntomas en español (de México), validada y fiable para la evaluación ambulatoria de pacientes COVID-19, que puede ser contestable por el paciente y por el personal de salud.

MicroRNA signature and integrative omics analyses define prognostic clusters and key pathways driving prognosis in patients with neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are mutationally quiet (low number of mutations/Mb), and epigenetic mechanisms drive their development and progression. We aimed at comprehensively characterising the microRNA (miRNA) profile of NENs, and exploring downstream targets and their epigenetic modulation. In total, 84 cancer-related miRNAs were analysed in 85 NEN samples from lung and gastroenteropancreatic (GEP) origin, and their prognostic value was evaluated by univariate and multivariate models. Transcriptomics (N = 63) and methylomics (N = 30) were performed to predict miRNA target genes, signalling pathways and regulatory CpG sites. Findings were validated in The Cancer Genome Atlas cohorts and in NEN cell lines. We identified a signature of eight miRNAs that stratified patients in three prognostic groups (5-year survival of 80%, 66% and 36%). Expression of the eight-miRNA gene signature correlated with 71 target genes involved in PI3K-Akt and TNFα-NF-kB signalling. Of these, 28 were associated with survival and validated in silico and in vitro. Finally, we identified five CpG sites involved in the epigenetic regulation of these eight miRNAs. In brief, we identified an 8-miRNA signature able to predict survival of patients with GEP and lung NENs, and identified genes and regulatory mechanisms driving prognosis in NEN patients.

Effector-Memory B-Lymphocytes and Follicular Helper T-Lymphocytes as Central Players in the Immune Response in Vaccinated and Nonvaccinated Populations against SARS-CoV-2.

Vaccines have been recognized as having a central role in controlling the COVID-19 pandemic; however, most vaccine development research is focused on IgG-induced antibodies. Here, we analyzed the generation of IgGs related to SARS-CoV-2 and the changes in B- and T-lymphocyte proportions following vaccination against COVID-19. We included samples from 69 volunteers inoculated with the Pfizer-BioNTech (BNT162b2), Astra Zeneca (AZD1222 Covishield), or Sputnik V (Gam-COVID-Vac) vaccines. IgGs related to SARS-CoV-2 increased after the first vaccine dose compared with the nonvaccinated group (Pfizer, p = 0.0001; Astra Zeneca, p < 0.0001; Sputnik V, p = 0.0089). The results of the flow cytometry analysis of B- and T-lymphocytes showed a higher proportion of effector-memory B-lymphocytes in both first and second doses when compared with the nonvaccinated subjects. FcRL4+ cells were increased in second-dose-vaccinated COVID-19(−) and recovered COVID-19(+) participants when compared with the nonvaccinated participants. COVID-19(−) participants showed a lower proportion of follicular helper T-lymphocytes (TFH) in the second dose when compared with the first-vaccine-dose and nonvaccinated subjects. In conclusion, after the first vaccine dose, immunization against SARS-CoV-2 induces IgG production, and this could be mediated by TFH and effector-memory B-lymphocytes. Our data can be used in the design of vaccine schedules to evaluate immuno-bridging from a cellular point of view.

Occupational Safety and Health Staging Framework for Decent Work.

The 2030 United Nations Goal 8 for sustainable development focuses on decent work. There is utility in identifying the occupational safety and health aspects of Goal 8, as they pertain to the four pillars of decent work: job creation, social protection, rights of workers, and social dialogue. A workgroup of the International Commission on Occupational Health and collaborators addressed the issue of decent work and occupational safety and health (OSH) with the objective of elaborating a framework for guidance for practitioners, researchers, employers, workers, and authorities. This article presents that framework, which is based on an examination of the literature and the perspectives of the workgroup. The framework encompasses the intersection of the pillars of decent (employment creation, social protection, rights of workers, and social dialogue) work with new and emerging hazards and risks related to various selected determinants: new technologies and new forms of work; demographics (aging and gender); globalization; informal work; migration; pandemics; and OSH policies and climate change. The OSH field will need an expanded focus to address the future of decent work. This focus should incorporate the needs of workers and workforces in terms of their well-being. The framework identifies a starting point for the OSH community to begin to promote decent work.

Perioperative Chemotherapy for Liver Metastasis of Colorectal Cancer: Lessons Learned and Future Perspectives.

OPINION STATEMENT: Colorectal cancer (CRC) is a major public health problem and the 2nd leading-cause of cancer-related death worldwide. Around 30% of patients present with metastatic disease and 50% of those with early disease will eventually relapse. The metastatic spread occurs mainly to the liver, which is the exclusive site in 30-40% of the cases. Surgery is the main curative option for liver recurrence, but only one out of five patients are eligible for resection. Moreover, even if surgery is feasible, recurrence rate is high, occurring in up to 75% of patients. Therefore, additional treatment to improve these disappointing outcomes has been sought. Adjuvant and perioperative chemotherapy aim to eradicate early micrometastatic disease, decreasing recurrence rates, and improving survival outcomes. Different chemotherapy regimens, mainly extrapolated from the adjuvant experience, have showed conflicting results, with improvements in disease free but not in overall survival. The addition of targeted therapies to chemotherapy has improved response rates and resectability when administered preoperatively, but did not have an impact on survival in the adjuvant setting. There is a need to critically synthetize the available evidence on perioperative and conversion therapy from the past years, and appraise areas of current research and potential future directions.

Kinetic Changes in B7 Costimulatory Molecules and IRF4 Expression in Human Dendritic Cells during LPS Exposure.

A key aspect of the inflammatory phenomenon is the involvement of costimulatory molecules expressed by antigen-presenting cells (APCs) and their ability to secrete cytokines to set instructions for an adaptive immune response and to generate tolerance or inflammation. In a novel integrative approach, we aimed to evaluate the kinetic expression of the membrane and soluble B7 costimulatory molecules CD86, ICOS-L, PDL1, PDL2, the transcription factor Interferon Regulatory Factor 4 (IRF4), and the cytokines produced by monocyte-derived dendritic cells (Mo-DCs) after challenging them with different concentrations of stimulation with E. coli lipopolysaccharide (LPS) for different lengths of time. Our results showed that the stimuli concentration and time of exposure to an antigen are key factors in modulating the dynamic expression pattern of membrane and soluble B7 molecules and cytokines.

COVID-19 vaccination coverage and vaccine hesitancy among people with opioid use disorder in Barcelona, Spain.

INTRODUCTION: People with substance use disorders are considered a priority group for SARS-CoV-2 vaccination as they are at elevated risk of COVID-19 and its severe complications. However, data are scarce about vaccination coverage in a real-world setting. METHODS: A descriptive study was conducted in people with opioid use disorder (OUD) from three public centres for outpatient drug addiction treatment in Barcelona, Spain, who received brief medical advice and were referred to vaccination clinic sites. RESULTS: Three hundred and sixty-two individuals were included: 277 (77%) were men with a mean age of 48.1 ± 8.9 years and 77% were Spanish. Most (90%) participants engaged in polysubstance use and all individuals were on opioid agonist therapy. Psychiatric comorbidity was present in 56% subjects and 32% individuals had ≥1 chronic disease, 30% had HIV and 13% hepatitis C. There were 258 fully vaccinated individuals (71%; 95% confidence interval [CI] 67, 76). Age (odds ratio [OR] 1.04; 95% CI 1.01, 1.08; P < 0.01) and Charlson Comorbidity Index (OR 1.67; 95% CI 1.11, 2.5; P < 0.01) were associated with full vaccination. The vaccination hesitancy causes cited were complacency (53, 51%), convenience (40, 39%) and confidence (11, 10%). DISCUSSION AND CONCLUSIONS: More than two-thirds of our sample of people with OUD were fully vaccinated. Complacency and convenience represented a significant barrier to complete vaccination among people with OUD on opioid agonist therapy referred to vaccination clinic sites. Additional measures are necessary to increase vaccination, especially for younger individuals and those with less medical comorbidity. Integrating vaccination services in drug outpatient centres could be a useful alternative.

Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors.

BACKGROUND: VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. METHODS: Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×1013 viral particles (vp)/patient (Part I), and 3.3×1012 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×1013 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×1013 vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×1013 vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. CONCLUSIONS: Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma. TRIAL REGISTRATION NUMBER: NCT02045602.

SARS-CoV-2 Seroprevalence among the Health Care Staff of an Ophthalmological Reference Centre, a Cross Sectional Study.

PURPOSE: During the COVID-19 pandemic, healthcare workers (HCWs) are at a considerable risk of being infected with SARS-CoV-2; among them, HCWs from ophthalmology departments are more prone to develop severe symptoms. In Mexico City, the prevalence of SARS-CoV-2 infection among HCWs is 30%. The present work aims to describe the seroprevalence among HCWs at an Ophthalmological Reference Centre in Mexico City. METHODS: A self-report questionnaire, RT-PCR test and detection of serum IgG/IgM antibodies against SARS-CoV-2 were performed among HCWs at the Institute of Ophthalmology "Conde de Valenciana". RESULTS: A total of 169 HCWs participated in the study. None of the participants declared severe symptoms, and only 15% showed three or more symptoms. The results showed that 32% of the participants were RT-PCR+ (54/169), and 20% (35/169) presented IgG antibodies against SARS-CoV-2. Thirteen percent of the RT-PCR+ subjects were IgG positive, and 7.6% of the RT-PCR- participants were IgG positive. The presence of three or more symptoms correlated with the presence of IgG antibodies, as well as Ct values of < 32 (p < 0,05). CONCLUSION: Most of the HCW cohort showed mild symptoms, and 69% of the RT-PCR+ participants did not show IgG antibodies against SARS-CoV-2. Seroprevalence was significantly associated with the presentation of COVID-19-associated symptoms.

Development and Evaluation of a Set of Spike and Receptor Binding Domain-Based Enzyme-Linked Immunosorbent Assays for SARS-CoV-2 Serological Testing.

The implementation and validation of anti-SARS-CoV-2 IgG serological assays are reported in this paper. S1 and RBD proteins were used to coat ELISA plates, and several secondary antibodies served as reporters. The assays were initially validated with 50 RT-PCR positive COVID-19 sera, which showed high IgG titers of mainly IgG1 isotype, followed by IgG3. Low or no IgG2 and IgG4 titers were detected. Then, the RBD/IgG assay was further validated with 887 serum samples from RT-PCR positive COVID-19 individuals collected at different times, including 7, 14, 21, and 40 days after the onset of symptoms. Most of the sera were IgG positive at day 40, with seroconversion happening after 14-21 days. A third party conducted an additional performance test of the RBD/IgG assay with 406 sera, including 149 RT-PCR positive COVID-19 samples, 229 RT-PCR negative COVID-19 individuals, and 28 sera from individuals with other viral infections not related to SARS-CoV-2. The sensitivity of the assay was 99.33%, with a specificity of 97.82%. All the sera collected from individuals with infectious diseases other than COVID-19 were negative. Given the robustness of this RBD/IgG assay, it received approval from the sanitary authority in Mexico (COFEPRIS) for production and commercialization under the name UDISTEST-V2G®.

Single-step genomic prediction of Eucalyptus dunnii using different identity-by-descent and identity-by-state relationship matrices.

Genomic selection based on the single-step genomic best linear unbiased prediction (ssGBLUP) approach is becoming an important tool in forest tree breeding. The quality of the variance components and the predictive ability of the estimated breeding values (GEBV) depends on how well marker-based genomic relationships describe the actual genetic relationships at unobserved causal loci. We investigated the performance of GEBV obtained when fitting models with genomic covariance matrices based on two identity-by-descent (IBD) and two identity-by-state (IBS) relationship measures. Multiple-trait multiple-site ssGBLUP models were fitted to diameter and stem straightness in five open-pollinated progeny trials of Eucalyptus dunnii, genotyped using the EUChip60K. We also fitted the conventional ABLUP model with a pedigree-based covariance matrix. Estimated relationships from the IBD estimators displayed consistently lower standard deviations than those from the IBS approaches. Although ssGBLUP based in IBS estimators resulted in higher trait-site heritabilities, the gain in accuracy of the relationships using IBD estimators has resulted in higher predictive ability and lower bias of GEBV, especially for low-heritability trait-site. ssGBLUP based on IBS and IBD approaches performed considerably better than the traditional ABLUP. In summary, our results advocate the use of the ssGBLUP approach jointly with the IBD relationship matrix in open-pollinated forest tree evaluation.

Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance.

PURPOSE: High-throughput "-omic" technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. METHODS: Plasma samples from 77 NETs and 68 controls were profiled by GC-MS, CE-MS and LC-MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. RESULTS: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. CONCLUSIONS: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

Design of carbon supports for metal-catalyzed acetylene hydrochlorination.

For decades, carbons have been the support of choice in acetylene hydrochlorination, a key industrial process for polyvinyl chloride manufacture. However, no unequivocal design criteria could be established to date, due to the complex interplay between the carbon host and the metal nanostructure. Herein, we disentangle the roles of carbon in determining activity and stability of platinum-, ruthenium-, and gold-based hydrochlorination catalysts and derive descriptors for optimal host design, by systematically varying the porous properties and surface functionalization of carbon, while preserving the active metal sites. The acetylene adsorption capacity is identified as central activity descriptor, while the density of acidic oxygen sites determines the coking tendency and thus catalyst stability. With this understanding, a platinum single-atom catalyst is developed with stable catalytic performance under two-fold accelerated deactivation conditions compared to the state-of-the-art system, marking a step ahead towards sustainable PVC production.

Chemotherapy in NEN: still has a role?

Neuroendocrine neoplasms (NENs) comprise a broad spectrum of tumors with widely variable biological and clinical behavior. Primary tumor site, extent of disease, tumor differentiation and expression of so matostatin receptors, proliferation and growth rates are the major prognostic factors that determine the therapeutic strategy. Treatment options for advanced disease have considerably expanded in recent years, particularly for well differentiated tumors (NETs). Novel drugs approved over the past decade in this context include somatostatin analogues and 177Lu-oxodotreotide for somatostatin-receptor-positive gastroenteropancreatic (GEP) NETs, sunitinib for pancreatic NETs (P-NETs), and everolimus for P-NETs and non-functioning lung or gastrointestinal NETs. Nevertheless, chemotherapy remains an essential component of the treatment armamentarium of patients with NENs, particularly of patients with P-NETs or those with bulky, symptomatic or rapidly progressive tumors (generally G3 or high-G2 NENs). In this manuscript we will comprehensively review available evidence related to the use of chemotherapy in lung and GEP NENs and will critically discuss its role in the treatment algorithm of this family of neoplasms.

Poor Survival in COVID-19 Associated with Lymphopenia and Higher Neutrophile-Lymphocyte Ratio.

BACKGROUND: Immune cell counts in blood in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be useful prognostic biomarkers of disease severity, mortality, and response to treatment. OBJECTIVES: To analyze sub-populations of lymphocytes at hospital admission in survivors and deceased from severe pneumonia due to coronavirus disease-2019 (COVID-19). METHODS: We conducted a cross-sectional study of healthcare workers confirmed with SARS-CoV-2 in convalescents (control group) and healthy controls (HC) diagnosed with severe COVID-19. Serum samples were taken at hospital admission and after recovery. Serum samples ≥ 25 days after onset of symptoms were analyzed for lymphocyte subpopulations through flow cytometry. Descriptive statistics, Kruskall-Wallis test, receiver operating characteristic curve, calculation of sensitivity, specificity, predictive values, and Kaplan-Meier analysis were performed. RESULTS: We included 337 patients: 120 HC, 127 convalescents, and 90 severe COVID-19 disease patients (50 survivors, 40 deceased). For T cells, total lymphocytes ≥ 800/µL, CD3+ ≥ 400/µL, CD4+ ≥ 180/µL, CD8+ ≥ 150/µL, B cells CD19+ ≥ 80/µL, and NK ≥ 34/µL subsets were associated with survival in severe COVID-19 disease patients. All subtypes of lymphocytes had higher concentrations in survivors than deceased, but similar between HC and convalescents. Leukocytes ≥ 10.150/µL or neutrophils ≥ 10,000/µL were associated with increased mortality. The neutrophil-to-lymphocyte ratio (NLR) ≥ 8.5 increased the probability of death in severe COVID-19 (odds ratio 11.68). CONCLUSIONS: Total lymphocytes; NLR; and levels of CD3+, CD4+, CD8+, and NK cells are useful as biomarkers of survival or mortality in severe COVID-19 disease and commonly reach normal levels in convalescents.

Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials.

Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel-Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59-2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71-0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3-4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.