Utility of Thymosin ?-1 (Zadaxin?) as a co-adjuvant in influenza vaccines: a review

Influenza constitutes a serious problem for healthcare and social services worldwide, owing to its pattern and the severity of its complications in some categories of subjects at risk, such as the elderly and immunocompromised individuals. The only really effective means of combating influenza is vaccination. The elderly and immunocompromised subjects are refractory or low responders to vaccination. The need for ever more immunogenic and efficacious influenza vaccines, especially for subjects at risk, has prompted the development of adjuvated vaccines. With a view to enhancing the immune response in the elderly and in subjects at risk, the possibility of co-administering immunostimulants as Thymosin ?-1 (T?1) with influenza vaccines has been investigated. T?1 is a biologically active peptide made up of 28 amino acids that can enhance T-cells, dendritic cell and antibody responses, modulate cytokines and chemokines production. Several studies were conducted and showed that T?1 ameliorate the performance of influenza vaccination in elderly and subjects at risk. Although further studies on co-adjuvants are necessary, the future prospects of producing ever more efficacious influenza vaccines appear very promising

END-DIALYSIS OVERWEIGHT AND CHRONIC INFLAMMATION. A DANGEROUS CONNECTION

INTRODUCTION AND AIMS: Attaining dry body weight is paramount in dialysis practice, but this goal is not always reached. We hypothesized that the amount of enddialysis overweight (edOW), could be associated to increased chronic inflammation and mortality. Aim of the study: to evaluate the effect of edOW on serum C-reattive protein(hsCRP) concentrations and on survival in a cohort of 182 prevalent HD patients (pts) followed for 36 months. METHODS: In 182 pts (117 men, age 65612 years, vintage 48 months; range 6-336), edOW was present in 98/182 (54%) pts. Mean value was 0.460.2 Kg (range: 0.1-1.4). In the 98 pts with edOW (Group 1) and in the other 84 (Group 2) we evaluated: Ultrafiltration rate(UFR), hsCRPdry body weight (dBW), Kt/V, protein catabolic rate (PCRn), interdialytic weight gain (IDWG), mean arterial pressure (MAP). Unpaired Student’s t test was employed to compare groups, linear regression analysis to test correlations, log-rank test and Kaplan-Meier curves to evaluate survival. RESULTS: Mean UFR was 11.762.8 ml/Kg/hour, dBW 64612 Kg, hsCRP 6.6 (0.2-36) mg/L, Kt/V 1.2760.09, PCRn 1.0660.10 g/Kg/day, IDWG 2.860.4 Kg, MAP 9766.5 mmHg. edOW and hsCRP were directly and significantly correlated (r= 0.67; p<0.0001). Comparison between pts with (Group 1) and without (Group 2) edOW showed significant differences in: UFR (12.762.6 vs 10.962.6 ml/Kg/hour; p< 0.0001), hsCRP (13.068.1 vs 5.265.3 mg/L; p< 0.0001), and PCRn (1.0360.09 vs 1.0860.10 g/Kg/day; p<0.004). 98 pts (54%) died during follow-up for cardiovascular complications in 69% of cases. Survival curves showed significantly greater mortality in Group 1 vs Group 2 in relation to the amount of edOW, and hsCRP (p<0.0001). CONCLUSIONS: : edOW and chronic inflammation are directly correlated in HD pts, and both are associated to a greater long-term risk of mortality

A Dominant, Recombination-Defective Allele of Dmc1 Causing Male-Specific Sterility

DMC1 is a meiosis-specific homolog of bacterial RecA and eukaryotic RAD51 that can catalyze homologous DNA strand invasion and D-loop formation in vitro. DMC1-deficient mice and yeast are sterile due to defective meiotic recombination and chromosome synapsis. The authors identified a male dominant sterile allele of Dmc1, Dmc1(Mei11), encoding a missense mutation in the L2 DNA binding domain that abolishes strand invasion activity. Meiosis in male heterozygotes arrests in pachynema, characterized by incomplete chromosome synapsis and no crossing-over. Young heterozygous females have normal litter sizes despite having a decreased oocyte pool, a high incidence of meiosis I abnormalities, and susceptibility to premature ovarian failure. Dmc1(Mei11) exposes a sex difference in recombination in that a significant portion of female oocytes can compensate for DMC1 deficiency to undergo crossing-over and complete gametogenesis. Importantly, these data demonstrate that dominant alleles of meiosis genes can arise and propagate in populations, causing infertility and other reproductive consequences due to meiotic prophase I defects

SCALA – Sistema de Comunicação Alternativa para Letramento de Pessoas com Autismo: implementação de um sistema de busca avançada

O trabalho em questão objetiva descrever sobre o processo de desenvolvimento de um sistema de busca avançada por pictogramas, através de palavras-chave e elementos de seleção para o sistema SCALAWEB. Ao longo do texto são abordados exemplos e conceituações de tecnologias assistivas de comunicação alternativa, uma síntese sobre o sistema SCALAWEB e seus objetivos, as tecnologias e ferramentas utilizadas na implementação do sistema avançado de busca proposta para o mesmo. Ainda, são especificados o projeto, desenvolvimento e integração do sistema de busca avançada no SCALAWEB, sua forma de funcionamento, características, arquitetura e contexto de uso dentro das tecnologias assistivas, em especial ao TEA (Transtorno do Espectro Autista). Por fim, os resultados preliminares e trabalhos futuros são expostos, bem como as conclusões acerca do artigo.Área: Tecnología en Educación.Red de Universidades con Carreras en Informática (RedUNCI

SCALA – Sistema de Comunicação Alternativa para Letramento de Pessoas com Autismo: implementação de um sistema de busca avançada

O trabalho em questão objetiva descrever sobre o processo de desenvolvimento de um sistema de busca avançada por pictogramas, através de palavras-chave e elementos de seleção para o sistema SCALAWEB. Ao longo do texto são abordados exemplos e conceituações de tecnologias assistivas de comunicação alternativa, uma síntese sobre o sistema SCALAWEB e seus objetivos, as tecnologias e ferramentas utilizadas na implementação do sistema avançado de busca proposta para o mesmo. Ainda, são especificados o projeto, desenvolvimento e integração do sistema de busca avançada no SCALAWEB, sua forma de funcionamento, características, arquitetura e contexto de uso dentro das tecnologias assistivas, em especial ao TEA (Transtorno do Espectro Autista). Por fim, os resultados preliminares e trabalhos futuros são expostos, bem como as conclusões acerca do artigo.Área: Tecnología en Educación.Red de Universidades con Carreras en Informática (RedUNCI

SCALA – Sistema de Comunicação Alternativa para Letramento de Pessoas com Autismo: implementação de um sistema de busca avançada

O trabalho em questão objetiva descrever sobre o processo de desenvolvimento de um sistema de busca avançada por pictogramas, através de palavras-chave e elementos de seleção para o sistema SCALAWEB. Ao longo do texto são abordados exemplos e conceituações de tecnologias assistivas de comunicação alternativa, uma síntese sobre o sistema SCALAWEB e seus objetivos, as tecnologias e ferramentas utilizadas na implementação do sistema avançado de busca proposta para o mesmo. Ainda, são especificados o projeto, desenvolvimento e integração do sistema de busca avançada no SCALAWEB, sua forma de funcionamento, características, arquitetura e contexto de uso dentro das tecnologias assistivas, em especial ao TEA (Transtorno do Espectro Autista). Por fim, os resultados preliminares e trabalhos futuros são expostos, bem como as conclusões acerca do artigo.Área: Tecnología en Educación.Red de Universidades con Carreras en Informática (RedUNCI

Human Tumor-Derived Heat Shock Protein 96 Mediates In Vitro Activation and In Vivo Expansion of Melanoma- and Colon Carcinoma-Specific T Cells

Abstract Heat shock proteins (hsp) 96 play an essential role in protein metabolism and exert stimulatory activities on innate and adaptive immunity. Vaccination with tumor-derived hsp96 induces CD8+ T cell-mediated tumor regressions in different animal models. In this study, we show that hsp96 purified from human melanoma or colon carcinoma activate tumor- and Ag-specific T cells in vitro and expand them in vivo. HLA-A*0201-restricted CD8+ T cells recognizing Ags expressed in human melanoma (melanoma Ag recognized by T cell-1 (MART-1)/melanoma Ag A (Melan-A)) or colon carcinoma (carcinoembryonic Ag (CEA)/epithelial cell adhesion molecule (EpCAM)) were triggered to release IFN-γ and to mediate cytotoxic activity by HLA-A*0201-matched APCs pulsed with hsp96 purified from tumor cells expressing the relevant Ag. Such activation occurred in class I HLA-restricted fashion and appeared to be significantly higher than that achieved by direct peptide loading. Immunization with autologous tumor-derived hsp96 induced a significant increase in the recognition of MART-1/Melan-A27–35 in three of five HLA-A*0201 melanoma patients, and of CEA571–579 and EpCAM263–271 in two of five HLA-A*0201 colon carcinoma patients, respectively, as detected by ELISPOT and HLA/tetramer staining. These increments in Ag-specific T cell responses were associated with a favorable disease course after hsp96 vaccination. Altogether, these data provide evidence that hsp96 derived from human tumors can present antigenic peptides to CD8+ T cells and activate them both in vitro and in vivo, thus representing an important tool for vaccination in cancer patients

Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases

Purpose: Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases. Patients and methods: This phase III study recruited patients 18 years of age and older with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS). Results: From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; P = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; P = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; P = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths. Conclusions: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases

Nivolumab plus ipilimumab in melanoma patients with asymptomatic brain metastases: 7-year outcomes and quality of life from the multicenter phase III NIBIT-M2 trial

Background: The primary analysis of the phase III NIBIT-M2 study showed a 41% 4-year overall survival (OS) of melanoma patients with asymptomatic brain metastases treated with ipilimumab plus nivolumab. Methods: Here, we report the 7-year efficacy outcomes and the Health-Related Quality of Life (HRQoL) analyses of the NIBIT-M2 study. Results: As of May 1, 2023, at a median follow-up of 67 months (mo), the median OS was 8.5 (95% CI: 6.6-10.3), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-69.9) mo for the fotemustine (F) Arm A, ipilimumab plus fotemustine Arm B, and ipilimumab plus nivolumab Arm C, respectively. The 7-year OS rate was 10.0% (95% CI: 0-22.5) in Arm A, 10.3% (95% CI: 0-22.6) in Arm B, and 42.8% (95% CI: 23.4-62.2) in Arm C. HRQoL was preserved in all treatment arms. Most functional scales evaluated from baseline to W12 were preserved, with a lower mean score decrease for EORTC Quality of Life Questionnaire (QLQ)-C30 and an increase for EORTC QLQBrain neoplasm (BN20) in patients receiving ipilimumab plus nivolumab. Conclusions: With the longest follow-up available to date in melanoma patients with asymptomatic brain metastases, the NIBIT-M2 study continues to show persistent therapeutic efficacy of I ipilimumab plus nivolumab while preserving HRQoL

CHRONIC INFLAMMATION AND END-DIALYSIS OVERWEIGHT. A 36 MONTH PROSPECTIVE OBSERVATIONAL STUDY

Introduction and Aims: Attaining dry body weight is paramount in dialysis practice, but this goal is not always reached.We hypothesized that the amount of end-dialysis overweight (edOW), could be associated to increased chronic inflammation and mortality. Aim of the study: to evaluate the effect of edOWon serum C-reattive protein (hsCRP) concentrations and on survival in a cohort of 182 prevalent HD patients ( pts) followed for 36 months. Methods: In 182 pts (117 men, age 65±12 years, vintage 48 months; range 6-336), edOWwas present in 98/182 (54%) pts. Mean value was 0.4±0.2 Kg (range: 0.1-1.4). In the 98 pts with edOW(Group 1) and in the other 84 (Group 2) we evaluated: Ultrafiltration rate(UFR), hsCRPdry body weight (dBW), Kt/V, protein catabolic rate (PCRn), interdialytic weight gain (IDWG), mean arterial pressure (MAP). Unpaired Student’s t test was employed to compare groups, linear regression analysis to test correlations, log-rank test and Kaplan-Meier curves to evaluate survival. Results: Mean UFR was 11.7±2.8 ml/Kg/hour, dBW 64±12 Kg, hsCRP 6.6 (0.2-36) mg/L, Kt/V 1.27±0.09, PCRn 1.06±0.10 g/Kg/day, IDWG 2.8±0.4 Kg, MAP 97±6.5 mmHg. edOWand hsCRP were directly and significantly correlated (r= 0.67; p<0.0001). Comparison between pts with (Group 1) and without (Group 2) edOW showed significant differences in: UFR (12.7±2.6 vs 10.9±2.6 ml/Kg/hour; p< 0.0001), hsCRP (13.0±8.1 vs 5.2±5.3 mg/L; p< 0.0001), and PCRn (1.03±0.09 vs 1.08±0.10 g/Kg/day; p<0.004). 98 pts (54%) died during follow-up for cardiovascular complications in 69% of cases. Survival curves showed significantly greater mortality in Group 1 vs Group 2 in relation to the amount of edOW, and hsCRP (p<0.0001). Conclusions: edOWand chronic inflammation are directly correlated in HD pts, and both are associated to a greater long-term risk of mortality