BackgroundNo standard therapies beyond first line are established for advanced squamous cell anal carcinoma (aSCAC). Earlier preliminary data suggest activity of epidermal growth factor receptor ...(EGFR) inhibition and programmed cell death ligand (PD-(L))1 blockade in patients with previously treated disease. Aim of this study was to explore activity and safety of avelumab with/without cetuximab in patients with aSCAC.MethodsIn this open-label, non-comparative, ‘pick the winner’, multicenter randomized phase II trial (NCT03944252), patients with aSCAC progressing after one or more lines of treatment were randomized 1:1 to the anti-PD-L1 agent avelumab alone (arm A) or combined with cetuximab (arm B). Overall response rate (ORR) was the primary endpoint. With one-sided α error set at 0.05 and power of 80%, at least 4 responses out of 27 patients per arm had to be observed to declare the study positive. Secondary endpoints were progression free survival (PFS), overall survival (OS), and safety.ResultsThirty patients per arm were enrolled. Three patients in arm A and five in arm B achieved partial response: primary endpoint was reached in combination arm. ORR was 10% (95% CI 2.1 to 26.5) and 17% (95% CI 5.6 to 34.7) in arms A and B; disease control rate was 50% (95% CI 31.3 to 68.7) in arm A and 57 (95% CI 37.4–74.5) in arm B. At a median follow-up of 26.7 months (IQR 26.5–26.9), median PFS was 2.0 months (95% CI 1.8 to 4.0) in arm A and 3.9 (95% CI 2.1 to 5.6) in arm B. Median OS was 13.9 months (95% CI 7.7 to 19.4) in arm A and 7.8 (95% CI 6.2 to 11.2) in arm B. Acceptable safety profile was observed in both arms.ConclusionsCARACAS study met its primary endpoint in arm B, documenting promising activity of dual EGFR and PD-L1 blockade in aSCAC.
Methylcitric acid (MCA) analysis has been mainly utilized for the diagnosis of propionate disorders or as a second‐tier test in newborn screening, but its utility for patients monitoring still needs ...to be established. We explored the potential contribution of MCA in the long‐term management of organic acidurias. We prospectively evaluated plasma MCA and its relationship with disease biomarkers, clinical status, and disease burden in 22 patients, 13 with propionic acidemia (PA) and nine with methylmalonic acidemia (MMA) on standard treatment and/or after transplantation. Samples were collected at scheduled routine controls or during episodes of metabolic decompensation (MD), 10 patients were evaluated after transplantation (six liver, two combined liver and kidney, 2 kidney). MCA levels were higher in PA compared to MMA and its levels were not influenced by the clinical status (MD vs well state). In MMA, MCA was higher in elder patients and, along with fibroblast growth factor 21 (FGF21) and plasma methylmalonic acid, negatively correlated with GFR. In both diseases, MCA correlated with ammonia, glycine, lysine, C3, and the C3/C2, C3/C16 ratios. The disease burden showed a direct correlation with MCA and FGF21, for both diseases. All transplanted patients showed a significant reduction of MCA in comparison to baseline values, with some differences dependent on the type of transplantation. Our study provided new insights in understanding the disease pathophysiology, showing similarities between MCA and FGF21 in predicting disease burden, long‐term complications and in evaluating the impact of organ transplantation.
Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl‐CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, ...5′‐deoxy‐adenosylcobalamin. It is characterized by life‐threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte‐targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut‐type (N = 91), cblB‐type (15), and cblA‐type MMA (17), as well as from an Italian cohort of mut‐type (N = 19) and cblB‐type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1‐13C‐propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury (lipocalin‐2 LCN2). Biomarker concentrations are higher in patients with the severe mut0‐type and cblB‐type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.
The High Voltage Padova Test Facility (HVPTF) is an experimental device for investigating High Voltage Direct Current insulation in vacuum, in support of the realization of MITICA, the prototype of a ...neutral beam injector for ITER. Inside a high vacuum chamber, two stainless steel electrodes, separated by a few centimetres gap, can achieve a voltage difference up to 800 kV. During the conditioning process of the electrodes, current micro-discharges (MD) and associated X-rays are observed, along with a global increase of gas emission (H 2 and CO 2 are detected by the Residual Gas Analyser). During the last five years, different X-rays detectors have been installed on HVPTF, with the aim to investigate the physical processes behind the conditioning.In this contribution, the fine dynamics of the micro-discharge phenomenon is studied with the purpose to sketch a possible physical interpretation of this mechanism. In particular, the time evolution, during the electrode conditioning, of the MD fine dynamics seems to be related with the increasing asymmetry between the MD current peak values collected by the positive and the negative electrodes. The possible (increasing) contribution of the vacuum chamber, operating as a third electrode, is investigated, by means of a toy model: the different current contributions collected by the two electrodes are evaluated, in particular those generated by secondary electron emission. The rate between anode and cathode currents evaluated by the toy model is in good agreement with the experimental one.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a multifactorial etiology. The primary aim of this study was to estimate HCV and HBV infection prevalence in a ...cohort of SLE and Cutaneous Lupus Erythematosus (CLE). We assessed the frequency of these infections in our cohort and the possible associations with disease clinical/laboratory features and disease activity status. The prevalence of chronic HBV infection was 2.2% in the CLE group, while no HBsAg positive patients were identified in the SLE group. Conversely, the prevalence of anti-HCV positive was 2.2% in the SLE group while no anti-HCV positive patients were identified in the CLE group. We found no significant association between anti-HBc positive status and clinical manifestations or disease activity status in either group of patients. Hemodialysis resulted significantly associated with anti-HBc positivity in SLE. In the present study, we found HBsAg positivity in CLE patients but not in the Systemic form (SLE); conversely, a similar prevalence of anti-HBc antibodies in both groups was observed. A possible protective role exerted by SLE in HBV infection may be hypothesized. A higher frequency of HCV infection in SLE compared to CLE suggests a possible involvement of HCV in some SLE-related clinical and immunological features.
Abstract The ability of HCV to mutate in response to cytotoxic T lymphocyte (CTL) pressure is increasingly recognized, but the influence of such a mechanism in viral persistence and final disease ...outcome has not been ascertained. In this study, we performed a detailed longitudinal analysis of cell mediated immunity and HCV evolution in two self limiting and two chronically evolving HCV acutely infected patients, one of whom transiently controlled viremia. Aminoacid mutations in immunodominant regions of viruses were observed in all patients, although they conferred viral escape from CTL responses only in chronically infected individuals. Resurgence of viremia coincided with the replacement of the original virus quasispecies with mutant viruses that had escaped recognition by primary CD8+ T cell responses and infection persisted in the presence of variant viruses which were less efficiently recognized by preexisting and de novo induced T cell responses.
Background. A single-nucleotide polymorphism (SNP; rs12979860) near the IL28B gene has been associated with spontaneous and treatment-induced hepatitis C virus clearance. We investigated predictors ...of spontaneous disease resolution in a cohort of patients with acute hepatitis C (AHC), analyzing epidemiological, clinical and virological parameters together with IL28B.rs12979860 genotypes and cell-mediated immunity (CMI). Methods. Fifty-six symptomatic AHC patients were enrolled and followed prospectively. CMI was measured in 31 patients at multiple time points by interferon-γ enzyme-linked immunospot assay and was correlated to the IL28B.rs12979860 SNP. Results. Eighteen patients had a self-limiting AHC that was associated with female sex (P = .028), older age (P = .018), alanine aminotransferase level >1000 U/L (P = .027), total bilirubin level >7 mg/dL (P = .036), and IL28B. rs12979860 genotype CC (P = .030). In multivariate analysis, only CC genotype was independently associated with self-limiting AHC (odds ratio, 5.3; 95% confidence interval, 1.1–26.5). Patients with the CC genotype with self-limiting AHC had a stronger (P = .02) and broader (P = .013) CMI than patients with the CT genotype with chronically evolving AHC. In patients with chronically evolving disease, CC genotype was associated with a broader CMI compared to CT genotype (P = .028). A negative CMI was more frequently associated with CT genotype among persistently infected patients (P = .043) and with persistent infection among CT patients (P = .033). Conclusions. Self-limiting AHC was independently associated with CC genotype. The correlation between IL28B.rs12979860 genotypes and CMI is suggestive of a possible important role of CMI in favoring hepatitis C virus clearance in CC patients.
Cellular immune responses are induced during hepatitis C virus (HCV) infection and acute‐phase CD8+ T cells are supposed to play an important role in controlling viral replication. In chimpanzees, ...failure of CD8+ T cells to control HCV replication has been associated with acquisition of mutations in MHC class I‐restricted epitopes. In humans, although selection of escape mutations in an immunodominant CTL epitope has been recently described, the overall impact of immune escape during acute HCV infection is unclear. Here, by performing an in depth analysis of the relationship between early cellular immune responses and viral evolution in a chronically evolving HCV acutely infected individual, we demonstrate: (i) the presence of a potent and focused CD8+ T cell response against a novel epitope in the NS3 protein, (ii) the elimination of the quasi‐species harboring the original amino acid sequence within this epitope, and (iii) the selection for a virus population bearing amino acid changes at a single residue within the cytotoxic T cell epitope that strongly diminished T cell recognition. These results support the view that acute‐phase CD8+ T cell responses exert a biologically relevant pressure on HCV replication and that viruses escaping this host response could have a significant survival advantage.
Background/Aims Several studies suggest that the evolutionary rate of HVR1 sequence in acute HCV hepatitis derives from the action of a continuous immune-driven positive selection. However, these ...studies have not been performed examining the relationship between HVR1 evolution and the development of specific immunity to autologous HVR1 sequences. Methods We performed a longitudinal analysis of HVR1 sequences and specific antibodies and CD4+ T cells in ten HCV acutely infected patients with different clinical outcomes (recovery versus persistence). Results We showed that although both recovered and chronically evolving individuals developed IFN-γ+ T cells specific for Core and NS sequences, HVR1-specific CD4+ T cells were detected only in patients clearing the virus. On the contrary, all patients displayed anti-HVR1 antibodies that recognized sequences exclusively carried by autologous viruses. Measurements of genetic diversity and the number of non-synonymous per synonymous substitutions within HVR1 sequences before and after antibody appearance showed an increase of these parameters only in concomitance with the appearance of anti-HVR1 antibodies. Conclusions The evidence that anti-HVR1 antibodies favor HVR1 variant selection suggests that viral complexity in chronically infected patients could represent a virus adaptive strategy to escape the continuous selective process mediated by anti-HVR1 antibodies.
A pesquisa teve como objetivo avaliar os atributos de qualidade e de durabilidade dos ovos de duas diferentes linhagens de poedeiras, com dietas contendo aditivos artificiais ou naturais, em ...diferentes períodos de armazenamento. Foram quantificadas durante o armazenamento as variáveis perda de peso, pH da gema e albúmen, gravidade específica, índice de gema (IG) e foi realizada também classificação por peso e Unidade Haugh (UH). Os resultados foram avaliados segundo teste de Tukey (P≤0,05). As linhagens diferiram quanto à classificação extra dos ovos, com maior porcentagem para a Isa Brown. Os ovos obtidos das poedeiras Carijó apresentaram maior porcentagem de gema (Carijó 30,66 e Isa-Brown 24,55). O tempo de armazenamento fez com que a porcentagem de gema aumentasse nas duas linhagens (Carijó 30,66 tempo zero para 34,85 depois de 36 dias; e Isa- Brown de 24,55 para 27,48). As dietas com aditivos artificiais ou naturais não influenciaram a porcentagem de clara (% Clara 58,72 Controle; 59,52 Aditivo; 60,11 Urucum 1,5%; 59,43 e de gema %Gema 27,64 Controle; 27,90 Aditivo; 27,21 Urucum 1,5%; 27,66 Urucum 2%). O pH da clara diferiu entre os tratamentos no tempo inicial e aos 36 dias de armazenamento, mas o pH da gema não diferiu durante todo o armazenamento. O índice de gema diferiu nos tempos de armazenamento, mas não diferiu considerando os tratamentos. Em dietas com aditivos artificiais ou naturais, as linhagens e os tempos de armazenamento influenciam na qualidade e durabilidade dos ovos.The research has the aim of evaluating quality and durability attributes of eggs from two hens lines feed with and without natural or synthetics additives, at several storage periods. During storage, weight lost, albumen and yolk pH, specific gravity andyolk index (IG) were quantified , as well as, weight classification and Haugh Unit (HU) The results were analyzed by Tukey test (P≤0.05). Quality differences are bigger by lines and storage time and the extra classification of eggs were higher for Isa Brown. The egg of Carijó hens presented more yolk percentage (Carijó 30.66 e Isa-Brown 24.55). The storage higher increased yolk percentage (Carijó 30.66 time zero for 34.85 after 36 days; and Isa- Brown 24.55 for 27.48). Two lines diets with natural or synthetics additives didn't influence the white and yolk percentage (%white 58.72 Control; 59.52 Aditive; 60.11 Urucum 1.5%; 59.43 e de yolk and 27.64 Control; 27.90 Aditive; 27.21 Urucum 1.5%; 27.66 Urucum 2%). Clear pH differs among treatments at initial time and at 36 days of storage, but the yolk pH didn't chage during all storage. The yolk index differed in the storage time, but not at treatments. So, it's possible to concluded that diets with natural and synthetics additives, lines and storage times had influenced quality and durability attributes in the eggs.
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