Multidimensional insights involving electrochemical and in silico investigation into the corrosion inhibition of newly synthesized pyrazolotriazole derivatives on carbon steel in a HCl solution

Herein, the anti-corrosion of carbon steel in 1 M HCl by two newly synthesized pyrazolotriazole derivatives, namely, 6-methyl-1H-pyrazolo[5,1-c][1,2,4]triazole-7-carbonitrile (CPT) and 1-acetyl-6-methyl-1H-pyrazolo[5,1-c][1,2,4]triazole-7-carbothioamide (MPT), was studied using electrochemical, density functional theory (DFT), and molecular dynamics (MD) simulation techniques. The experimental results showed that the concentrations of inhibitors had a significant influence on their inhibition efficiencies. Potentiodynamic polarization curves indicated that the two pyrazolotriazoles were mixed-type inhibitors. DFT calculations were employed to explore the molecular activity, and MD simulations were performed to obtain the interaction energy between the inhibitor molecules and the iron surface. The findings obtained using the theoretical calculation techniques were consistent with those obtained via experiments.

Anti-corrosion of carbon steel in 1 M HCl by 6-methyl-1H-pyrazolo[5,1-c][1,2,4]triazole-7-carbonitrile and 1-acetyl-6-methyl-1H-pyrazolo[5,1-c][1,2,4]triazole-7-carbothioamide, was studied using electrochemical, DFT and molecular dynamics simulation techniques.     

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe salt wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.     

Differential capacity of T cell priming in naive donors of promiscuous CD4+ T cell epitopes of HCV NS3 and Core proteins

To understand the inter-individual and virus-independent variability of CD4+ T cell responses to HCV components, we evaluated the effect on these responses of HLA II molecules in uninfected healthy donors. Using HLA II-specific binding assays, we identified, in the Core and NS3 proteins, 21 long fragments and 24 15-mer peptides that bound to four to eight of the most preponderant HLA II molecules. We then evaluated the priming capacity of eight long promiscuous peptides in 12 HLA-unrelated healthy donors. The NS3 1250-1264 peptide primed T cells in all the naive donors, while five others were stimulating in at least half of the individuals. We also report sequences that bind to multiple HLA II molecules but are weakly immunogenic. We therefore conclude that (i) broad HLA II specificity is only a prerequisite for a peptide to be stimulating in multiple individuals, and (ii) promiscuous peptides widely differ in their capacity to prime CD4+ T cells from uninfected healthy donors. We suggest that these priming differences result from inter-individual variations in the peptide-specific T cell repertoire. Interestingly, five of the most immunogenic peptides we identified correspond to frequently targeted T cell epitopes in infected patients.     

Chemoembolization in hepatocellular carcinoma: multivariate analysis of survival prognostic factors after the first session

AIM: The aim of the study was to determine whether simple routine parameters evaluating the first session of transarterial chemoembolization (variation in alfa-fetoprotein concentration, tumor lipiodol uptake, and post-embolization syndrome) can predict survival of patients treated for hepatocellular carcinoma. METHODS: Seventy-two patients treated with transarterial chemoembolization and evaluated one month after the first sessions with CT scan were included. Transarterial chemoembolization session included hepatic arteriography, lipiodol and doxorubicin (50 mg) emulsion injection, followed by gelatin sponge embolization. The following variables were studied in univariate and multivariate analysis: 6 recorded at the first session (age, cirrhosis etiology, Child-Pugh class, tumor number, largest lesion size, and alpha-fetoprotein concentration), and 5 recorded after the first session (variation in alfa-fetoprotein concentration, tumor lipiodol uptake, post-embolization syndrome, mean interval between each session, and associated treatment). RESULTS: Mean follow-up was 22.7 months (4-106). Mean survival was 30.4 months (95% CI: 23. 3-37.5). Actuarial survival at 1, 2, 3 and 5 years was respectively 65.5%, 44%, 29.5%, and 18%. The only independent prognostic factors in multivariate analysis were the Child Pugh class and the mean interval between sessions (P<0.001 and<0.01 respectively). None of our criteria evaluating the first TACE session significantly influenced survival. CONCLUSION: The 3 parameters (variation in alpha-fetoprotein concentration, tumor lipiodol uptake and post-embolization syndrome) after the first transarterial chemoembolization did not predict survival. They could not be used to determine which patient could benefit from repeated transarterial chemoembolization sessions.     

Tim-3 mediates T cell trogocytosis to limit antitumor immunity

T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1–positive (PD-1⁺) Tim-3⁺CD8⁺ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3⁺ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen–specific CD8⁺ T cells and PD-1⁺Tim-3⁺ CD8⁺ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8⁺ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8⁺ T cells impeded the trogocytosis of CD8⁺ TILs in vivo. Trogocytosed CD8⁺ T cells presented tumor peptide–major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.     

Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690

BACKGROUND: The clinical antitumor activity of recombinant interferon alpha2b (IFNalpha2b) has been well documented in patients with advanced and high-risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNalpha2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients). METHODS: This study evaluated peripheral blood lymphocytes (PBLs) for phenotypic markers and cytotoxic functions at 1 month, 3 months, and 12 months in the HDI arm, the LDI arm, and the OBS arm and examined correlations between changes observed in PBLs or in tumors with regard to treatment dosage and disease outcome. Tumor biopsy samples were studied for response to IFNalpha2b at a range of concentrations in vitro. RESULTS: Baseline blood phenotypic and functional assays did not predict disease outcome; however, modulation of these immunologic assays by IFNalpha2b treatment was observed and was associated with IFNalpha2b dosage. Tumor cell class II major histocompatibility antigen expression (human leukocyte/lymphocyte antigen DR) and adhesion molecule expression (ICAM-1) were modulated by exposure to IFNalpha2b in a dose dependent manner. Blood natural killer (NK) cell function, T-cell function, and subset distribution were modulated early by patients in the HDI arm and later by patients in the LDI arm. None of the variables tested in these studies predicted recurrence free survival. The numbers of patients studied were smaller than may be needed to detect potentially clinically significant changes. CONCLUSIONS: These data demonstrate changes in immunologic parameters associated with IFNalpha2b treatment and dosage that may account for some of the differences in the clinical efficacy of this modality. The current results also suggest the need for further study of newer molecular intermediates of IFNalpha2b and T-cell response to specific antigens of melanoma.