Effect of initial periodontal therapy on metallothionein levels in smokers and non-smokers with periodontitis.

The aim of this study was to determine the effect of non-surgical periodontal therapy (NSPT) on mRNA expression of metallothionein (MT) and its levels in serum, saliva and gingival crevicular fluid (GCF) of smokers (S) and non-smokers (NS) with periodontitis (P).A total of 100 participants were included: 48 periodontally healthy (PH) subjects (24 S [PH + S] and 24 NS [PH + NS]) and 52 patients with P (27 S [P + S] and 25 NS [P + NS]). Clinical parameters were recorded, and biofluids (serum, saliva and GCF) and gingival tissue samples were obtained at baseline in all groups and 3 months after NSPT in P groups. MT levels in biofluids were determined by ELISA. In gingival tissues, MT-mRNA expression was quantified using real-time PCR. mRNA expression of MT and its levels in biofluids were significantly higher in P + S compared to other groups, and the differences between P + NS and PH + S were non-significant. A significant decrease was observed for MT levels in biofluids, and MT-mRNA expression in periodontitis patients after NSPT. In conclusion, smoking and periodontitis are associated with higher MT expression which decreases after NSPT. MT as an oxidative stress biomarker and its therapeutic role in periodontitis should be investigated in future studies.Clinical trial registration: The study was prospectively registered at Clinical Trials Registry-India (ctri.nic.in) as CTRI/2018/08/015427 on August 23, 2018.

PD-L1 expression in rare and aggressive thyroid cancers: A preliminary investigation for a role of immunotherapy.

Background and Aim: Programmed cell death ligand-1 (PD-L1) immunoexpression status determines the response to immunotherapy in many cancers. Limited data exist on PD-L1 status in aggressive thyroid tumors. We investigated PD-L1 expression across thyroid cancers and correlated it with their molecular profile. Materials and Methods: Sixty-five cases of differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) were assessed for PD-L1 expression (clone SP263, VENTANA). The differentiated cases encompassed the aggressive hobnail and tall cell subtypes of papillary thyroid carcinoma (PTC) besides classical PTC and follicular thyroid carcinoma (FTC). Ten nodular goiters (NG) were also evaluated. Tumor proportion score (TPS) and H-score were calculated. BRAFV600E and H-/K-/N-RAS were assessed using allele-specific real-time polymerase chain reaction (PCR). Fisher's exact and Kruskal-Wallis tests were used to investigate the associations between the categorical variables and compare PD-L1 scores with the mutation status. Results: Most PTC (87%) and ATC (73%) cases were PD-L1 positive (TPS ≥1%), with significantly higher positivity rates than NG (20%). TPS >50% was seen in 60% ATC and 7% PTC cases. The median TPS and H-score of ATC were 56 (0-96.6) and 168 (0-275), respectively, and of PTC were 9.6 (4-16.8) and 17.8 (6.6-38.6), respectively. The scores were similar across the PTC subtypes. Only one case each of FTC and PDTC was PD-L1 positive. PD-L1 expression correlated significantly with BRAFV600E, but not with RAS mutation. Conclusions: ATC showed intense and diffuse PD-L1 staining. Although most PTCs were PD-L1 positive, the expression was weaker and patchy, irrespective of the histological subtype. Results of this pilot study indicate that ATC is most likely to respond to immunotherapy. PTC, FTC, and PDTC may be less amenable to immunotherapy. PD-L1 expression correlated significantly with BRAFV600E, allowing for combined targeted therapy.

Cross-neutralization of SARS-CoV-2 by HIV-1 specific broadly neutralizing antibodies and polyclonal plasma.

Cross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical features such as extensive somatic hypermutations, long complementary determining region (CDR) lengths, tyrosine sulfation and presence of insertions/deletions, enabling them to effectively neutralize diverse HIV-1 viruses despite extensive variations within the core epitopes they recognize. As some of the HIV-1 bnAbs have evolved to recognize the dense viral glycans and cross-reactive epitopes (CREs), we assessed if these bnAbs cross-react with SARS-CoV-2. Several HIV-1 bnAbs showed cross-reactivity with SARS-CoV-2 while one HIV-1 CD4 binding site bnAb, N6, neutralized SARS-CoV-2. Furthermore, neutralizing plasma antibodies of chronically HIV-1 infected children showed cross neutralizing activity against SARS-CoV-2 pseudoviruses. Collectively, our observations suggest that human monoclonal antibodies tolerating extensive epitope variability can be leveraged to neutralize pathogens with related antigenic profile.

Spatio-temporal patterns and factors controlling the hydrogeochemistry of the river Jhelum basin, Kashmir Himalaya.

River Jhelum is a major source of water for growing population and irrigation in the Kashmir Himalaya. The region is trending towards water scarcity as well as quality deterioration stage due to its highly unregulated development. The existence of few literature on various aspects of the basin prompts us to study the spatio-temporal variability of its physicochemical parameters and thereby to understand the regulating hydrogeochemical mechanisms based on 50 samples collected during high flow (June 2008) and low flow (January 2009) periods. The water chemistry exhibited significant spatial variability reflecting the mixing processes in the basin. The seasonal effect does change the concentration of ions significantly with modest variability in the order of ionic abundance. The Ca(2+) ion among cations and HCO3 (-) ion among anions dominate the ionic budget and correlates significantly with the diverse lithology of the basin. Three major water types, i.e., Ca-Mg-HCO3 (72 %), Ca-HCO3 (12 %), and Mg-Ca-HCO3 (16 %), suggest that the chemical composition of water is dominantly controlled by carbonate lithology, besides a significant contribution from silicates. However, at certain sites, the biological processes and anthropogenic activities play a major role. Relatively, the lower ionic concentration during high flow period (summer season) suggested the significant influence of higher discharge via dilution effect. The higher discharge due to higher rainfall and snow melting in response to rising temperature in this period leads to strong flushing of human and agricultural wastes into the river. The factor analysis also reflected the dominant control of varied lithology and anthropogenic sources on the water quality based on the four significant factors explaining collectively about 70-81 % of the total data variance. A two-member chloride mixing model used to estimate the discharge contribution of tributaries to the main river channel showed reliable results. It may be mentioned that the regular and continuous contamination through anthropogenic sources is likely to jeopardize and degrade the water quality in the near future. Thus, critical management approaches and strategies are very imperative for its future sustainability.

Assessment of the severity of acute pancreatitis by contrast-enhanced computerized tomography in 350 patients.

BACKGROUND: This prospective study has been conducted with the aim to assess the severity of acute pancreatitis. METHODS: The study included 350 consecutive patients with acute pancreatitis admitted over a period of five years. All these patients were subjected to detailed history and clinical examination and investigations to ascertain the diagnosis. The severity was assessed by contrast - enhanced computed tomography (CT). Data collected were tabulated and subjected to appropriate statistical analysis. RESULTS: On the basis of the CT Severity Index (CTSI), the severity of acute pancreatic was classified into Group A (mild), Group B (moderate), or Group C (severe). Group C patients had the most complications (in 77 [91.67%] patients), and Group A patients had the least (in 7 [6.25%] patients). Mortality was found to be highest among Group C (14 [16.67%] patients), indicating the severe nature of disease in these patients, while no mortality was noted in Group A patients. The mean duration of hospital stay of patients in Group A was 9.25 days, Group B 12.0 days and Group C 24.58 days. CONCLUSION: The use of contrast-enhanced computed tomography as a routine investigation in patients to predict a severe attack of acute pancreatitis early in the course of the disease decreases overall mortality and burden of disease.

CXCR7 mediated Giα independent activation of ERK and Akt promotes cell survival and chemotaxis in T cells.

Chemokine receptors CXCR7 and CXCR4 bind to the same ligand stromal cell derived factor-1alpha (SDF-1α/CXCL12). We assessed the downstream signaling pathways mediated by CXCL12-CXCR7 interaction in Jurkat T cells. All experiments were carried out after functionally blocking the CXCR4 receptor. CXCL12, on binding CXCR7, induced phosphorylation of extra cellular regulated protein kinases (ERK 1/2) and Akt. Selective inhibition of each signal demonstrated that phosphorylated ERK 1/2 is essential for chemotaxis and survival of T cells whereas activation of Akt promotes only cell survival. Another interesting finding of this study is that CXCL12-CXCR7 interaction under normal physiological conditions does not activate the p38 pathway. Furthermore, we observed that the CXCL12 signaling via CXCR7 is Giα independent. Our findings suggest that CXCR7 promotes cell survival and does not induce cell death in T cells. The CXCL12 signaling via CXCR7 may be crucial in determining the fate of the activated T cells.