Mechanistic Insights into Cellular and Molecular Targets of Zinc Oxide Quantum Dots (ZnO QDs) in Fungal Pathogen, Candida albicans: One Drug Multi-Targeted Therapeutic Approach.

Rationally designed multitargeted drugs, known as network therapeutics/multimodal drugs, have emerged as versatile therapeutic solutions to combat drug-resistant microbes. Here, we report novel mechanistic insights into cellular and molecular targets of ZnO quantum dots (QDs) against Candida albicans, a representative of fungal pathogens. Stable, monodispersed 4-6 nm ZnO QDs were synthesized using a wet chemical route, which exhibited dose-dependent inhibition on the growth dynamics of Candida. Treatment with 200 µg/mL ZnO QDs revealed an aberrant morphology and a disrupted cellular ultrastructure in electron microscopy and led to a 23% reduction in ergosterol content and a 53% increase in intracellular reactive oxygen species. Significant increase in steady-state fluorescence polarization and fluorescence lifetime decay of membrane probe 1,6-diphenyl-1,3,5-hexatriene (DPH) in treated cells, respectively, implied reduction in membrane fluidity and enhanced microviscosity. The observed reduction in passive diffusion of fluorescent Rhodamine 6G across the membrane validated the intricate relationship between ergosterol, membrane fluidity, and microviscosity. An inverse relationship existing between ergosterol biosynthetic genes, ERG11 and ERG3 in treated cells, related well with displayed higher susceptibilities. Furthermore, treated cells exhibited impaired functionality and downregulation of ABC drug efflux pumps. Multiple cellular targets of ZnO QDs in Candida were validated by in silico molecular docking. Thus, targeting ERG11, ERG3, and ABC drug efflux pumps might emerge as a versatile, nano-ZnO-based strategy in fungal therapeutics to address the challenges of drug resistance.

Primary Central Nervous System Lymphoma: Long-Term Treatment Outcomes and Cost-Analysis from a Retrospective Study of High-Dose Methotrexate Based Chemoimmunotherapy and Reduced Dose Radiation Therapy Approach.

Standard treatment of primary central nervous system lymphoma (PCNSL) in countries with limited resources remains conventional chemotherapy, with or without whole brain radiotherapy (WBRT). To evaluate the treatment outcomes, prognostic factors and costs in patients with PCNSL treated with high-dose Methotrexate, vincristine and procarbazine, plus Rituximab (MVP-R) followed by consolidation with reduced dose (rd) WBRT and Cytarabine chemotherapy. We conducted an institutional audit of the first line treatment of patients with PCNSL, who were treated with MVP-R regimen, WBRT, or both between September 2011 and January 2020. Long term neuro-cognitive toxicity was recorded on follow up. The 5-year overall survival (OS) was the primary end point. Of 54 patients, 42 were evaluable [median age: 54 years (19-73 years)]. The commonest subtype was activated B-cell subtype (90%). At presentation, multiple and deep brain lesions were reported in 38 and 73% patients, respectively. Combined chemoimmunotherapy was given to 41 patients and WBRT to 29 patients. 27 patients (65%) achieved a complete response, and 22 received rdWBRT. 7 patients with partial response received conventional dose WBRT. Among tested prognostic factors, response to treatment was the single most significant determinant. At a median follow-up of 58 months, the 5-year progression free survival was 42%, and 5-year OS was 60%. The median direct hospital costs incurred by most patients for investigations and treatment were $1976.45 and $12,078.49, respectively. MVP-R is a well-tolerated regimen with substantial long term outcomes. Among all prognostic factors, response to therapy is the most significant.

Genomic characterization and epidemiology of an emerging SARS-CoV-2 variant in Delhi, India.

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.