Harnessing Porphyrin Accumulation in Liver Cancer: Combining Genomic Data and Drug Targeting.

The liver, a pivotal organ in human metabolism, serves as a primary site for heme biosynthesis, alongside bone marrow. Maintaining precise control over heme production is paramount in healthy livers to meet high metabolic demands while averting potential toxicity from intermediate metabolites, notably protoporphyrin IX. Intriguingly, our recent research uncovers a disrupted heme biosynthesis process termed 'porphyrin overdrive' in cancers that fosters the accumulation of heme intermediates, potentially bolstering tumor survival. Here, we investigate heme and porphyrin metabolism in both healthy and oncogenic human livers, utilizing primary human liver transcriptomics and single-cell RNA sequencing (scRNAseq). Our investigations unveil robust gene expression patterns in heme biosynthesis in healthy livers, supporting electron transport chain (ETC) and cytochrome P450 function without intermediate accumulation. Conversely, liver cancers exhibit rewired heme biosynthesis and a massive downregulation of cytochrome P450 gene expression. Notably, despite diminished drug metabolism, gene expression analysis shows that heme supply to the ETC remains largely unaltered or even elevated with patient cancer progression, suggesting a metabolic priority shift. Liver cancers selectively accumulate intermediates, which are absent in normal tissues, implicating their role in disease advancement as inferred by expression analysis. Furthermore, our findings in genomics establish a link between the aberrant gene expression of porphyrin metabolism and inferior overall survival in aggressive cancers, indicating potential targets for clinical therapy development. We provide in vitro proof-of-concept data on targeting porphyrin overdrive with a drug synergy strategy.

Uncovering Porphyrin Accumulation in the Tumor Microenvironment.

Heme, an iron-containing tetrapyrrole, is essential in almost all organisms. Heme biosynthesis needs to be precisely regulated particularly given the potential cytotoxicity of protoporphyrin IX, the intermediate preceding heme formation. Here, we report on the porphyrin intermediate accumulation within the tumor microenvironment (TME), which we propose to result from dysregulation of heme biosynthesis concomitant with an enhanced cancer survival dependence on mid-step genes, a process we recently termed "Porphyrin Overdrive". Specifically, porphyrins build up in both lung cancer cells and stromal cells in the TME. Within the TME's stromal cells, evidence supports cancer-associated fibroblasts (CAFs) actively producing porphyrins through an imbalanced pathway. Conversely, normal tissues exhibit no porphyrin accumulation, and CAFs deprived of tumor cease porphyrin overproduction, indicating that both cancer and tumor-stromal porphyrin overproduction is confined to the cancer-specific tissue niche. The clinical relevance of our findings is implied by establishing a correlation between imbalanced porphyrin production and overall poorer survival in more aggressive cancers. These findings illuminate the anomalous porphyrin dynamics specifically within the tumor microenvironment, suggesting a potential target for therapeutic intervention.

Behavioral Change in Determinants of the Choice of Fuels amongst Rural Households after the Introduction of Clean Fuel Program: A District-Level Case Study.

Consumption of energy is a determinant of the socioeconomic status of many citizens across the globe. The majority of rural households in India are dependent on biomass fuels. Existing data on the factors affecting fuel switching in rural India are insufficient to analyze a behavioral change among families. This paper evaluates the influence of four variables income, education, cost of fuel, and clean fuel supply on fuel adoption decisions. To understand the study population's behavioral change, a Household Survey is conducted in 20 villages (in India's rural district). Along with field observation, data are also collected on energy usage at the household level using a formal questionnaire. Binary logistic regression is applied to establish a link between the variables. Both biomass fuels and Liquefied Petroleum Gas are used mostly for cooking. The prevalence of energy stacking behavior is observed even among middle and upper-income families. Modest evidence for the "energy ladder" hypothesis is seen, however, a "switch over" to cleaner fuels is not.

Aspects of working with female sex workers: Perspectives of NGOs implementing targeted intervention projects in HIV/AIDS.

CONTEXT: HIV continues to be a major global public health issue. Links between sex work and HIV vulnerability have been recognized since the earliest days of the epidemic. Targeted Interventions (TIs) are aimed at offering prevention and care services to high risk populations within communities. Present research is an endeavor to grasp the different aspects indigenous to NGOs implementing TI projects. AIM: To understand the perspectives of NGOs implementing TIs projects for prevention of HIV/AIDS in Female Sex Workers. SETTINGS AND DESIGN: A cross sectional qualitative study. METHODS AND MATERIALS: Six NGOs registered with District AIDS Control Society, working for implementation of TIs projects for FSWs in a Metropolitan City were studied. Statistical Analysis: Data was analysed with SPSS version 20. RESULTS: Rapid turnover of ORWs is major constraint faced by project managers in recruitment of ORWs. In PEs' recruitment, availability of candidates is major constraint. Stigma related to STI clinic and interference of key stakeholders are the major barriers preventing service utilization by FSWs. Client's dislike for using condom is one of the major barriers in condom utilization by FSWs. CONCLUSION: The realistic problems, constraints experienced by the programme managers became evident during the study. Integration of programs into the existing system and interventions should be tailor-made to local needs. Here lies the opportunity of 'Operational Research' for the institute like NACO to have the practical insights from TI projects.

Study of determinants of immunization status among under-five children attending OPD in a rural health center of the tertiary health care institute.

CONTEXT: The risk of morbidities from vaccine-preventable diseases is highest in those who experience barriers in accessing immunization services. This spectrum could be affordability, accessibility, lack of awareness about immunization services and their health benefits or other limiting factors. The present study aimed to identify maternal and other determinants of immunization status. AIM: To identify maternal and other determinants of immunization status of under-five children. SETTINGS AND DESIGN: An OPD based cross sectional survey. METHODS AND MATERIALS: Non-randomized sample of 194 children (1-5 years) and mothers attending OPD in study duration were examined and interviewed. STATISTICAL ANALYSIS: Data was analysed with SPSS version 20 applying appropriate tests. RESULTS: Out of 194 children, 128 (65.98%) were completely immunized, 45 (23.2%) were partially immunized and 21 (10.82%) were not immunized. Study showed significant association between immunization status and sex of children (P 0.0004), permanent residence (P 0.00001), birth order (P 0.0007), institutional births (P 0.00001), presence of the immunization card (P 0.00001), distance from centre (P 0.0002), age (P 0.00001) and education of mothers (P 0.0001). Association with Religion was statistically non-significant (P 0.0071). Nearness of immunization centre was the main motivating factor for full immunization, whereas unawareness about the need of immunization was prime cause of partial and non-immunization. CONCLUSION: Present study depicts low immunization completion rate and highlights determinants associated with it. This could be addressed through strong political commitment, infrastructure development and community outreach to achieve the goal of universal immunization.

Effect of idol immersion on water quality and Tilapia fish in Futala, Gandhisagar and Ambazari lakes of Nagpur, India.

INTRODUCTION: Idol immersion activity is one of the sources of heavy metal pollution in the lakes of India. Futala, Gandhisagar and Ambazari lakes of Nagpur city are highly involved with idol immersion activity. CASE DESCRIPTION: In this study, water and Tilapia fish (Oreochromis mossambicus) of Futala, Gandhisagar and Ambazari lakes were analyzed for heavy metals by using inductively coupled plasma optical emission spectrometry (ICP-OES). DISCUSSION AND EVALUATION: The results were high compared with the Bureau of Indian Standards (BIS) for water quality and Food and Agriculture Organization (FAO)/World Health Organization (WHO) for fish. The results showed appreciable high levels of heavy metal as lead, cadmium, copper, iron and manganese in water and fish in study lakes. It was observed that Gandhi Sagar lake was more contaminated after the idol immersion activity. Concentrations of Pb and Cd in fish of Gandhisagar lake were found high levels, ranged 0.83 and 0.47 µg/g respectively. CONCLUSION: The results of the present investigation indicate the unsafe condition for human consumption and environmental health.