Study of water supply & sanitation practices in India using geographic information systems: some design & other considerations in a village setting

Background & objectives: Availability of clean water and adequate sanitation facilities are of prime importance for limiting diarrhoeal diseases. We examined the water and sanitation facilities of a village in southern India using geographic information system (GIS) tools. Methods: Places of residence, water storage and distribution, sewage and places where people in the village defaecated were mapped and drinking water sources were tested for microbial contamination in Nelvoy village, Vellore district, Tamil Nadu. Results: Water in the village was found to be microbiologically unfit for consumption. Analysis using direct observations supplemented by GIS maps revealed poor planning, poor engineering design and lack of policing of the water distribution system causing possible contamination of drinking water from sewage at multiple sites. Interpretation & conclusions: Until appropriate engineering designs for water supply and sewage disposal to suit individual village needs are made available, point-of-use water disinfection methods could serve as an interim solution

Sialidase sensitivity of rotaviruses revisited

Rotaviruses have been designated as 'sialidase sensitive' or 'sialidase insensitive', based on how their entry into cells is affected by treating cells with sialidases. A new study uses multiple methods, including saturation transfer difference NMR spectroscopy, to elucidate interesting interactions involving terminal and internal sialic acid moieties, concluding that 'sialidase insensitive' does not mean 'sialic acid independent'

Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas

Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1 promoter methylation (BRCA1meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1 and BRCA2 (BRCAmut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCA perturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with BRCA1meth and BRCAmut states, BRCA1meth uniformly associates with poor outcomes. Exposure of BRCA1meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1 methylation and increased BRCA1 expression and platinum resistance. These data suggest that, unlike BRCAmut cancers, where BRCA loss is a genetically fixed deficiency state, BRCA1meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of BRCA mutations results in more accurate predictions of patient response when compared to either HRD status or BRCA status alone. This underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa

A Red Meat-Derived Glycan Promotes Inflammation and Cancer Progression

A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of “red meat” of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption

Water handling, sanitation and defecation practices in rural southern India: a knowledge, attitudes and practices study

Diarrhoea and water-borne diseases are leading causes of mortality in developing countries. To understand the socio-cultural factors impacting on water safety, we documented knowledge, attitudes and practices of water handling and usage, sanitation and defecation in rural Tamilnadu, India, using questionnaires and focus group discussions, in a village divided into an upper caste Main village and a lower caste Harijan colony. Our survey showed that all households stored drinking water in wide-mouthed containers. The quantity of water supplied was less in the Harijan colony, than in the Main village (P < 0.001). Residents did not associate unsafe water with diarrhoea, attributing it to 'heat', spicy food, ingesting hair, mud or mosquitoes. Among 97 households interviewed, 30 (30.9%) had toilets but only 25 (83.3%) used them. Seventy-two (74.2%) of respondents defecated in fields, and there was no stigma associated with this traditional practice. Hand washing with soap after defecation and before meals was common only in children under 15 years (86.4%). After adjusting for other factors, perception of quantity of water received (P < 0.001), stated causation of diarrhoea (P = 0.02) and low socio-economic status (P < 0.001) were significantly different between the Main village and the Harijan colony. Traditional practices may pose a significant challenge to programmes aimed at toilet usage and better sanitation

Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing

Abstract Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient’s tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient’s tumor identified several therapeutic choices, including Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient’s CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient’s CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments

Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing.

Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient\u27s tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient\u27s tumor identified several therapeutic choices, including Bruton\u27s tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient\u27s CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient\u27s CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments

Serum IgG Response to Cryptosporidium Immunodominant Antigen gp15 and Polymorphic Antigen gp40 in Children with Cryptosporidiosis in South India ▿

The surface-associated glycopeptides gp40, one of the most polymorphic Cryptosporidium antigens, and gp15, one of the most immunodominant Cryptosporidium antigens, are putative vaccine candidates because they mediate infection in vitro and induce immune responses in vivo. We evaluated antibody responses to these antigens before and after the first episode of symptomatic cryptosporidiosis in 51 children from a birth cohort study in an area in South India where Cryptosporidium is endemic and a major cause of parasitic diarrhea. IgG levels to gp15 and to homotypic and heterotypic gp40 antigens were measured in pre- and postdiarrheal sera by enzyme-linked immunosorbent assay (ELISA). There was a significant IgG response to gp15 (P < 0.001) following the first episode of cryptosporidial diarrhea. Using a general additive model, we determined the estimated time of the peak IgG response to gp15 to be 9.3 weeks (confidence interval, 5.2 to 13.4) following the diarrheal episode. In a subset of 30 children infected with Cryptosporidium hominis subtype Ia, there was a significant difference in IgG responses to homotypic C. hominis Ia and to heterotypic Cryptosporidium parvum II gp40 antigens (P = 0.035). However, there was also a significant correlation (P = 0.001) in the responses to both antigens in individual children, suggesting that while responses are in part subtype specific, there is significant cross-reactivity to both antigens. This is the first report of the characterization of immune responses to cryptosporidiosis in Indian children and the first study to investigate human immune responses to the polymorphic gp40 antigen. However, further studies are needed to determine whether immune responses to these antigens are protective against subsequent infections