Bangladesh arsenic mitigation programs: lessons from the past

Ensuring access to safe drinking water by 2015 is a global commitment by the Millennium Development Goals (MDGs). In Bangladesh, significant achievements in providing safe water were made earlier by nationwide tubewell-installation programme. This achievement was overshadowed in 1993 by the presence of arsenic in underground water. A total of 6 million tubewells have been tested for arsenic since then, the results of which warranted immediate mitigation. Mitigation measures included tubewell testing and replacing; usage of deeper wells; surface water preservation and treatment; use of sanitary dug wells, river sand and pond sand filters; rainwater collection and storage; household-scale and large-scale arsenic filtrations; and rural pipeline water supply installation. Shallow tubewell installation was discouraged. Efforts have been made to increase people's awareness. This paper describes the lessons learned about mitigation efforts by the authors from experience of arsenic-related work. In spite of national mitigation plans and efforts, a few challenges still persist: inadequate coordination between stakeholders, differences in inter-sectoral attitudes, inadequate research to identify region-specific, suitable safe water options, poor quality of works by various implementing agencies, and inadequate dissemination of the knowledge and experiences to the people by those organizations. Issues such as long-time adaptation using ground water, poor surface water quality including bad smell and turbidity, and refusal to using neighbor's water have delayed mitigation measures so far. Region-specific mitigation water supply policy led by the health sector could be adopted with multisectoral involvement and responsibility. Large-scale piped water supply could be arranged through Public Private Partnerships (PPP) in new national approach

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition

Signatures of mutational processes in human cancer.

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy