Comparing Socio- epidemiological, Clinical Features and Treatment Outcome of Adolescent and Adult TB in Bardhman and Malda districts of West Bengal state in India

Data from five tuberculosis treatment units was collected from Malda and Bardhman districts in West Bengal, India for treatment success rate and dropout rates. The objective was to study, compare and contrast the socio- epidemiological and clinical features of TB between adults and adolescents including treatment success and dropout rates under the revised national tuberculosis control program of government of India. The study cohort was of the year 2011; both primary and secondary data was collected using patient TB cards, TB registers and interviews with patient and/ or patient guardians. Of a total of 1,327 patients registered during this period in the five treatment units, data from 729 registered patients was randomly selected for the study. The cohort data was studied for adolescents aged between 10-19 years and adults aged between 20-45 years. Our results show that adolescents had higher education than adults, had similar socio- economic status, and proportionately had more extra pulmonary tuberculosis than adults. Unlike adult women, females comprise a much higher proportion of TB patients in the adolescent cohort, possibly showing that the protective effect that adult women have against tuberculosis is not as strong among adolescent girls. Finally, treatment success rates are much higher in adolescents than adults. In conclusion, the socio-demographics, clinical picture and treatment outcomes for TB among adolescents are different than that of adults

Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras-driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision-cut slices from Kras-driven non-small-cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen-activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short-term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3-kinase-mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology-associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations

Identification of Novel p53 Pathway Activating Small-Molecule Compounds Reveals Unexpected Similarities with Known Therapeutic Agents

Peer reviewe

HDAC inhibitor confers radiosensitivity to prostate stem-like cells

Background: Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction. Methods: Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2β1integrinhi/CD133+), transit-amplifying (TA, α2β1integrinhi/CD133−) and committed basal (CB, α2β1integrinlo) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser. Results: Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation. Interpretation: Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction

Racial Disparity in Hypertensive Disorders of Pregnancy in New York State: A 10-Year Longitudinal Population-Based Study

Objectives. We studied trends of hypertensive disorders of pregnancy by residential socioeconomic status (SES) and racial/ethnic subgroups in New York State over a 10-year period. Methods. We merged New York State discharge data for 2.5 million women hospitalized with delivery from 1993 through 2002 with 2000 US Census data. Results. Rates of diagnoses for all hypertensive disorders combined and for preeclampsia individually were highest among Black women across all regions and neighborhood poverty levels. Although hospitalization rates for preeclampsia decreased over time for most groups, differences in rates between White and Black women increased over the 10-year period. The proportion of women living in poor areas remained relatively constant over the same period. Black and Hispanic women were more likely than White women to have a form of diabetes and were at higher risk of preeclampsia; preeclampsia rates were higher in these groups both with and without diabetes than in corresponding groups of White women. Conclusions. An increasing trend of racial/ethnic disparity in maternal hypertension rates occurred in New York State during the past decade. This trend was persistent after stratification according to SES and other risk factors. Additional research is needed to understand the factors contributing to this growing disparity

Human prostate epithelium lacks Wee1A-mediated DNA damage-induced checkpoint enforcement

Cellular DNA damage triggers the DNA damage response pathway and leads to enforcement of cell cycle checkpoints, which are essential for the maintenance of genomic integrity and are activated in early stages of tumorigenesis. A special feature of prostate cancer is its high incidence and multifocality. To address the functionality of DNA damage checkpoints in the prostate, we analyzed the responses of human primary prostate epithelial cells (HPECs) and freshly isolated human prostate tissues to γ-irradiation. We find that γ-irradiation activates the ataxia telangiectasia mutated-associated DNA damage response pathway in the HPECs but that the clearance of phosphorylated histone H2AX (γH2AX) foci is delayed. Surprisingly, γ-irradiated HPECs were unable to enforce cell cycle checkpoint arrest and had sustained cyclin-dependent kinase 2 (Cdk2)-associated kinase activity because of a lack of inhibitory Cdk phosphorylation by Wee1A tyrosine kinase. We further show that HPECs express low levels of Wee1A and that ectopic Wee1A efficiently rescues the checkpoints. We recapitulate the absence of checkpoint responses in epithelium of ex vivo irradiated human prostate tissue despite robust induction of γH2AX. The findings show that prostate epithelium has a surprising inability to control checkpoint arrest, the lack of which may predispose to accrual of DNA lesions