The background and predisposing causes of leprosy in Poona district, British India

The subject of leprosy is a large one, and it is not proposed to carry this study of it further at this time. On return to India, the author hopes to continue the study of leprosy in Poona District, and to make an effort to place the control of the disease on a better footing. From study of the land and the people, their habits, their diseases, their mental equipment, their means of subsistence, and the public resources available, some more satisfactory method of control of leprosy may emerge. The present position is in the highest degree unsatisfactory. For thousands of lepers in the District there exists one Leper Asylum and a few clinics, and only some 300 lepers at most are under control.ROGERS, 1931, animadverts against compulsory segregation as failing to stamp out or materially to reduce the prevalence of leprosy among backward races within a reasonable time. MUIR, 1932,(160), believes that segregation in India could not possibly be carried our for frightening patients "underground," and because of lack of finance. On the other hand, we have seen the success which has attended strict measures of isolation and control in Norway, (40) Withoug going further into the matter, it is enough to emphasise that in Poona District segregation of lepers has never been tried, strictly and efficiently, nor probably in any part of India, .and one would be better convinced of the truth of the opinions of ROGERS and of MUIR in this respect, if segregation or isolation had been tried. There is at least enough evidence, of its value to expect that one should "move heaven and earth," at least to give it a proper trial. Further, the problem of leprosy looks staggering when considered for the whole of India, but if one adopts a District as the unit of campaign, it does not look so hopeless. If one imagines the position of a state in India, small, independent, caring for no man, which determines to essay the proper control of leprosy within its borders, one cam visualise even success. Some degree of ruthlessness in the control of the liberty of the subject, and in the control of frontiers, and in the enforcement of anti- leprosy laws, and in the expenditure of money, would be demanded, but Norway has taught us that it can be done. Of course there are many difficulties:, but in India it has never been tried.In Poona District we have not even enough accommodation for the ordinary cure of the lepers who come to us. We are forced to treat 70 lepers in a clinic, because there is no room for them in a proper leper hospital. This position at least should be remedied, and if a modern leper hospital to contain 1,000 persons were built in Poona District, one is convinced that it would find occupants.Finally, one would like to suggest the anti-leprosy measures which need to be developed in Poona Districts: (a) All measures to spread general education and literacy. (b) Specific education about leprosy, among the people and among the existing medical personnel. (c) Increase in medical anti- leprosy staff. (d) Visiting every town and village in the District, and enumeration of lepers by careful and even bacteriological methods of diagnosis; at the same time carrying out propaganda and instituting treatment centres. (e) Building adequate leper hospitals: lepers require a great deal of ordinary medical care which at present is not possible, and there is a vast field in leper sugery alone. (f) Concerting of measures which aim at the 'bonification' of the people, as improvement of agriculture, housing, water supply, control of diseases, spread of knowledge of dietary and the like. (g) If enough courage and enough money be obtainable, securing in the end strict control and isolation of all known lepers

A co-ordinated interaction between CTCF and ER in breast cancer cells.

BACKGROUND: CCCTC-binding factor (CTCF) is a conserved zinc finger transcription factor that is involved in both intra- and interchromasomal looping. Recent research has shown a role for CTCF in estrogen receptor (ER) biology, at some individual loci, but a multi-context global analysis of CTCF binding and transcription activity is lacking. RESULTS: We now map CTCF binding genome wide in breast cancer cells and find that CTCF binding is unchanged in response to estrogen or tamoxifen treatment. We find a small but reproducible set of CTCF binding events that overlap with both the nuclear receptor, estrogen receptor, and the forkhead protein FOXA1. These overlapping binding events are likely functional as they are biased towards estrogen-regulated genes, compared to regions lacking either CTCF or ER binding. In addition we identify cell-line specific CTCF binding events. These binding events are more likely to be associated with cell-line specific ER binding events and are also more likely to be adjacent to genes that are expressed in that particular cell line. CONCLUSION: The evolving role for CTCF in ER biology is complex, but is likely to be multifunctional and possibly influenced by the specific genomic locus. Our data suggest a positive, pro-transcriptional role for CTCF in ER-mediated gene expression in breast cancer cells. CTCF not only provides boundaries for accessible and 'protected' transcriptional blocks, but may also influence the actual binding of ER to the chromatin, thereby modulating the estrogen-mediated gene expression changes observed in breast cancer cells.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Methylation panel is a diagnostic biomarker for Barrett’s oesophagus in endoscopic biopsies and non-endoscopic cytology specimens

Objective Barrett’s Oesophagus is a premalignant condition that occurs in the context of gastro-oesophageal reflux. However, most Barrett’s cases are undiagnosed because of reliance on endoscopy. We have developed a non-endoscopic tool; the Cytosponge™ which when combined with TFF3 immunohistochemistry can diagnose Barrett’s. We investigated whether a quantitative methylation test that is not reliant on histopathological analysis could be used to diagnose Barrett’s oesophagus. Design Differentially methylated genes between Barrett’s and normal squamous oesophageal biopsies were identified from whole methylome data and confirmed using MethyLight PCR in biopsy samples of squamous oesophagus, gastric cardia and Barrett’s oesophagus. Selected genes were then tested on Cytosponge™ BEST2 trial samples comprising a pilot cohort (n=20 cases, n=10 controls) and a validation cohort (n=149 cases, n=129 controls). Results Eighteen genes were differentially methylated in patients with Barrett’s compared to squamous controls. Hypermethylation of TFPI2, TWIST1, ZNF345 and ZNF569 was confirmed in Barrett’s biopsies compared with biopsies from squamous oesophagus and gastric cardia (p<0.05). When tested in Cytosponge™ samples these four genes were hypermethylated in patients with Barrett’s oesophagus compared to patients with reflux symptoms (p<0.001). The optimum biomarker to diagnose Barrett’s was TFPI2 with a sensitivity and specificity of 82.2% and 95.7 % respectively. Conclusion TFPI2, ZNF345 and ZNF569 CpG methylation has promise as a diagnostic biomarker panel for Barrett’s when used in combination with a simple and cost effective non-endoscopic cell collection device.The BEST2 study was funded by Cancer Research UK (C14478/ A12088). RCF receives core funding from the Medical Research Council. The study received infrastructure support from the Cambridge Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the Experimental Cancer Medicine Centre

Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells.

BACKGROUND: The forkhead transcription factor FOXM1 is a key regulator of the cell cycle. It is frequently over-expressed in cancer and is emerging as an important therapeutic target. In breast cancer FOXM1 expression is linked with estrogen receptor (ERα) activity and resistance to endocrine therapies, with high levels correlated with poor prognosis. However, the precise role of FOXM1 in ER positive breast cancer is not yet fully understood. RESULTS: The study utilizes chromatin immunoprecipitation followed by high-throughput sequencing to map FOXM1 binding in both ERα-positive and -negative breast cancer cell lines. The comparison between binding site distributions in the two cell lines uncovered a previously undescribed relationship between binding of FOXM1 and ERα. Further molecular analyses demonstrated that these two factors can bind simultaneously at genomic sites and furthermore that FOXM1 regulates the transcriptional activity of ERα via interaction with the coactivator CARM1. Inhibition of FOXM1 activity using the natural product thiostrepton revealed down-regulation of a set of FOXM1-regulated genes that are correlated with patient outcome in clinical breast cancer samples. CONCLUSIONS: These findings reveal a novel role for FOXM1 in ERα transcriptional activity in breast cancer and uncover a FOXM1-regulated gene signature associated with ER-positive breast cancer patient prognosis

Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia.

ObjectiveInflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia.Study designA sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios.ResultsHigher 5-α-pregnan-3β,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia.ConclusionsAmong women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth

Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma.

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture

Hypersensitive K303R oestrogen receptor-α variant not found in invasive carcinomas

INTRODUCTION: Genetic abnormalities or mutations in premalignant breast lesions may have a role in progression toward malignancy or influence the behaviour of subsequent disease. The A908G (Lys303→Arg) change in the gene encoding oestrogen receptor-α (ER-α) creates a hypersensitivity to oestradiol and would have significant consequences if present in breast carcinoma, especially those treated with endocrine therapy. We have therefore examined a panel of endocrine-treated invasive carcinomas for the presence of this mutation. METHODS: Sequencing of control DNA was shown to detect mutation present in as little as 15% of the starting material. Enrichment for the mutation by using MboII restriction digestion allowed the detection of mutant present at 1% or less. We applied these techniques to genomic DNA and cDNA from 136 invasive breast carcinomas. RESULTS: No evidence of the A908G mutation was found with either technique. The incidence of this mutation in our panel of tumours is therefore significantly less than previously reported. CONCLUSION: The fact that the mutation was not found leads us to believe that this mutation is absent from most cells in invasive carcinomas and furthermore that the major expression product of the ER-α gene in cancers does not contain the K303R mutation. It is therefore unlikely to influence the effectiveness of endocrine treatment

Range of pathologies diagnosed using a minimally invasive capsule sponge to evaluate patients with reflux symptoms.

AIMS: Reflux symptoms are highly prevalent and non-specific; hence, in the absence of alarm symptoms, endoscopy referral decisions are challenging. This study evaluated whether a non-endoscopic Cytosponge could detect benign oesophageal pathologies and thus have future potential in triaging patients with persistent symptoms. METHODS AND RESULTS: Two complementary cohorts were recruited: (i) patients with reflux symptoms and no prior endoscopy (n = 409), and (ii) patients with reflux symptoms referred for endoscopy (n = 411). All patients were investigated using the Cytosponge and endoscopy. Significant epithelial inflammation was present in 130 (16%) Cytosponge samples, 32 of which had ulcer slough. Candida and significant inflammation was detected in a further 22 (2.3%) cases; epithelial infiltration with >15 eosinophils/high-power field reflecting possible eosinophilic oesophagitis (EOE) in five (0.6%); and viral inclusions suggestive of herpes oesophagitis in one (0.1%). No significant pathology was detected in the majority, 662 (81%), of Cytosponge samples. Cytosponge and endoscopy findings were in agreement in 574 (70%) cases, in 165 (67%) of the discordant cases one investigation showed mild inflammation while the other was negative, with an additional 22 (8.9%) differing on the extent of inflammation. Eighteen cases with severe inflammation, six with candida and two with EOE were detected only at endoscopy, while 18 with candida and significant inflammation, 13 with ulcer slough, one probable EOE and one viral oesophagitis were identified on the Cytosponge only. CONCLUSIONS: The Cytosponge detects a range of benign oesophageal pathologies, and therefore has potential clinical utility in the triaging of patients with troublesome reflux symptoms. This warrants further investigation.The BEST study was funded by the Medical Research Council. The BEST2 project was funded by Cancer Research UK. RCF has programmatic funding from the Medical Research Council and infrastructure support from the Cambridge NIHR Biomedical Research Centre and the Cambridge Experimental Medicine Centre. ALP is an NIHR Academic Clinical Fellow and holds the Pang Kam Ping Fellowship in Medicine at Queens’ College, Cambridge. The Addenbrooke’s Hospital Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/his.1303