25 research outputs found

    PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition

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    The importance of metabolism in tumor initiation and progression is becoming increasingly clear. Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Phosphatase and Tensin homolog deleted from chromosome ten (PTEN) is one of the most commonly mutated tumor suppressors in cancer and operates in multiple roles, rendering it a hub for understanding cancer biology and for developing targeted therapy. PTEN’s canonical function is its ability to antagonize the phosphoinositide 3-kinase (PI3K) pathway by dephosphorylating the lipid second messenger phosphatidylinositol (3,4,5) tri-phosphate (PIP3). This thesis focuses on the effects of PTEN loss on cellular metabolism, and the therapeutic vulnerability that stems from metabolic alterations. First, we discovered that loss of Pten in mouse embryonic fibroblasts (MEFs) increases cellular proliferation and the number of replication forks per cell, launching our investigation into metabolic pathways that may be altered to support increased growth. Indeed, we found that Pten-/- cells exhibited a dependence on glutamine for their faster rate of growth, and that glutamine was channeled into the de novo synthesis of pyrimidines. The next chapter examined dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for pyrimidine ring synthesis in the de novo pyrimidine synthesis pathway. We found that PTEN-deficient primary cells and cancer cell lines were more sensitive to inhibition of DHODH than PTEN WT cells were, and that the growth inhibition could be rescued by metabolites downstream of DHODH. Furthermore, we found that xenografted human triple negative breast cancer tumors in mice could be diminished by treatment with leflunomide, a DHODH inhibitor. In the following chapter, we aimed to identify the mechanisms leading to cell death in PTEN mutant cells upon DHODH inhibition. We found that inherent defects in checkpoint regulation in PTEN-deficient cells were exacerbated by the stress of obstructed de novo pyrimidine synthesis, leading to a buildup of DNA damage at replication forks and ultimately chromosomal breaks. This was instigated by AKT-mediated phosphorylation of TOPBP1 that caused inadequate ATR activation, as well as AKT-mediated phosphorylation and inactivation of CHK1. In sum, the findings of this thesis indicate that enhanced glutamine flux to de novo pyrimidine synthesis in PTEN mutant cells generates vulnerability to DHODH inhibition. The integration of altered glutamine regulation with PTEN’s effect on replication, DNA damage, and the checkpoint response manifests as synthetic lethality upon DHODH inhibition in cells with PTEN inactivation. Inhibition of DHODH could thus be a promising therapy for patients with PTEN mutant cancers

    Classifier-Based Text Simplification for Improved Machine Translation

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    Machine Translation is one of the research fields of Computational Linguistics. The objective of many MT Researchers is to develop an MT System that produce good quality and high accuracy output translations and which also covers maximum language pairs. As internet and Globalization is increasing day by day, we need a way that improves the quality of translation. For this reason, we have developed a Classifier based Text Simplification Model for English-Hindi Machine Translation Systems. We have used support vector machines and Na\"ive Bayes Classifier to develop this model. We have also evaluated the performance of these classifiers.Comment: In Proceedings of International Conference on Advances in Computer Engineering and Applications 201

    Physician behaviour for antimicrobial prescribing for paediatric upper respiratory tract infections: a survey in general practice in Trinidad, West Indies

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    BACKGROUND: Upper respiratory tract infections (URTIs) are among the most frequent reasons for physician office visits in paediatrics. Despite their predominant viral aetiology, URTIs continue to be treated with antimicrobials. We explored general practitioners' (GPs) prescribing behaviour for antimicrobials in children (≀ 16 years) with URTIs in Trinidad, using the guidelines from the Centers for Disease Control and Prevention (CDC) as a reference. METHODS: A cross-sectional study was conducted on 92 consenting GPs from the 109 contacted in Central and East Trinidad, between January to June 2003. Using a pilot-tested questionnaire, GPs identified the 5 most frequent URTIs they see in office and reported on their antimicrobial prescribing practices for these URTIs to trained research students. RESULTS: The 5 most frequent URTIs presenting in children in general practice, are the common cold, pharyngitis, tonsillitis, sinusitis and acute otitis media (AOM) in rank order. GPs prescribe at least 25 different antibiotics for these URTIs with significant associations for amoxicillin, co-amoxiclav, cefaclor, cefuroxime, erythromycin, clarithromycin and azithromycin (p < 0.001). Amoxicillin alone or with clavulanate was the most frequently prescribed antibiotic for all URTIs. Prescribing variations from the CDC recommendations were observed for all URTIs except for AOM (50%), the most common condition for antibiotics. Doctors practicing for >30 years were more likely to prescribe antibiotics for the common cold (p = 0.014). Severity (95.7%) and duration of illness (82.5%) influenced doctors' prescribing and over prescribing in general practice was attributed to parent demands (75%) and concern for secondary bacterial infections (70%). Physicians do not request laboratory investigations primarily because they are unnecessary (86%) and the waiting time for results is too long (51%). CONCLUSIONS: Antibiotics are over prescribed for paediatric URTIs in Trinidad and amoxicillin with co-amoxiclav were preferentially prescribed. Except for AOM, GPs' prescribing varied from the CDC guidelines for drug and duration. Physicians recognise antibiotics are overused and consider parents expecting antibiotics and a concern for secondary bacterial infections are prescribing pressures. Guidelines to manage URTIs, ongoing surveillance programs for antibiotic resistance, public health education on non-antibiotic strategies, and postgraduate education for rational pharmacotherapy in general practice would decrease inappropriate antibiotic use in URTIs

    Antibiotic prescriptions for oral diseases in India: evidence from national prescription data

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    Introduction: The key objective of this research was to describe the prescription rate of various antibiotics for dental problems in India and to study the relevance of the prescriptions by analysing antibiotic types associated with different dental diagnoses, using a large-scale nationally representative dataset. Methods: We used a 12-month period (May 2015 to April 2016) medical audit dataset from IQVIA (formerly IMS Health). We coded the dental diagnosis provided in the medical audit data to the International Statistical Classification of Diseases and Related Health Problems (ICD-11) and the prescribed antibiotics for the diagnosis to the Anatomic Therapeutic Chemical (ATC) -2020 classification of the World Health Organization. The primary outcome measure was the medicine prescription rate per 1,000 persons per year (PRPY1000). Results: Our main findings were—403 prescriptions per 1,000 persons per year in the year 2015 -2016 for all dental ailments. Across all ATC level 1 classification, ‘Diseases of hard tissues’ made up the majority of the prescriptions. ‘Beta-lactam’, ‘Penicillin,’ and ‘Cephalosporins’ were the most commonly prescribed antibiotics for dental diagnoses followed by ‘Macrolides’ and ‘Quinolones’. ‘Dental caries’, ‘Discoloration of tooth’, and ‘Toothache’ were the most common reasons for ‘Beta-Lactams’ and ‘Penicillin’ prescriptions. Conclusion: To conclude our study reports first ever country (India) level estimates of antibiotic prescription by antibiotic classes, age groups, and ICD-11 classification for dental ailments

    Antibiotic prescriptions for oral diseases in India: evidence from national prescription data

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    IntroductionThe key objective of this research was to describe the prescription rate of various antibiotics for dental problems in India and to study the relevance of the prescriptions by analysing antibiotic types associated with different dental diagnoses, using a large-scale nationally representative dataset.MethodsWe used a 12-month period (May 2015 to April 2016) medical audit dataset from IQVIA (formerly IMS Health). We coded the dental diagnosis provided in the medical audit data to the International Statistical Classification of Diseases and Related Health Problems (ICD-11) and the prescribed antibiotics for the diagnosis to the Anatomic Therapeutic Chemical (ATC) -2020 classification of the World Health Organization. The primary outcome measure was the medicine prescription rate per 1,000 persons per year (PRPY1000).ResultsOur main findings were-403 prescriptions per 1,000 persons per year in the year 2015 -2016 for all dental ailments. Across all ATC level 1 classification, 'Diseases of hard tissues' made up the majority of the prescriptions. 'Beta-lactam', 'Penicillin,' and 'Cephalosporins' were the most commonly prescribed antibiotics for dental diagnoses followed by 'Macrolides' and 'Quinolones'. 'Dental caries', 'Discoloration of tooth', and 'Toothache' were the most common reasons for 'Beta-Lactams' and 'Penicillin' prescriptions.ConclusionTo conclude our study reports first ever country (India) level estimates of antibiotic prescription by antibiotic classes, age groups, and ICD-11 classification for dental ailments

    Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

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    BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden
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