tbuckley/cabot-search huggingface dataset:
Abstract P6-03-02: Functional genomic screening identifies USP11 as a novel therapeutic target in breast cancer
Authors: Darran P O'Connor, Lisa Dwane, Aisling E O'Connor, Annette M Dirac, Rene Bernards, William M Gallagher
Journal: Cancer Research (2015)

Abstract The estrogen receptor (ER) is the principal driver of growth and differentiation in breast cells and de-regulated receptor function is a key feature of almost 75% of breast cancers. Here, we investigated the role of de-ubiquitinating enzymes (DUBs), which act to remove ubiquitin moieties from proteins, in regulating the transcriptional activity of ER in breast cancer. To identify DUBs involved in the regulation of ER transcriptional activity, we performed an RNAi loss-of-function screen using a library of shRNA vectors targeting all known human DUB genes (108 genes/432 shRNAs in total). We found that suppression of a number of DUBs markedly repressed or enhanced the activity of an estrogen-response-element (ERE) luciferase reporter to estradiol (E2). In particular, suppression of the BRCA2-associated DUB, USP11, was found to down-regulate ERα transcriptional activity (both in the presence and absence of E2), as demonstrated by a pronounced decrease in estrogen-response element (ERE) luciferase reporter activity. Subsequent validation of the screen using multiple individual hairpins and ZR-75-1 stable USP11 knockdown cells confirmed the suppression of ERE-reporter activity and further revealed a notable reduction in expression of the endogenous ER target genes TFF1 and PgR following USP11 knockdown. In vitro phenotypic analysis also revealed a global decrease in cell survival, decreased ERK and AKT phosphorylation and increased sensitivity to DNA-damaging agents in USP11 knockdown cell lines compared to non-targeting controls. In silico analysis of publically available breast cancer gene expression datasets revealed a highly significant association between high USP11 mRNA levels and poor prognosis. We observed a highly significant correlation between high expression of USP11 mRNA in ER positive patients and poor overall survival (OS)(HR 1.51, CI 1.07-2.14, p=0.018) and distant metastasis-free survival (DMFS)(HR 1.35, CI 1.04-1.73, p=0.023). This correlation was also significant in ER positive patients who had received endocrine therapy (OS, HR 3.4, CI 1.2-9.81, p=0.014), DMFS, HR 2.16, CI 1.23-3.8, p=0.0083). These results suggest a role for USP11 in driving cellular growth and identify USP11 as a rationale and novel therapeutic target in breast cancer. Citation Format: Darran P O'Connor, Lisa Dwane, Aisling E O'Connor, Annette M Dirac, Rene Bernards, William M Gallagher. Functional genomic screening identifies USP11 as a novel therapeutic target in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-03-02.
Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study.
Authors: C K Osborne, B Blumenstein, E D Crawford, C A Coltman, A Y Smith, B W Lambuth, R A Chapman
Journal: Journal of Clinical Oncology (1990)

Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer, although it has been used most frequently in patients with far-advanced, refractory disease. To evaluate the effects of chemotherapy given earlier in the course of the disease, the Southwest Oncology Group (SWOG) performed a randomized trial between September 1982 and October 1986 comparing endocrine therapy (diethylstilbestrol [DES] or orchiectomy) alone followed by cyclophosphamide-Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy at progression versus initial combined chemo-endocrine therapy. One hundred forty-three patients were registered, and only six were declared ineligible. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared with endocrine therapy alone (48%). A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm (P = .059). Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy, while two others had stable disease. Despite the difference in initial response rate, time to treatment failure and survival were identical in the two treatment arms. Seventy-seven percent of patients on the initial endocrine therapy alone arm have died (median survival, 25.6 months) compared with 78% on the chemo-endocrine therapy arm (median survival, 22.0 months). No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model. Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy. Eighty-six percent of patients treated by orchiectomy have died compared with only 65% of those treated with DES. These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer.
Atrial fibrillation and stroke risk in relation to COPD and chronic productive cough
Authors: Ulf Nilsson, Bengt Johansson, Berne Eriksson, Anders Blomberg, Bo Lundbäck, Anne Lindberg
Journal: European Respiratory Journal (2013)

Background: Chronic productive cough (CPC) predicts incident COPD and is a prognostic factor in COPD. Concomitant cardiovascular disease is common in COPD but the relationship between atrial fibrillation (AF), risk for stroke in AF, COPD and CPC in population-based cohorts is not well described

Aim: To study the prevalence of AF in subjects with and without COPD and CPC, respectively, and the risk for stroke in AF assessed by CHA2DS2-VASc Score.

Methods: The population-based OLIN COPD study in Sweden was recruited in 2002-04; 993 subjects with FEV1/FVC ≤0.70 (COPD) and 993 age- and gender- matched non-COPD subjects. The study population has been invited to annual examinations, and in 2005 complete data on interview, ECG and spirometry was collected from 1603 participants.

Results: CPC was reported by 42.1% in COPD vs. 23.0% in non-COPD, and was more common in men than in women (31.4% vs. 26.8%, p=0.043). The proportion of smokers was higher among those with CPC compared to those without CPC (33.4% vs. 15.3%, p<0.001). The overall prevalence of AF was 3.4%, with no significant difference between COPD and non-COPD (3.2% vs. 3.5%). AF was more common in subjects with CPC than in subjects without CPC (5.5% vs. 2.6%, p=0.003), and those with CPC had lower mean FEV1/FVC compared to those without CPC (0.69 vs. 0.75, p<0.001). Stroke risk in AF, CHA2DS2-VASc Score was higher among subjects with AF and CPC compared to in those without CPC (3.48 vs 2.41, p=0.017), and a significant difference remained when age was excluded from the CHA2DS2-VASc Score (1.93 vs. 1.17, p=0.036).

Conclusion: CPC was related to increased prevalence of AF, and the risk for stroke in AF seems to increase with concomitant CPC.
Is the body mass index a determinant of inflammatory status and quality of life in asthma
Authors: Raquel Lόpez Reyes, Miguel Perpiña Tordera
Journal: European Respiratory Journal (2011)

Introduction:  The aim of our study was to determine the relationship between body mass index (BMI), alveolar nitric oxide (CaNO), and the health status of asthmatics by applying the quality of life questionnaire Sydney-modified (AQLQ-S).   Material and methods:  We studied 139 asthmatics (GINA) between 15 and 75 yr of age (men 45 and women 94) and several degrees of severity. We measured anthropometric variables, baseline spirometry, and nitric oxide exhaled (eNO) at multiple flows (50, 100, 150, 200 and 250 ml/s). Bronchial nitric oxide flux (JaNO) and CaNO were assessed according to Tsoukias model. All patients completed the AQLQ-S questionnaire. For comparisons between two groups, T-student test was used. The relations between NO parameters and other markers were analyzed with partial correlations adjusted for asthma severity.   Results:  The mean BMI was 26.46±4.97 kg/m 2 ,CaNO 3.89±4,7 ppb and JaNO 2401±2307 nl/sec.There were no statistically significant differences in values of CaNO and JaNO between obese asthmatic group and non obese. The AQLQ-S scores obtained were (mean ± SD): total score: 5.62±1.08; shortness of breath: 5.73±1.14; mood: 5.21±1.24, social restriction: 5.92±1.25; and concern: 5.69±1.10   Conclusions:  Obesity determines deterioration in the quality of life of patients with asthma especially in two dimensions: 1) shortness of breath and 2) social restriction. CaNO and JaNO show no relation to the inflammatory state that involves obesity and have no expression in the health questionnaire score used.
Impact of metformin use on risk of recurrence in high-grade endometrial cancers.
Authors: Emily Meichun Ko, Jason Franasiak, Leslie Horn Clark, Paola A. Gehrig, Victoria Lin Bae-Jump
Journal: Journal of Clinical Oncology (2012)

5009 Background: Obesity and diabetes (DM) have been linked to increased recurrence rates and worse survival in endometrial cancer. Metformin is widely used as the first line treatment for type II DM. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce cancer-related deaths among DM patients. However, no studies have assessed the effect of metformin use on endometrial cancer outcomes. Methods: A retrospective cohort analysis was conducted of all grade 3 endometrial cancer patients with DM at a single institution from 2005-2010. Clinical-pathologic data was abstracted, including metformin, insulin, sulfonamide and thiazolidinedione use at the time of cancer diagnosis. Statistical analysis were performed using summary statistics and multivariate cox analysis, with two tailed p-values &lt;0.05 considered significant. Results: 55/329 patients with grade 3 cancer had DM. Mean age was 68.3 (sd 8.4), and BMI 35.7 (sd 9.4). Stage distribution consisted of 58.2% stage I, 7.3% stage II, 27.3% stage III, and 7.3% stage IV. Histology included 41.8% endometrioid, and 58.2% serous or clear cell. 56.4% of diabetics used metformin and 43.6% did not. Mean follow-up was 21.6 months (sd 15.0). After adjusting for BMI, myometrial invasion, stage, histology, adjuvant treatment, and non-metformin DM medications, metformin use was significantly associated with decreased cancer recurrence (HR 0.06, 95CI 0.01, 0.40; p&lt;0.004). Conclusions: Metformin use was associated with a decreased risk of recurrence in high-grade endometrial cancer, suggesting that it may have a role as adjuvant and maintenance therapy for this obesity-driven disease. [Table: see text]
Abstract 55: Intra-arrest Hypothermia Fails to Improve Long-Term Survival and Neurological Outcomes in Akt1-Deficient Mice Following Resuscitation
Authors: David G Beiser, Huashan Wang, Mei Han, Terry L Vanden Hoek
Journal: Circulation (2011)

INTRODUCTION: In a mouse model of cardiac arrest, we have previously demonstrated that intra-arrest hypothermia (IH), cooling the body to 30 - 32°C, improves cardiac function and long-term neurologically intact survival rates in C57Bl/6J, wild-type (WT), mice following return of spontaneous circulation (ROSC). Heart Akt is also activated by IH at 4 h post-ROSC. By contrast, IH does not improve post-ROSC cardiac function or increase cardiac Akt activity in Akt1 deficient (Akt1+/-) mice. However, the effect of IH on long-term outcomes in Akt1+/- is unknown. METHODS: Anesthetized adult female (n = 20) Akt1+/- mice underwent 8 min of KCl-induced asystolic cardiac arrest. After 6 min, mice were randomized to continued normothermia (NT, 37°C) or IH (30°C) followed by re-warming to 37°C at 60 min post-ROSC. Following ROSC, animals were ventilated and invasively monitored for 2 h. At 2 h, vascular catheters were removed, wounds surgically closed, and animals were weaned from positive pressure ventilation over 4 h. Neurologic assessments were performed at regular intervals over 72 h. RESULTS: NT and IH groups were hemodynamically similar at baseline, during CPR, and at 2 h post-ROSC. ROSC rates were similar in the NT and IH groups (9/10 vs. 10/10, p=0.30). Survival rates (see figure) and neurologic function scores were similar between treatment groups at 6 h, 24 h, and 72 h. CONCLUSION: The loss of an Akt1 allele abrogates long-term therapeutic benefits of IH in a mouse model of cardiac arrest. These results suggest that Akt1 signaling may play an important role in IH protection.
Without proper research funding, how can medical education be evidence based?
Authors: J. Archer, C. McManus, K. Woolf, L. Monrouxe, J. Illing, A. Bullock, T. Roberts
Journal: BMJ (2015)

<h3><b>Abstract</b></h3> The major microtubule-organizing center (MTOC) in animal cells, the centrosome, comprises a pair of centrioles surrounded by pericentriolar material (PCM), which nucleates and anchors microtubules. Centrosome assembly depends on PCM binding to centrioles, PCM self-association and dynein­mediated PCM transport, but the self-assembly properties of PCM in interphase cells are poorly understood. Here, we used experiments and modeling to study centriole-independent features of interphase PCM assembly. We showed that when centrioles are lost due to PLK4 depletion or inhibition, dynein-based PCM transport and PCM self-clustering are sufficient to form a single compact MTOC, which generates a dense radial microtubule array. Interphase PCM self-assembly depends on γ-tubulin, pericentrin, CDK5RAP2 and ninein, but not NEDD1, CEP152 or CEP192. Formation of a compact acentriolar MTOC is inhibited by AKAP450-dependent PCM recruitment to the Golgi or by randomly organized CAMSAP2-stabilized microtubules, which keep PCM mobile and prevent its coalescence. Linking of CAMSAP2 to a minus-end-directed motor leads to the formation of an MTOC, but MTOC compaction requires cooperation with pericentrin-containing self-clustering PCM. Our data reveal that interphase PCM contains a set of components that can self-assemble into a compact structure and organize microtubules, but PCM self-organization is sensitive to motor-and microtubule-based rearrangement.
A large randomised controlled intervention trial to prevent gastric cancer by eradication of<i>Helicobacter pylori</i>in Linqu County, China: baseline results and factors affecting the eradication
Authors: Kai-feng Pan, Lian Zhang, Markus Gerhard, Jun-ling Ma, Wei-dong Liu, Kurt Ulm, Jian-xi Wang, Lei Zhang, Yang Zhang, Monther Bajbouj, Lan-fu Zhang, Ming Li, Michael Vieth, Rui-yong Liu, Michael Quante, Le-hua Wang, Stepan Suchanek, Tong Zhou, Wei-xiang Guan, Roland Schmid, Meinhard Classen, Wei-cheng You
Journal: Gut (2015)

<h3>Objective</h3> To clarify the full range of benefits and adverse consequences of <i>Helicobacter pylori</i> eradication as a strategy for gastric cancer prevention, the community-based intervention trial was launched in Linqu County, China. <h3>Design</h3> A total of 184 786 residents aged 25–54 years were enrolled in this trial and received <sup>13</sup>C-urea breath test. <i>H. pylori</i> positive participants were assigned into two groups, either receiving a 10-day quadruple anti-<i>H. pylori</i> treatment or lookalike placebos together with a single dosage of omeprazole and bismuth. <h3>Results</h3> The prevalence of <i>H. pylori</i> in trial participants was 57.6%. A total of 94 101 subjects completed the treatment. The overall <i>H. pylori</i> eradication rate was 72.9% in the active group. Gender, body mass index, history of stomach disease, baseline delta over baseline-value of <sup>13</sup>C-urea breath test, missed medication doses, smoking and drinking were independent predictors of eradication failure. The missed doses and high baseline delta over baseline-value were important contributors in men and women (all P<sub>trend</sub>&lt;0.001). However, a dose-response relationship between failure rate and smoking or drinking index was found in men (all P<sub>trend</sub>&lt;0.001), while high body mass index (P<sub>trend</sub>&lt;0.001) and history of stomach disease were significant predictors in women. The treatment failure rate increased up to 48.8% (OR 2.87, 95% CI 2.24 to 3.68) in men and 39.4% (OR 2.67, 95% CI 1.61 to 4.42) in women with multiple factors combined. <h3>Conclusions</h3> This large community-based intervention trial to eradicate <i>H. pylori</i> is feasible and acceptable. The findings of this trial lead to a distinct evaluation of factors influencing eradication that should be generally considered for future eradication therapies. <h3>Trial registration number</h3> ChiCTR-TRC-10000979 in accordance with WHO ICTRP requirements.
Parasuicide in Central London 1984-1988
Authors: G N Fuller, A J Rea, J F Payne, A F Lant
Journal: Journal of the Royal Society of Medicine (1989)

Experience of a central London unit dedicated to the care of patients following parasuicide between 1984 and 1988 is reviewed. There were 1160 admissions, which accounted for 11% of all acute adult medical admissions. The female to male ratio was 1.3, with a peak rate for females below 25 years and for males between 20 and 35. Unemployment was found to be a risk factor for parasuicide in men. Benzodiazepines were the most frequently used drug in parasuicide (35%), followed by paracetamol (13%) and aspirin (9%).
Exercise tolerance and symptoms after standard rrehabilitation in emphysema-like COPD patients
Authors: Ernesto Crisafulli, Elena Venturelli, Gianluca Biscione, Guido Vagheggini, Andrea Iattoni, Sasha Lucic, Nicolino Ambrosino, Franco Pasqua, Enrico M. Clini
Journal: European Respiratory Journal (2011)

In this retrospective analysis on a cohort of 823 COPD patients (age 71±8 yrs, FEV 1  56±18% pr.) admitted in 3 centres, we aimed at describing the effect of standard rehabilitation on exercise tolerance and symptoms in the subgroup of emphysema-like individuals, as defined by lung function parameters.  Pre-to-post changes (D) in exercise tolerance (6MWT), Borg dyspnea (D), fatigue (F) and SatO 2  nadir (N) on effort, perceived breathlessness (MRC), and quality-of-life (SGRQ) were reported. Proportion of patients reaching the minimally clinical important difference (MCID) in 6MWT, D, F, MRC and SGRQ were also recorded. Outcomes were then compared between the Emphysema ( E , n=283) and the COPD ( C , n=540) subgroups.  Lung functions were different by definition when comparing the two groups, with similar age, body mass, exercise tolerance, and breathlessness at baseline.  D-6MWD (+72±47 and +62±42 m, p=0.002), D-D (-2.3±1.7 and -1.9±1.3 point, p=0.002), D-F (-2.2±1.9 and -1.9±1.6 point, p=0.070), and D-N (+1.4±3.0 and +0.5±3.3 point, p=0.002) were higher, whereas a larger proportion of patients improved at the MCID in 6MWT (62% and 54%, p=0.040) in group E when compared with group C. Using a multivariate logistic regression model, we found that higher normalised PaO 2 , and lower 6MWT, and FRC at baseline significantly correlated with D-6MWT within the E group (p  This study generates the hypothesis that COPD patients with emphysema phenotype are more likely to gain exercise tolerance and perceived symptoms after standard rehabilitation.
Development of symptom assessment tool for terminal cancer patients
Authors: S. Koh, K. Lee, Y. Hong, J. Kang, I. Woo, M. Lee, S. Choi
Journal: Journal of Clinical Oncology (2007)

19634 Background: A symptom assessment is important to control the terminal cancer patients’ symptoms successfully and improve their quality of life. Our research team has developed the objective assessment method for the terminal patients’ symptoms and compared the results with the patient self-reported outcomes using Memorial Symptom Assessment Scale (MSAS). Methods: From September in 2004, the 121 inpatients without anti-cancer therapy in terminal stage of cancer were evaluated in Kangnam St. Mary's Hospital. The 17 common symptoms were graded as four categories; none(0), mild(1), moderate(2), and severe(3) with reference to NCI-CTC and WHO toxicity criteria. An attending physician assessed 17 symptoms at the similar hour every day. Among the inpatients, those who had clear consciousness and could communicate normally were investigated every week to evaluate the frequency and severity of common symptoms and their distress degree using MSAS. Results: Only 54 patients (44.6%) could be examined to evaluate the symptoms by MSAS. However, the symptoms estimated by our assessment tool were less serious in the terms of severity and distress degree than that patients felt actually. This tendency was shown more obviously in the mental symptoms; Drowsiness (p=0.0001), Nervousness (p=0.0001), and Anxiety (p=0.005). However, the physical symptoms had no statistical difference between the results from patients and physician. Conclusions: Patient-reported outcomes using MSAS could be obtained from 44.6% of the inpatients with terminal cancer every week. However, the objective assessment tool to evaluate the common symptoms of terminal cancer patients can be applied for all patients including the incommunicable, every day. Furthermore, this assessment tool may be more suitable for examining the physical symptoms of terminal cancer patients. No significant financial relationships to disclose.
Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review
Authors: H.J.M.J. Crijns, S.M. Straus, C. Gispen-de Wied, L.T.W. de Jong-van den Berg
Journal: British Journal of Dermatology (2010)

Journal Article Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review Get access H.J.M.J. Crijns, H.J.M.J. Crijns Medicines Evaluation Board, The Hague, the NetherlandsDepartment of PharmacoEpidemiology & PharmacoEconomics, Graduate school of SHARE, University of Groningen, Ant Deusinglaan 1, 9713 AV Groningen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar S.M. Straus, S.M. Straus Medicines Evaluation Board, The Hague, the NetherlandsDepartment of Medicinal Informatics, Erasmus Medical Center, Rotterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar C. Gispen‐de Wied, C. Gispen‐de Wied Medicines Evaluation Board, The Hague, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar L.T.W. de Jong‐van den Berg L.T.W. de Jong‐van den Berg Department of PharmacoEpidemiology & PharmacoEconomics, Graduate school of SHARE, University of Groningen, Ant Deusinglaan 1, 9713 AV Groningen, the Netherlands L.T.W de Jong‐van den Berg. E‐mail: l.t.w.de.jong‐van.den.berg@rug.nl Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 164, Issue 2, 1 February 2011, Pages 238–244, https://doi.org/10.1111/j.1365-2133.2010.09976.x Published: 01 February 2011