tbuckley/cabot-search huggingface dataset:
Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer.
Authors: A Sella, R Kilbourn, R Amato, C Bui, A A Zukiwski, J Ellerhorst, C J Logothetis
Journal: Journal of Clinical Oncology (1994)

PURPOSE A phase II clinical trial was performed to assess the antitumor activity and toxicity of ketoconazole in combination with doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) in patients with androgen-independent prostate cancer (AI PCa). PATIENTS AND METHODS Thirty-nine consecutive patients whose disease progressed following castration were treated with oral ketoconazole (1,200 mg) daily and Adriamycin (20 mg/m2 in a 24-hour infusion) once weekly. Antitumor activity was assessed by the level of prostatic-specific antigen (PSA) decline. RESULTS PSA levels decreased &gt; or = 50% from baseline in 21 (55%; 95% confidence interval, 38% to 71%) of 38 assessable patients. We observed partial responses (PRs) in seven (58%) of 12 patients with measurable soft tissue disease (in the lung, lymph nodes, and liver). Two patients with history of atherosclerotic heart disease had a sudden cardiac death. Serious toxic reactions included grade III to V stomatitis and grade III to IV acral erythema in 11 patients (29%), and grade III to IV anal and urethral mucositis in five patients (13%). Grade III to IV neutropenia occurred in 11 patients (29%). Seventeen patients (45%) required hospitalization for complications. Fifteen patients (39%) developed hypokalemia, and 24 patients (63%) developed clinical adrenal insufficiency. CONCLUSION The combination of ketoconazole and Adriamycin has a 55% PSA response rate in patients with AI PCa and is worthy of additional study. This treatment results in frequent adrenal insufficiency. Therefore, future studies should incorporate routine corticosteroid replacement. The cardiac complications caused by this combination should be studied further before it is widely used.
Renal vascular complications of systemic lupus erythematosus.
Authors: G B Appel, C L Pirani, V D'Agati
Journal: Journal of the American Society of Nephrology (1994)

Journal of the American Society of Nephrology : JASN 4(8):p 1499-1515, February 1994. | DOI: 10.1681/ASN.V481499
Med12 gain-of-function mutation causes leiomyomas and genomic instability
Authors: Priya Mittal, Yong-hyun Shin, Svetlana A. Yatsenko, Carlos A. Castro, Urvashi Surti, Aleksandar Rajkovic
Journal: Journal of Clinical Investigation (2015)

Uterine leiomyomas are benign tumors that can cause pain, bleeding, and infertility in some women. Mediator complex subunit 12 (MED12) exon 2 variants are associated with uterine leiomyomas; however, the causality of MED12 variants, their genetic mode of action, and their role in genomic instability have not been established. Here, we generated a mouse model that conditionally expresses a Med12 missense variant (c.131G>A) in the uterus and demonstrated that this alteration alone promotes uterine leiomyoma formation and hyperplasia in both WT mice and animals harboring a uterine mesenchymal cell–specific Med12 deletion. Compared with WT animals, expression of Med12 c.131G>A in conditional Med12–KO mice resulted in earlier onset of leiomyoma lesions that were also greater in size. Moreover, leiomyomatous, Med12 c.131G>A variant–expressing uteri developed chromosomal rearrangements. Together, our results show that the common human leiomyoma–associated MED12 variant can cause leiomyomas in mice via a gain of function that drives genomic instability, which is frequently observed in human leiomyomas.
Comorbidity between chronic obstructive pulmonary disease and type 2 diabetes in adult twins
Authors: Howraman Meteran, Backer Vibeke, Kyvik Kirsten Ohm, Axel Skytthe, Simon Francis Thomsen
Journal: European Respiratory Journal (2012)

Aim : To examine the relationship between chronic bronchitis and chronic obstructive pulmonary disease (COPD), and type 2 diabetes in adult twins.   Methods : Questionnaire data on chronic bronchitis and hospital data on diagnosed COPD on 13,649 twins, 50-71 years of age, from the Danish Twin Registry, were cross-linked with hospital discharge diagnosis data on type 2 diabetes from the Danish National Patient Registry.   Results : The risk of type 2 diabetes was higher in subjects with symptoms of chronic bronchitis compared with subjects without symptoms of chronic bronchitis (3.5 vs. 2.3%), OR=1.53 (1.09 - 2.15), p=0.013; and in subjects with diagnosed COPD compared with subjects without diagnosed COPD (6.6 vs. 2.3%), OR=2.97 (1.95-4.53), p=0.000. The results were significant after adjusting for age, sex, and smoking. Correlations between genetic effects on chronic bronchitis and type 2 diabetes; and between genetic effects on diagnosed COPD and type 2 diabetes, respectively, were 0.25 (0.00-0.59), p=0.130 and 0.35 (0.00-0.72), p=0.134.   Conclusions : Patients with chronic bronchitis and COPD have an increased risk of type 2 diabetes independently of sex, age, and smoking. Furthermore, comorbidity between these diseases seemed not to be explained by shared genetic factors. The increased risk of type 2 diabetes must be accommodated in the management of patients with chronic bronchitis and COPD.
Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma
Authors: A J Novak, Y W Asmann, M J Maurer, C Wang, S L Slager, L S Hodge, M Manske, T Price-Troska, Z-Z Yang, M T Zimmermann, G S Nowakowski, S M Ansell, T E Witzig, E McPhail, R Ketterling, A L Feldman, A Dogan, B K Link, T M Habermann, J R Cerhan
Journal: Blood Cancer Journal (2015)

Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P<0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P=7.4 × 10(-12)) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.
Actual usage of medical facilities by asthmatics in two French rural settings: a preliminary study
Authors: A Taytard, JF Tessier, M Gervais, JP Gachie, C Douet, L Kombou, J Vergeret, P Freour
Journal: European Respiratory Journal (1990)

Until recently the medical management of asthmatic patients with respect to their socio-cultural environment had only been superficially studied. Four hundred and fifty eight adult asthmatics were identified through a two-stage questionnaire in two rural districts of south west France. The study has mainly demonstrated: 1) the large number of subjects experiencing more than one attack per week (33% in Gironde, 40% in Lot et Garonne); 2) the large number of subjects feeling disabled in their occupational and day-to-day life (52% in Gironde, 54% in Lot et Garonne); 3) the absence of a relationship between the severity of the disease and the use of medical facilities in the community. Despite the frequency of the attacks and the perceived disability, 27% of the patients felt that their asthma did not require any treatment and up to 60% did not seek medical help even during an attack; 4) the role of population density, type of dwelling and social status in the management of asthma. We conclude that under-treatment is widespread in these two rural settings and is closely related with the association of at least two of these three characteristics: 1) living in a low population density area; 2) living in an isolated dwelling; and 3) being a farm owner.
Some Patients Don't Need Analgesics after Surgery
Authors: H J McQuay, R A Moore, J W Lloyd, R E S Bullingham, P J D Evans
Journal: Journal of the Royal Society of Medicine (1982)

Postoperative analgesic requirements of 410 patients undergoing elective orthopaedic limb surgery were studied. Premedication and anaesthetic were standardized with no narcotic. Twenty-three patients required no analgesic at all during their hospital stay. The importance of acknowledging the existence of this group of patients is discussed. The distribution of time to first analgesic requirement for the other patients was obtained. The importance of knowing the distribution for particular operative procedures and the effect of analgesic interventions such as premedication is discussed.
An application of electron paramagnetic resonance to evaluate nitric oxide and its quenchers.
Authors: T Yoshioka, N Iwamoto, K Ito
Journal: Journal of the American Society of Nephrology (1996)

Electron paramagnetic resonance (EPR) spectrometry has been used for detection of free radicals, including nitric oxide (NO). The method was applied to evaluate if lazaroids, nonspecific scavengers of oxygen-derived free radicals, can reduce another radical species, namely, NO. When solutions containing 0 to 10 microM lazaroids (U78517F, U83836E, and U74500A) were mixed with NO (approximately 8.0 microM), and with a spin-trap agent specific to NO (10 microM carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3 oxide, c-PTIO), the spectrum of NO-c-PTIO determined by the EPR decreased with increasing concentrations of lazaroids. An identical study with 1 to 1000 microM methylprednisolone or dexamethasone, which are prototypes of lazaroids, failed to reduce NO. In a separate study, rat red blood cells preloaded with U78517F were exposed to NO. EPR spectrometry demonstrated that hemoglobin in these cells were less nitrosylated compared with the cells not preloaded with U78517F. An ability of lazaroids to quench NO in vivo was evaluated by an intravenous injection of sodium nitrite (4 mumol/kg body weight) into rats pretreated with 10 mg/kg lazaroids (U78517F and U74500A). The nitrosylation of RBC hemoglobin was markedly attenuated in rats pretreated with lazaroids compared with those with vehicle. Thus, these lipophilic compounds protected cells from NO-induced nitrosylation both in vitro and in vivo. Lazaroids may be applicable as anti-NO agents.
Liquefied petroleum gas associated airflow obstruction in manual cigarette lighter refilling workers
Authors: Subhabrata Moitra, Paul Blanc
Journal: European Respiratory Journal (2013)

Background:  Manual gas cigarette lighter refilling with butane/propane liquefied petroleum gas (LPG) is a common low-income occupation in India. This includes devices intended to be disposable. Although this job task releases LPG in the worker’s breathing zone, the respiratory effects of this occupation have not been studied.   Methods:  We studied 105 exposed LPG refillers (mean age 40.7±7.2 years) and 72 referents (42.3±10.2 years). We quantified exposure based on reported average daily use of LPG (mean exposure among refillers (56.4±24.5 ml) and performed routine spirometry. We compared age, height, ever smoking, forced expiratory volume in one sec (FEV 1 ), forced vital capacity, (FVC), and FEV 1 /FVC ratio for exposed vs. referents using the Mann-Whitney U test. Multiple linear regression models estimated the LPG exposure response (daily use, mls) within the group of refilling workers, adjusting for age, height, and smoking status.   Results:  There were no statistically significant differences in age, height or smoking between exposed and referents. Exposed vs. referent status was associated with a 160 ml FEV 1  decrement (2.40±0.3 vs. 2.24±0.3 L; p 1 /FVC (both p 1  (100±25 ml), FVC (50±25 ml) and FEV 1 /FVC (2.5%) scaled per 1 SD in daily LPG use (p   Conclusion:  Use of LPG as a fuel during manual gas lighter refilling is associated with airflow obstruction. This could represent an acute or chronic LPG-mediated effect.   Clinical Relevance:  Excess exposure to LPG should be assessed as a potentially preventable risk factor for airway disease.
A proof-of-concept randomized-controlled trial of omalizumab in patients with severe difficult to control nonatopic asthma
Authors: Gilles Garcia, Antoine Magnan, Raphaël Chiron, Pierre-Olivier Girodet, Vincent Le Gros, Marc Humbert
Journal: European Respiratory Journal (2012)

While up to 50% of severe asthma patients have no evidence of allergy, IgE has been linked to asthma in epidemiological and immunopathological studies, irrespective of atopic status. Omalizumab (OMA), an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with poorly controlled severe persistent allergic asthma. Therefore biological and clinical effects of OMA were investigated in patients with refractory nonatopic asthma.   Methods:  41 patients with severe nonatopic asthma uncontrolled despite daily high-dose inhaled corticosteroids (with or without maintenance oral corticosteroids) plus a long-acting β 2 -agonist were randomized to receive OMA or placebo in a 1:1 ratio. Primary end-point was change in expression of high-affinity IgE receptor FceRI on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact on lung function and clinical parameters was also assessed.   Results:  When compared to placebo, OMA treatment resulted in a statistically significant reduction in FceRI expression on blood basophils and pDC2 (p 1  compared to baseline (+9.9%; p=0.029). The placebo-adjusted absolute change in FEV 1  with OMA was +250 ml (p=0.032). A trend toward improvement in global evaluation of treatment effectiveness scale and asthma exacerbations rate was also observed.   Conclusion:  Omalizumab treatment may have a therapeutic role in severe nonatopic asthma. These findings support further investigation to assess the clinical efficacy of omalizumab in severe persistent nonatopic asthma.  Funded by: Novartis Pharma SAS.
Extended administration of oral etoposide and oral cyclophosphamide for the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.
Authors: S M Grunberg, J Crowley, R Livingston, I Gill, S K Williamson, T O'Rourke, T Braun, M E Marshall, J K Weick, S P Balcerzak
Journal: Journal of Clinical Oncology (1993)

PURPOSE We designed an all-oral regimen of etoposide and cyclophosphamide for use in advanced non-small-cell lung cancer. PATIENTS AND METHODS Eligible patients were chemotherapy-naive and had histologically confirmed assessable or measurable stage IV non-small-cell lung cancer. Patients received etoposide 50 mg/m2/d orally days 1 through 14 and cyclophosphamide 50 mg/m2/d orally days 1 through 14 every 28 days. Doses on later cycles were adjusted for myelosuppression. RESULTS Sixty-six patients (64 eligible patients) received 192 cycles of oral extended etoposide/cyclophosphamide therapy (median, two cycles; range, zero to 15). Therapy was well tolerated with the mean dose per cycle being 104% of the originally scheduled dose. Two patients (3%) achieved a complete response and six (9%) achieved a partial response. Leukopenia, anemia, nausea/vomiting, and alopecia were the most common toxicities. Median survival was 6 months, and the 1-year survival rate was 25.6%, comparable to more intensive treatments. CONCLUSION Oral extended etoposide/cyclophosphamide is a well-tolerated alternative for the treatment of stage IV non-small-cell lung cancer and can be used as a basis for the design of further outpatient regimens.
Transcription factor ISL1 is essential for pacemaker development and function
Authors: Xingqun Liang, Qingquan Zhang, Paola Cattaneo, Shaowei Zhuang, Xiaohui Gong, Nathanael J. Spann, Cizhong Jiang, Xinkai Cao, Xiaodong Zhao, Xiaoli Zhang, Lei Bu, Gang Wang, H.S. Vincent Chen, Tao Zhuang, Jie Yan, Peng Geng, Lina Luo, Indroneal Banerjee, Yihan Chen, Christopher K. Glass, Alexander C. Zambon, Ju Chen, Yunfu Sun, Sylvia M. Evans
Journal: Journal of Clinical Investigation (2015)

The sinoatrial node (SAN) maintains a rhythmic heartbeat; therefore, a better understanding of factors that drive SAN development and function is crucial to generation of potential therapies, such as biological pacemakers, for sinus arrhythmias. Here, we determined that the LIM homeodomain transcription factor ISL1 plays a key role in survival, proliferation, and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including animals harboring an SAN-specific Isl1 deletion, revealed that ISL1 within SAN is a requirement for early embryonic viability. RNA-sequencing (RNA-seq) analyses of FACS-purified cells from ISL1-deficient SANs revealed that a number of genes critical for SAN function, including those encoding transcription factors and ion channels, were downstream of ISL1. Chromatin immunoprecipitation assays performed with anti-ISL1 antibodies and chromatin extracts from FACS-purified SAN cells demonstrated that ISL1 directly binds genomic regions within several genes required for normal pacemaker function, including subunits of the L-type calcium channel, Ank2, and Tbx3. Other genes implicated in abnormal heart rhythm in humans were also direct ISL1 targets. Together, our results demonstrate that ISL1 regulates approximately one-third of SAN-specific genes, indicate that a combination of ISL1 and other SAN transcription factors could be utilized to generate pacemaker cells, and suggest ISL1 mutations may underlie sick sinus syndrome.
Association Between alpha-Tocopherol, gamma-Tocopherol, Selenium, and Subsequent Prostate Cancer
Authors: K. J. Helzlsouer
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Selenium and α-tocopherol, the major form of vitamin E in supplements, appear to have a protective effect against prostate cancer. However, little attention has been paid to the possible role of γ-tocopherol, a major component of vitamin E in the U.S. diet and the second most common tocopherol in human serum. A nested case–control study was conducted to examine the associations of α-tocopherol, γ-tocopherol, and selenium with incident prostate cancer. Methods: In 1989, a total of 10 456 male residents of Washington County, MD, donated blood for a specimen bank. A total of 117 of 145 men who developed prostate cancer and 233 matched control subjects had toenail and plasma samples available for assays of selenium, α-tocopherol, and γ-tocopherol. The association between the micronutrient concentrations and the development of prostate cancer was assessed by conditional logistic regression analysis. All statistical tests were two-sided. Results: The risk of prostate cancer declined, but not linearly, with increasing concentrations of α-tocopherol (odds ratio highest versus lowest fifth = 0.65; 95% confidence interval = 0.32–1.32; Ptrend = .28). For γ-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth (Ptrend = .002). The association between selenium and prostate cancer risk was in the protective direction with individuals in the top four fifths of the distribution having a reduced risk of prostate cancer compared with individuals in the bottom fifth (Ptrend = .27). Statistically significant protective associations for high levels of selenium and α-tocopherol were observed only when γ-tocopherol concentrations were high. Conclusions: The use of combined α- and γ- tocopherol supplements should be considered in upcoming prostate cancer prevention trials, given the observed interaction between α-tocopherol, γ-tocopherol, and selenium.
Clinical Assessment of Breast Cancer Risk Based on Family History
Authors: Kaylene Ready, Banu Arun
Journal: Journal of the National Comprehensive Cancer Network (2010)

Family history is a key component of breast cancer risk assessment. Family history provides clues as to the likelihood of a hereditary breast cancer syndrome and the need for a cancer genetics referral and can be used in the setting of a breast cancer risk assessment model to estimate a woman's risk. Appropriate breast cancer screening and risk reduction management plans rely on an accurate assessment of a patient's family history. This article reviews the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer Risk Reduction and provides insight into the application of the guidelines in clinical practice.
COPD admissions in London: What general practice characteristics are associated?
Authors: Lucy Jamieson, Hannah Thornton, Timothy Harries, Peter Schofield, Katherine Jackson, Patrick White
Journal: European Respiratory Journal (2013)

Background  Chronic obstructive pulmonary disease (COPD) is the commonest cause of emergency admissions in London. There is much dispute about medical care factors that influence COPD admissions.  Aim  To examine the influence of healthcare organisation (Primary Care Trust – PCT) and practice characteristics on NHS COPD admissions in London.  Method  Retrospective analysis of routinely collected data on COPD admissions of patients registered with London general practices (2005–2010) and of practice characteristics and performance data. Admission data were obtained from Hospital Episode Statistics (HES). Practice characteristics and performance data were obtained from the NHS Information Centre (Quality and Outcomes Framework - QOF). Negative binomial regression was used to assess the association between practice characteristics and COPD admission rates.  Results  Data on 51,352 COPD admissions of patients from 1,530 practices in 31 London PCTs showed mean annual COPD admissions/10,000 patients/GP list were stable between 2006 (17.5; 95%CI 16.9-18.1) and 2009 (16.8; 95%CI 16.2-17.3).  There was wide variation (median; IQR) in practice list size (4,807; 3,079–7,143), diagnosed COPD prevalence (0.89; 0.61–1.25), and deprivation rank (10,060; 5,266-17,154). Practice quality varied little: QOF total points/points available (median 0.955; IQR 0.931-0.974); QOF smoking points/available (1.0004; 1.0003-1.0005).  COPD prevalence (B=1.006; 95%CI 1.005-1.007) and deprivation (B=1.0003; 95%CI 1.0002-1.0004) were only factors significantly associated with COPD admissions.  Discussion  A wide range of practice COPD admission rates was observed. Practice characteristics were not predictors of COPD admission rates.
Lurbinectedin (Pm01183) on Days (D) 1 &amp; 8 in Combination with Capecitabine (Xel) in Patients (Pts) with Metastatic Breast (Mbc), Colorectal (Crc) or Pancreatic (Pac) Cancer
Authors: T. Sauri, P. Aftimos, S. Szyldergemajn, E. Elez, P. Barthelemy, R. Moreno, A. Soto-Matos, S. Extremera, J. Tabernero, A. Awada
Journal: Annals of Oncology (2014)