tbuckley/cabot-search huggingface dataset:
Phase I/II trial of a twice-daily regimen of temozolomide and celecoxib for treatment of relapsed/refractory glioblastoma multiforme and anaplastic astrocytoma
Authors: S. Pannullo, S. Hariharam, J. Serventi, R. Hayes, C. Balmaceda, J. Burton
Journal: Journal of Clinical Oncology (2004)

1549 Background: Combination therapy using agents with different mechanisms of action and non-overlapping toxicity may be a safe and effective strategy in cancer therapy. As seen in Phase I of this trial, BID temozolomide [Temodar (TMZ)] in combination with celecoxib (Celebrex) is a safe treatment regimen for malignant glioma. Phase II of this clinical trial tests the hypothesis that celecoxib combined with a BID schedule of TMZ is a more effective therapy for recurrent/progressive malignant glioma. Methods: Patients received a loading dose of 200 mg/m2 of TMZ followed by 9 doses of 90 mg/m2 TMZ BID for 5 days of every 28 day cycle. Celecoxib was given to a maximum dose of 480 mg/m2 for 10 days. The regimen was well-tolerated by most patients. Hematologic toxicity was mild and did not recur following TMZ dose reduction. Results: 36 patients (22 M, 14 F) received 141 cycles of therapy. Interim responses were evaluated after 2 cycles. In the 29 patients evaluable for response, 5/29 (17%) had a partial response (PR), 21/29 (72.5%) had stable disease (SD), and 3/29 (10.5%) had progressive disease, resulting in an overall response rate of 90% at 2 months. One patient had a CR after 7 cycles. One patient had a PR for 13 cycles but developed spinal cord tumor. Average duration of response was 5.2 months (range, 2–13). The 6-month PFS for 23 evaluable patients was 8/23(35%) and 6-month overall survival rate of 19/23(83%). Conclusions: A regimen of twice-daily TMZ and celecoxib is a safe and potentially effective regimen for the treatment of recurrent high-grade glioma. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Autoimmune manifestations in aged mice arise from early-life immune dysregulation
Authors: Tamer I. Mahmoud, Jingya Wang, Jodi L. Karnell, Qiming Wang, Shu Wang, Brian Naiman, Phillip Gross, Philip Z. Brohawn, Chris Morehouse, Jordan Aoyama, Clive Wasserfall, Laura Carter, Mark A. Atkinson, David V. Serreze, Helen Braley-Mullen, Tomas Mustelin, Roland Kolbeck, Ronald Herbst, Rachel Ettinger
Journal: Science Translational Medicine (2016)

Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren's syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren's pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.
Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences, and Countermeasures
Authors: Gregory D. M. Potter, Debra J. Skene, Josephine Arendt, Janet E. Cade, Peter J. Grant, Laura J. Hardie
Journal: Endocrine Reviews (2016)

Abstract Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.
GW26-e4458 A long-term misdiagnosis of catecholaminergic polymorphic ventricular tachycardia as epilepsy caused by RyR2 mutation
Authors: Xin Liu, Juxiang Li, Yang Shen, Jinzhu Hu, Wenfeng He, Qiongqiong Zhou, Wengen Zhu, Jiejing Jin, Kui Hong
Journal: Journal of the American College of Cardiology (2015)
Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis
Authors: Jeri W. Nieves, Chris Gennings, Pam Factor-Litvak, Jonathan Hupf, Jessica Singleton, Valerie Sharf, Björn Oskarsson, J. Americo M. Fernandes Filho, Eric J. Sorenson, Emanuele D’Amico, Ray Goetz, Hiroshi Mitsumoto
Journal: JAMA Neurology (2016)

There is growing interest in the role of nutrition in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS).To evaluate the associations between nutrients, individually and in groups, and ALS function and respiratory function at diagnosis.A cross-sectional baseline analysis of the Amyotrophic Lateral Sclerosis Multicenter Cohort Study of Oxidative Stress study was conducted from March 14, 2008, to February 27, 2013, at 16 ALS clinics throughout the United States among 302 patients with ALS symptom duration of 18 months or less.Nutrient intake, measured using a modified Block Food Frequency Questionnaire (FFQ).Amyotrophic lateral sclerosis function, measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), and respiratory function, measured using percentage of predicted forced vital capacity (FVC).Baseline data were available on 302 patients with ALS (median age, 63.2 years [interquartile range, 55.5-68.0 years]; 178 men and 124 women). Regression analysis of nutrients found that higher intakes of antioxidants and carotenes from vegetables were associated with higher ALSFRS-R scores or percentage FVC. Empirically weighted indices using the weighted quantile sum regression method of "good" micronutrients and "good" food groups were positively associated with ALSFRS-R scores (β [SE], 2.7 [0.69] and 2.9 [0.9], respectively) and percentage FVC (β [SE], 12.1 [2.8] and 11.5 [3.4], respectively) (all P < .001). Positive and significant associations with ALSFRS-R scores (β [SE], 1.5 [0.61]; P = .02) and percentage FVC (β [SE], 5.2 [2.2]; P = .02) for selected vitamins were found in exploratory analyses.Antioxidants, carotenes, fruits, and vegetables were associated with higher ALS function at baseline by regression of nutrient indices and weighted quantile sum regression analysis. We also demonstrated the usefulness of the weighted quantile sum regression method in the evaluation of diet. Those responsible for nutritional care of the patient with ALS should consider promoting fruit and vegetable intake since they are high in antioxidants and carotenes.
GW26-e2358 Current status regarding the cardiovascular disease-related risk levels among the hypertensive population of different ethnicities in Xinjiang, China
Authors: Mintao Gai, Yining Yang, Xiang Xie, Xiaomei Li, xiang Ma, Fen Liu, Zhenyan Fu, Bangdang Chen, Xiaocui Chen, Yitong Ma
Journal: Journal of the American College of Cardiology (2015)
Anabolic steroid use: Table 1
Authors: John H M Brooks, Imtiaz Ahmad, Graham Easton
Journal: BMJ (2016)

#### What you need to know

A 27 year old man weight-trains five times a week and has used anabolic steroids orally for six months. He is concerned about long term health consequences.

Anabolic steroids are synthetic testosterone derivatives usually taken without medical advice to increase muscle mass or improve athletic performance. Risk factors include male sex (<2% female),1 body dysmorphic disorder,2 competitive sport participants, and bodybuilders. Steroid induced muscle gain is possible even without training.4 There are an estimated three million users in Europe.5

Establish the substances involved and pattern of use. Testosterone derivatives are known as “roids” or “juice”. Some nutritional supplements may also contain steroids.7

Ask about duration and pattern of use, including “cycling” of different combinations of drugs over 6-12 weeks, “stacking” of more than one different steroid, and “pyramiding” by using variable doses to improve effectiveness and reduce side effects. Users may periodically abstain to allow normal hormonal production to return (“post-cycle therapy”) to try and prevent hypothalamic-pituitary-gonadal …
The Amount of Mitochondrial Apoptosis Exerts Prognostic Impact on Normal Karyotype Acute Myeloid Leukemia.
Authors: Giovanni Del Poeta, Maria Ilaria Del Principe, Francesco Buccisano, Luca Maurillo, Benedetta Neri, Licia Ottaviani, Fabrizio Luciano, Daniela Piccioni, Maria Irno Consalvo, Emanuele Ammatuna, Antonio Bruno, Paolo de Fabritiis, Valter Gattei, Adriano Venditti, Francesco Lo Coco, Sergio Amadori
Journal: Blood (2008)
Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy
Authors: Javier Díez
Journal: European Journal of Heart Failure (2016)

Abstract Natriuretic peptides ( NPs ) promote diuresis, natriuresis and vasodilation in early chronic heart failure ( CHF ), countering renin–angiotensin–aldosterone system ( RAAS ) and sympathetic nervous system ( SNS ) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial ( ANP ) or brain ( BNP ) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system ( NPS ) in CHF . First, there is reduced availability of active forms of NPs , namely BNP . Second, target organ responsiveness becomes diminished. Third, the counter‐regulatory hormones of the RAAS and SNS , and endothelin‐1 become over‐activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP , or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS , in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF .
Is intravesical BCG alone still the only truly effective intravesical therapy for high risk non-muscle invasive bladder cancer?
Authors: Savino Mauro Di Stasi, Claus Riedl, Cristian Verri, Francesco Celestino, Francesco De Carlo, Antonella Giannantoni, Germano Zampa, Marco Valenti
Journal: Journal of Clinical Oncology (2015)

e15544 Background: In a randomized trial it have been shown that intravesical sequential bacillus Calmette-Guerin (BCG) and mitomycin (MMC) is superior to BCG alone in patients with pT1 urothelial bladder cancer. A 5-year and 10-year contemporary cost-effectiveness study of these 2 treatment strategies suggest that sequential therapy is a cost-effective treatment for patients with high-risk non–muscle-invasive bladder cancer. After an additional 6 years of follow-up, we report estimated 10-year results. Methods: From 1994 through 2002, we randomly assigned 212 patients with pT1 bladder cancer to 81 mg BCG infused over 120 min once a week for 6 weeks (n = 105) or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by MMC 40 mg for 30 min, once a week as one cycle for three cycles (n = 107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and MMC had 40 mg of MMC once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression, overall and disease-specific survival. Results: Median follow-up was 121 months (IQR 70.5–163.5). Patients assigned sequential BCG and MMC had higher disease-free interval than did those assigned BCG alone (79 months [95% CI 27–139] vs 26 months [11–113]; difference between groups 53 months [39–67], log-rank p = 0.0002). Patients assigned sequential BCG and MMC also had lower recurrence (45% [35–55] vs 62% [50–72], difference between groups 17% [6–28], log-rank p = 0.0002); progression (12% [3–21] vs 28% [17.5–38.5], difference between groups 16% [5–27], log-rank p = 0.003); overall mortality (44% [33–55] vs 59% [43–75], difference between groups 15% [2–28], log-rank p = 0.01); and disease-specific mortality (9% [2.5– 15.5] vs 23% [11–34], difference between groups 14% [4–24], log-rank p = 0.0055). Conclusions: The data of this study, cost-effectiveness analysis, and positive experiences reported by others, suggest that intravesical sequential BCG and MMC therapy can be potentially integrated into hospital and health system as a standard of care. Clinical trial information: NCT01442519.
Prostate volume as an independent predictor of prostate cancer and high-grade disease on prostate needle biopsy
Authors: A. J. Woodruff, T. M. Morgan, J. L. Wright, C. R. Porter
Journal: Journal of Clinical Oncology (2008)

5165 Background: The relationship between prostate volume and the risk of prostate cancer remains a significant question. Evidence suggests that decreased gland size is a risk factor for increased cancer detection. Some have suggested that smaller glands are more likely to harbor higher grade cancer. We sought to further evaluate this relationship using a prospectively collected PNB database. Methods: We analyzed 507 consecutive patients undergoing 10–12 core PNB between 9/04 and 8/07 by a single urologist. Data were collected prospectively including age, family history, DRE, PSA, Gleason grade, IPSS, total gland and transitional zone (TZ) volumes on ultrasound. Gland and TZ volumes were categorized by quartiles. Multivariate logistic regression was used to assess the relationship between gland volumes and PNB result. A separate analysis was performed for identification of high grade disease. Results: Increasing total gland volume independently decreased the risk of cancer with an OR of 0.35 (95% CI 0.14–0.90) in the highest quartile compared to the lowest quartile. The highest TZ volume quartile had an OR of 0.37 (CI 0.15–0.94) for having a positive PNB compared with the lowest quartile. Increasing total gland and TZ volume quartiles were associated with an increased risk of high grade cancer (p<0.05 for trend). Men in the second quartile of prostate volume had a significantly lower risk of high grade disease than the men in the smallest quartile (OR=0.27,CI 0.09- 0.83). In the largest volume quartiles for total gland and TZ, the risk of high grade cancer was reduced by 80% (OR=0.20,CI 0.05–0.78) and 87% (OR=0.13,CI 0.03–0.53), respectively, compared to the lowest quartiles. Conclusions: There is a highly important relationship between gland size and the diagnosis of prostate cancer on PNB which cannot be explained by volume sampling error in larger glands alone. The independent effect exerted by increasing TZ size is consistent with BPH as the principal driver of elevated serum PSA in men with larger prostates. Men with smaller glands not only have a greater risk of prostate cancer, but a greater risk of high grade disease. Identifying molecular and hormonal factors responsible for this phenomenon will be important in furthering our understanding of this disease. No significant financial relationships to disclose.
Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study
Authors: Arnaud Pigneux, Marie C. Béné, Philippe Guardiola, Christian Recher, Jean-Francois Hamel, Mathieu Sauvezie, Jean-Luc Harousseau, Olivier Tournilhac, Francis Witz, Christian Berthou, Martine Escoffre-Barbe, Denis Guyotat, Nathalie Fegueux, Chantal Himberlin, Mathilde Hunault, Martine Delain, Bruno Lioure, Eric Jourdan, Frederic Bauduer, Francois Dreyfus, Jean-Yves Cahn, Jean-Jacques Sotto, Norbert Ifrah
Journal: Journal of Clinical Oncology (2016)

Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m2 on days 1 to 5, cytarabine 100 mg/m2 on days 1 to 7, and lomustine 200 mg/m2 on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m2 on day 1, cytarabine 100 mg/m2 on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 109/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.
Higher MMP9 and FGF2 Protein Levels and Elevated MMP9/TIMP Ratios Were Associated with JAK2V617F Mutation Regardless of Allele Burden in Myelofibrosis
Authors: Luciene Terezina Lima, Daniela Prudente Teixeira Nunes, Guilherme Wataru Gomes, Maria de Lourdes L. F. Chauffaille, Maria Regina Regis Silva, Cesar Cilento Ponce, Fabiola Attié Castro, Marcos Tadeu Santos, Elvira M Guerra-Shinohara
Journal: Blood (2014)
Notch Inhibition in Alloreactive CD4+ and CD8+ T Cells Blocks Graft-Versus-Host Disease by Inducing a Hyporesponsive Program with Features of T Cell Anergy
Authors: Ashley R Sandy, Jooho Chung, Ivy T Tran, Gloria T Shan, Ann Friedman, Timothy S Blackwell, Pavan Reddy, Philip D King, Ivan Maillard
Journal: Blood (2012)
Evidence for QTLs Influencing the Endogenous Thrombin Potential (ETP) and Protein C Concentrations in a Dutch Family with Unexplained Thrombophilia.
Authors: Michael W.T. Tanck, Iris M. Wichers, Joost C.M. Meijers, Harry R. Büller, Pieter H. Reitsma, Saskia Middeldorp
Journal: Blood (2007)
Survival Advantage for Patients (pts) with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) Treated with Imatinib.
Authors: Jorge Cortes, Moshe Talpaz, Susan O’Brien, Guillermo Garcia-Manero, Farhad Ravandi-Kashami, Francis Giles, Stefan Faderl, William Wierda, Jianqin Shan, Mary Beth Rios, Hagop Kantarjian
Journal: Blood (2004)
European drug agency launches website giving open access to trial data
Authors: Nigel Hawkes
Journal: BMJ (2016)

The European Medicines Agency’s new website giving open access to clinical data on medicinal products has gone live (https://clinicaldata.ema.europa.eu).

The agency said that that the first two drugs whose clinical reports could be accessed on the site are carfilzomib, for the treatment of multiple myeloma, and lesinurad, a gout treatment.

It intends to add all clinical reports on all drugs submitted to the agency on or after its open access policy came into force on 1 January 2015.1 An indication of the scale of the operation is that for these two drugs alone the data comprise 260 000 pages and include 100 separate clinical reports.

Guido Rasi, the agency’s executive director, said that the launch was an important step towards transparency …
GW26-e2477 Impact of Gestational Diabetes Mellitus on Pregnant, Obstetric and Neonatal Outcomes: a 10-Year Retrospective Double Cohort Study
Authors: Guanghua Wang, Liang Zheng, Juanli Wu, Jing Wu, Miaomiao Zhao, Siyun Yu, Qiaoyu Jiang, Jie Zhang, Qian zhou, Jue Li
Journal: Journal of the American College of Cardiology (2015)
Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study
Authors: Daniel R Gomez, George R Blumenschein, J Jack Lee, Mike Hernandez, Rong Ye, D Ross Camidge, Robert C Doebele, Ferdinandos Skoulidis, Laurie E Gaspar, Don L Gibbons, Jose A Karam, Brian D Kavanagh, Chad Tang, Ritsuko Komaki, Alexander V Louie, David A Palma, Anne S Tsao, Boris Sepesi, William N William, Jianjun Zhang, Qiuling Shi, Xin Shelley Wang, Stephen G Swisher, John V Heymach
Journal: The Lancet Oncology (2016)