tbuckley/cabot-search huggingface dataset:
A Mechanism-Based Combination Therapy Reduces Local Tumor Growth and Metastasis in an Orthotopic Model of Prostate Cancer
Authors: Boleslav Kosharskyy, Nicolas Solban, Sung K. Chang, Imran Rizvi, Yuchiao Chang, Tayyaba Hasan
Journal: Cancer Research (2006)

Abstract Therapy-induced stimulation of angiogenic molecules can promote tumor angiogenesis leading to enhanced tumor growth and cancer metastasis. Several standard and emerging therapies, such as radiation and photodynamic therapy (PDT), can induce angiogenic molecules, thus limiting their effectiveness. PDT is approved for the treatment of several cancers; however, its induction of vascular endothelial growth factor (VEGF) creates conditions favorable to enhanced tumor growth and metastasis, therefore mitigating its cytotoxic and antivascular effects. This is the first report showing that subcurative PDT in an orthotopic model of prostate cancer (LNCaP) increases not only VEGF secretion (2.1-fold) but also the fraction of animals with lymph node metastases. PDT followed by administration of an antiangiogenic agent, TNP-470, abolished this increase and reduced local tumor growth. On the other hand, administration of TNP-470 before PDT was less effective at local tumor control. In addition, animals in all groups, except in the PDT + TNP-470 group, had a weight loss of &amp;gt;3 g at the time of sacrifice; the weight of the animals in the PDT + TNP-470 group did not change. The significant reduction (P &amp;lt; 0.05) in tumor weight and volume observed between the PDT + TNP-470 group and the control group suggests that the combination of PDT and antiangiogenic treatment administered in the appropriate sequence was not only more effective at controlling local tumor growth and metastases but also reduced disease-related toxicities. Such molecular response-based combinations merit further investigations as they enhance both monotherapies and lead to improved treatment outcomes. (Cancer Res 2006; 66(22): 10953-8)
Prognostic Significance and Molecular Associations of 18q Loss of Heterozygosity: A Cohort Study of Microsatellite Stable Colorectal Cancers
Authors: Shuji Ogino, Katsuhiko Nosho, Natsumi Irahara, Kaori Shima, Yoshifumi Baba, Gregory J. Kirkner, Jeffrey A. Meyerhardt, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2009)

Loss of heterozygosity (LOH) at chromosome 18q frequently occurs late during colon cancer development and is inversely associated with microsatellite instability (MSI). 18q LOH has been reported to predict shorter survival in patients with colorectal cancer, whereas MSI-high status has been associated with superior prognosis. However, it is unclear whether 18q LOH in colorectal cancer has any prognostic implication independent of MSI status and other potential predictors of clinical outcome.Among 555 non-MSI-high colorectal cancers (stage I to IV) in two independent prospective cohort studies, we examined 18q LOH in relation to other molecular events and patient survival. Cox proportional hazard models computed hazard ratio of death, adjusted for clinical and tumoral characteristics, including KRAS, BRAF, PIK3CA, beta-catenin, p53, CpG island methylator phenotype, LINE-1 methylation, and John Cunningham (JC) virus T antigen.In multivariate logistic regression, 18q LOH was independently associated with JC virus T antigen (odds ratio [OR] = 1.93; P = .0077), body mass index > or = 30 kg/m(2) (obesity; OR = 2.01; P = .014), high tumor grade (OR = 0.40; P = .018), KRAS mutation (OR = 0.66; P = .40), and LINE-1 hypomethylation (for a 30% decrease; OR = 1.92; P = .045). Five-year colorectal cancer-specific survival was 75% among patients with 18q LOH-positive tumors and 74% among those with 18q LOH-negative tumors (log-rank P = .80). Five-year overall survival was 70% among patients with 18q LOH-positive tumors and 68% among those with 18q LOH-negative tumors (log-rank P = .54). Multivariate analysis did not show prognostic significance of 18q LOH.In our large prospective study of patients with non-MSI-high colorectal cancer, 18q LOH or allelic imbalance was not associated with patient survival.
Exercise-induced changes in urinary water and mineral output during the menstrual cycle.
Authors: D N Prashad, P A Fletcher, M Cooper
Journal: British Journal of Sports Medicine (1987)

This study monitors changes in urinary excretion of water and minerals before and after exercise in pre-menopausal women and in those using oral contraception. Resting urine flow rate was lower and sodium output significantly higher (p less than 0.02) during the normal post-menstrual phase than during other phases of the cycle. These changes were unrelated to glomerular filtration rate and might impede maximal performance. After exercise an oliguria and hyponatriuresis were most pronounced during the menstrual phase. In addition the resting urinary output of calcium and magnesium were unrelated to normal oestrogenic and progestegenic cyclic surges. Amongst oral contraceptive users, resting excretion of water, minerals and creatinine were all significantly lower than general menstrual cycle values (p less than 0.01) and further reductions in salts and water output occurred with exercise. Basal calcium and magnesium excretion rates were significantly lower than general menstrual cycle values (p less than 0.05). Renal conservation of water and salts for 'pill' takers may affect renal homeostasis. The consequences of mineral retention are unknown.
Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore
Authors: Magdalena Juhaszova, Dmitry B. Zorov, Suhn-Hee Kim, Salvatore Pepe, Qin Fu, Kenneth W. Fishbein, Bruce D. Ziman, Su Wang, Kirsti Ytrehus, Christopher L. Antos, Eric N. Olson, Steven J. Sollott
Journal: Journal of Clinical Investigation (2004)

Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3β (GSK-3β). Alternatively, receptor tyrosine kinase or certain G protein–coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3β, via protein kinase B/Akt and mTOR/p70s6k pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3β on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.
Hemodialysis Acutely Improves Hepatic CYP3A4 Metabolic Activity
Authors: Thomas D Nolin, Kofi Appiah, Scott A Kendrick, Phuong Le, Ellen McMonagle, Jonathan Himmelfarb
Journal: Journal of the American Society of Nephrology (2006)

The uremic syndrome remains poorly understood despite the widespread availability of dialysis for almost four decades. To date, assessment of the biologic activity of uremic toxins has focused primarily on in vitro effects, rather than on specific biochemical pathways or enzymatic activity in vivo. The activity of cytochrome P450 (CYP) 3A4, the most important enzyme in human drug metabolism, is decreased in uremia. The purpose of this study was to assess the effect of hemodialysis and hence varying concentrations of uremic toxins on CYP3A4 activity using the 14C-erythromycin breath test and the traditional phenotypic trait measure, 20-min 14CO2 flux. CYP3A4 activity increased by 27% postdialysis (P = 0.002 compared with predialysis) and was significantly inversely related to plasma blood urea nitrogen concentration (rs= -0.50, P = 0.012), but not to several middle molecules. This is the first study in humans characterizing uremia as a state in which hepatic CYP3A4 activity is acutely improved by hemodialysis.
Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca <sup>2+</sup> Release
Authors: David M. Harris, Geoffrey D. Mills, Xiongwen Chen, Hajime Kubo, Remus M. Berretta, V. Scott Votaw, Luis F. Santana, Steven R. Houser
Journal: Circulation Research (2005)

Depressed contractility of failing myocytes involves a decreased rate of rise of the Ca2+ transient. Synchronization of Ca2+ release from the junctional sarcoplasmic reticulum (SR) is responsible for the rapid rise of the normal Ca2+ transient. This study examined the idea that spatially and temporally dyssynchronous SR Ca2+ release slows the rise of the cytosolic Ca2+ transient in failing feline myocytes. Left ventricular hypertrophy (LVH) with and without heart failure (HF) was induced in felines by constricting the ascending aorta. Ca2+ transients were measured in ventricular myocytes using confocal line scan imaging. Ca2+ transients were induced by field stimulation, square wave voltage steps, or action potential (AP) voltage clamp. SR Ca2+ release was significantly less well spatially and temporally synchronized in field-stimulated HF versus control or LVH myocytes. Surprisingly, depolarization of HF cells to potentials where Ca2+ currents (ICa) were maximal resynchronized SR Ca2+ release. Correspondingly, decreases in the amplitude of ICa desynchronized SR Ca2+ release in control, LVH, and HF myocytes to the same extent. HF myocytes had significant loss of phase 1 AP repolarization and smaller ICa density, which should both reduce Ca2+ influx. When normal myocytes were voltage clamped with HF AP profiles SR Ca2+ release was desynchronized. SR Ca2+ release becomes dyssynchronized in failing feline ventricular myocytes because of reductions in Ca2+ influx induced in part by alterations in early repolarization of the AP. Therefore, therapies that restore normal early repolarization should improve the contractility of the failing heart.
The Retinoid Antagonist MX781 Induces Clusterin Expression in Prostate Cancer Cells via Heat Shock Factor-1 and Activator Protein-1 Transcription Factors
Authors: Yolanda Bayon, Maria A. Ortiz, Francisco J. Lopez-Hernandez, Philip H. Howe, F. Javier Piedrafita
Journal: Cancer Research (2004)

Abstract Retinoids mediate numerous biological responses through the transcriptional activation of nuclear retinoid receptors. Due to their antiproliferative activity, retinoids have shown promise as anticancer agents. Synthetic analogs have been described that selectively activate one subset of the retinoid receptors or inhibit their transcriptional activity. Some of these compounds exhibit strong anticancer activity, which is associated with their ability to induce apoptosis. Here we describe that the retinoid antagonist MX781 causes a substantial increase of clusterin mRNA and protein levels in prostate carcinoma cells. In contrast, retinoic acid and other synthetic agonists and antagonists show no effect on clusterin mRNA/protein levels. Induction of clusterin mRNA is associated with transcriptional activation of the clusterin promoter, which requires the proximal −218-bp region containing binding sites for heat shock factor (HSF)-1, activator protein (AP)-2, and AP-1 transcription factors. MX781 slightly induces AP-1 DNA binding activity, and mutation of the AP-1 site differentially affects the activation of the clusterin promoter in a cell type-specific manner. In contrast, a robust increase of HSF-1 DNA binding activity is observed in all cancer cell lines examined, and mutation of the heat shock element site in the clusterin promoter completely abolishes MX781-induced transcriptional activation in PC3 and DU145 cells. Other agonist retinoid-related molecules also induce AP-1 activity, but not HSF-1, and elicit no effect on clusterin expression levels. These data point to HSF-1 as an important factor regulating clusterin expression in response to MX781, although AP-1 activity may also participate in a cell type-specific manner.
Group A Streptococcus: allelic variation, population genetics, and host-pathogen interactions
Authors: Sean D. Reid, Nancy P. Hoe, Laura M. Smoot, James M. Musser
Journal: Journal of Clinical Investigation (2001)

GAS's revival has also taught the importance of understanding the molecular basis of pathogen variation, not merely as a means to discriminate between clinically relevantstrains, but to provide data relevant to pathogenesis, host adaptation, and the origin of new pathogenic forms.
Prospective, Multicenter Study of Ventricular Assist Device Infections
Authors: Rachel J. Gordon, Alan D. Weinberg, Francis D. Pagani, Mark S. Slaughter, Pat S. Pappas, Yoshifumi Naka, Daniel J. Goldstein, Walter P. Dembitsky, Julie C. Giacalone, Jennifer Ferrante, Deborah D. Ascheim, Alan J. Moskowitz, Eric A. Rose, Annetine C. Gelijns, Franklin D. Lowy, Sarah Fox, Christina L. Leventhal, Colleen Gallagher, Katharine Idrissi, Margaret Flannery, Rosie Te-Frey, Roger Swayze, Robert M. Adamson, Brian E. Jaski, Gina Gravitt, Chris Kohlmyer, Suzanne Chillcott, Marcia Stahovich, Timothy B. Icenogle, Mark Puhlman, Alfred Tector, Maggie Miller, Niloo M. Edwards, Jan Yakey, Jim Long, Michael Acker, Joseph P. Donnelly, Deb Dougherty, Robert Dowling, Pam Adkisson
Journal: Circulation (2013)

Background— Ventricular assist devices (VADs) improve survival and quality of life in patients with advanced heart failure, but their use is frequently complicated by infection. There are limited data on the microbiology and epidemiology of these infections. Methods and Results— One hundred fifty patients scheduled for VAD implantation were enrolled (2006–2008) at 11 US cardiac centers and followed prospectively until transplantation, explantation for recovery, death, or for 1 year. Eighty-six patients (57%) received HeartMate II devices. Data were collected on potential preoperative, intraoperative, and postoperative risk factors for infection. Clinical, laboratory, and microbiological data were collected for suspected infections and evaluated by an infectious diseases specialist. Thirty-three patients (22%) developed 34 VAD-related infections with an incidence rate of 0.10 per 100 person-days (95% confidence interval, 0.073–0.142). The median time to infection was 68 days. The driveline was the most commonly infected site (n=28); 18 (64%) were associated with invasive disease. Staphylococci were the most common pathogen (47%), but pseudomonas or other Gram-negative bacteria caused 32% of infections. A history of depression and elevated baseline serum creatinine were independent predictors of VAD infection (adjusted hazard ratio=2.8 [ P =0.007] and 1.7 [ P =0.023], respectively). The HeartMate II was not associated with a decreased risk of infection. VAD infection increased 1-year mortality (adjusted hazard ratio=5.6; P &lt;0.0001). Conclusions— This prospective, multicenter study demonstrates that infection frequently complicates VAD placement and is a continuing problem despite the use of newer, smaller devices. Depression and renal dysfunction may increase the risk of VAD infection. VAD infection is a serious consequence because it adversely affects patient survival. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01471795.
Measuring and Improving Physician Compliance with Clinical Practice Guidelines: A Controlled Interventional Trial
Authors: A. Gray Ellrodt
Journal: Annals of Internal Medicine (1995)

Objective: To determine factors that may lead physicians not to comply with clinical practice guidelines. Design: Retrospective analysis of patients whose physicians were not compliant with discharge recommendations from a prospective, controlled interventional trial of a guideline to reduce hospital length of stay for patients admitted for chest pain. Setting: A large community teaching hospital. Participants: Patients admitted with chest pain who were not discharged according to a practice guideline. Results: 79 (34%) of 230 patients with chest pain classified as being at low risk by concurrent or retrospective review were not discharged by day 3 (the guideline recommendation). Of these 79 patients, 33 (42%) were misclassified at concurrent review (10 were falsely classified as being at high risk and 23 were falsely classified as being at low risk). Of 46 correctly classified patients, 11 (14%) were classified as having noncompliant physicians because of health care system inefficiencies. The status of 7 (9%) patients was changed to high risk between initial classification and potential discharge. For 15 patients (19%), no obvious reason for delayed discharge was found, but they had a higher severity of illness than did low-risk patients discharged according to the guideline as measured by mean time-insensitive predictive instrument scores (41.3% ±[SD] 14.1% compared with 31.5% ±14.3%; P = 0.017). In 13 patients (16%), physicians refused to follow the guideline recommendations. Conclusions: In measuring and attempting to improve physician compliance with a length-of-stay guideline, physician refusal accounts for a small percentage (16%) of noncompliance. Implementation issues, health care system inefficiency, and severity of illness were the predominant reasons why physicians did not comply with guidelines. Our study further supports the principle that clinical practice guidelines should complement rather than be a substitute for physician judgment.
Sprycel for Chronic Myeloid Leukemia and Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Resistant to or Intolerant of Imatinib Mesylate
Authors: Michael Brave, Vicki Goodman, Edvardas Kaminskas, Ann Farrell, William Timmer, Sarah Pope, Ravi Harapanhalli, Haleh Saber, David Morse, Julie Bullock, Angela Men, Carol Noory, Roshni Ramchandani, Leslie Kenna, Brian Booth, Joga Gobburu, Xiaoping Jiang, Rajeshwari Sridhara, Robert Justice, Richard Pazdur
Journal: Clinical Cancer Research (2008)

On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval.Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response.The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention.This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.
Prenatal origins of bronchiolitis: protective effect of optimised asthma management during pregnancy: Table 1
Authors: Joerg Mattes, Vanessa E Murphy, Heather Powell, Peter G Gibson
Journal: Thorax (2013)

<h3>Objective</h3> Maternal asthma is the most common chronic disease complicating pregnancy and is a risk factor for bronchiolitis in infancy. Recurrent episodes of bronchiolitis are strongly associated with the development of childhood asthma. <h3>Methods</h3> We conducted a follow-up study of infants born to women with asthma who completed a double-blind randomised controlled trial during pregnancy. In this trial, pregnant women with asthma were assigned to treatment adjustment by an algorithm using clinical symptoms (clinical group) or the fraction of exhaled nitric oxide (FeNO group) and we showed that the FeNO group had significantly lower asthma exacerbation rates in pregnancy. <h3>Results</h3> 146 infants attended the 12-month follow-up visit. Infants born to mothers from the FeNO group were significantly less likely to have recurrent episodes of bronchiolitis in the first year of life (OR 0.08, 95% CI 0.01 to 0.62; p=0.016) as compared with the clinical group. <h3>Conclusions</h3> Optimised management of asthma during pregnancy may reduce recurrent episodes of bronchiolitis in infancy, which could potentially modulate the risk to develop or the severity of emerging childhood asthma.
Molecular Profiling and Targeted Therapy for Advanced Thoracic Malignancies: A Biomarker-Derived, Multiarm, Multihistology Phase II Basket Trial
Authors: Ariel Lopez-Chavez, Anish Thomas, Arun Rajan, Mark Raffeld, Betsy Morrow, Ronan Kelly, Corey Allan Carter, Udayan Guha, Keith Killian, Christopher C. Lau, Zied Abdullaev, Liqiang Xi, Svetlana Pack, Paul S. Meltzer, Christopher L. Corless, Alan Sandler, Carol Beadling, Andrea Warrick, David J. Liewehr, Seth M. Steinberg, Arlene Berman, Austin Doyle, Eva Szabo, Yisong Wang, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2015)

We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently.We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification.Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years).This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.