tbuckley/cabot-search huggingface dataset:
Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications
Authors: Lee D. Kaiser, Allen S. Melemed, Alaknanda J. Preston, Hilary A. Chaudri Ross, Donna Niedzwiecki, Gwendolyn A. Fyfe, Jacqueline M. Gough, William D. Bushnell, Cynthia L. Stephens, M. Kelsey Mace, Jeffrey S. Abrams, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2010)

Although much is known about the safety of an anticancer agent at the time of initial marketing approval, sponsors customarily collect comprehensive safety data for studies that support supplemental indications. This adds significant cost and complexity to the study but may not provide useful new information. The main purpose of this analysis was to assess the amount of safety and concomitant medication data collected to determine a more optimal approach in the collection of these data when used in support of supplemental applications.Following a prospectively developed statistical analysis plan, we reanalyzed safety data from eight previously completed prospective randomized trials.A total of 107,884 adverse events and 136,608 concomitant medication records were reviewed for the analysis. Of these, four grade 1 to 2 and nine grade 3 and higher events were identified as drug effects that were not included in the previously established safety profiles and could potentially have been missed using subsampling. These events were frequently detected in subsamples of 400 patients or larger. Furthermore, none of the concomitant medication records contributed to labeling changes for the supplemental indications.Our study found that applying the optimized methodologic approach, described herein, has a high probability of detecting new drug safety signals. Focusing data collection on signals that cause physicians to modify or discontinue treatment ensures that safety issues of the highest concern for patients and regulators are captured and has significant potential to relieve strain on the clinical trials system.
Unlocking the DEAD-box: a key to cryptococcal virulence?
Authors: Lena J. Heung, Maurizio Del Poeta
Journal: Journal of Clinical Investigation (2005)

The DEAD-box RNA helicases are enzymes involved in many critical aspects of RNA metabolism within both eukaryotic and prokaryotic organisms. Several studies have shown that these proteins may have important functions in mediating microbial pathogenesis. A new study in this issue of the JCI identifies the first DEAD-box RNA helicase in the pathogenic fungus Cryptococcus neoformans and proposes novel roles for this family of proteins in the development and progression of cryptococcosis.
Bone Marrow-Derived Cells Do Not Incorporate Into the Adult Growing Vasculature
Authors: Tibor Ziegelhoeffer, Borja Fernandez, Sawa Kostin, Matthias Heil, Robert Voswinckel, Armin Helisch, Wolfgang Schaper
Journal: Circulation Research (2003)

Bone marrow-Derived cells have been proposed to form new vessels or at least incorporate into growing vessels in adult organisms under certain physiological and pathological conditions. We investigated whether bone marrow-Derived cells incorporate into vessels using mouse models of hindlimb ischemia (arteriogenesis and angiogenesis) and tumor growth. C57BL/6 wild-type mice were lethally irradiated and transplanted with bone marrow cells from littermates expressing enhanced green fluorescent protein (GFP). At least 6 weeks after bone marrow transplantation, the animals underwent unilateral femoral artery occlusions with or without pretreatment with vascular endothelial growth factor or were subcutaneously implanted with methylcholanthrene-induced fibrosarcoma (BFS-1) cells. Seven and 21 days after surgery, proximal hindlimb muscles with growing collateral arteries and ischemic gastrocnemius muscles as well as grown tumors and various organs were excised for histological analysis. We failed to colocalize GFP signals with endothelial or smooth muscle cell markers. Occasionally, the use of high-power laser scanning confocal microscopy uncovered false-positive results because of overlap of different fluorescent signals from adjacent cells. Nevertheless, we observed accumulations of GFP-positive cells around growing collateral arteries (3-fold increase versus nonoccluded side, P<0.001) and in ischemic distal hindlimbs. These cells were identified as fibroblasts, pericytes, and primarily leukocytes that stained positive for several growth factors and chemokines. Our findings suggest that in the adult organism, bone marrow-Derived cells do not promote vascular growth by incorporating into vessel walls but may function as supporting cells.
Delayed adjuvant tamoxifen: Ten-year results of a collaborative randomized controlled trial in early breast cancer (TAM-02 trial)
Authors: T. Delozier, O. Switsers, J.Y. Génot, J.M. Ollivier, M. Héry, M. Namer, M. Fresney, P. Kerbrat, C. Veyret, B. de Lafontan, M. Janvier, J. Macé-Lesech
Journal: Annals of Oncology (2000)
Cardiac cycle length modulates cardiovascular regulation that is dependent on previous beat contraction history.
Authors: B K Slinker
Journal: Circulation Research (1991)

Previous studies of the beat-to-beat regulation of left ventricular performance in the intact cardiovascular system have shown that the performance of the left ventricle on any one beat is influenced by the mechanical events of the previous beat, so-called previous beat contraction history. The general hypothesis investigated in this study is that previous beat contraction history occurs because of the perturbation of one or more biochemical processes with time courses that are long relative to one cardiac cycle. If this is true, then previous beat contraction history should depend on the interval between beats and, therefore, should extend beyond the previous beat to two, or even three, previous beats as heart rate is increased. Hemodynamic responses to random preload and afterload changes were measured in 11 anesthetized open-chest dogs on right heart bypass at three paced heart rates. Multiple linear regression was used to analyze these hemodynamic sequences and identify variables from the previous one, two, or three beats that were important in the mechanical history dependence of left ventricular function. The results of this analysis showed that under baseline conditions, all 11 hearts showed one beat of history dependence, with only two of 11 hearts showing a dependence on the previous two or three beats. At the highest heart rate, all 11 hearts still showed one beat of history dependence, but 10 of 11 hearts showed two beats of history dependence, and four of 11 showed three beats of history dependence (p less than 0.05). A general framework for the mechanism underlying these findings, which relates previous beat contraction history to the interval-dependent mechanical restitution phenomenon, is proposed and discussed.
Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II–Based Regulation of Voltage-Gated Na <sup>+</sup> Channel in Cardiac Disease
Authors: Olha M. Koval, Jedidiah S. Snyder, Roseanne M. Wolf, Ryan E. Pavlovicz, Patric Glynn, Jerry Curran, Nicholas D. Leymaster, Wen Dun, Patrick J. Wright, Natalia Cardona, Lan Qian, Colleen C. Mitchell, Penelope A. Boyden, Philip F. Binkley, Chenglong Li, Mark E. Anderson, Peter J. Mohler, Thomas J. Hund
Journal: Circulation (2012)

Background— Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na + channel (Na v 1.5) by Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated. Methods and Results— We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na v 1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na v 1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na v 1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium. Conclusions— We identify the mechanism for 2 human arrhythmia variants that affect Na v 1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na v 1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na v 1.5 in congenital and acquired cardiac disease.
Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling
Authors: Suk Woo Nam, Jik Young Park, Adaikalavan Ramasamy, Shirish Shevade, Amirul Islam, Philip M. Long, Cheol Keun Park, Soo Eun Park, Su Young Kim, Sug Hyung Lee, Won Sang Park, Nam Jin Yoo, Edison T. Liu, Lance D. Miller, Jung Young Lee
Journal: Hepatology (2005)

Abstract Progression of hepatocellular carcinoma (HCC) is a stepwise process that proceeds from pre-neoplastic lesions—including low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs)—to advanced HCC. The molecular changes associated with this progression are unclear, however, and the morphological cues thought to distinguish pre-neoplastic lesions from well-differentiated HCC are not universally accepted. To understand the multistep process of hepato-carcinogenesis at the molecular level, we used oligo-nucleotide microarrays to investigate the transcription profiles of 50 hepatocellular nodular lesions ranging from LGDNs to primary HCC (Edmondson grades 1-3). We demonstrated that gene expression profiles can discriminate not only between dysplastic nodules and overt carcinoma but also between different histological grades of HCC via unsupervised hierarchical clustering with 10,376 genes. We identified 3,084 grade-associated genes, correlated with tumor progression, using one-way ANOVA and a one-versus-all unpooled t test. Functional assignment of these genes revealed discrete expression clusters representing grade-dependent biological properties of HCC. Using both diagonal linear discriminant analysis and support vector machines, we identified 240 genes that could accurately classify tumors according to histological grade, especially when attempting to discriminate LGDNs, HGDNs, and grade 1 HCC. In conclusion , a clear molecular demarcation between dysplastic nodules and overt HCC exists. The progression from grade 1 through grade 3 HCC is associated with changes in gene expression consistent with plausible functional consequences. Supplementary material for this article can be found on the Hepatology website ( http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html ). (Hepatology 2005;42:809–818.)
PREVIOUSLY RESPONDING NO-OPTION PATIENTS WITH RESIDUAL OR RECURRENT REFRACTORY ANGINA PECTORIS AND DOCUMENTED ISCHEMIA BENEFIT FROM REPEAT INTRAMYOCARDIAL INJECTION OF AUTOLOGOUS BONE MARROW CELLS
Authors: Imke Mann, Sander Rodrigo, Jan van Ramshorst, S. Beeres, Albert De Roos, Jeroen Bax, Willem E. Fibbe, Martin Schalij, Douwe Atsma
Journal: Journal of the American College of Cardiology (2014)
Prediction of <i>BRCA1</i> Status in Patients with Breast Cancer Using Estrogen Receptor and Basal Phenotype
Authors: Sunil R. Lakhani, Jorge S. Reis-Filho, Laura Fulford, Frederique Penault-Llorca, Marc van der Vijver, Suzanne Parry, Timothy Bishop, Javier Benitez, Carmen Rivas, Yves-Jean Bignon, Jenny Chang-Claude, Ute Hamann, Cees J. Cornelisse, Peter Devilee, Matthias W. Beckmann, Carolin Nestle-Krämling, Peter A. Daly, Neva Haites, Jenny Varley, Fiona Lalloo, Gareth Evans, Christine Maugard, Hanne Meijers-Heijboer, Jan G.M. Klijn, Edith Olah, Barry A. Gusterson, Silvana Pilotti, Paolo Radice, Siegfried Scherneck, Hagay Sobol, Jocelyne Jacquemier, Teresa Wagner, Julian Peto, Michael R. Stratton, Lesley McGuffog, Douglas F. Easton
Journal: Clinical Cancer Research (2005)

To investigate the proportion of breast cancers arising in patients with germ line BRCA1 and BRCA2 mutations expressing basal markers and developing predictive tests for identification of high-risk patients.Histopathologic material from 182 tumors in BRCA1 mutation carriers, 63 BRCA2 carriers, and 109 controls, collected as part of the international Breast Cancer Linkage Consortium were immunohistochemically stained for CK14, CK5/6, CK17, epidermal growth factor receptor (EGFR), and osteonectin.All five basal markers were commoner in BRCA1 tumors than in control tumors (CK14: 61% versus 12%; CK5/6: 58% versus 7%; CK17: 53% versus 10%; osteonectin: 43% versus 19%; EGFR: 67% versus 21%; P < 0.0001 in each case). In a multivariate analysis, CK14, CK5/6, and estrogen receptor (ER) remained significant predictors of BRCA1 carrier status. In contrast, the frequency of basal markers in BRCA2 tumors did not differ significant from controls.The use of cytokeratin staining in combination with ER and morphology provides a more accurate predictor of BRCA1 mutation status than previously available, that may be useful in selecting patients for BRCA1 mutation testing. The high percentage of BRCA1 cases positive for EGFR suggests that specific anti-tyrosine kinase therapy may be of potential benefit in these patients.
Clinical Management of Multiple Melanoma Brain Metastases
Authors: Sharad Goyal, Ann W. Silk, Sibo Tian, Janice Mehnert, Shabbar Danish, Sinthu Ranjan, Howard L. Kaufman
Journal: JAMA Oncology (2015)

The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving.
Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration
Authors: Rong Dong, Kate Cwynarski, Alan Entwistle, Federica Marelli-Berg, Francesco Dazzi, Elizabeth Simpson, John M. Goldman, Junia V. Melo, Robert I. Lechler, Ilaria Bellantuono, Anne Ridley, Giovanna Lombardi
Journal: Blood (2003)
Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis
Authors: Aidan G. Gilmartin, Maureen R. Bleam, Mark C. Richter, Symon G. Erskine, Ryan G. Kruger, Lenore Madden, Daniel F. Hassler, Gary K. Smith, Richard R. Gontarek, Mary P. Courtney, David Sutton, Melody A. Diamond, Jeffrey R. Jackson, Sylvie G. Laquerre
Journal: Cancer Research (2009)

Abstract Polo-like kinase 1 (Plk1) is a conserved serine/threonine kinase that plays an essential role in regulating the many processes involved in mitotic entry and progression. In humans, Plk1 is expressed primarily during late G2 and M phases and, in conjunction with Cdk1/cyclin B1, acts as master regulatory kinases for the myriad protein substrates involved in mitosis. Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types. We have identified a potent, selective, reversible, ATP-competitive inhibitor of Plk1, GSK461364A, capable of inhibiting cell growth of most proliferating cancer cell lines tested. We observe distinct cell cycle effects of GSK461364A depending on the dose used. The predominant phenotype for cells treated with GSK461364A is prometaphase arrest with characteristic collapsed polar polo spindle. At high concentrations, GSK461364A delays mitotic entry in G2 followed by gradual progression into terminal mitosis; in some cell lines, this correlates with decreased apoptosis. Cell culture growth inhibition by GSK461364A can be cytostatic or cytotoxic but leads to tumor regression in xenograft tumor models under proper dose scheduling. Finally, we describe pharmacodynamic biomarkers of GSK461364A activity (pHH3 and Plk1) that are currently being evaluated in human cancer clinical trials. [Cancer Res 2009;69(17):6969–77]
Background Comparison of Typical Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Japanese Patients
Authors: Takashi Ueta, Ryo Obata, Yuji Inoue, Aya Iriyama, Hidenori Takahashi, Takuhiro Yamaguchi, Yasuhiro Tamaki, Yasuo Yanagi
Journal: Ophthalmology (2009)
A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer
Authors: Pamela N. Munster, Eric H. Rubin, Simon Van Belle, Evan Friedman, Jaclyn K. Patterson, Kristien Van Dyck, Xiadong Li, Wendy Comisar, Jeffery A. Chodakewitz, John A. Wagner, Marian Iwamoto
Journal: Clinical Cancer Research (2009)

This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval.A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat.Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated.Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.
Proprioceptive Coupling within Motor Neurons Drives C. elegans Forward Locomotion
Authors: Quan Wen, Michelle D. Po, Elizabeth Hulme, Sway Chen, Xinyu Liu, Sen Wai Kwok, Marc Gershow, Andrew M. Leifer, Victoria Butler, Christopher Fang-Yen, Taizo Kawano, William R. Schafer, George Whitesides, Matthieu Wyart, Dmitri B. Chklovskii, Mei Zhen, Aravinthan D.T. Samuel
Journal: Neuron (2012)
Clinical, Biologic, and Prognostic Differences on the Basis of Primary Tumor Site in Neuroblastoma: A Report From the International Neuroblastoma Risk Group Project
Authors: Kieuhoa T. Vo, Katherine K. Matthay, John Neuhaus, Wendy B. London, Barbara Hero, Peter F. Ambros, Akira Nakagawara, Doug Miniati, Kate Wheeler, Andrew D.J. Pearson, Susan L. Cohn, Steven G. DuBois
Journal: Journal of Clinical Oncology (2014)

Purpose Neuroblastoma (NB) is a heterogeneous tumor arising from sympathetic tissues. The impact of primary tumor site in influencing the heterogeneity of NB remains unclear. Patients and Methods Children younger than age 21 years diagnosed with NB or ganglioneuroblastoma between 1990 and 2002 and with known primary site were identified from the International Neuroblastoma Risk Group database. Data were compared between sites with respect to clinical and biologic features, as well as event-free survival (EFS) and overall survival (OS). Results Among 8,369 children, 47% had adrenal tumors. All evaluated clinical and biologic variables differed statistically between primary sites. The features that were &gt; 10% discrepant between sites were stage 4 disease, MYCN amplification, elevated ferritin, elevated lactate dehydrogenase, and segmental chromosomal aberrations, all of which were more frequent in adrenal versus nonadrenal tumors (P &lt; .001). Adrenal tumors were more likely than nonadrenal tumors (adjusted odds ratio, 2.09; 95% CI, 1.67 to 2.63; P &lt; .001) and thoracic tumors were less likely than nonthoracic tumors (adjusted odds ratio, 0.20; 95% CI, 0.11 to 0.39; P &lt; .001) to have MYCN amplification after controlling for age, stage, and histologic grade. EFS and OS differed significantly according to the primary site (P &lt; .001 for both comparisons). After controlling for age, MYCN status, and stage, patients with adrenal tumors had higher risk for events (hazard ratio, 1.13 compared with nonadrenal tumors; 95% CI, 1.03 to 1.23; P = .008), and patients with thoracic tumors had lower risk for events (HR, 0.79 compared with nonthoracic; 95% CI, 0.67 to 0.92; P = .003). Conclusion Clinical and biologic features show important differences by NB primary site, with adrenal and thoracic sites associated with inferior and superior survival, respectively. Future studies will need to investigate the biologic origin of these differences.
Risk of Incident Diabetes in Patients With Gout: A Cohort Study
Authors: Seoyoung C. Kim, Jun Liu, Daniel H. Solomon
Journal: Arthritis & Rheumatology (2014)

Objective Patients with hyperuricemia or gout often have metabolic syndrome. Few prospective studies have examined the risk of incident diabetes mellitus (DM) in patients with gout, and there are no data to indicate whether the risk of DM in gout differs by sex. Therefore, this cohort study was undertaken to examine the overall and sex‐specific incidence rates of DM in patients with gout. Methods Using data from a US commercial insurance plan (2003–2012), the overall and sex‐specific incidence rates of DM in patients with gout (ages ≥40 years) were compared to those in patients with osteoarthritis (OA). Incident DM was defined as a diagnosis of DM and at least one dispensing of an antidiabetic drug. The sex‐specific effect of gout on DM risk was also examined. Results The primary study cohorts consisted of 54,075 patients with gout and 162,225 patients with OA, matched for age, sex, and index date. In both cohorts, the mean age of the patients was 56.2 years, and 84.8% were men. Over a mean followup of 1.9 years, the incidence rate of DM was 1.91 per 100 person‐years in patients with gout and 1.12 per 100 person‐years in patients with OA. Multivariable Cox models adjusted for age, comorbidities, medications, and health care utilization factors revealed that gout was associated with an increased risk of DM (hazard ratio 1.45, 95% confidence interval [95% CI] 1.37–1.54) in both sexes. The impact of gout on the risk of incident DM was greater in women (hazard ratio 1.78, 95% CI 1.51–2.09) than in men (hazard ratio 1.41, 95% CI 1.33–1.50), with a significant interaction between gout and sex in relation to the risk of incident DM ( P = 0.0009). Conclusion Gout was associated with an increased risk of developing DM compared to that in patients with OA after adjustment for potential confounders. In addition, the risk of incident DM associated with gout was higher among women than among men.