tbuckley/cabot-search huggingface dataset:
Clinical trial end points for high-grade glioma: the evolving landscape
Authors: D. A. Reardon, E. Galanis, J. F. DeGroot, T. F. Cloughesy, J. S. Wefel, K. R. Lamborn, A. B. Lassman, M. R. Gilbert, J. H. Sampson, W. Wick, M. C. Chamberlain, D. R. Macdonald, M. P. Mehta, M. A. Vogelbaum, S. M. Chang, M. J. Van den Bent, P. Y. Wen
Journal: Neuro-Oncology (2011)

To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the "gold-standard" end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being.
Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial
Authors: Jens Volkmann, Alexander Wolters, Andreas Kupsch, Jörg Müller, Andrea A Kühn, Gerd-Helge Schneider, Werner Poewe, Sascha Hering, Wilhelm Eisner, Jan-Uwe Müller, Günther Deuschl, Marcus O Pinsker, Inger-Marie Skogseid, Geir Ketil Roeste, Martin Krause, Volker Tronnier, Alfons Schnitzler, Jürgen Voges, Guido Nikkhah, Jan Vesper, Joseph Classen, Markus Naumann, Reiner Benecke
Journal: The Lancet Neurology (2012)
Follow up after a family based genetic screening programme for familial hypercholesterolaemia: is screening alone enough?
Authors: M. C van Maarle
Journal: BMJ (2002)

Familial hypercholesterolaemia is an autosomal dominant disorder of lipoprotein metabolism, with an estimated frequency of 1 in 500 in Western countries; it results in excess mortality from coronary artery disease.1 Now that the genetic defects can be detected and statins are available to lower lipids effectively, genetic screening has been considered.2–3 In 1994 a family based genetic screening programme for familial hypercholesterolaemia started in the Netherlands. The programme's effectiveness rests on the evidence based treatment of newly identified patients. We therefore assessed the subsequent preventive care and short term clinical outcome in people testing positive for familial hypercholesterolaemia as a proxy for the expected long term level of coronary artery disease.4

The foundation for tracing hereditary hypercholesterolaemia performs cascade screening in families of patients with clinically diagnosed familial hypercholesterolaemia with a known mutation, actively …
Human and mouse mast cells use the tetraspanin CD9 as an alternate interleukin-16 receptor
Authors: Jian C. Qi, Jing Wang, Sravan Mandadi, Kumiko Tanaka, Basil D. Roufogalis, Michele C. Madigan, Kenneth Lai, Feng Yan, Beng H. Chong, Richard L. Stevens, Steven A. Krilis
Journal: Blood (2005)
Ingested Arsenic, Cigarette Smoking, and Lung Cancer Risk
Authors: Chi-Ling Chen, Lin-I Hsu, Hung-Yi Chiou, Yu-Mei Hsueh, Shu-Yuan Chen, Meei-Maan Wu, Chien-Jen Chen, for the Blackfoot Disease Study Group
Journal: JAMA (2004)

Context Arsenic has been documented as a lung carcinogen in humans in only a few follow-up studies, which were limited by a small number of cases or the lack of information on cigarette smoking. ObjectivesTo elucidate the dose-response relationship between ingested arsenic and lung cancer and to assess the effect of cigarette smoking on the arsenic-lung cancer association.Design, Setting, and Participants A total of 2503 residents in southwestern and 8088 in northeastern arseniasis-endemic areas in Taiwan were followed up for an average period of 8 years.Information on arsenic exposure, cigarette smoking, and other risk factors was collected at enrollment through standardized questionnaire interview. Main Outcome MeasuresThe incidence of lung cancer was ascertained through linkage with national cancer registry profiles in Taiwan (January 1985-December 2000).The joint effect of arsenic and cigarette smoking was estimated by both etiologic fraction and synergy index.Results There were 139 newly diagnosed lung cancer cases during a follow-up period of 83783 person-years.After adjustment for cigarette smoking and other risk factors, there was a monotonic trend of lung cancer risk by arsenic level in drinking water of less than 10 to 700 µg/L or more (PϽ.001).The relative risk was 3.29 (95% confidence interval, 1.60-6.78)for the highest arsenic level compared with the lowest.The etiologic fraction of lung cancer attributable to the joint exposure of ingested arsenic and cigarette smoking ranged from 32% to 55%.The synergy indices ranged from 1.62 to 2.52, indicating a synergistic effect of ingested arsenic and cigarette smoking on lung cancer. ConclusionsThere was a significant dose-response trend of ingested arsenic on lung cancer risk, which was more prominent among cigarette smokers.The risk assessment of lung cancer induced by ingested arsenic should take cigarette smoking into consideration.
Protein kinase Cδ mediates retinoic acid and phorbol myristate acetate–induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation
Authors: Ke-Wen Zhao, Xi Li, Qian Zhao, Ying Huang, Dong Li, Zhen-Gang Peng, Wu-Zhong Shen, Ji Zhao, Quansheng Zhou, Zhu Chen, Peter J. Sims, Therese Wiedmer, Guo-Qiang Chen
Journal: Blood (2004)
Prostate Cancer–Associated Gene Expression Alterations Determined from Needle Biopsies
Authors: David Z. Qian, Chung-Ying Huang, Catherine A. O'Brien, Ilsa M. Coleman, Mark Garzotto, Lawrence D. True, Celestia S. Higano, Robert Vessella, Paul H. Lange, Peter S. Nelson, Tomasz M. Beer
Journal: Clinical Cancer Research (2009)

To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia.Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR.Comparative analyses identified 954 transcript alterations associated with cancer (q < 0.01%), including 149 differentially expressed genes with no known functional roles. Gene expression changes associated with ischemia and surgical removal of the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched in categories related to cellular metabolism, energy use, signal transduction, and molecular transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy.Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.
Clinically Inapparent Bilateral Adrenal Masses Due to Histoplasmosis
Authors: Vineet Narang, Tapan Sinha, Arjun S. Sandhu, Shailesh C. Karan, Ananad Srivastava, Gurwinder S. Sethi, Raghav Talwar, P. Prusty, Narinder Kotwal, Nirupam Adlakha, Anil Aggarwal
Journal: European Urology (2008)
Sphingosine kinase regulation and cardioprotection
Authors: J. S. Karliner
Journal: Cardiovascular Research (2008)

Activation of sphingosine kinase/sphingosine-1-phosphate (SK/S1P)-mediated signalling has been recognized as critical for cardioprotection in response to acute ischaemia/reperfusion injury. Incubation of S1P with cultured cardiac myocytes subjected to hypoxia or treatment of isolated hearts either before ischaemia or at the onset of reperfusion (pharmacologic pre- or postconditioning) results in reduced myocyte injury. Synthetic agonists active at S1P receptors mimic these responses. Gene-targeted mice null for the SK1 isoform whose hearts are subjected to ischaemia/reperfusion injury exhibit increased infarct size and respond poorly either to ischaemic pre- or postconditioning. Measurements of cardiac SK activity and S1P parallel these observations. Ischaemic postconditioning combined with sphingosine and S1P rescues the heart from prolonged ischaemia. These observations may have considerable relevance for future therapeutic approaches to acute and chronic myocardial injury.
P17.77 * PRELIMINARY DATA ON THE PATTERN OF CARE IN GRADE III GLIOMA PATIENTS IN 6 LOMBARDIA HOSPITALS, 2012-2013
Authors: A. Salmaggi, A. Fiumani, G. Grimod, E. Marchioni, F. Imbesi, R. Merli, A. Innocenti, M. Caroli, A. Silvani
Journal: Neuro-Oncology (2014)

The standard of care in grade III gliomas is still controversial; concerning anaplastic astrocytoma, the addition of chemotherapy to post-surgery radiation therapy is being assessed in the CATNON EORTC trial, whereas long-term follow-up data on grade III gliomas with oligodendroglial component suggest a strong impact of chemotherapy on survival, especially in patients positive for 1p/19q LOH. We have collected data on the pattern of care in grade III glioma patients prospectively treated in 6 Hospitals in Lombardia over the last 2 years. 78 patients were diagnosed (42 M, 36 F), with a median age of 50 (range 17-79). Histological diagnosis was AA in 49, AOD in 10, AOA in 19. The disease onset was characterized by seizures in 35 patients, intracranial hypertension in 7 and by focal non-epileptic neurological signs in 27. Surgery was total/subtotal resection in 43, partial resection in 18, biopsy in 17. Molecular biology data were available in 23/49 of the AA group (10 with methylated MGMT, 8 unmethylated MGMT, 1 with LOH 1p/10q) and in 16/29 of AOD/AOA group (12 with LOH for 1p/19q). Data about post-surgical treatment were available in 71 ot the 78 patients (42 AA and 29 AOD/AOA). Concerning AA, 3 patients died within 3 months from surgery (1 for encephalitis, 1 for early progression, 1 for perioperative complications). In the reamining 39, 37 were treated with both RT and CT (of whom 27 with the Stupp schedule and 10 with adjuvant temozolomide), 2 were treated with RT only. Toxicities included one fatal herpetic encephalitis, one Herpes Zoster, 4 grade 3-4 platelet toxicity, one case of pancytopenia. In AOD and AOA patients, 27 out of 29 were treated with radiotherapy and only 2 with upfront chemotherapy aiming to differe RT. 4 of the 27 received only radiotherapy, while 23 were treated by both RT and CT (of whom 5 with the Stupp schedule and 18 with adjuvant CT). 2 patients had to interrupt CT due to piastrinopenia. Overall, the results stress the need to implement molecular biology analyses and confirm the heterogeneity in the clinical approach to newly diagnosed grade III gliomas. In AA, both the Stupp schedule and adjuvant CT after RT are used, whereas in gliomas with oligodendroglial component a low number of patients start being treated with upfront chemoterapy if they present favourable prognostic factors.
Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF
Authors: Graeme J Hankey, Manesh R Patel, Susanna R Stevens, Richard C Becker, Günter Breithardt, Antonio Carolei, Hans-Christoph Diener, Geoffrey A Donnan, Jonathan L Halperin, Kenneth W Mahaffey, Jean-Louis Mas, Ayrton Massaro, Bo Norrving, Christopher C Nessel, John F Paolini, Risto O Roine, Daniel E Singer, Lawrence Wong, Robert M Califf, Keith AA Fox, Werner Hacke
Journal: The Lancet Neurology (2012)
Cholinergic Atrial Fibrillation in a Computer Model of a Two-Dimensional Sheet of Canine Atrial Cells With Realistic Ionic Properties
Authors: James Kneller, Renqiang Zou, Edward J. Vigmond, Zhiguo Wang, L. Joshua Leon, Stanley Nattel
Journal: Circulation Research (2002)

Classical concepts of atrial fibrillation (AF) have been rooted in Moe’s multiple-wavelet hypothesis and simple cellular-automaton computer model. Recent experimental work has raised questions about the multiple-wavelet mechanism, suggesting a discrete “driver region” underlying AF. We reexplored the theoretical basis for AF with a 2-dimensional computer model of a 5×10-cm sheet of atrial cells with realistic ionic and coupling properties. Vagal actions were formulated based on patch-clamp studies of acetylcholine (ACh) effects. In control, a single extrastimulus resulted in a highly meandering unstable spiral wave. Simulated electrograms showed fibrillatory activity, with a dominant frequency (DF, 6.5 Hz) that correlated with the mean rate. Uniform ACh reduced core meander of the spiral wave by ≈70% (as measured by the standard deviation of spiral-wave tip position) and accelerated the DF to 17.0 Hz. Simulated vagally induced refractoriness heterogeneity caused wavefront breakup as accelerated reentrant activity in regions of short refractoriness impinged on regions unable to respond in a 1:1 fashion because of longer refractoriness. In 7 simulations spanning the range of conditions giving sustained AF, 5 were maintained by single dominant spiral waves. On average, 3.0±1.3 wavelets were present (range, 1 to 7). Most wavelets were short-lived and did not contribute to AF maintenance. In contrast to predictions of the multiple-wavelet hypothesis, but in agreement with recent experimental evidence, our model indicates that AF can result from relatively stable primary spiral-wave generators and is significantly organized. Our results suggest that vagal AF may arise from ACh-induced stabilization of the primary spiral-wave generator and disorganization of the heterogeneous tissue response. The full text of this article is available at http://www.circresaha.org.
Association of the p22phox Component of NAD(P)H Oxidase With Susceptibility to Diabetic Nephropathy in Patients With Type 1 Diabetes
Authors: Andrea D. Hodgkinson, Beverley A. Millward, Andrew G. Demaine
Journal: Diabetes Care (2003)

OBJECTIVE—Increased production of reactive oxygen species (ROS) in diabetes is thought to play a major role in the pathogenesis of diabetic microvascular complications such as nephropathy and retinopathy. The NAD(P)H oxidase complex is an important source of ROS in the vasculature. The p22 subunit is polymorphic with a C242T variant that changes histidine-72 for a tyrosine in the potential heme binding site, together with a A640G in the 3′ untranslated region. The aim was to investigate the frequency of these polymorphisms in 268 patients with type 1 diabetes with or without microvascular complications. RESEARCH DESIGN AND METHODS—There was a highly significant increase in the frequency of the T/T242 genotype in patients with nephropathy compared with those with retinopathy alone or no microvascular disease after 20 years’ diabetes duration (uncomplicated) or normal healthy control subjects (33.3 vs. 6.5, 5.7, and 0.0%, respectively, P &amp;lt; 0.000001). Furthermore, the T242/G640 haplotype was found in 39.4% of the patients with nephropathy but in only 26.5% of the patients with retinopathy and 15.3 and 10.6% of the uncomplicated and normal control subjects, respectively. RESULTS—When these variants of NAD(P)H oxidase were analyzed together with aldose reductase (5′ALR2) susceptibility genotypes, &amp;gt;46.0% of the patients with nephropathy possessed a T242 allele with the Z-2 5′ALR2 allele compared with only 11.2% of the uncomplicated patients (P &amp;lt; 0.00003). CONCLUSIONS—In conclusion, these results suggest NAD(P)H oxidase together with the polyol pathway may contribute to the pathogenesis of diabetic nephropathy.
Modulation of the Tumor Microvasculature by Phosphoinositide-3 Kinase Inhibition Increases Doxorubicin Delivery <i>In Vivo</i>
Authors: Naseer Qayum, Jaehong Im, Michael R. Stratford, Eric J. Bernhard, W. Gillies McKenna, Ruth J. Muschel
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Because effective drug delivery is often limited by inadequate vasculature within the tumor, the ability to modulate the tumor microenvironment is one strategy that may achieve better drug distribution. We have previously shown that treatment of mice bearing tumors with phosphoinositide-3 kinase (PI3K) inhibitors alters vascular structure in a manner analogous to vascular normalization and results in increased perfusion of the tumor. On the basis of that result, we asked whether inhibition of PI3K would improve chemotherapy delivery. Experimental Design: Mice with xenografts using the cell line SQ20B bearing a hypoxia marker or MMTV-neu transgenic mice with spontaneous breast tumors were treated with the class I PI3K inhibitor GDC-0941. The tumor vasculature was evaluated by Doppler ultrasound, and histology. The delivery of doxorubicin was assessed using whole animal fluorescence, distribution on histologic sections, high-performance liquid chromatography on tumor lysates, and tumor growth delay. Results: Treatment with GDC-0941 led to approximately three-fold increases in perfusion, substantially reduced hypoxia and vascular normalization by histology. Significantly increased amounts of doxorubicin were delivered to the tumors correlating with synergistic tumor growth delay. The GDC-0941 itself had no effect on tumor growth. Conclusion: Inhibition of PI3K led to vascular normalization and improved delivery of a chemotherapeutic agent. This study highlights the importance of the microvascular effects of some novel oncogenic signaling inhibitors and the need to take those changes into account in the design of clinical trials many of which use combinations of chemotherapeutic agents. Clin Cancer Res; 18(1); 161–9. ©2011 AACR.
THE CONCENTRATING ACTIVITY OF THE GALL BLADDER
Authors: Peyton Rous, Philip D. McMaster
Journal: The Journal of Experimental Medicine (1921)

The bile coming at one time from different portions of the liver of the dog has nearly the same amount of pigment per cubic centimeter. With this determined we have studied the power of the gall bladder to concentrate bile directed to it, using as criterion the pigment strength of a sample collected throughout the period of experiment from a duct branch. The extent and rapidity of the concentration are alike remarkable. A gall bladder emptied at the beginning of one experiment and left to fill from the liver, concentrated the 49.8 cc. of bile reaching it in 22(1/2) hours to 4.6 cc., that is to say reduced its bulk 10.8 times; while another bladder left distended with a bile of known constitution and receiving in addition fresh increments from the liver concentrated the secretion 8.9 times in 22 hours. A series of five emptied bladders concentrated the bile coming to them in about 24 hours on the average 7.1 times, or a little more than the 6.4 times of seven organs left full. The conditions in both cases were relatively unfavorable to the withdrawal of fluid from the bile because this takes place by osmosis and diffusion, with the ultimate Delta always that of the blood, and the secretion in our animals was notably rich in solids as an indirect result of the operation. The rapidity with which fluid is withdrawn through the wall of the bladder may be judged from some experiments in which a bag was connected with the tip of the organ by a large cannula. Merely in its passage through the bladder the bile was concentrated 2.3 to 4.8 times. The finding indicates a potential source of error in observations upon samples of bile obtained from fistulous channels of which the bladder forms a part. The bile ducts do not withdraw fluid from the secretion they convey but tend to dilute it, as we shall show in a companion paper. The restriction of the concentrating activity to the receptaculum chyli is good evidence that the latter has special significance for the organism. The nature of this significance is briefly discussed.
Selective Coronary Arteriography
Authors: Gerald B. Lee
Journal: JAMA (1968)

Selective coronary arteriography has been developed during the past decade in an attempt to provide a visual display of the anatomical structure and pathological changes of the coronary arteries. Nonselective methods of coronary arteriography have failed in the past to show consistently the details of the coronary arterial tree. On the other hand, with improved selective methods, coronary arteriography has become a valuable adjunct in the diagnosis of coronary heart disease. It is now possible to arrive at a more precise diagnosis when the complete clinical evaluation is correlated with the objective findings of coronary arteriography. We feel that selective coronary studies are done best by a team composed of an internist and a roentgenologist. <h3>Technique</h3> Selective arteriography may be performed by various techniques, each with advantages and disadvantages. Since the technique of Sones has been widely publicized,<sup>1</sup>specific details will not be presented here. In contrast to the
Interleukin 4 as an essential factor for in vitro clonal growth of murine connective tissue-type mast cells.
Authors: Y Hamaguchi, Y Kanakura, J Fujita, S Takeda, T Nakano, S Tarui, T Honjo, Y Kitamura
Journal: The Journal of Experimental Medicine (1987)

We investigated the biological activity of IL-4 to murine connective tissue-type mast cells (CTMC). When purified peritoneal mast cells, typical CTMC, were incubated with pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCM) in methylcellulose, about one-fifth of mast cells showed clonal growth. Recombinant IL-4 alone did not stimulate the clonal growth, and purified IL-3 alone induced development of a small number of tiny clusters. In contrast, addition of IL-4 to IL-3 increased the number of clusters by a factor of 10. The number and size of clusters induced by the combination of IL-3 and IL-4 were comparable to those of mast cell clusters induced by PWM-SCM. The present results indicate that IL-4 is an essential factor for in vitro clonal growth of CTMC.