tbuckley/cabot-search huggingface dataset:
Disparities in Breast Cancer Outcomes: Receipt of Chemotherapy Is Only Part of the Story
Authors: Victoria S. Blinder
Journal: Journal of Clinical Oncology (2012)

Each year, ASCO organizes a wide array of high-quality meetings that provide educational and scientific programs to advance our understanding of cancer.At each of ASCO's meetings, you can expect an engaging and interactive agenda featuring high-level scientific or clinical abstracts and educational sessions led by world-class faculty.Join us to earn CME credit, network with colleagues, and interact with cancer experts.Join us for the Markers in Cancer meeting October 11-13 in Hollywood, Florida.This joint meeting by ASCO, EORTC, and NCI will present the latest advances in cancer biomarkers to assess drug efficacy, improve prognostic and predictive evaluations and imaging, and enhance clinical trial development, and will include a Diagnostic Development Tutorial on October 10-11.For more information, visit markersincancer.org.
MB-02 * SONIC HEDGEHOG INDUCES YB-1 IN A YAP-DEPENDENT MANNER TO REGULATE Igf2 EXPRESSION AND PROLIFERATION IN CEREBELLAR GRANULE NEURON PROGENITORS AND MEDULLOBLASTOMA CELLS
Authors: A. Dey, M. Robitaille, M. Remke, C. Maier, A. Malhotra, A. Gregorieff, J. Wrana, M. Taylor, S. Angers, A. Kenney
Journal: Neuro-Oncology (2015)

Interactions between the developmentally essential Sonic hedgehog (Shh) and Insulin-like Growth Factor (IGF) pathways play prominent roles in medulloblastoma (MB), the most common malignant pediatric brain tumor. MB patients undergo surgery, chemotherapy, and radiation, a regimen that carries devastating side effects, emphasizing the need for targeted therapies to improve survival and quality of life. Post-natal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the SHH-associated subgroup of MB, is driven by Shh and IGF in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3 and is required for IGF2 expression in CGNPs. We show that YB-1 is induced by Shh in CGNPs in a YAP-dependent manner and is found in the germinal layer of the developing cerebellum. We observed that YB-1 is up-regulated across human medulloblastoma subclasses and is elevated in a mouse model for the Shh medulloblastoma subclass. Finally, shRNA-mediated knockdown experiments reveal that YB-1 activity is required for CGNP and medulloblastoma cell (MBC) proliferation in primary cultures and organotypic slice cultures. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and medulloblastoma cells and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.
Relationship Between Dopamine D<sub>2</sub> Occupancy, Clinical Response, and Side Effects: A Double-Blind PET Study of First-Episode Schizophrenia
Authors: Shitij Kapur, Robert Zipursky, Corey Jones, Gary Remington, Sylvain Houle
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Since all antipsychotics block dopamine D2 receptors, the authors investigated how well D2 receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. METHOD: In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2.5 mg/day of haloperidol. After 2 weeks of treatment, D2 receptor occupancy was determined with [11C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. RESULTS: The patients showed a wide range of D2 occupancy (38%–87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D2 occupancy exceeded 65%, 72%, and 78%, respectively. CONCLUSIONS: The study confirms that D2 occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a “target and trigger” hypothesis of antipsychotic action, i.e., that the D2 receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D2 occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.
Senescence Sensitivity of Breast Cancer Cells Is Defined by Positive Feedback Loop between CIP2A and E2F1
Authors: Anni Laine, Harri Sihto, Christophe Come, Mathias T. Rosenfeldt, Aleksandra Zwolinska, Minna Niemelä, Anchit Khanna, Edward K. Chan, Veli-Matti Kähäri, Pirkko-Liisa Kellokumpu-Lehtinen, Owen J. Sansom, Gerard I. Evan, Melissa R. Junttila, Kevin M. Ryan, Jean-Christophe Marine, Heikki Joensuu, Jukka Westermarck
Journal: Cancer Discovery (2013)

Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53-p21 pathway.
Soluble proteins delivered to dendritic cells via pH-sensitive liposomes induce primary cytotoxic T lymphocyte responses in vitro.
Authors: S Nair, F Zhou, R Reddy, L Huang, B T Rouse
Journal: The Journal of Experimental Medicine (1992)

Effective immunity to many infectious agents, particularly viruses, requires a CD8+ cytotoxic T lymphocyte (CTL) response. Understanding how to achieve CTL induction with soluble proteins is important for vaccine development since such antigens are usually not processed appropriately to induce CTL. In the present report, we have demonstrated that a potent primary CTL response against a soluble protein can be achieved by delivering antigen in pH-sensitive liposomes to dendritic cells (DC) either in vivo or in vitro. Since the pH-sensitive liposome delivery system is efficient and easy to use, the approach promises to be valuable both in the study of basic mechanisms in antigen processing, and as a practical means of immunization.
Paclitaxel Given Once Per Week With or Without Bevacizumab in Patients With Advanced Angiosarcoma: A Randomized Phase II Trial
Authors: Isabelle L. Ray-Coquard, Julien Domont, Emmanuelle Tresch-Bruneel, Emmanuelle Bompas, Philippe A. Cassier, Olivier Mir, Sophie Piperno-Neumann, Antoine Italiano, Christine Chevreau, Didier Cupissol, François Bertucci, Jacques-Olivier Bay, Olivier Collard, Esma Saada-Bouzid, Nicolas Isambert, Corinne Delcambre, Stéphanie Clisant, Axel Le Cesne, Jean-Yves Blay, Nicolas Penel
Journal: Journal of Clinical Oncology (2015)

Purpose The aim of this randomized, phase II trial was to explore the activity and safety of adding bevacizumab to paclitaxel once per week in treatment of angiosarcomas (AS). Methods Patients were treated with paclitaxel alone (90 mg/m2 per week for six cycles of 28 days each; arm A) or with paclitaxel combined with bevacizumab (10 mg/kg once every 2 weeks; arm B). In the combination treatment arm, bevacizumab was administered after the six cycles of chemotherapy as maintenance therapy (15 mg/kg once every 3 weeks) until intolerance or progression occurred. Stratification factors were superficial versus visceral AS and de novo versus radiation-induced AS. The primary end point was the 6-month progression-free survival (PFS) rate, which was based on RECIST, version 1.1. Statistical assumptions were P0 = 20%, P1 = 40%, a = 10%, and b = 20%. P0 was the PFS rate at 6 months defining inactive drug, and P1 was the PFS rate at 6 months defining promising drug. Results A total of 52 patients were enrolled, and 50 were randomly assigned in 14 centers. The most common primary sites were the breast (49%) and skin (12%). There were 17 (34%) visceral and 24 (49%) radiation-induced AS. The performance status was 0 in 24 patients (49%) and 1 in the remaining 25 patients (51%). The median follow-up time was 14.5 months. Both treatment regimens were considered active, with 6-month PFS rates of 54% (14 of 26) in arm A and 57% (14 of 24) in arm B. The median overall survival rates were 19.5 months in arm A and 15.9 months in arm B. Toxicity was higher with the combination arm and included one fatal drug-related toxicity (intestinal occlusion). Conclusion The primary objective was met in both treatment arms. However, the present data do not support additional clinical investigation of combined paclitaxel/bevacizumab for the treatment of advanced AS.
Frequency- and Afterload-Dependent Cardiac Modulation In Vivo by Troponin I With Constitutively Active Protein Kinase A Phosphorylation Sites
Authors: Eiki Takimoto, David G. Soergel, Paul M.L. Janssen, Linda B. Stull, David A. Kass, Anne M. Murphy
Journal: Circulation Research (2004)

Acute β-adrenergic stimulation enhances cardiac contractility, accelerates muscle relaxation, and amplifies the inotropic and lusitropic response to increased stimulation frequency. These effects are modulated by phosphorylation of calcium handling and myofilament proteins such as troponin I (TnI) by protein kinase A (PKA). To more directly delineate the role of TnI PKA phosphorylation, transgenic mice were generated that overexpress cardiac TnI in which the serine residues normally targeted by PKA are mutated to aspartic acid to mimic constitutive phosphorylation (TnIDD 22,23 ). Native cardiac TnI was near completely replaced in one transgenic line as assessed by in vitro phosphorylation, and this led to reduced calcium sensitivity of myofibrillar MgATPase, as expected. TnIDD 22,23 mice had mildly enhanced basal systolic and diastolic function, and displayed marked augmentation of frequency-dependent inotropy and relaxation, with a peak frequency response 2-fold greater in mutants than controls ( P &lt;0.005). Increasing afterload prolonged relaxation more in nontransgenic than TnIDD 22,23 ( P &lt;0.02), whereas contractile responses to afterload were similar between these strains. Isoproterenol treatment eliminated the differential force-frequency and afterload response between TnIDD 22,23 and controls. In contrast to in vivo studies, isolated isometric trabeculae from nontransgenic and TnIDD 22,23 mice had similar basal, isoproterenol-, and frequency-stimulated function, suggesting that muscle shortening may be important to TnI PKA effects. These results support a novel role for cardiac TnI PKA phosphorylation in the rate-dependent enhancement of systolic and diastolic function in vivo and afterload sensitivity of relaxation. These results have implications for cardiac failure in which force-frequency modulation is blunted and afterload relaxation sensitivity increased in association with diminished PKA TnI phosphorylation.
Early evidence implicating the brain derived neurotrophic factor (BDNF) val66met polymorphism in the pathogenesis of oesophageal visceral sensitivity
Authors: D. H. Vasant, A. Payton, T. Algladi, S. Mistry, S. Hamdy
Journal: Gut (2011)

<h3>Introduction</h3> Functional gastrointestinal disorders are common clinical conditions where visceral hypersensitivity has been strongly implicated. It is recognised that genetic factors may be an important factor in visceral sensation and may guide future pharmaceutical targets.1 One genetic biomarker, Brain Derived Neurotrophic Factor (BDNF) is a neurotrophic factor known to modulate pain, which is linked to a common polymorphism (Val66Met). The aim of this proof of concept study was to investigate if there is an association between presence of BDNF Val66Met polymorphism and oesophageal pain thresholds to electrical stimulation. <h3>Methods</h3> Healthy volunteers (n=43, 22 males, 21 Females, mean age 31.6 years) were recruited and completed health screening questionnaires including the Hospital Anxiety and Depression Scale (HADS) before providing a saliva specimen for genotyping. All volunteers were tested for sensory (ST) and pain (PT) thresholds in the proximal (PO) and distal oesophagus (DO) using electrical stimuli (ES) to a swallowed intraluminal catheter with 2 pairs of bipolar electrodes, positioned 5 and 20 cm below the upper oesophageal sphincter. As a control, ST and PT were also tested using ES on the hand and on the foot. <h3>Results</h3> 29/43 (67%) volunteers had BDNF Val/Val genotype. 14/43 (33%) had BDNF polymorphism (non-Val/Val). Mean ST and PT for oesophagus, hand and foot are shown in table 1. When BDNF status was considered, non-Val/Val subjects had consistently lower thresholds in the oesophagus, with significantly reduced values in the lowest quartile for PO PT (mean ± SEM; 21.8 ± 3.8 vs 35.7 ± 1.61 mA) p=0.02, but not for DO, Hand or Foot. Mean HADS for Anxiety (4.33) and Depression (1.43) were similar for both BDNF groups. <h3>Conclusion</h3> Our study shows proof of concept evidence that BDNF polymorphism may be an important genetic factor in visceral hyperalgesia. A larger scale study combined with monitoring and control of psychosocial factors is thus merited.
The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma
Authors: H.R. Kim, S.M. Lim, H.J. Kim, S.K. Hwang, J.K. Park, E. Shin, M.K. Bae, S.-H.I. Ou, J. Wang, S.S. Jewell, D.R. Kang, R.A. Soo, H. Haack, J.H. Kim, H.S. Shim, B.C. Cho
Journal: Annals of Oncology (2013)
Psychosis and autism as two developmental windows on a disordered social brain
Authors: Sophie van Rijn, Hanna Swaab, André Aleman
Journal: Behavioral and Brain Sciences (2008)

Abstract With regard to social-cognitive deficits in autism and psychosis, Crespi &amp; Badcock's (C&amp;B's) theory does not incorporate the developmental context of the disorders. We propose that there is significant overlap in social-cognitive impairments, but that the exact manifestation of social-cognitive deficits is highly dependent on the dynamics of cognitive development and hence different in autism as compared to psychosis.
Appearance of aac(6′)-Ib-cr gene among extended-spectrum β-lactamase-producing Enterobacteriaceae in a French hospital
Authors: V. Fihman, M.F. Lartigue, H. Jacquier, F. Meunier, N. Schnepf, L. Raskine, J. Riahi, M.-J. Sanson-le Pors, B. Berçot
Journal: Journal of Infection (2008)
Characterization of the <i>galU</i> Gene of <i>Streptococcus pneumoniae</i> Encoding a Uridine Diphosphoglucose Pyrophosphorylase: A Gene Essential for Capsular Polysaccharide Biosynthesis
Authors: Marta Mollerach, Rubens López, Ernesto García
Journal: The Journal of Experimental Medicine (1998)

The galU gene of Streptococcus pneumoniae has been cloned and sequenced. Escherichia coli cells harboring the recombinant plasmid pMMG2 (galU) overproduced a protein that has been shown to correspond to a uridine 5′-triphosphate:glucose-1-phosphate uridylyltransferase (uridine diphosphoglucose [UDP-Glc] pyrophosphorylase) responsible for the synthesis of UDP-Glc, a key compound in the biosynthesis of polysaccharides. A gene very similar to the S. pneumoniae galU has been found in a partial nucleotide sequence of the Streptococcus pyogenes genome. Knockout galU mutants of type 1 pneumococci are unable to synthesize a detectable capsule. An identical result was found in type 3 S. pneumoniae cells in spite of the fact that these bacteria contain a type-specific gene (cap3C) that also encodes a UDP-Glc pyrophosphorylase. Since eukaryotic UDP-Glc pyrophosphorylases appear to be completely unrelated to their prokaryotic counterparts, we postulate that GalU may be an appropriate target for the search of new drugs to control the pathogenicity of bacteria like pneumococcus and S. pyogenes.
Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China
Authors: Stephanie J London, Jian-Min Yuan, Fung-Lung Chung, Yu-Tang Gao, Gerhard A Coetzee, Ronald K Ross, Mimi C Yu
Journal: The Lancet (2000)
Unexpected Acute Neurologic Toxicity in the Treatment of Children With Acute Lymphoblastic Leukemia
Authors: N. J. Winick, W. P. Bowman, B. A. Kamen, E. S. Roach, N. Rollins, D. Jacaruso, G. R. Buchanan
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Unexpected Acute Neurologic Toxicity in the Treatment of Children With Acute Lymphoblastic Leukemia Get access Naomi J. Winick, Naomi J. Winick * Department of Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center, Dallas, Tex., and Cook-Ft. Worth Children's Medical Center, Ft. Worth, Tex. * Correspondence to: Naomi J. Winick, M. D., Department of Pediatrics, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, TX 75235-9063. Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Paul Bowman, W. Paul Bowman Department of Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center, Dallas, Tex., and Cook-Ft. Worth Children's Medical Center, Ft. Worth, Tex. Search for other works by this author on: Oxford Academic PubMed Google Scholar Barton A. Kamen, Barton A. Kamen Department of Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center, Dallas, Tex., and Cook-Ft. Worth Children's Medical Center, Ft. Worth, Tex. Search for other works by this author on: Oxford Academic PubMed Google Scholar E. Steve Roach, E. Steve Roach Department of Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center, Dallas, Tex., and Cook-Ft. Worth Children's Medical Center, Ft. Worth, Tex. Search for other works by this author on: Oxford Academic PubMed Google Scholar Nancy Rollins, Nancy Rollins Department of Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center, Dallas, Tex., and Cook-Ft. Worth Children's Medical Center, Ft. Worth, Tex. Search for other works by this author on: Oxford Academic PubMed Google Scholar Diana Jacaruso, Diana Jacaruso Department of Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center, Dallas, Tex., and Cook-Ft. Worth Children's Medical Center, Ft. Worth, Tex. Search for other works by this author on: Oxford Academic PubMed Google Scholar George R. Buchanan George R. Buchanan Department of Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center, Dallas, Tex., and Cook-Ft. Worth Children's Medical Center, Ft. Worth, Tex. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 4, 19 February 1992, Pages 252–256, https://doi.org/10.1093/jnci/84.4.252 Published: 19 February 1992 Article history Received: 22 July 1991 Revision received: 06 December 1991 Accepted: 09 December 1991 Published: 19 February 1992
Nuclear RNA Foci in the Heart in Myotonic Dystrophy
Authors: Ami Mankodi, Xiaoyan Lin, Burns C. Blaxall, Maurice S. Swanson, Charles A. Thornton
Journal: Circulation Research (2005)

The disease mechanism underlying myotonic dystrophy type 1 (DM1) pathogenesis in skeletal muscle may involve sequestration of RNA binding proteins in nuclear foci of expanded poly(CUG) RNA. Here we report evidence for a parallel mechanism in the heart. Accumulation of expanded poly(CUG) RNA in nuclear foci is associated with sequestration of muscleblind proteins and abnormal regulation of alternative splicing in DM1 cardiac muscle. A toxic effect of RNA with an expanded repeat may contribute to cardiac disease in DM1.
Urinary Albumin Excretion as a Predictor of the Development of Hypertension in the General Population
Authors: Auke H. Brantsma, Stephan J.L. Bakker, Dick de Zeeuw, Paul E. de Jong, Ronald T. Gansevoort
Journal: Journal of the American Society of Nephrology (2006)

The hypothesis that high urinary albumin excretion (UAE; indicating mild renal damage) may precede development of hypertension was tested, and the relation among UAE, GFR, and development of hypertension was investigated. Data of 4635 patients of a prospective cohort study who participated in an extensive screening in 1997 to 1998 and 2001 to 2003 at our outpatient unit and were normotensive at baseline were used. Hypertension was defined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria, UAE was measured in two consecutive 24-h urine samples, and GFR was calculated with the modified Modification of Diet in Renal Disease formula. Mean follow-up was 4.3 yr. Baseline UAE was significantly associated with the risk for developing hypertension (odds ratio 2.29; 95% confidence interval 1.77 to 2.95 per 10-fold increase of UAE). This association was independent of potential confounders. An interaction between UAE and GFR was found (P = 0.030), indicating that with elevated UAE and lowered GFR, but still within the normal range, the risk for developing hypertension was highest. In conclusion, these findings support the hypothesis that mild renal damage may precede the development of hypertension.