tbuckley/cabot-search huggingface dataset:
Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E
Authors: Song Yi Ko, Huifang Guo, Nicolas Barengo, Honami Naora
Journal: Clinical Cancer Research (2009)

A critical step of protein synthesis involves the liberation of the mRNA cap-binding translation initiation factor eIF4E from 4EBP inhibitory binding proteins, and its engagement to the scaffolding protein eIF4G. eIF4E is a candidate target for cancer therapy because it is overexpressed or activated in many types of tumors and has tumorigenic properties. Our aim was to design and evaluate 4EBP-based peptides for their antitumor activity in ovarian cancer.The ability of peptides to bind and inhibit eIF4E was determined by immunoprecipitation and by assaying cap-dependent reporter synthesis. To target ovarian tumors, the lead candidate 4EBP peptide was fused to an analog of gonadotropin-releasing hormone (GnRH). Cellular uptake of peptide, and effects on cell viability and cell death were determined. The antitumor activity of fusion peptide was evaluated in female nude mice bearing i.p. ovarian tumor xenografts.4EBP-based peptides bound eIF4E, prevented eIF4E from binding eIF4G, and inhibited cap-dependent translation. GnRH agonist-4EBP fusion peptide was taken up by, and inhibited the growth of, GnRH receptor-expressing tumor cells, but not receptor-negative cells. Intraperitoneal tumor burden was significantly smaller in mice treated with fusion peptide than in mice treated with saline (P < 0.001). Ascites was also reduced in peptide-treated mice. Significant cytotoxic effects to host tissues were not observed. On the other hand, treatment with GnRH agonist alone did not inhibit tumor growth or ascites.Because ovarian cancer is rarely cured by conventional chemotherapies, GnRH-4EBP fusion peptide may be of therapeutic potential for treatment of this disease.
Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue
Authors: Markus Mayrhofer, Sebastian DiLorenzo, Anders Isaksson
Journal: Genome biology (2013)

Whole-genome sequencing of tumor tissue has the potential to provide comprehensive characterization of genomic alterations in tumor samples. We present Patchwork, a new bioinformatic tool for allele-specific copy number analysis using whole-genome sequencing data. Patchwork can be used to determine the copy number of homologous sequences throughout the genome, even in aneuploid samples with moderate sequence coverage and tumor cell content. No prior knowledge of average ploidy or tumor cell content is required. Patchwork is freely available as an R package, installable via R-Forge (http://patchwork.r-forge.r-project.org/).
1α,25-Dihydroxyvitamin D <sub>3</sub> Induces Vascular Smooth Muscle Cell Migration via Activation of Phosphatidylinositol 3-Kinase
Authors: Michela C. Rebsamen, Jianxin Sun, Anthony W. Norman, James K. Liao
Journal: Circulation Research (2002)

The steroid hormone 1α,25-dihydroxyvitamin D 3 [1α, 25-(OH) 2 D 3 ] promotes vascular smooth muscle cell (VSMC) growth and calcification, but the precise mechanism by which 1α, 25-(OH) 2 D 3 regulates VSMC migration is unknown. In rat aortic SMCs, we found that 1α, 25-(OH) 2 D 3 (0.1 to 100 nmol/L) induced a dose-dependent increase in VSMC migration. This response required the activation of phosphatidylinositol 3-kinase (PI3 kinase) because 1α, 25-(OH) 2 D 3 -induced migration was completely abolished by the PI3 kinase inhibitors, LY294002 (10 μmol/L) or wortmannin (30 nmol/L). Furthermore, the RNA polymerase inhibitor, 5,6-dichlorobenzimidazole riboside (50 μmol/L), did not affect 1α, 25-(OH) 2 D 3 -induced VSMC migration, suggesting that gene transcription is not involved in this rapid response. Using analogs of 1α, 25-(OH) 2 D 3 , which have been characterized for their abilities to induce either transcriptional or nontranscriptional responses of 1α, 25-(OH) 2 D 3 , we found that 1α,25-dihydroxylumisterol, which is a potent agonist of the rapid, nongenomic responses, was equipotent with 1α, 25-(OH) 2 D 3 in inducing PI3 kinase activity and VSMC migration. Moreover, 1β, 25-(OH) 2 D 3 , which specifically antagonizes the nongenomic actions of 1α, 25-(OH) 2 D 3 , abolished 1α, 25-(OH) 2 D 3 -induced PI3 kinase activity and VSMC migration, whereas the inhibitor of the genomic actions of vitamin D, (23S)-25-dehydro-1α-OH-D 3 -26,23-lactone, did not affect these responses. These results indicate that 1α, 25-(OH) 2 D 3 induces VSMC migration independent of gene transcription via PI3 kinase pathway, and suggest a possible mechanism by which 1α, 25-(OH) 2 D 3 may contribute to neointima formation in atherosclerosis and vascular remodeling.
Rearrangements of the tal-1 locus as clonal markers for T cell acute lymphoblastic leukemia.
Authors: O G Jonsson, R L Kitchens, R J Baer, G R Buchanan, R G Smith
Journal: Journal of Clinical Investigation (1991)

Normal and aberrant immune receptor gene assembly each produce site-specific DNA rearrangements in leukemic lymphoblasts. In either case, these rearrangements provide useful clonal markers for the leukemias in question. In the t(1;14)(p34;q11) translocation associated with T cell acute lymphoblastic leukemia (T-ALL), the breakpoints on chromosome 1 interrupt the tal-1 gene. A site-specific deletion interrupts the same gene in an additional 26% of T-ALL. Thus, nearly one-third of these leukemias contain clustered rearrangements of the tal-1 locus. To test whether these rearrangements can serve as markers for residual disease, we monitored four patients with T-ALL; three of the leukemias contained a deleted (tald) and one a translocated (talt) tal-1 allele. These alleles were recognized by a sensitive amplification/hybridization assay. tald alleles were found in the blood of one patient during the 4th mo of treatment but not thereafter. Using a quantitative assay to measure the fraction of tald alleles in DNA extracts, we estimated that this month 4 sample contained 150 tald copies per 10(6) genome copies. The patient with t(1;14)(p34;q11) (talt) leukemia developed a positive assay during the 20th mo of treatment. By standard criteria, all four patients remain in complete remission 11-20 mo into treatment. We conclude that tal-1 rearrangements provide useful clonal markers for approximately 30% of T-ALLs.
PTEN Expression in Melanoma: Relationship with Patient Survival, Bcl-2 Expression, and Proliferation
Authors: Maryann Mikhail, Elsa Velazquez, Richard Shapiro, Russell Berman, Anna Pavlick, Lian Sorhaindo, Joanna Spira, Carmen Mir, Katherine S. Panageas, David Polsky, Iman Osman
Journal: Clinical Cancer Research (2005)

Inactivation of the tumor suppressor gene, phosphatase and tensin homologue (PTEN), is a major alteration in preclinical melanoma models. We investigated the clinical relevance of PTEN expression in the primary melanoma patients with extended follow-up.We correlated PTEN expression with clinicopathologic variables and outcome in 127 primary melanomas (median follow-up, 12.8 years). We evaluated the associations between PTEN expression and proliferation and resistance to apoptosis (assessed by Ki-67 and Bcl-2, respectively). We also examined the effect of a favorable phenotype, defined as retained PTEN, low proliferative index, and low expression of Bcl-2 on disease-free survival and overall survival.Altered PTEN, Bcl-2, and Ki-67 expressions were observed in 55 of 127 (43.3%), 61 of 127 (48%), and 43 of 114 (37.7%) of cases, respectively. Decreased PTEN expression correlated significantly with the ulceration (P = 0.01). Rates of disease-free survival and overall survival in patients with favorable phenotype were 72% and 74% at 5 years versus 64% and 64% in patients with an unfavorable phenotype. At 10 years, the rates of disease-free survival and overall survival were 72% and 68% for patients with a favorable phenotype but declined to 60% and 55% in patients with an unfavorable phenotype. However, relationships between both PTEN and Bcl2 and patient survival were not significant as well as the associations between PTEN and Bcl-2 or Ki-67.Our data suggest that altered PTEN expression is common in primary melanomas and is associated with aggressive tumor behavior. However, PTEN alone provided limited prognostic value. Our findings show the need to examine molecular alterations identified in preclinical studies using an adequately large cohort of patients with extended follow-up to better assess the magnitude of their clinical relevance.
Blockade of Platelet-Derived Growth Factor Receptor-Beta by CDP860, a Humanized, PEGylated di-Fab', Leads to Fluid Accumulation and Is Associated With Increased Tumor Vascularized Volume
Authors: G.C. Jayson, G.J.M. Parker, S. Mullamitha, J.W. Valle, M. Saunders, L. Broughton, J. Lawrance, B. Carrington, C. Roberts, B. Issa, D.L. Buckley, S. Cheung, K. Davies, Y. Watson, K. Zinkewich-Péotti, L. Rolfe, A. Jackson
Journal: Journal of Clinical Oncology (2004)

Purpose CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-β). Studies in animals have suggested that PDGFR-β inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. Patients and Methods Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. Results Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P &lt; .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. Conclusion These observations suggest that inhibition of PDGFR-β might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.
Diversity of CRISPR-Cas immune systems and molecular machines
Authors: Rodolphe Barrangou
Journal: Genome biology (2015)

Bacterial adaptive immunity hinges on CRISPR-Cas systems that provide DNA-encoded, RNA-mediated targeting of exogenous nucleic acids. A plethora of CRISPR molecular machines occur broadly in prokaryotic genomes, with a diversity of Cas nucleases that can be repurposed for various applications.
Physician assisted suicide
Authors: J. T. D'Olimpio
Journal: JAMA (1995)

To the Editor.  —I read, with dismay, the article by Ms Alpers and Dr Lo 1 that characterized Oregon's physician-assisted suicide law as a bold experiment. Chillingly, it ratifies this act as a fait accompli that physicians need to accept by cooperating in compiling relevant empirical data on such a practice.  As a clinician trained in medical oncology and as a medical director of a hospice program in New York, I believe physicians should take an active stance against this practice. It should not be accepted as a reality, as the authors do so dispassionately. Such detached language by these authors completely misses the point as to why this law is unworkable and ultimately impossible to regard with any degree of professional respect, integrity, and relevance.  Improving care of terminally ill patients requires a degree of medical expertise and compassion and a clinical knowledge base most physicians simply do not
Long-Term Effectiveness of a Quality Improvement Program for Patients With Type 2 Diabetes in General Practice
Authors: Carry M. Renders, Gerlof D. Valk, Lonneke V. Franse, François G. Schellevis, Jacques Th.M. van Eijk, Gerrit van der Wal
Journal: Diabetes Care (2001)

OBJECTIVE—To assess the long-term effectiveness of a quality improvement program on care provided and patient outcomes in patients with diabetes. RESEARCH DESIGN AND METHODS—A nonrandomized trial was performed with 312 patients with type 2 diabetes in the intervention group and 77 patients with type 2 diabetes in the reference group. The follow-up period was 42 months. The quality improvement program focused on improving both the provision of diabetes care and the patient outcomes. The program consisted of clinical practice guidelines, postgraduate education, audit and feedback, templates to register diabetes care, and a recall system. Data on the care provided were abstracted from medical records. Main outcomes on the provision of care were annual number of patient visits, blood pressure, and HbA1c and blood lipid levels. Main patient outcomes were blood pressure and HbA1c and blood lipid levels. Multilevel analysis was used to adjust for dependency between repeated observations within one patient and for clustering of patients within general practices. RESULTS—Patients in the intervention group received care far more in accordance with the guidelines than patients in the reference group. Odds ratios ranged from 2.43 (95% CI 1.01–5.82) for the measurement of urine albumin to 12.08 (4.70–31.01) for the measurement of blood pressure. No beneficial effect was found on any patient outcome. CONCLUSIONS—The quality improvement program improved the provision of diabetes care, but this was not accompanied by any effect on patient outcomes.
Are clinical genomes already becoming semi-routine for patient care?
Authors: Mark Boguski
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
Fractionated high-dose-rate brachytherapy in primary carcinoma of the nasopharynx.
Authors: P C Levendag, P I Schmitz, P P Jansen, W M Eijkenboom, A G Visser, I K Kolkman-Deurloo, D Sipkema, L L Visch, S Senan
Journal: Journal of Clinical Oncology (1998)

A growing body of data suggests that local control in nasopharyngeal cancer (NPC) is related to the radiation dose administered. We conducted a single-institution study of high-dose radiotherapy (RT), which incorporated high-dose-rate (HDR) brachytherapy (BT). These results were analyzed together with data obtained from controls who did not receive BT.The BT group comprised 42 consecutive patients of whom 29 patients were staged according to the tumor, node, metastasis system as T1 through 3, 13 patients were T4, and 34 patients were N+ disease. BT was administered on an outpatient basis by means of a specially designed flexible nasopharyngeal applicator, and the dose distributions were optimized. Treatment for T1 through 3 tumors comprised 60 Gy of external-beam radiotherapy (ERT) followed by six fractions of 3 Gy BT (two fractions per day). Patients with parapharyngeal tumor extension and/or T4 tumors received 70 Gy ERT and four fractions of 3 Gy BT. The no-BT group consisted of all patients treated from 1965 to 1991 (n = 109), of whom 82 patients had stages T1 through 3, 27 patients had T4, and 80 patients had N+ disease. Multivariate Cox proportional hazards analyses were performed by using the end points time to local failure (TTLF), time to distant failure (TTDF), disease-free survival (DFS), cause-specific survival (CSS), and the prognostic factors age, tumor stage, node stage, and grade. Because the overall treatment time varied substantially in the no-BT group, the dependence of local failure (LF) on the physical dose as well as the biologic effective dose (BED) corrected for the overall treatment time (OTT) (BEDcor10) was studied.The BT group had a superior 3-year local relapse-free rate (86% v 60%; univariate analysis, P = .004). Multivariate analysis showed hazards ratios for BT versus no-BT of 0.24 for TTLF (P = .003), 0.35 for TTDF (P = .038), 0.31 for DFS (P < .001), and 0.44 for CSS (P = .01). The best prognostic group consisted of patients with T1 through 3, N0 through 2b tumors treated with BT who attained a 5-year TTLF of 94% and CSS of 91%. In contrast, the worst prognostic group, i.e., 5-year TTLF of 47% and CSS of 24%, was composed of patients with T4 and/or N2c through 3 tumors who did not receive BT.High doses of radiation (73 to 95 Gy) can be administered to patients with NPC with minimal morbidity by means of optimized HDR-BT. The use of a BT boost proved to be of significant benefit, particularly in patients with T1 through 3, N0 through 2b disease. The steep dose-effect relationship seen for the physical dose and the BEDcor10 indicates that the results are dose related. The analysis has identified a poor prognostic group in whom treatment intensification with chemotherapy (CHT) is indicated.
Histone Deacetylase Inhibition and Blockade of the Glycolytic Pathway Synergistically Induce Glioblastoma Cell Death
Authors: Vivian Egler, Serdar Korur, Mike Failly, Jean-Louis Boulay, Roland Imber, Maria M. Lino, Adrian Merlo
Journal: Clinical Cancer Research (2008)

Abstract Purpose: High-grade gliomas are difficult to treat due to their location behind the blood-brain barrier and to inherent radioresistance and chemoresistance. Experimental Design: Because tumorigenesis is considered a multistep process of accumulating mutations affecting distinct signaling pathways, combinations of compounds, which inhibit nonoverlapping pathways, are being explored to improve treatment of gliomas. Histone deacetylase inhibitors (HDI) have proven antitumor activity by blocking cell proliferation, promoting differentiation, and inducing tumor cell apoptosis. Results: In this report, we show that the HDIs trichostatin A, sodium butyrate, and low nanomolar doses of LAQ824 combined with the glycolysis inhibitor 2-deoxy-d-glucose induce strong apoptosis in cancer cell lines of brain, breast, and cervix in a p53-independent manner. HDIs up-regulate p21, which is blocked by concomitant administration of 2-deoxy-d-glucose. Conclusions: We propose simultaneous blockade of histone deacetylation and glycolysis as a novel therapeutic strategy for several major cancers.
Health of women after severe obstetric complications in Burkina Faso: a longitudinal study
Authors: Véronique Filippi, Rasmané Ganaba, Rebecca F Baggaley, Tom Marshall, Katerini T Storeng, Issiaka Sombié, Fatoumata Ouattara, Thomas Ouedraogo, Mélanie Akoum, Nicolas Meda
Journal: The Lancet (2007)
Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML
Authors: Violaine Havelange, Parvathi Ranganathan, Susan Geyer, Deedra Nicolet, Xiaomeng Huang, Xueyan Yu, Stefano Volinia, Steven M. Kornblau, Michael Andreeff, Carlo M. Croce, Guido Marcucci, Clara D. Bloomfield, Ramiro Garzon
Journal: Blood (2014)
The Development of Behavior in Human Infants, Premature and Newborn
Authors: P H Wolff, R Ferber
Journal: Annual Review of Neuroscience (1979)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Lack of Efficacy of Bevacizumab Plus Irinotecan in Children With Recurrent Malignant Glioma and Diffuse Brainstem Glioma: A Pediatric Brain Tumor Consortium Study
Authors: Sridharan Gururangan, Susan N. Chi, Tina Young Poussaint, Arzu Onar-Thomas, Richard J. Gilbertson, Sridhar Vajapeyam, Henry S. Friedman, Roger J. Packer, Brian N. Rood, James M. Boyett, Larry E. Kun
Journal: Journal of Clinical Oncology (2010)

A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG).Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast-enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ.Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure.BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.
Can Patient Risk Factors Outperform Antiemetic Guidelines?
Authors: David Warr, Carlo DeAngelis, Edward Chow
Journal: JAMA Oncology (2015)

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