tbuckley/cabot-search huggingface dataset:
An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study
Authors: Timothy M Miller, Alan Pestronk, William David, Jeffrey Rothstein, Ericka Simpson, Stanley H Appel, Patricia L Andres, Katy Mahoney, Peggy Allred, Katie Alexander, Lyle W Ostrow, David Schoenfeld, Eric A Macklin, Daniel A Norris, Georgios Manousakis, Matthew Crisp, Richard Smith, C Frank Bennett, Kathie M Bishop, Merit E Cudkowicz
Journal: The Lancet Neurology (2013)

Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis.In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222.Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated.This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders.The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.
Chemokine receptor expression in EBV-associated lymphoproliferation in hu/SCID mice: implications for CXCL12/CXCR4 axis in lymphoma generation
Authors: Erich Piovan, Valeria Tosello, Stefano Indraccolo, Anna Cabrelle, Ilenia Baesso, Livio Trentin, Rita Zamarchi, Hirokazu Tamamura, Nobutaka Fujii, Gianpietro Semenzato, Luigi Chieco-Bianchi, Alberto Amadori
Journal: Blood (2004)
Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum–paclitaxel-based chemotherapy, the GINECO experience
Authors: J. Alexandre, I. Ray-Coquard, F. Selle, A. Floquet, P. Cottu, B. Weber, C. Falandry, D. Lebrun, E. Pujade-Lauraine
Journal: Annals of Oncology (2010)
The Care People Need and the Education of Physicians
Authors: Jamie H. Von Roenn, Charles von Gunten
Journal: Journal of Clinical Oncology (2011)

cancer. J Clin Oncol 28:1467-1472, 2010 25. Neubauer MA, Hoverman JR, Kolodziej M, et al: Cost effectiveness of evidence-based treatment guidelines for the treatment of non-small-cell lung cancer in the community setting. J Oncol Pract 6:12-18, 2010 26. Hoverman JR, Cartwright TH, Patt DA, et al: Pathways, outcomes, and costs in colon cancer: Retrospective evaluations in 2 distinct databases. Am J Manag Care 17:SP45-SP52, 2011 (suppl 5 developing) 27. Campion FX, Larson LR, Kadlubek PJ, et al: Advancing performance measurement in oncology. Am J Manag Care 17:SP32-SP36, 2011 (suppl 5 developing) 28. Meyerhardt JA: Beyond standard adjuvant therapy for colon cancer: Role of nonstandard interventions. Semin Oncol 38:533-541, 2011 29. Paskett ED, Harrop JP, Wells KJ: Patient navigation: An update on the state of the science. CA Cancer J Clin 61:237-249, 2011 30. [No authors listed]: Cancer survivors: Still room for improvement. Lancet Oncol 12:609, 2011
Prognostic factors for lung function in systemic sclerosis: prospective study of 105 cases
Authors: M. Gilson, D. Zerkak, J. Wipff, D. Dusser, A. T. Dinh-Xuan, V. Abitbol, S. Chaussade, P. Legmann, A. Kahan, Y. Allanore
Journal: European Respiratory Journal (2009)

The aims of the present study were to identify prognostic factors for systemic sclerosis (SSc)-related interstitial lung disease and to clarify the possible causative role of manometric oesophageal involvement. Consecutive SSc patients underwent pulmonary function tests and oesophageal manometry. They were included in the study if pulmonary function tests were repeated >12 months after baseline. The primary end-point was a decrease of >or=10% of the predicted value in forced vital capacity (FVC). The secondary end-points were a decrease of >or=15% pred in lung carbon monoxide diffusing capacity (D(L,CO)) and a decrease of >or=20% pred in FVC. Of the 105 patients (45 diffuse SSc; median disease duration 2.0 yrs), 23 (23%) had a FVC of <80% pred, 60 (59%) had a D(L,CO) of <80% pred and 57 (54%) showed severe oesophageal hypomotility at baseline. Over 72+/-46 months, 29 (28%) patients displayed a decrease of >or=10% pred in FVC, 39 (40%) of 98 patients displayed D(L,CO) decline and 19 (18%) patients displayed a decrease of >or=20% pred in FVC. On multivariate analysis, diffuse SSc was a significant predictor for a decrease of >or=10% pred in FVC (p = 0.01). No other predictor of a decrease in pulmonary function was identified. Only diffuse SSc was predictive of a decrease in pulmonary function in this early-SSc cohort. This does not support preliminary data suggestive of a causative role of oesophageal involvement.
Value of serum PABA as a pancreatic function test.
Authors: C Lang, K Gyr, I Tonko, D Conen, G A Stalder
Journal: Gut (1984)

In a total of 71 subjects (19 controls, 24 patients with non-pancreatic gastrointestinal disease, and 27 patients with pancreatic disease) an oral pancreatic function test using N-benzoyl-L-tyrosyl-PABA (BT-PABA) was performed with simultaneous determination of the serum para-aminobenzoic acid (PABA). Urinary excretion of PABA was significantly less (p less than 0.001) in patients with chronic pancreatitis (n = 12) and pancreatic carcinoma (n = 10) than in controls and in patients with non-pancreatic disease. The serum concentration curve in patients with chronic pancreatitis was significantly flattened (p less than 0.001) compared with that of the control group and the patients with non-pancreatic gastrointestinal disease. The discrimination between the controls and the patients with chronic pancreatitis was best at 120 minutes after administration of BT-PABA (lower limit of normal: 2.8 micrograms/ml). The results of our study show that determination of PABA serum concentration two hours after administration of BT-PABA is as valuable an index of pancreatic function as the urinary excretion of PABA.
Normalization of CD4 <sup>+</sup> T cell metabolism reverses lupus
Authors: Yiming Yin, Seung-Chul Choi, Zhiwei Xu, Daniel J. Perry, Howard Seay, Byron P. Croker, Eric S. Sobel, Todd M. Brusko, Laurence Morel
Journal: Science Translational Medicine (2015)

Systemic lupus erythematosus is associated with enhanced CD4 + T cell metabolism and can be reversed by metabolic modulators.
PREDICTION OF ENDOCRINE RESPONSE IN BREAST CANCER BY IMMUNOCYTOCHEMICAL DETECTION OF OESTROGEN RECEPTOR IN FINE-NEEDLE ASPIRATES
Authors: R.Charles Coombes, Uta Berger, RichardA Mcclelland, PeterA Trott, TrevorJ Powles, Patricia Wilson, Jean-Claude Gazet, HubertT Ford
Journal: The Lancet (1987)
Macaques vaccinated with live-attenuated SIV control replication of heterologous virus
Authors: Matthew R. Reynolds, Andrea M. Weiler, Kim L. Weisgrau, Shari M. Piaskowski, Jessica R. Furlott, Jason T. Weinfurter, Masahiko Kaizu, Taeko Soma, Enrique J. León, Caitlin MacNair, Dan P. Leaman, Michael B. Zwick, Emma Gostick, Solomon K. Musani, David A. Price, Thomas C. Friedrich, Eva G. Rakasz, Nancy A. Wilson, Adrian B. McDermott, Rosanne Boyle, David B. Allison, Dennis R. Burton, Wayne C. Koff, David I. Watkins
Journal: The Journal of Experimental Medicine (2008)

An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by ∼2 logs between weeks 2–32 (P ≤ 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8+ T cells in this control. Furthermore, transient depletion of peripheral CD8+ lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I–restricted CD8+ T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8+ T cell responses can control replication of heterologous challenge viruses.
Induction of Drug Metabolism: The Role of Nuclear Receptors
Authors: Christoph Handschin, Urs A. Meyer
Journal: Pharmacological Reviews (2003)

Induction of drug metabolism was described more than 40 years ago. Progress in understanding the molecular mechanism of induction of drug-metabolizing enzymes was made recently when the important roles of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of transcription factors, were discovered to act as sensors for lipophilic xenobiotics, including drugs. CAR and PXR bind as heterodimeric complexes with the retinoid X receptor to response elements in the regulatory regions of the induced genes. PXR is directly activated by xenobiotic ligands, whereas CAR is involved in a more complex and less well understood mechanism of signal transduction triggered by drugs. Most recently, analysis of these xenobiotic-sensing nuclear receptors and their nonmammalian precursors such as the chicken xenobiotic receptor suggests an important role of PXR and CAR also in endogenous pathways, such as cholesterol and bile acid biosynthesis and metabolism. In this review, recent findings regarding xenosensors and their target genes are summarized and are put into an evolutionary perspective in regard to how a living organism has derived a system that is able to deal with potentially toxic compounds it has not encountered before.
Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling
Authors: L. Vincent
Journal: Journal of Clinical Investigation (2005)

The molecular and cellular pathways that support the maintenance and stability of tumor neovessels are not well defined. The efficacy of microtubule-disrupting agents, such as combretastatin A4 phosphate (CA4P), in inducing rapid regression of specific subsets of tumor neovessels has opened up new avenues of research to identify factors that support tumor neoangiogenesis. Herein, we show that CA4P selectively targeted endothelial cells, but not smooth muscle cells, and induced regression of unstable nascent tumor neovessels by rapidly disrupting the molecular engagement of the endothelial cell-specific junctional molecule vascular endothelial-cadherin (VE-cadherin) in vitro and in vivo in mice. CA4P increases endothelial cell permeability, while inhibiting endothelial cell migration and capillary tube formation predominantly through disruption of VE-cadherin/beta-catenin/Akt signaling pathway, thereby leading to rapid vascular collapse and tumor necrosis. Remarkably, stabilization of VE-cadherin signaling in endothelial cells with adenovirus E4 gene or ensheathment with smooth muscle cells confers resistance to CA4P. CA4P synergizes with low and nontoxic doses of neutralizing mAbs to VE-cadherin by blocking assembly of neovessels, thereby inhibiting tumor growth. These data suggest that the microtubule-targeting agent CA4P selectively induces regression of unstable tumor neovessels, in part through disruption of VE-cadherin signaling. Combined treatment with anti-VE-cadherin agents in conjunction with microtubule-disrupting agents provides a novel synergistic strategy to selectively disrupt assembly and induce regression of nascent tumor neovessels, with minimal toxicity and without affecting normal stabilized vasculature.
Effect of cigarette smoking on evolution of ventilatory lung function in young adults: an eight year longitudinal study.
Authors: M S Jaakkola, P Ernst, J J Jaakkola, L W N'gan'ga, M R Becklake
Journal: Thorax (1991)

There are few data on the quantitative effects of cigarette smoking on lung function in young adults. These effects are important in the understanding of the early stages of chronic airflow obstruction.A longitudinal study over eight years was carried out to estimate quantitatively the effect of cigarette smoking on ventilatory lung function in young adults and to examine the possibility that the effect is modified by other factors. The study population were 15 to 40 years of age at initial examination, when they underwent spirometry and completed an interviewer administered questionnaire on respiratory health. Eight years later 391 of the subjects were re-examined (38% response rate). The quantitative effect of cigarette smoking during the study period on the average change of forced expiratory volume in one second (FEV1) over time (delta FEV1) was estimated in two linear regression models that included potential confounders and other determinants of outcome.The first model showed a significant dose-response relation between the average rate of smoking during the study period and delta FEV1, giving an estimate of annual change in FEV1 of -0.42 ml for each cigarette smoked per day (-8.4 ml for each pack) (p = 0.04). In the second model, which took smoking before the study period as a potential confounder, the effect of smoking during the study period was slightly smaller (-0.33 ml/year for each cigarette smoked per day). This indicated that smoking before the study period had a marginal latent effect on delta FEV1 during the study. However, neither the effect of smoking before the study nor that of smoking during the study was significant, presumably because of collinearity. Interactions between cigarette smoking and gender, wheezing, atopy, and exposure to environmental tobacco smoke during the growth period were not significant with respect to their effect on the relation between cigarette smoking and delta FEV1.Cigarette smoking has a dose related adverse effect on the evolution of ventilatory lung function in young adulthood.
The Dynamics and Evolutionary Potential of Domain Loss and Emergence
Authors: A. D. Moore, E. Bornberg-Bauer
Journal: Molecular Biology and Evolution (2011)

The wealth of available genomic data presents an unrivaled opportunity to study the molecular basis of evolution. Studies on gene family expansions and site-dependent analyses have already helped establish important insights into how proteins facilitate adaptation. However, efforts to conduct full-scale cross-genomic comparisons between species are challenged by both growing amounts of data and the inherent difficulty in accurately inferring homology between deeply rooted species. Proteins, in comparison, evolve by means of domain rearrangements, a process more amenable to study given the strength of profile-based homology inference and the lower rates with which rearrangements occur. However, adapting to a constantly changing environment can require molecular modulations beyond reach of rearrangement alone. Here, we explore rates and functional implications of novel domain emergence in contrast to domain gain and loss in 20 arthropod species of the pancrustacean clade. Emerging domains are more likely disordered in structure and spread more rapidly within their genomes than established domains. Furthermore, although domain turnover occurs at lower rates than gene family turnover, we find strong evidence that the emergence of novel domains is foremost associated with environmental adaptation such as abiotic stress response. The results presented here illustrate the simplicity with which domain-based analyses can unravel key players of nature's adaptational machinery, complementing the classical site-based analyses of adaptation.
TNF-α gene promoter polymorphisms and risk of venous thromboembolism in gastrointestinal cancer patients undergoing chemotherapy
Authors: M. Roselli, P. Ferroni, C. Rolfo, M. Peeters, R. Palmirotta, V. Formica, G. Ludovici, A. Laudisi, M.L. De Marchis, F. La Farina, A. Russo, F. Guadagni
Journal: Annals of Oncology (2013)
Phase II Trial of Biweekly Infusional Fluorouracil, Folinic Acid, and Oxaliplatin in Patients With Advanced Gastric Cancer
Authors: Salah-Eddin Al-Batran, Akin Atmaca, Susanna Hegewisch-Becker, Dirk Jaeger, Sabine Hahnfeld, Mathias J Rummel, Gernot Seipelt, Andreas Rost, Jacqueline Orth, Alexander Knuth, Elke Jaeger
Journal: Journal of Clinical Oncology (2004)

To evaluate the toxicity and activity of infusional fluorouracil (FU), folinic acid (FA), and oxaliplatin, administered every 2 weeks in patients with metastatic gastric cancer.Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed.All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths.Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.
Activation of the BCL2 Promoter in Response to Hedgehog/GLI Signal Transduction Is Predominantly Mediated by GLI2
Authors: Gerhard Regl, Maria Kasper, Harald Schnidar, Thomas Eichberger, Graham W. Neill, Michael P. Philpott, Harald Esterbauer, Cornelia Hauser-Kronberger, Anna-Maria Frischauf, Fritz Aberger
Journal: Cancer Research (2004)

Aberrant activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of basal cell carcinoma (BCC). The zinc finger transcription factors GLI1 and GLI2 are considered mediators of the HH signal in epidermal cells, although their tumorigenic nature and their relative contribution to tumorigenesis are only poorly understood. To shed light on the respective role of these transcription factors in epidermal neoplasia, we screened for genes preferentially regulated either by GLI1 or GLI2 in human epidermal cells. We show here that expression of the key antiapoptotic factor BCL2 is predominantly activated by GLI2 compared with GLI1. Detailed promoter analysis and gel shift assays identified three GLI binding sites in the human BCL2 cis-regulatory region. We found that one of these binding sites is critical for conferring GLI2-specific activation of the human BCL2 promoter and that the selective induction of BCL2 expression depends on the zinc finger DNA binding domain of GLI2. In vivo, GLI2 and BCL2 were coexpressed in the outer root sheath of hair follicles and BCC and in plasma cells that infiltrated BCC tumor islands. On the basis of the latter observation, we analyzed plasma cell-derived tumors and found strong expression of GLI2 and BCL2 in neoplastic cells of plasmacytoma patients, implicating HH/GLI signaling in the development of plasma cell-derived malignancies. The results reveal a central role for GLI2 in activating the prosurvival factor BCL2, which may represent an important mechanism in the development or maintenance of cancers associated with inappropriate HH signaling.
Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcγRIIA
Authors: Michael P. Reilly, Scott M. Taylor, Nealie K. Hartman, Gowthami M. Arepally, Bruce S. Sachais, Douglas B. Cines, Mortimer Poncz, Steven E. McKenzie
Journal: Blood (2001)
<i>miR-23a</i> Promotes the Transition from Indolent to Invasive Colorectal Cancer
Authors: Sohail Jahid, Jian Sun, Robert A. Edwards, Diana Dizon, Nicole C. Panarelli, Jeffrey W. Milsom, Shaheen S. Sikandar, Zeynep H. Gümüş, Steven M. Lipkin
Journal: Cancer Discovery (2012)

Abstract Colorectal cancer is a classic example of a tumor that progresses through multiple distinct stages in its evolution. To understand the mechanisms regulating the transition from indolent to invasive disease, we profiled somatic copy number alterations in noninvasive adenomas and invasive adenocarcinomas from Apc and DNA mismatch repair (MMR) mutant mouse models. We identified a recurrent amplicon on mouse chromosome 8 that encodes microRNA (miRNA) 23a and -27a (miR). miR-23a and -27a levels are upregulated in mouse intestinal adenocarcinomas, primary tumors from patients with stage I/II colorectal cancers, as well as in human colorectal cancer cell lines and cancer stem cells. Functionally, miR-23a promotes the migration and invasion of colorectal cancer cells and stem cells, whereas miR-27a primarily promotes proliferation. We computationally and experimentally validated that metastasis suppressor 1 (MTSS1) is a direct miR-23a target and similarly validated that the ubiquitin ligase FBXW7 is a direct miR-27a target. Analyses of computationally predicted target genes in microarray data sets of patients with colorectal cancers are consistent with a role for miR-23a, but not miR-27a, specifically in invasive colorectal cancers. Significance: Understanding the mechanisms regulating the transition from indolent adenomas to invasive and metastatic colorectal cancers is critical to improving patient outcomes. Our study highlights roles of miR-23a and miR-27a in tumor progression and supports a potential mechanistic role for miR-23a in the transition from indolent to invasive colorectal cancers. Cancer Discov; 2(6); 540–53. © 2012 AACR. This article is highlighted in the In This Issue feature, p. 473