tbuckley/cabot-search huggingface dataset:
Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study
Authors: Jochen Hampe, Jochen Grebe, Susanna Nikolaus, Camilla Solberg, Peter JP Croucher, Silvia Mascheretti, Jörgen Jahnsen, Björn Moum, Bodo Klump, Michael Krawczak, Muddassar M Mirza, Ulrich R Foelsch, Morten Vatn, Stefan Schreiber
Journal: The Lancet (2002)
Voreloxin, a First-in-Class Anticancer Quinolone Derivative, in Relapsed/Refractory Solid Tumors: A Report on Two Dosing Schedules
Authors: Ranjana H. Advani, Herbert I. Hurwitz, Michael S. Gordon, Scot W. Ebbinghaus, David S. Mendelson, Heather A. Wakelee, Ute Hoch, Jeffrey A. Silverman, Nancy A. Havrilla, Craig J. Berman, Judith A. Fox, Roberta S. Allen, Daniel C. Adelman
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity. Experimental Design: Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history. Results: In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m2). At 60 mg/m2, four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m2, two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for &amp;gt;29 days (n = 1). Therefore, the MTD was 48 mg/m2 (HP patients) and 60 mg/m2 (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m2). At 18 mg/m2, two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (&amp;gt;14 days each). The MTD was 15 mg/m2. Voreloxin exhibited low clearance (2 L/h/m2), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria. Conclusions: Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia. Clin Cancer Res; 16(7); 2167–75. ©2010 AACR.
An unusual mucous cyst of the lung.
Authors: F J Sambrook Gowar
Journal: Thorax (1978)

A 68-year-old woman presented with a multilocular mucous cyst of the lung. At operation numerous seedling cysts were present on the parietal pleura, and the appearances strongly resembled those found in pseudomucinous cystadenoma of the ovary. The histological features suggested that the lesion was an unusual benign mucous cyst of the bronchus. After lobectomy and removal of pleural masses the patient has remained free from recurrence for five years.
Activation of AMP-activated protein kinase α2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo
Authors: Shuangxi Wang, Cheng Zhang, Miao Zhang, Bin Liang, Huaiping Zhu, Jiyeon Lee, Benoit Viollet, Lijun Xia, Yun Zhang, Ming-Hui Zou
Journal: Nature Medicine (2012)
<i>CXCR1</i>and<i>CXCR2</i>haplotypes synergistically modulate cystic fibrosis lung disease
Authors: Michael S.D. Kormann, Andreas Hector, Veronica Marcos, Lauren E. Mays, Matthias Kappler, Thomas Illig, Norman Klopp, Sonja Zeilinger, Melanie Carevic, Nikolaus Rieber, Olaf Eickmeier, Stefan Zielen, Amit Gaggar, Barbara Moepps, Matthias Griese, Dominik Hartl
Journal: European Respiratory Journal (2011)

Cystic fibrosis (CF) lung disease severity is largely independent on the CF transmembrane conductance regulator (<i>CFTR</i>) genotype, indicating the contribution of genetic modifiers. The chemokine receptors CXCR1 and CXCR2 have been found to play essential roles in the pathogenesis of CF lung disease. Here, we determine whether genetic variation of <i>CXCR1</i> and <i>CXCR2</i> influences CF lung disease severity. Genomic DNA of CF patients in Germany (n=442) was analysed for common variations in <i>CXCR1</i> and <i>CXCR2</i> using a single-nucleotide polymorphism (SNP) tagging approach. Associations of <i>CXCR1</i> and <i>CXCR2</i> SNPs and haplotypes with CF lung disease severity, CXCR1 and CXCR2 expression, and neutrophil effector functions were assessed. Four SNPs in <i>CXCR1</i> and three in <i>CXCR2</i> strongly correlated with age-adjusted lung function in CF patients. SNPs comprising haplotypes <i>CXCR1</i>_Ha and <i>CXCR2</i>_Ha were in high linkage disequilibrium and patients heterozygous for the <i>CXCR1-2</i> haplotype cluster (<i>CXCR1-2</i>_Ha) had lower lung function compared with patients with homozygous wild-type alleles (forced expiratory volume in 1 s ≤70% predicted, OR 7.24; p=2.30×10<sup>−5</sup>). CF patients carrying <i>CXCR1-2</i>_Ha showed decreased CXCR1 combined with increased CXCR2 mRNA and protein expression, and displayed disturbed antibacterial effector functions. <i>CXCR1</i> and <i>CXCR2</i> genotypes modulate lung function and antibacterial host defence in CF lung disease.
Optimal Selection of Individuals for <i>BRCA</i> Mutation Testing: A Comparison of Available Methods
Authors: Paul A. James, Rebecca Doherty, Marion Harris, Bickol N. Mukesh, Alvin Milner, Mary-Anne Young, Clare Scott
Journal: Journal of Clinical Oncology (2006)

Several methods have been described that estimate the likelihood that a family history of cancer is a result of a mutation in the BRCA1 or BRCA2 genes. We examined the performance of six different methods with the aim of identifying an optimal strategy for selecting individuals for mutation testing in clinical practice.Two hundred fifty-seven families who had completed BRCA1 and BRCA2 mutation screening were assessed by six models representing the major methodologies used to assess the likelihood of a pathogenic mutation. The performance of each method as a selection criterion was compared with the result of mutation testing to produce sensitivity, specificity, and receiver operating curve data. The impact of incorporating breast cancer pathology data in the assessment was also analyzed.The highest accuracy was achieved by the Bayesian probabilistic model (BRCAPRO). The formal probabilistic methods were significantly more accurate than clinical scoring methods. The methods were further improved by the incorporation of information on breast cancer pathology (tumor grade and estrogen receptor/progesterone receptor status). The resulting combined probability figure was highly accurate when selecting individuals for BRCA1 testing. Some BRCA2 mutation carriers were missed by all of the models examined.Formal probabilistic models provide significantly greater accuracy in the selection of families for gene testing than the use of clinical criteria or scoring methods. The accuracy is further enhanced by incorporating information on the pathology of breast cancers occurring in the families.
Efficacy and Safety of Lebrikizumab in Severe Uncontrolled Asthma: Results from the Lute and Verse Phase II Randomized, Double-Blind, Placebo-Controlled Trials
Authors: Nicola A. Hanania, Michael J. Noonan, Jonathan Corren, Phillip Korenblat, Yanan Zheng, Wendy Putnam, Elaine Murray, Connie Abelardo, Heleen Scheerens, Romeo Maciuca, Sarah Gray, Ramona Doyle, Dana McClintock, John G. Matthews, Karl Yen
Journal: Journal of Allergy and Clinical Immunology (2014)
Insulator function and topological domain border strength scale with architectural protein occupancy
Authors: Kevin Van Bortle, Michael H Nichols, Li Li, Chin-Tong Ong, Naomi Takenaka, Zhaohui S Qin, Victor G Corces
Journal: Genome biology (2014)

Chromosome conformation capture studies suggest that eukaryotic genomes are organized into structures called topologically associating domains. The borders of these domains are highly enriched for architectural proteins with characterized roles in insulator function. However, a majority of architectural protein binding sites localize within topological domains, suggesting sites associated with domain borders represent a functionally different subclass of these regulatory elements. How topologically associating domains are established and what differentiates border-associated from non-border architectural protein binding sites remain unanswered questions.By mapping the genome-wide target sites for several Drosophila architectural proteins, including previously uncharacterized profiles for TFIIIC and SMC-containing condensin complexes, we uncover an extensive pattern of colocalization in which architectural proteins establish dense clusters at the borders of topological domains. Reporter-based enhancer-blocking insulator activity as well as endogenous domain border strength scale with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci. Analyses in mouse and human stem cells suggest that clustering of architectural proteins is a general feature of genome organization, and conserved architectural protein binding sites may underlie the tissue-invariant nature of topologically associating domains observed in mammals.We identify a spectrum of architectural protein occupancy that scales with the topological structure of chromosomes and the regulatory potential of these elements. Whereas high occupancy architectural protein binding sites associate with robust partitioning of topologically associating domains and robust insulator function, low occupancy sites appear reserved for gene-specific regulation within topological domains.
Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells?
Authors: Jessica Roos, Sabine Grösch, Oliver Werz, Peter Schröder, Slava Ziegler, Simone Fulda, Patrick Paulus, Anja Urbschat, Benjamin Kühn, Isabelle Maucher, Jasmin Fettel, Thomas Vorup-Jensen, Matthias Piesche, Carmela Matrone, Dieter Steinhilber, Michael J. Parnham, Thorsten J. Maier
Journal: Pharmacology & Therapeutics (2015)
Glucose dysregulation and hepatic steatosis in obese adolescents: Is there a link?
Authors: Anna M.G. Cali, Ana Mayra De Oliveira, Hyeonjin Kim, Shu Chen, Miguel Reyes‐Mugica, Sandra Escalera, James Dziura, Sara E. Taksali, Romy Kursawe, Melissa Shaw, Mary Savoye, Bridget Pierpont, R. Todd Constable, Sonia Caprio
Journal: Hepatology (2009)

Fatty liver is increasingly common in obese adolescents. We determined its association with glucose dysregulation in 118 (37M/81F) obese adolescents of similar age and percent total fat. Fast-magnetic resonance imaging (MRI) and simple MRI were used to quantify hepatic fat content and abdominal fat distribution. All subjects had a standard oral glucose tolerance test. Insulin sensitivity was estimated by the Matsuda Index and homeostasis model assessment of insulin resistance. Baseline total and high molecular weight (HMW)-adiponectin and interleukin (IL)-6 levels were measured. The cohort was stratified according to tertiles of hepatic fat content. Whereas age and %fat were comparable across tertiles, ethnicity differed in that fewer Blacks and more Whites and Hispanics were in the moderate and high category of hepatic fat fraction (HFF). Visceral and the visceral-to-subcutaneous fat ratio increased and insulin sensitivity decreased across tertiles. Two-hour plasma glucose rose with increasing hepatic steatosis (P < 0.008). 73.7% of the subjects in the high HFF had the metabolic syndrome compared to 19.5% and 30.6%, respectively, in the low and moderate categories. Both total and HMW-adiponectin decreased, and IL-6 increased with increasing hepatic steatosis. Conclusion: In obese adolescents, independent of total fat, increasing severity of fatty liver is associated with glucose dysregulation, metabolic syndrome, and with a proinflammatory milieu. (HEPATOLOGY 2009.)
Abstract 708: Toca 511 gene therapy in combination with 5-fluorocytosine for intratumoral production of 5-fluorouracil in a colon cancer metastasis model
Authors: Maria E. Rodriguez-Aguirre, Fernando Lopez Espinoza, Bryan Martin, Kader Yadiz, Tiffany T. Huang, Carlos E. Ibanez, Derek G. Ostertag, Noriyuki Kasahara, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins
Journal: Cancer Research (2014)

Abstract Despite advances in screening, colorectal cancer (CRC) remains the fourth most commonly diagnosed cancer and the second leading cause of cancer death for both men and women in the US. Approximately one half of patients with CRC develop liver metastases (mCRC). The standard treatment for mCRC is 5-fluorouracil (5-FU) based combination chemotherapy. 5-FU combination chemotherapy has extended the median survival of these patients from 6 to &amp;gt;20 months. We are pursuing a unique investigational approach to treat cancer via intratumoral production of 5-FU. Patients are first administered Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector (RRV) which selectively replicates and spreads in malignant cells and encodes an optimized yeast cytosine deaminase (CD) gene. In infected cells, the CD enzyme is expressed and converts 5-FC (flucytosine, an orally available anti-fungal drug) to the anti-cancer drug 5-FU in situ. The combination of Toca 511 with oral extended release 5-FC (Toca FC) is currently in clinical trials for recurrent High Grade Glioma (NCT01156584, NCT01470794, and NCT01985256). We tested the suitability of this approach for the treatment of mCRC in a mouse syngeneic liver metastasis model. CT-26-luciferase colon carcinoma cells were delivered via intrasplenic injection producing multiple tumor foci within the liver. Toca 511 was then delivered either by intrasplenic or intravenous injection followed by courses of 5-FC. Vector delivery to tumor was monitored by PCR. 5-FC and 5-FU were detected using LC/MS. The effect of treatment with Toca 511 and 5-FC in this mouse model of mCRC will be presented. Citation Format: Maria E. Rodriguez-Aguirre, Fernando Lopez Espinoza, Bryan Martin, Kader Yadiz, Tiffany T. Huang, Carlos E. Ibanez, Derek G. Ostertag, Noriyuki Kasahara, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins. Toca 511 gene therapy in combination with 5-fluorocytosine for intratumoral production of 5-fluorouracil in a colon cancer metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 708. doi:10.1158/1538-7445.AM2014-708
Tamibarotene As Maintenance Therapy for Acute Promyelocytic Leukemia: Results From a Randomized Controlled Trial
Authors: Katsuji Shinagawa, Masamitsu Yanada, Toru Sakura, Yasunori Ueda, Masashi Sawa, Junichi Miyatake, Nobuaki Dobashi, Minoru Kojima, Yoshihiro Hatta, Nobuhiko Emi, Shigehisa Tamaki, Hiroshi Gomyo, Etsuko Yamazaki, Katsumichi Fujimaki, Norio Asou, Keitaro Matsuo, Shigeki Ohtake, Yasushi Miyazaki, Kazunori Ohnishi, Yukio Kobayashi, Tomoki Naoe
Journal: Journal of Clinical Oncology (2014)

The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL.Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years.A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 10(9)/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non-high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated.In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.
Incidence of Adenocarcinoma among Patients with Barrett's Esophagus
Authors: Frederik Hvid-Jensen, Lars Pedersen, Asbjørn Mohr Drewes, Henrik Toft Sørensen, Peter Funch-Jensen
Journal: New England Journal of Medicine (2011)

Accurate population-based data are needed on the incidence of esophageal adenocarcinoma and high-grade dysplasia among patients with Barrett's esophagus.We conducted a nationwide, population-based, cohort study involving all patients with Barrett's esophagus in Denmark during the period from 1992 through 2009, using data from the Danish Pathology Registry and the Danish Cancer Registry. We determined the incidence rates (numbers of cases per 1000 person-years) of adenocarcinoma and high-grade dysplasia. As a measure of relative risk, standardized incidence ratios were calculated with the use of national cancer rates in Denmark during the study period.We identified 11,028 patients with Barrett's esophagus and analyzed their data for a median of 5.2 years. Within the first year after the index endoscopy, 131 new cases of adenocarcinoma were diagnosed. During subsequent years, 66 new adenocarcinomas were detected, yielding an incidence rate for adenocarcinoma of 1.2 cases per 1000 person-years (95% confidence interval [CI], 0.9 to 1.5). As compared with the risk in the general population, the relative risk of adenocarcinoma among patients with Barrett's esophagus was 11.3 (95% CI, 8.8 to 14.4). The annual risk of esophageal adenocarcinoma was 0.12% (95% CI, 0.09 to 0.15). Detection of low-grade dysplasia on the index endoscopy was associated with an incidence rate for adenocarcinoma of 5.1 cases per 1000 person-years. In contrast, the incidence rate among patients without dysplasia was 1.0 case per 1000 person-years. Risk estimates for patients with high-grade dysplasia were slightly higher.Barrett's esophagus is a strong risk factor for esophageal adenocarcinoma, but the absolute annual risk, 0.12%, is much lower than the assumed risk of 0.5%, which is the basis for current surveillance guidelines. Data from the current study call into question the rationale for ongoing surveillance in patients who have Barrett's esophagus without dysplasia. (Funded by the Clinical Institute, University of Aarhus, Aarhus, Denmark.).
How to write a scientific masterpiece
Authors: Ushma S. Neill
Journal: Journal of Clinical Investigation (2007)

I've been asked several times to give talks about various aspects of the scientific publishing enterprise, and sometimes to comment specifically on how to write a manuscript that will have maximal impact. While many in my audiences have felt that my presentations are designed for students and trainees, I hope everyone listens, as sometimes even established scientists are prone to making mistakes. I hope here to outline a few pointers that will help your manuscripts skate through the submission and peer review process. Some points may be elementary, but all bear repeating.
Historical Perspective on the Pathology of Myocardial Ischemia/Reperfusion Injury
Authors: Robert B. Jennings
Journal: Circulation Research (2013)

A selective history of the pathophysiological, structural, and metabolic changes found during an episode of severe myocardial ischemia in the canine heart is presented. The changes that cause ischemic injury to become irreversible are discussed in detail because these changes are the target of any successful therapy designed to prevent ischemic cell death. Of these, the disruption of the sarcolemma, an injury the development of which is accelerated in vivo by the contraction of viable tissue elsewhere in the heart traumatizing the ischemic area, plus the changes in high-energy phosphate and the total adenine nucleotide pool are considered to be the critical events leading to the development of irreversibility. The discovery of preconditioning with ischemia is discussed, together with a brief description of postconditioning. Finally, reperfusion injury is discussed in a summary fashion. The evidence for the fact that myocytes are salvaged by reperfusion is presented, as is the evidence that myocytes become unsalvageable by reperfusion as the duration of ischemia increases. The concept that some of the myocytes that die after successful reperfusion with arterial blood actually are killed by changes initiated by reperfusion, so-called lethal reperfusion injury, is attractive in that prevention of this change would lead to greater salvage; however, the prevalence of this phenomenon in clinical practice remains to be determined.
Risk factors for injuries in alpine skiing, telemark skiing and snowboarding – case-control study
Authors: Steinar Sulheim, Ingar Holme, Andreas Rødven, Arne Ekeland, Roald Bahr
Journal: British Journal of Sports Medicine (2011)

Background Alpine skiing and snowboarding have a substantial risk of injuries, but precise risk factor estimates are limited. Objective To determine the risk factors among skiers and snowboarders. Study design Case-control study. Methods Ski patrols reported cases (N=3277) in eight major Norwegian alpine resorts. Injury type and risk factors (age, gender, nationality, skill level, equipment, helmet use, ski school attendance, rented or own equipment) were recorded. An uninjured control group (N=2992) was obtained at the same resorts. A multivariate logistic regression analysis was used to assess the relationship between individual risk factors and risk of injury. Results The overall injury risk was increased among beginners (OR 2.72; 2.12 to 3.47), children (OR 1.72; 1.41 to 2.13), adolescents (OR 2.16; 1.72 to 2.66) and non-Nordic skiers (OR 1.80; 1.37 to 2.36). Snowboarders had a higher overall injury risk than skiers (OR 2.11; 1.81 to 2.46). Alpine skiers (OR 2.65; 1.47 to 4.80), beginners (OR 2.50; 1.61 to 3.85), children (OR 11.1; 6.7 to 20.0) and adolescents (OR 4.17; 2.44 to 7.14) were prone to lower leg fractures. Knee injuries occurred more frequently among alpine skiers (OR 1.82; 1.39 to 2.38), females (OR 1.67; 1.38 to 2.03) and beginners (OR 3.13; 2.50 to 3.85). Males (OR 1.85; 1.45 to 2.38), telemark skiers (OR 1.70; 1.30 to 2.23), children (OR 2.22; 1.37 to 3.57) and adults (OR 1.64; 1.11 to 2.37) had an increased risk for shoulder injuries. Conclusions Snowboarders, beginners, children and adolescents had an increased injury risk.