tbuckley/cabot-search huggingface dataset:
Hepatocellular Carcinoma: Consensus Recommendations of the National Cancer Institute Clinical Trials Planning Meeting
Authors: Melanie B. Thomas, Deborah Jaffe, Michael M. Choti, Jacques Belghiti, Steven Curley, Yuman Fong, Gregory Gores, Robert Kerlan, Phillipe Merle, Bert O'Neil, Ronnie Poon, Lawrence Schwartz, Joel Tepper, Francis Yao, Daniel Haller, Margaret Mooney, Alan Venook
Journal: Journal of Clinical Oncology (2010)

Hepatocelluar carcinoma (HCC) is the most common primary malignancy of the liver in adults and the third most common cause of cancer death worldwide. The incidence of HCC in the United States is rising steadily because of the prevalence of hepatitis C viral infection and other causes of hepatic cirrhosis. The majority of patients have underlying hepatic dysfunction, which complicates patient management and the search for safe and effective therapies. The Clinical Trials Planning Meeting (CTPM) in HCC was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to identify the key knowledge gaps in HCC and define clinical research priorities. The CTPM structured its review according to current evidence-based treatment modalities in HCC and prioritized the recommendations on the basis of the patient populations representing the greatest unmet medical need.
Anti-Neutrophil Cytoplasmic Antibodies and Effector CD4+ Cells Play Nonredundant Roles in Anti-Myeloperoxidase Crescentic Glomerulonephritis
Authors: Amanda-Jane Ruth, A. Richard Kitching, Rain Y.Q. Kwan, Dragana Odobasic, Joshua D.K. Ooi, Jennifer R. Timoshanko, Michael J. Hickey, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2006)

Most humans with microscopic polyarteritis and anti-myeloperoxidase (anti-MPO), anti-neutrophil cytoplasmic antibodies (ANCA) develop "pauci-immune" crescentic glomerulonephritis. For dissection of the roles of ANCA and cell-mediated effectors in microscopic polyarteritis, experimental autoimmune anti-MPO glomerulonephritis was induced by immunizing C57BL/6 mice with human MPO. Autoimmunity to mouse MPO (ANCA and CD4+ cell reactivity) was induced. Challenge with anti-glomerular basement membrane globulin resulted in accumulation of neutrophils, CD4+ cells and macrophages, and significant numbers of crescentic glomeruli compared with similarly challenged control-immunized mice. MPO-deficient (Mpo(-/-)) mice immunized with MPO developed similar immune responses to MPO but failed to recruit effector cells to glomeruli or develop significant crescent formation, suggesting that MPO is acting as a planted glomerular autoantigen. Effector CD4+ cell depletion in this model attenuated crescentic glomerulonephritis and effector cell influx without altering ANCA titers. However, B cell-deficient mice, with no ANCA, still developed severe crescentic glomerulonephritis with accumulation of effector cells. Intravital microscopy studies demonstrated that passive transfer of sera from MPO-immunized Mpo(-/-) mice to LPS-primed mice rapidly induced glomerular neutrophil accumulation and release of MPO. These studies provide in vivo evidence in a relevant vascular bed for both humoral and cellular anti-MPO responses as key inducers of injury. ANCA induces glomerular neutrophil infiltration and MPO deposition. Subsequently, anti-MPO CD4+ cells recognize MPO as a planted glomerular antigen and act with macrophages to amplify severe glomerular injury.
Exenatide Twice Daily Versus Premixed Insulin Aspart 70/30 in Metformin-Treated Patients With Type 2 Diabetes
Authors: Baptist Gallwitz, Michael Böhmer, Thomas Segiet, Andrea Mölle, Karsten Milek, Bernd Becker, Karin Helsberg, Helmut Petto, Natalie Peters, Oliver Bachmann
Journal: Diabetes Care (2011)

Hypoglycemia causes recurrent morbidity in patients with type 2 diabetes. This study evaluated if exenatide twice daily (BID) was noninferior to premixed insulin aspart 70/30 BID (PIA) for glycemic control and associated with less hypoglycemia.
Influence of Affinity and Antigen Internalization on the Uptake and Penetration of Anti-HER2 Antibodies in Solid Tumors
Authors: Stephen I. Rudnick, Jianlong Lou, Calvin C. Shaller, Yong Tang, Andres J.P. Klein-Szanto, Louis M. Weiner, James D. Marks, Gregory P. Adams
Journal: Cancer Research (2011)

Antibody drugs are widely used in cancer therapy, but conditions to maximize tumor penetration and efficacy have yet to be fully elucidated. In this study, we investigated the impact of antibody binding affinity on tumor targeting and penetration with affinity variants that recognize the same epitope. Specifically, we compared four derivatives of the C6.5 monoclonal antibody (mAb), which recognizes the same HER2 epitope (monovalent K(D) values ranging from 270 to 0.56 nmol/L). Moderate affinity was associated with the highest tumor accumulation at 24 and 120 hours after intravenous injection, whereas high affinity was found to produce the lowest tumor accumulation. Highest affinity mAbs were confined to the perivascular space of tumors with an average penetration of 20.4 ± 7.5 μm from tumor blood vessels. Conversely, lowest affinity mAbs exhibited a broader distribution pattern with an average penetration of 84.8 ± 12.8 μm. In vitro internalization assays revealed that antibody internalization and catabolism generally increased with affinity, plateauing once the rate of HER2 internalization exceeded the rate of antibody dissociation. Effects of internalization and catabolism on tumor targeting were further examined using antibodies of moderate (C6.5) or high-affinity (trastuzumab), labeled with residualizing ((111)In-labeled) or nonresidualizing ((125)I-labeled) radioisotopes. Significant amounts of antibody of both affinities were degraded by tumors in vivo. Furthermore, moderate- to high-affinity mAbs targeting the same HER2 epitope with monovalent affinity above 23 nmol/L had equal tumor accumulation of residualizing radiolabel over 120 hours. Results indicated equal tumor exposure, suggesting that mAb penetration and retention in tumors reflected affinity-based differences in tumor catabolism. Together, these results suggest that high-density, rapidly internalizing antigens subject high-affinity antibodies to greater internalization and degradation, thereby limiting their penetration of tumors. In contrast, lower-affinity antibodies penetrate tumors more effectively when rates of antibody-antigen dissociation are higher than those of antigen internalization. Together, our findings offer insights into how to optimize the ability of therapeutic antibodies to penetrate tumors.
Dysfunctional α‐globin genes in hemoglobin H disease in blacks: Variation in restriction fragment size permits the detection of the ‐α/‐α<sup>T</sup> genotype
Authors: S. Safaya, P. Mullaney, R. F. Rieder
Journal: American Journal of Hematology (1987)

Abstract Hemoglobin H (HbH) disease is most often due to deletion of three of the four α‐globin genes (genotype ‐ ‐ ‐ ‐/‐α). In black subjects although the ‐α/chromosome is common, the ‐ ‐/haplotype is very rare and few examples of HbH disease have been detected. We have studied three black siblings with HbH by restriction endonuclease mapping of the α‐like gene complex (5′‐ζ‐Ψζ‐Ψα2‐Ψα1‐α2‐α1‐3′) using ζ‐ and α‐ specific probes. The presence of size differences in the previously described hypervariable region between the ζ and ζΨ genes results in a restriction fragment length polymorphism which permitted the detection of single α genes on both number 16 chromosomes in these subjects. Quantitative DNA hybridization by a slot‐blot technique confirmed that their genomes contained two α‐globin genes. The results establish that in these black subjects HbH disease is associated with dysfunctional α‐globin genes (genotype: ‐α/‐α T ).
Commentaries on this month's Cardiovascular Controversy: the merits and demerits of animal experimentation From W J van der Giessen and P D Verdouw
Authors: W. J v. d. Giessen, P. D Verdouw
Journal: Cardiovascular Research (1994)

Commentaries on this month's Cardiovascular Controversy: the merits and demerits of animal experimentation From W J van der Giessen and P D Verdouw Get access Willem J van der Giessen, Willem J van der Giessen Thoraxcenter, Erasmus University Rotterdam, Rotterdam, The Netherlands. Search for other works by this author on: Oxford Academic PubMed Google Scholar Pieter D Verdouw Pieter D Verdouw Thoraxcenter, Erasmus University Rotterdam, Rotterdam, The Netherlands. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 28, Issue 7, July 1994, Pages 1115–1116, https://doi.org/10.1093/cvr/28.7.1115 Published: 01 July 1994
IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma
Authors: Fang-Ming Gu, Quan-Lin Li, Qiang Gao, Jia-Hao Jiang, Kai Zhu, Xiao-Yong Huang, Jin-Feng Pan, Jun Yan, Jin-Hui Hu, Zheng Wang, Zhi Dai, Jia Fan, Jian Zhou
Journal: Molecular Cancer (2011)

Abstract Background The Th17 subset and IL-17 have been found in increased frequencies within certain tumors. However, their relevance in cancer biology remains controversial. This study aimed to clarify the biological action of IL-17 on hepatocellular carcinoma (HCC). Methods Effects and underlying molecular mechanisms of IL-17 on human HCC were explored in vitro using exogenous IL-17 stimulation and in nude mice by implanting IL-17 overexpressed HCC cells. The clinical significance of IL-17 was investigated in tissue microarrays containing HCC tissues from 323 patients following hepatectomy using immunohistochemistry. Results Although exogenous IL-17 showed no direct effect on the growth rate of HCC cells in vitro , PCR and ELISA showed that IL-17 selectively augmented the secretion of diverse proinvasive factors and transwell showed a direct promotion of invasion of HCC cells by IL-17. Furthermore, transfection of IL-17 into HCC cells significantly promoted neoangiogenesis, neutrophil recruitment and tumor growth in vivo . Using siRNA mediated knockdown of AKT and STAT3, we suggested that the effects of IL-17 were operated through activation of the AKT signaling in HCC, which resulted in IL-6 production. Then, IL-6 in turn activated JAK2/STAT3 signaling and subsequently up-regulated its downstream targets IL-8, MMP2, and VEGF. Supporting these findings, in human HCC tissues, immunostaining indicated that IL-17 expression was significantly and positively associated with STAT3 phosphorylation, neutrophil infiltration and increased tumor vascularity. The clinical significance of IL-17 was authenticated by revealing that the combination of intratumoral IL-17+ cells and phospho-STAT3 served as a better prognosticator for postoperative tumor recurrence than either marker alone. Conclusions IL-17 mediated tumor-promoting role involves a direct effect on HCC cells through IL-6/JAK2/STAT3 induction by activating the AKT pathway.
Intragenomic Variation of Fungal Ribosomal Genes Is Higher than Previously Thought
Authors: U. K. Simon, M. Weiss
Journal: Molecular Biology and Evolution (2008)

Nuclear ribosomal genes in most eukaryotes are present in multiple copies and often used for taxonomic and phylogenetic analyses. We comprehensively examined intragenomic polymorphism levels of three nuclear ribosomal loci for four important plant pathogenic fungi by polymerase chain reaction amplification and cloning. Here, we show that single nucleotide polymorphisms are present in an unexpectedly high amount. This might have implications for studies of fungal evolution, phylogenetics, and population genetics. Furthermore, our work demonstrates that the majority of all ribosomal sequences obtained from one individual and gene is identical to the majority rule consensus sequence of all detected sequence variants. Due to the large number of polymorphisms found and the fact that the polymorphism level differed markedly even between ribosomal genes of one and the same individual, we assume that nuclear ribosomal genes might not always evolve in a strictly concerted manner.
Delayed rectifier outward current and repolarization in human atrial myocytes.
Authors: Z Wang, B Fermini, S Nattel
Journal: Circulation Research (1993)

Previous work has suggested that the primary time-dependent repolarizing current in human atrium is the transient outward current (Ito), but interventions known to alter the magnitude of the delayed rectifier current (IK) affect atrial electrophysiology and arrhythmias in humans. To explore the potential role of IK in human atrial tissue, we used the whole-cell configuration of the patch-clamp technique to record action potentials and ionic currents in isolated myocytes from human atrium. A delayed outward current was present in the majority of myocytes, activating with a time constant ranging from 348 +/- 61 msec (mean +/- SEM) at -20 mV to 129 +/- 25 msec at +60 mV. The reversal potential of tail currents was linearly related to log [K+]o with a slope of 55 mV per decade, and fully activated tail currents showed inward rectification. The potassium selectivity, kinetics, and voltage dependence were similar to those reported for IK in other cardiac preparations. In cells with both Ito and IK, IK greatly exceeded both components of Ito (Ito1 and Ito2) within 50 msec of a voltage step from -70 to +20 mV. Based on the relative magnitude of Ito and IK, three types of cells could be distinguished: type 1 (58% [73/126] of the cells) displayed a large Ito together with a clear IK, type 2 (13% [17/126] of the cells) displayed only IK, and type 3 (29% [36/126] of the cells) was characterized by a prominent Ito and negligible IK. Consistent differences in action potential morphology were observed, with type 2 cells having a higher plateau and steeper phase 3 slope and type 3 cells showing a triangular action potential and lesser phase 3 slope compared with type 1 cells. We conclude that IK is present in a majority of human atrial myocytes and may play a significant role in their repolarization and that previously observed variability in human atrial action potential morphology may be partially due to differences in the relative magnitude of time-dependent outward currents.
Diabetes Reporting as a Cause of Death
Authors: Laura N. McEwen, Catherine Kim, Mary Haan, Debashis Ghosh, Paula M. Lantz, Carol M. Mangione, Monika M. Safford, David Marrero, Theodore J. Thompson, William H. Herman
Journal: Diabetes Care (2006)

OBJECTIVE—To determine the frequency of reporting of diabetes on death certificates of decedents with known diabetes, define factors associated with reporting of diabetes, and describe trends in reporting over time. RESEARCH DESIGN AND METHODS—Data were obtained from 11,927 participants with diabetes who were enrolled in the Translating Research Into Action for Diabetes study, a multicenter prospective observational study of diabetes care in managed care. Data on decedents (n = 540) were obtained from the National Death Index. The primary dependent variable was the presence of ICD-10 codes for diabetes on the death certificate. Covariates included age at death, sex, race/ethnicity, education, income, duration of diabetes, type of diabetes, diabetes treatment, smoking status, and number of comorbidities. RESULTS—Diabetes was recorded on 39% of death certificates and as the underlying cause of death for 10% of decedents with diabetes. Diabetes was significantly less likely to be reported on the death certificates of decedents with diabetes dying of cancer. Predictors of recording diabetes anywhere on the death certificate included longer duration of diabetes and insulin treatment. Longer duration of diabetes, insulin treatment, and fewer comorbidities were associated with recording of diabetes as the underlying cause of death. CONCLUSIONS—Diabetes is much more likely to be reported on the death certificates of diabetic individuals who die of cardiovascular causes. Reporting of diabetes on death certificates has been stable over time. Death certificates underestimate the prevalence of diabetes among decedents and present a biased picture of the causes of death among people with diabetes.
Prevalence of peptic ulcer in Helicobacter pylori positive blood donors.
Authors: D Vaira, M Miglioli, P Mule, J Holton, M Menegatti, M Vergura, G Biasco, R Conte, R P Logan, L Barbara
Journal: Gut (1994)

This study aimed to determine the importance of raised antibodies to Helicobacter pylori in an asymptomatic population. A total of 128 asymptomatic blood donors who were seropositive for H pylori and consented to endoscopy were investigated. These subjects were from a population of 1010 blood donors screened for antibodies to H pylori. A questionnaire was completed to determine if any subjects had complained of symptoms, and they subsequently had endoscopy. Altogether 121 of 128 were positive for H pylori by histology and urease test and/or culture and all 121 had chronic active gastritis on histology. Twenty five of these subjects had peptic ulcer (20 duodenal, five gastric), a further 21 had erosive duodenitis, and two were found to have gastric cancer. H pylori associated peptic ulcer disease and duodenitis occur more frequently than previously recognised and this suggests that H pylori infection, even if asymptomatic, is of far greater clinical relevance than originally thought.
Bacterial cyanogenesis occurs in the cystic fibrosis lung
Authors: K. Sanderson, L. Wescombe, S. M. Kirov, A. Champion, D. W. Reid
Journal: European Respiratory Journal (2008)

The cystic fibrosis (CF) lung environment is poorly defined, but data suggest that bacteria may encounter reduced oxygen tensions and possibly an anaerobic environment. Pseudomonas aeruginosa produces the potent toxin cyanide under strictly microaerobic conditions. Evidence of bacterial cyanogenesis in the CF lung was investigated in the present study by measuring sputum cyanide concentrations. Sputum cyanide was measured in seven stable CF patients, as well as before and after intravenous antibiotic therapy during a hospital admission in a further eight patients experiencing acute exacerbations. All patients were chronically infected with P. aeruginosa . Comparative sputum data were obtained from nine CF patients with no documented P. aeruginosa infection and 10 healthy, nonsmoking normal controls. High levels of cyanide were detected in all the P. aeruginosa -infected stable CF patients (median (range) 0.56 (0.37–2.81) μg·mL −1 ), and in seven out of eight acute sputum samples (0.73 (0–1.43) μg·mL −1 ). In contrast, cyanide was not detectable in sputum from eight out of nine CF patients without P. aeruginosa infection or in any of the normal controls. Intravenous antibiotic treatment significantly reduced sputum cyanide levels (median 0.73 to median 0.0 µg·mL −1 ). The cyanide detected indicates that the cystic fibrosis lung provides a predominantly microaerobic environment for Pseudomonas aeruginosa . Cyanide is likely to be a potentially important virulence factor in Pseudomonas aeruginosa -infected cystic fibrosis patients.
Enhanced Chemosensitivity to Irinotecan by RNA Interference-Mediated Down-Regulation of the Nuclear Factor-κB p65 Subunit
Authors: Jun Guo, Udit N. Verma, Richard B. Gaynor, Eugene P. Frenkel, Carlos R. Becerra
Journal: Clinical Cancer Research (2004)

In preclinical tumor models, inhibition of nuclear factor-kappaB (NF-kappaB) has been associated with increased sensitivity to chemotherapeutic agents such as irinotecan (CPT-11). This is based on the fact that a variety of chemotherapy agents such as CPT-11 activate NF-kappaB to result in the expression of genes such as c-IAP1 and c-IAP2 that might be responsible for the inhibition of chemotherapy-induced apoptosis. In this study, RNA interference [small interfering RNA (siRNA)] was used to down-regulate the NF-kappaB p65 subunit in the HCT116 colon cancer cell line, and its role, in the presence and absence of CPT-11, was assessed on cell growth and apoptosis. Reduction of endogenous p65 by siRNA treatment significantly impaired CPT-11-mediated NF-kappaB activation, enhanced apoptosis, and reduced colony formation in soft agar. Furthermore, the in vivo administration of p65 siRNA reduced HCT116 tumor formation in xenograft models in the presence but not the absence of CPT-11 administration. These data indicate that the administration of siRNA directed against the p65 subunit of NF-kappaB can effectively enhance in vitro and in vivo sensitivity to chemotherapeutic agents.
Pacemaker lead extraction with the laser sheath: results of the pacing lead extraction with the excimer sheath (PLEXES) trial11No financial support was received for performing the procedures or collecting the data, or for data analysis.
Authors: Bruce L Wilkoff, Charles L Byrd, Charles J Love, David L Hayes, T.Duncan Sellers, Raymond Schaerf, Victor Parsonnet, Laurence M Epstein, Robert A Sorrentino, Christopher Reiser
Journal: Journal of the American College of Cardiology (1999)
Maternal Genistein Alters Coat Color and Protects <i> A <sup>vy</sup> </i> Mouse Offspring from Obesity by Modifying the Fetal Epigenome
Authors: Dana C. Dolinoy, Jennifer R. Weidman, Robert A. Waterland, Randy L. Jirtle
Journal: Environmental Health Perspectives (2006)

Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (A(vy/a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine-guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome.