tbuckley/cabot-search huggingface dataset:
KML001 Cytotoxic Activity Is Associated with Its Binding to Telomeric Sequences and Telomere Erosion in Prostate Cancer Cells
Authors: Pornima Phatak, Fangping Dai, Melody Butler, M.P. Nandakumar, Peter L. Gutierrez, Martin J. Edelman, Hans Hendriks, Angelika M. Burger
Journal: Clinical Cancer Research (2008)

Abstract Purpose: KML001 (sodium metaarsenite) is an orally bioavailable arsenic compound that has entered phase I/II clinical trials in prostate cancer. In this study, we elucidated the mode of action of KML001 and investigated its effects on telomerase and telomeres. Experimental Design: We compared telomere length to KML001 cytotoxic activity in a panel of human solid tumor cell lines. Duration of exposure and concentrations of KML001 that affect telomerase and telomeres were evaluated in relation to established mechanisms of arsenite action such as reactive oxygen species–related DNA damage induction. Binding of KML001 to telomeres was assessed by matrix-assisted laser desorption/ionization mass spectrometry. Results: We established a significant inverse correlation (r2 = 0.9) between telomere length and cytotoxicity. KML001 exhibited activity in tumor cells with short telomeres at concentrations that can be achieved in serum of patients. We found that telomerase is not directly inhibited by KML001. Instead, KML001 specifically binds to telomeric sequences at a ratio of one molecule per three TTAGGG repeats leading to translocation of the telomerase catalytic subunit into the cytoplasm. In prostate cancer cells with short telomeres, KML001 caused telomere-associated DNA damage signaling as shown by γ-H2AX induction and chromatin immunoprecipitation assays as well as a rapid telomere erosion shown by metaphase fluorescence in situ hybridization. These effects were not seen in a lung cancer cell line with long telomeres. Importantly, arsenification of telomeres preceded DNA lesions caused by reactive oxygen species production. Conclusions: Sodium metaarsenite is a telomere targeting agent and should be explored for the treatment of tumors with short telomeres.
Incidence of and survival following brain metastases among women with inflammatory breast cancer
Authors: S. Dawood, N.T. Ueno, V. Valero, E. Andreopoulou, L. Hsu, J. Lara, W. Woodward, T.A. Buchholz, G.N. Hortobagyi, M. Cristofanilli
Journal: Annals of Oncology (2010)
A Critical Analysis of the Clinical Use of Incretin-Based Therapies
Authors: Michael A. Nauck
Journal: Diabetes Care (2013)

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to an increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative provided below, Dr. Nauck provides a defense of incretin-based therapies and that benefits clearly outweigh any concern of risk.
Clinical utility of the polymerase chain reaction in the diagnosis of extrapulmonary tuberculosis
Authors: AH Kolk, LF Kox, J van Leeuwen, S Kuijper, HM Jansen
Journal: European Respiratory Journal (1998)

This study examines the diagnostic utility of the polymerase chain reaction (PCR) in 156 patients (five human immunodeficiency virus (HIV) seropositive) suspected of extrapulmonary tuberculosis. The results of PCR in 226 samples from 11 different sites were compared with the results of microscopy and culture. Positive culture results were predicted in 86% of samples by PCR but in only 31% by microscopy. Specificity of PCR was 92%. In cases with culture-proven tuberculosis, PCR identified all 11 microscopy positive cases and 19 of 24 (79%) of the microscopy-negative cases. In four patients, PCR excluded the diagnosis of tuberculosis in microscopy-positive samples, which were later shown to contain mycobacteria other than Mycobacterium tuberculosis or laboratory contaminants. In 20 patients (microscopy, PCR and culture negative) a trial of antituberculous drugs was given, but patients showed no improvement and treatment was stopped. In 17 patients, all culture negative (in nine PCR was positive, three of whom also had positive microscopy) the diagnosis was probable tuberculosis based on clinical findings and response to treatment. This polymerase chain reaction has a much higher sensitivity than microscopy and can facilitate therapeutic decisions for those with suspected extrapulmonary tuberculosis.
HOMOGRAFT IMMUNITY IN PREGNANCY
Authors: Jonathan T. Lanman, Llewellyn Herod
Journal: The Journal of Experimental Medicine (1965)

The mammalian fetus affixed to the uterine wall in some ways resembles a homograft, but maternal homograft immunity even when specifically directed against her fetuses fails to destroy them. The placental barrier appears to be critical in protecting the fetus against maternal immunologic attack. In order to evaluate the means by which it affords protection, we have measured in rabbits the transfer of cytotoxic antibody from mother to fetus. When the offspring were not the specific targets for maternal antibody, we found titers of cytotoxic antibody in the newborn animals at or near maternal levels in 16 of 18 cases (89 per cent), demonstrating the ability of this antibody to cross the rabbit placenta. When the offspring were appropriate targets for antibody, however, 11 of 18 newborn animals (61 per cent) had no demonstrable titer. We believe that in these latter cases, antibody had become fixed to antigenic sites and thereby had been removed from the fetal circulation. There was, however, no evidence of harm to any of the fetuses, either in survival (as demonstrated in a previous study) or in spleen or thymus weights or peripheral leukocyte and mononuclear cell counts. Cytotoxic antibody appears to reach the embryo early in gestation, since we found antibody in 8-day-old blastocyst fluid in each of 2 trials. We conclude that the fetus neither receives nor requires protection against cytotoxic antibody, and believe that fetal protection against maternal homograft immunity is afforded by a placental barrier to maternal mononuclear leukocytes.
The effect of exercise training on heart rate during coitus in the post myocardial infarction patient.
Authors: R A Stein
Journal: Circulation (1977)

The effect of interval exercise training on the peak coital heart rate in post myocardial infarction patients was studied. Sixteen men (ages 46-54) underwent a 16-week bicycle ergometer training program 12 to 15 weeks following their first myocardial infarction. Portable ECG tape recorders were used to record the ECG during coitus twice before and twice after the training program. The maximum minute oxygen consumption (VO2max) was measured in each subject during bicycle ergometer ECG examinations before and after the training program. A control group of six post myocardial infarction patients who were not trained was evaluated in the same manner. The exercise-trained group had an average increase in VO2max of 11.5%(2.7 to 3.0 L/min) and an average decrease in peak coital heart rate of 5.5%(127/min to 120/min). The control group demonstrated a 2% increase in VO2max and no significant change in peak coital heart rate. The increase in aerobic capacity (VO2max) and the consequent reduction in peak coital heart rate in our trained group suggests the potential value of exercise training in improving sexual function in the patient with angina during coitus.
Effects of Early Chemotherapeutic Treatment on Learning in Adolescent Mice: Implications for Cognitive Impairment and Remediation in Childhood Cancer Survivors
Authors: Emily B. Bisen-Hersh, Philip N. Hineline, Ellen A. Walker
Journal: Clinical Cancer Research (2013)

Among children diagnosed with acute lymphoblastic leukemia (ALL) and given chemotherapy-only treatment, 40% to 70% of survivors experience neurocognitive impairment. The present study used a preclinical mouse model to investigate the effects of early exposure to common ALL chemotherapeutics methotrexate (MTX) and cytarabine (Ara-C) on learning and memory.Preweanling mouse pups were treated on postnatal day (PND) 14, 15, and 16 with saline, MTX, Ara-C, or a combination of MTX and Ara-C. Nineteen days after treatment (PND 35), behavioral tasks measuring different aspects of learning and memory were administered.Significant impairment in acquisition and retention over both short (1 hour) and long (24 hours) intervals, as measured by autoshaping and novel object recognition tasks, was found following treatment with MTX and Ara-C. Similarly, a novel conditional discrimination task revealed impairment in acquisition for chemotherapy-treated mice. No significant group differences were found following the extensive training component of this task, with impairment following the rapid training component occurring only for the highest MTX and Ara-C combination group.Findings are consistent with those from clinical studies suggesting that childhood cancer survivors are slower at learning new information and primarily exhibit deficits in memory years after successful completion of chemotherapy. The occurrence of mild deficits on a novel conditional discrimination task suggests that chemotherapy-induced cognitive impairment may be ameliorated through extensive training or practice.
Src Activation Plays an Important Key Role in Lymphomagenesis Induced by FGFR1 Fusion Kinases
Authors: Mingqiang Ren, Haiyan Qin, Ruizhe Ren, Josephine Tidwell, John K. Cowell
Journal: Cancer Research (2011)

Chromosomal translocations and activation of the fibroblast growth factor (FGF) receptor 1 (FGFR1) are a feature of stem cell leukemia-lymphoma syndrome (SCLL), an aggressive malignancy characterized by rapid transformation to acute myeloid leukemia and lymphoblastic lymphoma. It has been suggested that FGFR1 proteins lose their ability to recruit Src kinase, an important mediator of FGFR1 signaling, as a result of the translocations that delete the extended FGFR substrate-2 (FRS2) interacting domain that Src binds. In this study, we report evidence that refutes this hypothesis and reinforces the notion that Src is a critical mediator of signaling from the FGFR1 chimeric fusion genes generated by translocation in SCLL. Src was constitutively active in BaF3 cells expressing exogenous FGFR1 chimeric kinases cultured in vitro as well as in T-cell or B-cell lymphomas they induced in vivo. Residual components of the FRS2-binding site retained in chimeric kinases that were generated by translocation were sufficient to interact with FRS2 and activate Src. The Src kinase inhibitor dasatinib killed transformed BaF3 cells and other established murine leukemia cell lines expressing chimeric FGFR1 kinases, significantly extending the survival of mice with SCLL syndrome. Our results indicated that Src kinase is pathogenically activated in lymphomagenesis induced by FGFR1 fusion genes, implying that Src kinase inhibitors may offer a useful option to treatment of FGFR1-associated myeloproliferative/lymphoma disorders.
Effects of the Prone Position on Respiratory Mechanics and Gas Exchange during Acute Lung Injury
Authors: PAOLO PELOSI, DANIELA TUBIOLO, DANIELE MASCHERONI, PIERLUIGI VICARDI, STEFANIA CROTTI, FRANCO VALENZA, LUCIANO GATTINONI
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We studied 16 patients with acute lung injury receiving volume-controlled ventilation to assess the relationships between gas exchange and respiratory mechanics before, during, and after 2 h in the prone position. We measured the end-expiratory lung volume (EELV, helium dilution), the total respiratory system (Cst,rs), the lung (Cst,L) and the thoracoabdominal cage (Cst,w) compliances (end- inspiratory occlusion technique and esophageal balloon), the hemodynamics, and gas exchange. In the prone position, PaO2 increased from 103.2 ± 23.8 to 129.3 ± 32.9 mm Hg (p < 0.05) without significant changes of Cst,rs and EELV. However, Cst,w decreased from 204.8 ± 97.4 to 135.9 ± 52.5 ml/ cm H2O (p < 0.01) and the decrease was correlated with the oxygenation increase (r = 0.62, p < 0.05). Furthermore, the greater the baseline supine Cst,w, the greater its decrease in the prone position (r = 0.82, p < 0.01). Consequently, the oxygenation changes in the prone position were predictable from baseline supine Cst,w (r = 0.80, p < 0.01). Returning to the supine position, Cst,rs increased compared with baseline (42.3 ± 14.4 versus 38.4 ± 13.7 ml/cm H2O; p < 0.01), mainly because of the lung component (57.5 ± 25.1 versus 52.4 ± 23.3 ml/cm H2O; p < 0.01). Thus, (1) baseline Cst,w and its changes may play a role in determining the oxygenation response in the prone position; (2) the prone position improves Cst,rs and Cst,L when the supine position is resumed.
The Process to Discover and Develop Biomarkers for Cancer: A Work in Progress
Authors: D. F. Ransohoff
Journal: JNCI Journal of the National Cancer Institute (2008)

JNCI | Editorials 1419 The process to discover and develop molecular biomarkers for cancer diagnosis (or prognosis) is a work in progress and is evolving. “Discovery” research — searching for markers by use of highthroughput technology without an a priori hypothesis — has produced few useful biomarkers over the last 10 years despite numerous claims in research publications and news reports about “95% sensitivity and 95% specificity” or better. The degree of disconnect between claims and products should make us ask why progress is so slow: Is it the normal stop-and-start of science? Or is there some systemic problem with the process that we currently use to discover and develop markers? After all, it took decades to evolve the process to discover and develop drug therapies. So, where does the evolution of the discovery and development of biomarkers stand and how can we improve the process? Although the process is complicated, there are two major questions to address in research. First, can a marker discriminate well? That is, can it discriminate cleanly and reliably (eg, reproducibly and not due to artifact or bias) between persons with early-stage cancer vs those without cancer (or good vs bad prognosis)? Second, does that discrimination, when coupled with an intervention such as surgery or chemotherapy, lead to improved outcome? Answering the second question requires a randomized clinical trial, a design that is powerful and well understood but also expensive and time consuming. A randomized clinical trial is not even considered until a marker clearly shows reliable discrimination that warrants such an effort. Failures in current marker research occur not at the randomized clinical trial stage but earlier, when results that appear to have promising discrimination in early discovery turn out not even to be reproducible. Pepe et al. ( 1 ) proposed a formal structure in 2001 “to guide the process of biomarker development” consisting of fi ve “phases [that] are generally ordered according to the strength of evidence that each provides in favor of the biomarker, from weakest to strongest [and] the results of earlier phases are generally necessary to design later phases.” The phase structure has been widely adopted for use in various research projects, including, as noted by Feng et al. ( 2 ), “by the EDRN [the National Cancer Institute’s (NCI) Early Detection Research Network], a number of Specialized Program of Research Excellence (SPORE) consor
Neural Substrates of Decision Making in Adults With Attention Deficit Hyperactivity Disorder
Authors: Monique Ernst, Alane S Kimes, Edythe D London, John A Matochik, Dana Eldreth, Satya Tata, Carlo Contoreggi, Michelle Leff, Karen Bolla
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The characteristics of attention deficit hyperactivity disorder (ADHD) include abnormalities in reward responsivity that may interfere with decision making. The study examined reward responsivity in ADHD by comparing the neural correlates of decision making in adults with childhood-onset ADHD and in healthy adults. METHOD: The neural correlates of performance on a decision-making task and a control task were compared in 10 adults with ADHD and 12 age-matched healthy volunteers by using [15O]H2O positron emission tomography. The decision-making task tested the ability to weigh short-term rewards against long-term losses. The control task matched all components of the decision-making task except for the decision-making process and related contingency. RESULTS: The ventral and dorsolateral prefrontal cortex and the insula were activated during performance of the decision-making task in both the ADHD and healthy groups; however, activation in the ADHD group was less extended and did not involve other regions, such as anterior cingulate and hippocampus, that subserve emotion/memory processes. Direct comparison of data from the ADHD subjects and the healthy volunteers suggested that the healthy subjects engaged the hippocampal and insular regions more than did the ADHD subjects and that the ADHD subjects recruited the caudal part of the right anterior cingulate more than did the healthy subjects. CONCLUSIONS: The findings suggest that the neural circuits engaged during decision making differ in subjects with ADHD and healthy comparison subjects. This difference may explain observed deficits in motivated behaviors in ADHD. A better understanding of the nature of these deficits could ultimately be applied to refine treatment strategies for ADHD.
Emotion and personality factors influence the neural response to emotional stimuli
Authors: Fionnuala C. Murphy, Michael P. Ewbank, Andrew J. Calder
Journal: Behavioral and Brain Sciences (2012)

Abstract Lindquist et al. assess the neural evidence for locationist versus psychological construction accounts of human emotion. A wealth of experimental and clinical investigations show that individual differences in emotion and personality influence emotion processing. These factors may also influence the brain's response to emotional stimuli. A synthesis of the relevant neuroimaging data must therefore take these factors into consideration.
GeneHopper: a web-based search engine to link gene-expression platforms through GenBank accession numbers
Authors: B Anders T Svensson, Arja J Kreeft, Gert-Jan B van Ommen, Johan T den Dunnen, Judith M Boer
Journal: Genome biology (2003)

Global gene-expression analysis is carried out using different technologies that are either array- or sequence-tag-based. To compare experiments that are performed on these different platforms, array probes and sequence tags need to be linked. An additional challenge is cross-referencing between species, to compare human profiles with those obtained in a mouse model, for example. We have developed the web-based search engine GeneHopper to link different expression resources based on UniGene clusters and HomoloGene orthologs databases of the National Center for Biotechnology Information (NCBI).
A constant affinity threshold for T cell tolerance
Authors: Dieter Naeher, Mark A. Daniels, Barbara Hausmann, Philippe Guillaume, Immanuel Luescher, Ed Palmer
Journal: The Journal of Experimental Medicine (2007)

T cell tolerance depends on the T cell receptor's affinity for peptide/major histocompatibility complex (MHC) ligand; this critical parameter determines whether a thymocyte will be included (positive selection) or excluded (negative selection) from the T cell repertoire. A quantitative analysis of ligand binding was performed using an experimental system permitting receptor–coreceptor interactions on live cells under physiological conditions. Using three transgenic mouse strains expressing distinct class I MHC–restricted T cell receptors, we determined the affinity that defines the threshold for negative selection. The affinity threshold for self-tolerance appears to be a constant for cytotoxic T lymphocytes.
Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis
Authors: N B Klarenbeek, R Koevoets, D M F M van der Heijde, A H Gerards, S ten Wolde, P J S M Kerstens, T W J Huizinga, B A C Dijkmans, C F Allaart
Journal: Annals of the Rheumatic Diseases (2011)

Objective To compare nine disease activity indices and the new American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) remission criteria in rheumatoid arthritis (RA) and to relate these to physical function and joint damage progression. Methods Five-year data from the BeSt study were used, a randomised clinical trial comparing four treatment strategies in 508 patients with recent-onset RA. Every three months disease activity was assessed with nine indices (Disease Activity Score (DAS), DAS-C reactive proteine (DAS-CRP), Disease Activity Score in 28 joints (DAS-28), DAS28-CRP, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and three DAS versions with adjusted tender joint scores) and categorized into remission, low, moderate and high disease activity (LDA, MDA, HDA). In addition, the recent ACR/EULAR clinical trial and practice remission was assessed 3-monthly with 28 and 68/66 joint counts. For each index, Generalized Estimating Equations analyses were performed to relate disease activity levels and the absence/presence of remission to 3-monthly assessments of physical functioning and annual radiological progression. Results From the composite indices, CDAI and SDAI were the most stringent definitions of remission and classified more patients as LDA. DAS28 and DAS28-CRP had the highest proportions of remission and MDA and a smaller proportion of LDA. ACR/EULAR remission percentages were comparable to CDAI/SDAI: remission percentages. The variant including CRP and 68/66 joint counts was the most stringent. For all indices, higher levels of disease activity were associated with decreased physical functioning and more radiological damage progression. Despite differences in classification between the indices, no major differences in relation to the two outcomes were observed. Conclusion The associations of nine composite indices and ACR/EULAR remission criteria with functional status and joint damage progression showed high accordance, whereas the proportions of patients classified in the disease activity levels differed.