tbuckley/cabot-search huggingface dataset:
8-Oxo-dGTPase, Which Prevents Oxidative Stress-Induced DNA Damage, Increases in the Mitochondria From Failing Hearts
Authors: Hiroyuki Tsutsui, Tomomi Ide, Tetsuya Shiomi, Dongchon Kang, Shunji Hayashidani, Nobuhiro Suematsu, Jing Wen, Hideo Utsumi, Naotaka Hamasaki, Akira Takeshita
Journal: Circulation (2001)

Background — Reactive oxygen species (ROS) can cause an oxidative modification of nucleotides, such as 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP), which can lead to defects in DNA replication. The misincorporation of 8-oxo-dGTP into DNA is prevented by 8-oxo-dGTPase, which hydrolyzes 8-oxo-dGTP into 8-oxo-dGMP. The changes in this defensive system have not yet been examined in failing hearts, in which the generation of ROS increases. Methods and Results — Myocardial infarction (MI) was created in mice by ligating the left coronary artery. Four weeks later, the left ventricle was dilated and contractility was diminished on echocardiography. The generation of ROS, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, increased in the noninfarcted left ventricle from MI mice. The formation of thiobarbituric acid-reactive substances also increased in the mitochondria from MI mice. 8-Oxo-dGTPase was detected in the mitochondrial fractions isolated from MI mice using a Western blot analysis with an antibody to its human homologue (hMTH1). Immunohistochemistry showed positive staining for hMTH1 was localized in the cardiac myocytes. Conclusions — The level of 8-oxo-dGTPase increased in the mitochondria isolated from post-MI hearts as oxidative stress increased, thus suggesting that a preventive mechanism is activated against ROS-induced DNA damage. As a result, 8-oxo-dGTPase is considered a useful marker of mitochondrial oxidative stress in heart failure.
Diagnosis and treatment of low back pain
Authors: B W Koes, M W van Tulder, S Thomas
Journal: BMJ (2006)

Low back pain is a considerable health problem in all developed countries and is most commonly treated in primary healthcare settings. It is usually defined as pain, muscle tension, or stiffness localised below the costal margin and above the inferior gluteal folds, with or without leg pain (sciatica). The most important symptoms of non-specific low back pain are pain and disability. The diagnostic and therapeutic management of patients with low back pain has long been characterised by considerable variation within and between countries among general practitioners, medical specialists, and other healthcare professionals.1 2 w1 Recently, a large number of randomised clinical trials have been done, systematic reviews have been written, and clinical guidelines have become available. The outlook for evidence based management of low back pain has greatly improved. This review presents the current state of science regarding the diagnosis and treatment of low back pain.

We used the Cochrane Library to identify relevant systematic reviews that evaluate the effectiveness of conservative, complementary, and surgical interventions. Medline searches were used to find other relevant systematic reviews on diagnosis and treatment of low back pain, with the keywords “low back pain”, “systematic review”, “meta-analysis”, “diagnosis”, and “treatment”. Our personal files were used for additional references. We also checked available clinical guidelines and used Clinical Evidence as source for clinically relevant information on benefits and harms of treatments.3 4

Most of us will experience at least one episode of low back pain during our life. Reported lifetime prevalence varies from 49% to 70% and point prevalences from 12% to 30% are reported in Western countries.w2 w3

The diagnostic process is mainly focused on the triage of patients with specific or non-specific low back pain. Specific low back pain is defined as symptoms caused by a specific pathophysiological mechanism, such …
Predictors of poor treatment outcome in multi- and extensively drug-resistant pulmonary TB
Authors: K. Kliiman, A. Altraja
Journal: European Respiratory Journal (2009)

Treatment outcome in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is often unsuccessful, but the particular determinants of poor treatment outcome have remained obscure. The present authors therefore analysed treatment effectiveness and predictors of poor treatment outcome in pulmonary MDR-TB and XDR-TB in Estonia, a European country with one of the highest MDR-TB and XDR-TB rates in the world. All culture-confirmed pulmonary MDR-TB and XDR-TB patients who started TB treatment in 2003-2005 were included. Multivariate analysis was performed on two models of predictors: 1) patients' HIV-status, demographic and socioeconomic characteristics; and 2) TB-related data. In the 235 MDR-TB patients, the proportion of overall successful treatment outcome was 60.4%, rising to 72.8% among adherent patients. Among the 54 XDR-TB patients, these proportions were 42.6% and 50.0%, respectively. Risk factors for poor treatment outcome in MDR-TB were HIV infection, previous TB treatment, resistance to ofloxacin and positive acid-fast bacilli (AFB) smear at the start of treatment. Predictors of poor treatment outcome in XDR-TB were urban residence and positive AFB smear. This country-wide study provides evidence that to improve treatment outcome in multidrug-resistant and extensively drug-resistant tuberculosis, special care should be taken to treat HIV-infected patients and urban residents, as well as to make efforts to diminish re-treatment cases by increasing patient adherence.
Interleukin 7 Regulates the Survival and Generation of Memory CD4 Cells
Authors: Robyn M. Kondrack, Judith Harbertson, Joyce T. Tan, Meghan E. McBreen, Charles D. Surh, Linda M. Bradley
Journal: The Journal of Experimental Medicine (2003)

Cytokines, particularly those of the common γ chain receptor family, provide extrinsic signals that regulate naive CD4 cell survival. Whether these cytokines are required for the maintenance of memory CD4 cells has not been rigorously assessed. In this paper, we examined the contribution of interleukin (IL) 7, a constitutively produced common γ chain receptor cytokine, to the survival of resting T cell receptor transgenic memory CD4 cells that were generated in vivo. IL-7 mediated the survival and up-regulation of Bcl-2 by resting memory CD4 cells in vitro in the absence of proliferation. Memory CD4 cells persisted for extended periods upon adoptive transfer into intact or lymphopenic recipients, but not in IL-7− mice or in recipients that were rendered deficient in IL-7 by antibody blocking. Both central (CD62L+) and effector (CD62L−) memory phenotype CD4 cells required IL-7 for survival and, in vivo, memory cells were comparable to naive CD4 cells in this regard. Although the generation of primary effector cells from naive CD4 cells and their dissemination to nonlymphoid tissues were not affected by IL-7 deficiency, memory cells failed to subsequently develop in either the lymphoid or nonlymphoid compartments. The results demonstrate that IL-7 can have previously unrecognized roles in the maintenance of memory in the CD4 cell population and in the survival of CD4 cells with a capacity to become memory cells.
Nongenotoxic p53 Activation Protects Cells against S-Phase–Specific Chemotherapy
Authors: Dominique Kranz, Matthias Dobbelstein
Journal: Cancer Research (2006)

Abstract Mutations in the tumor suppressor gene TP53 represent the most frequent genetic difference between tumor cells and normal cells. Here, we have attempted to turn this difference into an advantage for normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we first activated p53 in U2OS and HCT116 cells to induce cell cycle arrest. These arrested cells were found to be resistant to subsequent transient treatment with the nucleoside analogue gemcitabine, as revealed by clonogenic assays following drug removal. In contrast, isogenic cells lacking functional p53 continued to enter S phase regardless of nutlin-3 pretreatment and remained highly susceptible to gemcitabine-mediated cytotoxicity. The sequential treatment with nutlin-3 alone, followed by transient exposure to nutlin-3 plus gemcitabine, efficiently compromised the clonogenicity of tumor cells with deletions or mutations of p53 but largely spared the proliferation of nontransformed human keratinocytes. Nutlin-3 pretreatment also conferred protection of p53-proficient cells against cytosine arabinoside but not against doxorubicin or cisplatin. We propose that the cell cycle arrest function of p53 can be used to convert p53 from a killer to a protector of cells, with the potential to reduce unwanted side effects of chemotherapy. (Cancer Res 2006; 66(21): 10274-80)
Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation
Authors: Anne E. Dixon, Richard E. Pratley, Patrick M. Forgione, David A. Kaminsky, Laurie A. Whittaker-Leclair, Laurianne A. Griffes, Jayanthi Garudathri, Danielle Raymond, Mathew E. Poynter, Janice Y. Bunn, Charles G. Irvin
Journal: Journal of Allergy and Clinical Immunology (2011)
Silencing of protein kinase D2 induces glioma cell senescence via p53-dependent and -independent pathways
Authors: Eva Bernhart, Sabine Damm, Petra Heffeter, Andrea Wintersperger, Martin Asslaber, Saša Frank, Astrid Hammer, Heimo Strohmaier, Trevor DeVaney, Manuel Mrfka, Hans Eder, Christian Windpassinger, Christopher R. Ireson, Paul S. Mischel, Walter Berger, Wolfgang Sattler
Journal: Neuro-Oncology (2014)

Glioblastoma multiforme (GBM) is a highly aggressive tumor of the central nervous system with a dismal prognosis for affected patients. Aberrant protein kinase C (PKC) signaling has been implicated in gliomagenesis, and a member of the PKC-activated protein kinase D (PRKD) family, PRKD2, was identified as mediator of GBM growth in vitro and in vivo. The outcome of PRKD2 silencing and pharmacological inhibition on glioma cell proliferation was established with different glioma cell lines. Western blotting, senescence assays, co-immunoprecipitation, fluorescence activated cell sorting, quantitative PCR, and immunofluorescence microscopy were utilized to analyze downstream signaling. RNA-interference (21-mer siRNA) and pharmacological inhibition (CRT0066101) of PRKD2 profoundly inhibited proliferation of p53wt (U87MG, A172, and primary GBM2), and p53mut (GM133, T98G, U251, and primary Gli25) glioma cells. In a xenograft experiment, PRKD2 silencing significantly delayed tumor growth of U87MG cells. PRKD2 silencing in p53wt and p53mut cells was associated with typical hallmarks of senescence and cell cycle arrest in G1. Attenuated AKT/PKB phosphorylation in response to PRKD2 silencing was a common observation made in p53wt and p53mut GBM cells. PRKD2 knockdown in p53wt cells induced upregulation of p53, p21, and p27 expression, decreased phosphorylation of CDK2 and/or CDK4, hypophosphorylation of retinoblastoma protein (pRb), and reduced transcription of E2F1. In p53mut GM133 and primary Gli25 cells, PRKD2 silencing increased p27 and p15 and reduced E2F1 transcription but did not affect pRb phosphorylation. PRKD2 silencing induces glioma cell senescence via p53-dependent and -independent pathways.
Influence of Experimental Myocardial Infarction on Free Amino Acids of Dog Heart
Authors: MARTIN CHANIN, EUGENE ROBERTS, ALFRED GOLDMAN
Journal: Circulation Research (1956)

Free or easily extractable amino acids were determined by two-dimensional paper chromatography in infarcted and noninfarcted areas of the left ventricles of dog hearts after ligation of the anterior descending coronary artery. Changes in amino acid content in infarcted areas were characterized by decreases in some of the major ninhydrin-reactive constituents and appeared coincidentally with histologic signs of myocardial damage.
Fluorescence/Bioluminescence Resonance Energy Transfer Techniques to Study G-Protein-Coupled Receptor Activation and Signaling
Authors: Martin J. Lohse, Susanne Nuber, Carsten Hoffmann
Journal: Pharmacological Reviews (2012)

Fluorescence and bioluminescence resonance energy transfer (FRET and BRET) techniques allow the sensitive monitoring of distances between two labels at the nanometer scale. Depending on the placement of the labels, this permits the analysis of conformational changes within a single protein (for example of a receptor) or the monitoring of protein-protein interactions (for example, between receptors and G-protein subunits). Over the past decade, numerous such techniques have been developed to monitor the activation and signaling of G-protein-coupled receptors (GPCRs) in both the purified, reconstituted state and in intact cells. These techniques span the entire spectrum from ligand binding to the receptors down to intracellular second messengers. They allow the determination and the visualization of signaling processes with high temporal and spatial resolution. With these techniques, it has been demonstrated that GPCR signals may show spatial and temporal patterning. In particular, evidence has been provided for spatial compartmentalization of GPCRs and their signals in intact cells and for distinct physiological consequences of such spatial patterning. We review here the FRET and BRET technologies that have been developed for G-protein-coupled receptors and their signaling proteins (G-proteins, effectors) and the concepts that result from such experiments.
The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance in Cancer Cells
Authors: Zoltan Derdak, Nicholas M. Mark, Guido Beldi, Simon C. Robson, Jack R. Wands, György Baffy
Journal: Cancer Research (2008)

Abstract Cancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis after exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered NH2-terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer. [Cancer Res 2008;68(8):2813–9]
Clinical characteristics predicting early clinical failure after 72 h of antibiotic treatment in women with community-onset acute pyelonephritis: a prospective multicentre study
Authors: S.-H. Wie, M. Ki, J. Kim, Y.K. Cho, S.-K. Lim, J.S. Lee, K.T. Kwon, H. Lee, H.J. Cheong, D.W. Park, S.Y. Ryu, M.-H. Chung, H. Pai
Journal: Clinical Microbiology and Infection (2013)
Chronic Eosinophilic Leukemia/Hypereosinophilic Syndrome and Acute Leukemia
Authors: Neil Abramson
Journal: Journal of Clinical Oncology (2006)

Clinical Oncology, Frohling et al 1 stated that chronic eosinophilic leukemia/hypereosinophilic syndrome (HES) "is characterized by clonal eosinophilia, which can be associated with end-organ damage and transformation to acute leukemia."I assume that the authors are not suggesting a transformation to acute eosinophilic leukemia.The cited data by Cools et al 2 and numerous other articles on HES usually describe conversion to chronic leukemia rather than to acute leukemia.Acute leukemic cells are poorly differentiated and may produce nonspecific granules, unlike the specific eosinophilic granules that appear in myelocytes (and sometimes in promyelocytes).Some arti-cles that refer to acute leukemia from HES actually describe chronic myelogenous leukemia with eosinophilia and a later conversion to blast crisis (a transformed cell line) or de novo acute myeloid leukemia with eosinophilia (AML FAB4Eo).An acute leukemic cell that can differentiate to a cell producing eosinophilic granules is unlikely an acute leukemic cell.
A Prospectively-Designed Study to Determine the Association of a 17-Gene Genomic Prostate Score with Recurrence Following Surgery for Localised Prostate Cancer (Pca)
Authors: J. Cullen, I. Rosner, T. Brand, A. Ali, Y. Chen, N. Zhang, A. Tsiatis, D. Knezevic, T. Maddala, H.J. Lawrence, P. Febbo, S. Srivastava, I. Sesterhenn, D. McLeod
Journal: Annals of Oncology (2014)

Aim: Molecular markers of tumor aggressiveness can improve risk assessment for men with PCa. A large, racially diverse cohort of men (21% African-American -AA) with PCa in the Center for Prostate Disease Research multi-center national database was used to determine the association of the Oncotype DX® Genomic Prostate Score (GPS) with recurrence following radical prostatectomy (RP) for localized PCa. Methods: Archival biopsy specimens from 431 eligible men treated with RP for NCCN very low, low or intermediate risk PCa from 1990-2011 at 2 U.S. military medical centers were tested to validate the association between GPS and recurrence following RP, and adverse pathology (AP) at RP. Biochemical recurrence (BCR) was defined as 2 successive PSA levels > 0.2 ng/mL or initiation of salvage therapy for a rising PSA. AP was defined as high-grade (primary Gleason pattern 4 or any pattern 5) and/or pT3 disease. RPs were centrally reviewed by a uropathologist (IAS). Cox proportional hazards and logistic regression models were used. Results: GPS (scale 0-100) was successfully obtained in 402 cases (93%). 62 men (15%) experienced BCR, 5 developed metastases (MR) and 163 had AP at RP. In univariate analysis, PSA, biopsy GS and NCCN risk group were associated with BCR, but race was not. GPS was predictive of time to BCR by univariate analysis (HR/20 GPS units = 2.9; 95% CI: 2.0-4.2; p < 0.001), and after adjusting for age, NCCN risk group, and race ((HR/20 units = 2.7; p < 0.001). The gene groups in GPS most strongly associated with BCR included androgen signaling and stromal response genes. GPS was predictive of time to MR (HR/20 units = 3.8; p = 0.032). GPS was strongly associated with AP - OR/ 20 units = 3.3 (95% CI: 2.1–5.1; p < .001) and high-grade disease - OR/20 units = 2.5 (95% CI: 1.6–4.0; p < .001), adjusted for NCCN risk group. GPS values were similar between AA and Caucasians, and similarly predictive of disease outcome. Conclusions: GPS is a significant independent predictor of BCR, MR and AP in men treated with RP for localized PCa. Tumor aggressiveness, as measured by GPS, and clinical outcomes were similar in AA and Caucasians in this patient population with equal healthcare access.
Diet-Induced Unresolved ER Stress Hinders KRAS-Driven Lung Tumorigenesis
Authors: Giorgio Ramadori, Georgia Konstantinidou, Niranjan Venkateswaran, Tommasina Biscotti, Lorraine Morlock, Mirco Galié, Noelle S. Williams, Michele Luchetti, Alfredo Santinelli, Pier Paolo Scaglioni, Roberto Coppari
Journal: Cell Metabolism (2014)

Dietary effects on tumor biology can be exploited to unravel cancer vulnerabilities. Here, we present surprising evidence for anti-proliferative action of high-calorie-diet (HCD) feeding on KRAS-driven lung tumors. Tumors of mice that commenced HCD feeding before tumor onset displayed defective unfolded protein response (UPR) and unresolved endoplasmic reticulum (ER) stress. Unresolved ER stress and reduced proliferation are reversed by chemical chaperone treatment. Whole-genome transcriptional analyses revealed FKBP10 as one of the most downregulated chaperones in tumors of the HCD-pre-tumor-onset group. FKBP10 downregulation dampens tumor growth in vitro and in vivo. Providing translational value to these results, we report that FKBP10 is expressed in human KRAS-positive and -negative lung cancers, but not in healthy parenchyma. Collectively, our data shed light on an unexpected anti-tumor action of HCD imposed before tumor onset and identify FKBP10 as a putative therapeutic target to selectively hinder lung cancer.
Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage
Authors: Jitka Malcikova, Jana Smardova, Ludmila Rocnova, Boris Tichy, Petr Kuglik, Vladimira Vranova, Sona Cejkova, Miluse Svitakova, Hana Skuhrova Francova, Yvona Brychtova, Michael Doubek, Martin Brejcha, Martin Klabusay, Jiri Mayer, Sarka Pospisilova, Martin Trbusek
Journal: Blood (2009)
Comparison between theoretical and directly measured pulse propagation velocities in the aorta of the anaesthetised dog
Authors: S. E. GREENWALD, D. L. NEWMAN, N. L. R. BOWDEN
Journal: Cardiovascular Research (1978)

The propagation velocity (Cm) of the flow and pressure pulse has been measured in the abdominal aorta of anaesthetised dogs under vasoconstricted and vasodilated conditions. Simultaneously, measurements of the pressure strain elastic modulus (Ep) were obtained using a mercury in silastic strain gauge. These values of Ep were used to estimate a calculated propagation velocity (Cc) derived from the Moens Korteweg relationship. After Fourier analysing the pressure, flow and radius data it was found that Cc showed very little frequency dependence and that during vasodilatation Cm ≈ Cc to within a few percent for all harmonics above the first; whilst during vasoconstriction close agreement was observed at harmonics ≥ 6th. The mean values of Cm for these higher harmonics, and Cc for all harmonics, together with the mean propagation velocity (Cff) obtained from foot-to-foot time delays were, during vasodilation :Cm = 5.88 ± 1.2 (SD), Cc = 6.00 ± 1.04 and Cff = 5.79 ± 1.03 and during vasoconstriction Cm = 8.04 ± 1.27, Cc = 8.10 ± 1.04 and Cff = 8.00 ± 1.16. (units ms−1) Measurements in one dog of the impedance (ratio of pressure to flow) demonstrated that the contribution of peripheral reflections was negligible for the 6th and subsequent harmonics during vasoconstriction and above the first harmonic during vasodilatation, suggesting that the lack of agreement at lower frequencies between measured and calculated velocities was due to the presence of reflected waves. We conclude that within the frequency range in which reflected waves are negligible the Moens Korteweg equation in conjunction with measurements of pulse propagation velocity may be used to obtain accurate information on the elastic properties of the aorta.
MUC4, a Multifunctional Transmembrane Glycoprotein, Induces Oncogenic Transformation of NIH3T3 Mouse Fibroblast Cells
Authors: Sangeeta Bafna, Ajay P. Singh, Nicolas Moniaux, James D. Eudy, Jane L. Meza, Surinder K. Batra
Journal: Cancer Research (2008)

Abstract Numerous studies have established the association of MUC4 with the progression of cancer and metastasis. An aberrant expression of MUC4 is reported in precancerous lesions, indicating its early involvement in the disease process; however, its precise role in cellular transformation has not been explored. MUC4 contains many unique domains and is proposed to affect cell signaling pathways and behavior of the tumor cells. In the present study, to decipher the oncogenic potential of MUC4, we stably expressed the MUC4 mucin in NIH3T3 mouse fibroblast cells. Stable ectopic expression of MUC4 resulted in increased growth, colony formation, and motility of NIH3T3 cells in vitro and tumor formation in nude mice when cells were injected s.c. Microarray analysis showed increased expression of several growth-associated and mitochondrial energy production–associated genes in MUC4-expressing NIH3T3 cells. In addition, expression of MUC4 in NIH3T3 cells resulted in enhanced levels of oncoprotein ErbB2 and its phosphorylated form (pY1248-ErbB2). In conclusion, our studies provide the first evidence that MUC4 alone induces cellular transformation and indicates a novel role of MUC4 in cancer biology. [Cancer Res 2008;68(22):9231–8]