tbuckley/cabot-search huggingface dataset:
<i>PTEN</i> Deletion in Prostate Cancer Cells Does Not Associate with Loss of RAD51 Function: Implications for Radiotherapy and Chemotherapy
Authors: Michael Fraser, Helen Zhao, Kaisa R. Luoto, Cecilia Lundin, Carla Coackley, Norman Chan, Anthony M. Joshua, Tarek A. Bismar, Andrew Evans, Thomas Helleday, Robert G. Bristow
Journal: Clinical Cancer Research (2011)

Abstract Purpose: PTEN deletions in prostate cancer are associated with tumor aggression and poor outcome. Recent studies have implicated PTEN as a determinant of homologous recombination (HR) through defective RAD51 function. Similar to BRCA1/2-defective tumor cells, PTEN-null prostate and other cancer cells have been reported to be sensitive to PARP inhibitors (PARPi). To date, no direct comparison between PTEN and RAD51 expression in primary prostate tumors has been reported. Experimental Design: Prostate cancer cell lines and xenografts with known PTEN status (22RV1-PTEN+/+, DU145-PTEN+/−, PC3-PTEN−/−) and H1299 and HCT116 cancer cells were used to evaluate how PTEN loss affects RAD51 expression and PARPi sensitivity. Primary prostate cancers with known PTEN status were analyzed for RAD51 expression. Results: PTEN status is not associated with reduced RAD51 mRNA or protein expression in primary prostate cancers. Decreased PTEN expression did not reduce RAD51 expression or clonogenic survival following PARPi among prostate cancer cells that vary in TP53 and PTEN. PARPi sensitivity instead associated with a defect in MRE11 expression. PTEN-deficient cells had only mild PARPi sensitivity and no loss of HR or RAD51 recruitment. Clonogenic cell survival following a series of DNA damaging agents was variable: PTEN-deficient cells were sensitive to ionizing radiation, mitomycin-C, UV, H2O2, and methyl methanesulfonate but not to cisplatin, camptothecin, or paclitaxel. Conclusions: These data suggest that the relationship between PTEN status and survival following DNA damage is indirect and complex. It is unlikely that PTEN status will be a direct biomarker for HR status or PARPi response in prostate cancer clinical trials. Clin Cancer Res; 18(4); 1015–27. ©2011 AACR.
Re: Characterization of the ventricular conduction system in the developing mouse heart
Authors: R Anderson
Journal: Cardiovascular Research (2001)

To the Editor:

Franco and Icardo are to be congratulated on their study of the molecular characterization of the ventricular conduction system in the developing mouse [1]. The elegance of their immunocytochemical techniques, however, should not detract from information already available on both the disposition and development of the specialised atrioventricular conduction axis. Thus, at least two aspects of their account are open to criticism. First, the authors discuss the recent revisionist account of Racker and Kadish (their reference #37) as though this concept …
Methods for studying tooth root cementum by light microscopy
Authors: Brian L Foster
Journal: International Journal of Oral Science (2012)

The tooth root cementum is a thin, mineralized tissue covering the root dentin that is present primarily as acellular cementum on the cervical root and cellular cementum covering the apical root. While cementum shares many properties in common with bone and dentin, it is a unique mineralized tissue and acellular cementum is critical for attachment of the tooth to the surrounding periodontal ligament (PDL). Resources for methodologies for hard tissues often overlook cementum and approaches that may be of value for studying this tissue. To address this issue, this report offers detailed methodology, as well as comparisons of several histological and immunohistochemical stains available for imaging the cementum–PDL complex by light microscopy. Notably, the infrequently used Alcian blue stain with nuclear fast red counterstain provided utility in imaging cementum in mouse, porcine and human teeth. While no truly unique extracellular matrix markers have been identified to differentiate cementum from the other hard tissues, immunohistochemistry for detection of bone sialoprotein (BSP), osteopontin (OPN), and dentin matrix protein 1 (DMP1) is a reliable approach for studying both acellular and cellular cementum and providing insight into developmental biology of these tissues. Histological and immunohistochemical approaches provide insight on developmental biology of cementum. Light microscopy and chemical staining methods could help clarify how tooth cementum develops, a US scientist reveals. This thin layer of mineralized tissue that covers the roots of teeth can be one of two types: acellular or cellular. Since little is known about the tissue itself, Brian Foster of the National Institutes of Health, Maryland, USA, compared different staining techniques to differentiate acellular and cellular cementum from surrounding dentin, bone and ligament structures in mouse, porcine and human teeth. He found that Alcian blue stain and nuclear fast red counterstain were the most effective in distinguishing between cementum and surrounding tissues using light microscopy. Foster also found that using antibodies to highlight specific proteins in the tissue (immunohistochemistry) helped visualize the cementum layers and could provide insight into its biological development.
Epstein-Barr virus infection in Richter's transformation
Authors: Stephen M. Ansell, Chin-Yang Li, Ricardo V. Lloyd, Robert L. Phyliky
Journal: American Journal of Hematology (1999)

Chronic lymphocytic leukemia (CLL) may convert to a diffuse large cell lymphoma (Richter's syndrome) over time. In occasional cases of Richter's transformation, Epstein-Barr virus (EBV) has been identified in the lymphoma cells. To evaluate the association of EBV infection with Richter's syndrome, the biopsy specimens and clinical records of 25 patients who were seen at the Mayo Clinic between 1984–1996 were retrospectively evaluated for the presence of EBV by immunoperoxidase staining for expression of EBV latent membrane protein (LMP), as well as the expression of EBV RNA and DNA in the cells by in situ hybridization. Four of the 25 patients showed evidence of EBV in the diffuse large cell lymphoma cells—three patients with a B-cell phenotype were positive for LMP, EBV DNA, and RNA; and one patient with a T-cell phenotype had positive EBV RNA in the large cell lymphoma cells. The Richter's syndrome was treated with combination chemotherapy in 15 patients, three received radiotherapy, three were followed without further therapy after a splenectomy, two died before treatment could be started, and one patient had insufficient follow-up. One patient with evidence of EBV in large cell lymphoma cells was treated with acyclovir as initial therapy. The median survival of EBV-positive patients was three months compared with nine months for EBV-negative patients, but this difference was not statistically significant (P = 0.385). Evidence for EBV infection related to Richter's transformation was present in 16% of the patients in this study and may be associated with a poorer outcome. Primary therapy with acyclovir in one patient did not seem to be beneficial and other therapeutic modalities in patients with EBV-positive Richter's transformation need to be explored. Am J. Hematol. 60:99–104, 1999. © 1999 Wiley-Liss, Inc.
Forced oscillation total respiratory resistance and spontaneous breathing lung resistance in COPD patients
Authors: R Farré, R Peslin, M Rotger, J A Barberá, D Navajas
Journal: European Respiratory Journal (1999)

Forced-oscillation total respiratory resistance (Rrs) has been shown to underestimate spontaneous breathing lung resistance (RL,sb) in patients with airway obstruction, probably owing to upper airway shunting. The present study reinvestigates that relationship in seven severely obstructed chronic obstructive pulmonary disease patients using a technique that minimizes that artefact. Rrs at 8 and 16 Hz was computed for each successive forced oscillation cycle. Inspiratory and expiratory RL,sb were obtained by analysing transpulmonary pressure (Ptp) with a four-coefficient model, and compared to Rrs over the same periods. "Instantaneous" values of RL,sb were also obtained by computing the dynamic component of Ptp, and compared to simultaneous values of Rrs. In both respiratory phases, good agreement between Rrs and RL,sb was observed up to RL,sb values of approximately 15 hPa x s(-1) x L(-1) at 8 Hz and 10 hPa x s(-1) x L(-1) at 16 Hz. Instantaneous Rrs and RL,sb varied systematically during the respiratory cycle, exhibiting various amounts of flow- or volume-dependence in the seven patients; the amplitudes of their variations were significantly correlated, but Rrs was much more flow-dependent than RL,sb in three patients. Also, Rrs exceeded RL,sb at end-expiration in three instances, which could be related to expiratory flow limitation. In conclusion, total respiratory resistance is reliable up to much higher levels of airway obstruction than previously thought, provided upper airway shunting is avoided.
Differential Prognostic Impact of Comorbidity
Authors: William L. Read, Ryan M. Tierney, Nathan C. Page, Irene Costas, Ramaswamy Govindan, Edward L.J. Spitznagel, Jay F. Piccirillo
Journal: Journal of Clinical Oncology (2004)

Cancer patients with concurrent comorbid conditions have worse outcomes than patients with no comorbidities. We hypothesized that the prognostic impact of comorbidities would be greatest for patients with cancers associated with a long natural history and least in patients with aggressive cancers.Using the Barnes-Jewish Hospital Oncology Data Services cancer registry, we grouped 11,558 patients with breast, lung, colon, or prostate cancer by morphologic stage at diagnosis and then determined the 1-year overall survival rate for each group. Overall, severity of comorbidity was assessed from chart review and classified into one of four groups: none, mild, moderate, or severe. The relative prognostic impact of comorbidity was measured by the hazard ratio and adjusted for the prognostic impact of age, race, and sex.One-year overall survival rate ranged from 20% for 1,005 patients with distant spread of lung cancer to 98% for 3,325 patients with localized prostate cancer. Adjusted hazard ratio of moderate/severe comorbidity (relative to none/mild) ranged from 1.04 to 4.48. The correlation between overall survival rate and severity of comorbidity was statistically significant (r2 = 0.56; P < .001). The proportion of variance in outcome explained by comorbidity ranged from less than 1% to almost 9%, depending on tumor site and stage.Concurrent comorbidities had the greatest prognostic impact among groups with the highest survival rate and the least impact in groups with the lowest survival rate. These findings can be used to help determine the role comorbidity information should play in studies of cancer outcomes.
Progression of Myocardial Fibrosis Assessed With Cardiac Magnetic Resonance in Hypertrophic Cardiomyopathy
Authors: Giancarlo Todiere, Giovanni Donato Aquaro, Paolo Piaggi, Francesco Formisano, Andrea Barison, Pier Giorgio Masci, Elisabetta Strata, Lorenzo Bacigalupo, Mario Marzilli, Alessandro Pingitore, Massimo Lombardi
Journal: Journal of the American College of Cardiology (2012)
Pulmonary Arterial Hypertension
Authors: Michael D. McGoon, Raymond L. Benza, Pilar Escribano-Subias, Xin Jiang, Dave P. Miller, Andrew J. Peacock, Joanna Pepke-Zaba, Tomas Pulido, Stuart Rich, Stephan Rosenkranz, Samy Suissa, Marc Humbert
Journal: Journal of the American College of Cardiology (2013)
Cyclosporin A Inhibits Apoptosis of Human Endothelial Cells by Preventing Release of Cytochrome C From Mitochondria
Authors: Dirk H. Walter, Judith Haendeler, Jan Galle, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation (1998)

Background —Several experimental and clinical studies suggest that cyclosporin A (CSA) treatment reduces transplant atherosclerosis. Because oxidized LDL (oxLDL) is believed to play a key role in the development of atherogenesis, causing injury to the endothelium, and has been shown to induce apoptosis of endothelial cells, we investigated whether CSA inhibits oxLDL-induced apoptosis. Methods and Results —Apoptosis was induced in human umbilical venous endothelial cells (HUVECs) by incubation of 10 μg/mL oxLDL for 18 hours. Coincubation with CSA dose dependently decreased oxLDL-induced apoptosis, with a maximal effect at 10 μmol/L. In addition, tumor necrosis factor-α– and angiotensin II–induced apoptosis was significantly prevented by CSA treatment, suggesting a general apoptosis-suppressive effect of CSA. CSA has been shown to inhibit disruption of the mitochondrial membrane function, which plays a key role in apoptosis induction. Indeed, oxLDL treatment triggered the release of cytochrome C from the mitochondria into the cytosol, indicating disturbance of the mitochondrial membrane. CSA (10 μmol/L) completely inhibited the oxLDL-induced release of cytochrome C. Moreover, tumor necrosis factor-α– and angiotensin II–induced cytochrome C release was prevented by CSA treatment. Conclusions —OxLDL induces dysfunction of the mitochondrial membrane, leading to cytochrome C release into the cytosol, and thereby stimulates apoptosis of human endothelial cells. Apoptosis suppression by CSA correlates with the prevention of mitochondrial dysfunction and thus indicates the importance of mitochondrial destabilization in oxLDL-induced apoptosis signaling. The inhibition of apoptosis by CSA might preserve the function of the endothelium and may at least in part contribute to the antiatherogenic effects of CSA in transplant atherosclerosis.
Impact of Intertumoral Heterogeneity on Predicting Chemotherapy Response of BRCA1-Deficient Mammary Tumors
Authors: Sven Rottenberg, Marieke A. Vollebergh, Bas de Hoon, Jorma de Ronde, Philip C. Schouten, Ariena Kersbergen, Serge A.L. Zander, Marina Pajic, Janneke E. Jaspers, Martijn Jonkers, Martin Lodén, Wendy Sol, Eline van der Burg, Jelle Wesseling, Jean-Pierre Gillet, Michael M. Gottesman, Joost Gribnau, Lodewyk Wessels, Sabine C. Linn, Jos Jonkers, Piet Borst
Journal: Cancer Research (2012)

The lack of markers to predict chemotherapy responses in patients poses a major handicap in cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response in a mouse model for breast cancer associated with BRCA1 deficiency. Array-based expression profiling did not identify a single marker gene predicting docetaxel response, despite an increase in Abcb1 (P-glycoprotein) expression that was sufficient to explain resistance in several poor responders. Intertumoral heterogeneity explained the inability to identify a predictive gene expression signature for docetaxel. To address this problem, we used a novel algorithm designed to detect differential gene expression in a subgroup of the poor responders that could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as significance analysis of microarrays, detected a marker only if it correlated with response in a substantial fraction of tumors. For example, low expression of the Xist gene correlated with cisplatin hypersensitivity in most tumors, and it also predicted long recurrence-free survival of HER2-negative, stage III breast cancer patients treated with intensive platinum-based chemotherapy. Our findings may prove useful for selecting patients with high-risk breast cancer who could benefit from platinum-based therapy.
High-frequency respiratory input impedance measurements in infants assessed by the high speed interrupter technique
Authors: U Frey, M Silverman, R Kraemer, AC Jackson
Journal: European Respiratory Journal (1998)

High-frequency input impedance (Z(f)) measurements, including antiresonances, provide useful noninvasive information on airway geometry and especially airway wall mechanics in the canine and human adult respiratory system. A knowledge of airway wall mechanics would be particularly important in understanding flow limitation phenomena in infants. High-frequency Z(f) has not been measured in infants above 256 Hz, because the high impedance of the infantile respiratory system would be expected to result in low amplitudes of oscillatory flow at higher frequencies. The aim of this study was to develop a technique to measure high-frequency Z(f) in infants and to elucidate the nature of the antiresonance phenomena in the Z(f) spectrum in infants. Z(f) was measured from 32-900 Hz during rapid airflow interruption by the high-speed interrupter technique (HIT) in 18 infants (aged 24-149 weeks) with wheezing disorders. The HIT enables the excitement of higher flow amplitudes at high frequencies using a pseudostep forcing function. In all infants Z(f) showed a mean (SD) first antiresonance (far,1) of 172 (35) Hz (real part of Z(f) at far,1 (Z(f)re(far,1)): 4.9 (1.1) kPa x L(-1) x s) and in five infants a second antiresonance (far,2) of 564 (51) Hz (Z(f)re(far,2): 2.0 (0.7) kPa x L(-1) x s). The antiresonances were found to be related to wave propagation in the airways (acoustic antiresonances), because they increased by a factor of approximately 2 when He-O2 was inhaled. This implies that far,1 and its harmonics are a function of airway wall compliance. In conclusion, the first and second antiresonances may be helpful in understanding flow limitation in wheezing disorders in infants, because flow limitation is related not only to airway diameter but also to airway wall compliance.
Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial
Authors: Marie-Germaine Bousser, Pierre Amarenco, Angel Chamorro, Marc Fisher, Ian Ford, Kim M Fox, Michael G Hennerici, Heinrich P Mattle, Peter M Rothwell, Agnès de Cordoüe, Marie-Dominique Fratacci
Journal: The Lancet (2011)
Alternative Cleavage and Polyadenylation during Colorectal Cancer Development
Authors: Adam R. Morris, Arnold Bos, Begoña Diosdado, Koos Rooijers, Ran Elkon, Anne S. Bolijn, Beatriz Carvalho, Gerrit A. Meijer, Reuven Agami
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Alternative cleavage and polyadenylation (APA) of mRNAs is a phenomenon that alters 3′-untranslated region length leading to altered posttranscriptional regulation of gene expression. Changing APA patterns have been shown to result in misregulation of genes involved in carcinogenesis; therefore, we hypothesized that altered APA contributes to progression of colorectal cancer, and that measurement of APA may lead to discovery of novel biomarkers. Experimental Design: We used next-generation sequencing to directly measure global patterns of APA changes during colorectal carcinoma progression in 15 human patient samples. Results were validated in a larger cohort of 50 patients, including 5 normal/carcinoma pairs from individuals. Results: We discovered numerous genes presenting progressive changes in APA. Genes undergoing untranslated region (3′UTR) shortening were enriched for functional groups such as cell-cycle and nucleic acid–binding and processing factors, and those undergoing 3′UTR lengthening or alternative 3′UTR usage were enriched for categories such as cell–cell adhesion and extracellular matrix. We found indications that APA changes result from differential processing of transcripts because of increased expression of cleavage and polyadenylation factors. Quantitative PCR analysis in a larger series of human patient samples, including matched pairs, confirmed APA changes in DMKN, PDXK, and PPIE genes. Conclusions: Our results suggest that genes undergoing altered APA during human cancer progression may be useful novel biomarkers and potentially targeted for disease prevention and treatment. We propose that the strategy presented here may be broadly useful in discovery of novel biomarkers for other types of cancer and human disease. Clin Cancer Res; 18(19); 5256–66. ©2012 AACR.
Reply to A. Soultati et al
Authors: David Robert Spigel, Amy Christian Peterson
Journal: Journal of Clinical Oncology (2014)

We have read with interest the comment from Soultati et al in reference to the randomized phase II study of onartuzumab in combination with erlotinib in patients with advanced non–small-cell lung cancer (NSCLC). Soultati et al recognize that MET inhibition may not be best assessed using traditional response criteria and suggest reviewing our data to better define the pattern of disease progression. If progression was primarily due to new sites of distant disease and not growth of baseline lesions, this might potentially account for the low objective response rate observed in our study. A review of the imaging data from computed tomography scanning does not identify any differences in the proportion or patterns of disease progression between treatment arms. Since the phase II publication, the results of a recently completed phase III trial of onartuzumab and erlotinib in patients with advanced MET-positive NSCLC have been presented. Unfortunately there was no advantage for onartuzumab in terms of survival, progression-free survival, or response. Although this trial did not replicate the phase II results, targeting MET may still prove to be a useful strategy in more defined patient populations in which this is a key oncogenic driver of disease.
On the Climate of Algeria
Authors: J. H. Bennet
Journal: BMJ (1870)

about the streets in the deep sleep of fatigue ; everything and everybody looked utterly wretched and miserable.At every corner were the bloody skeletons and entrails of horses, off which every scrap of flesh had been cut; but bread was not to be had for love or money.In the hospital enceintte the same thing was going on.Four thousand men had collected there, and the debris they left behind required the hard work of relays of men, during several days, to remove.All the 2nd September, like the Ist, we were engaged in performing amputations, excisions, and in removing balls and pieces of shell deeply lodged, only interrupted, from time to time, by calls to see some fresh arrival.In the evening, after a hard day's work, we got a summons to say that in the town were large numbers of wounded untended.A party of us went down.In every second house, almost, there were wounded men; the theatre was full of them; the church was full of them; other public buildinigs were full of them.Some of these we had transported to our own hospital; to others we administered what comfort we could.Subsequently, aid arrived from other ambulances, and from the military medical officers; but for the first few days the encombrernent des mnalades, as the French call it, was almost enough to make one give up in despair.That evening, to my great relief, I heard from Dr. Frank, and that he was safe.When I saw the village in which he was in flames, and knew it had been the scene of a desperate fight, I feared we might never again see him alive.Indeed, at one time, and with too much reason, he had given himself up for lost.All by himself, he tied the carotid artery for a wound of the face, and performed other operations, but he had not sufficient help.There were two cases, he afterwards said, where amputation should have been performed at the hip-joint, but had to be left undone.