tbuckley/cabot-search huggingface dataset:
Ceramide Kinase Promotes Tumor Cell Survival and Mammary Tumor Recurrence
Authors: Ania W. Payne, Dhruv K. Pant, Tien-Chi Pan, Lewis A. Chodosh
Journal: Cancer Research (2014)

Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTC) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that ceramide kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously upregulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly upregulated in tumor cells following HER2/neu downregulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu downregulation. Consistent with our observations in mouse models, analysis of gene expression profiles from more than 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. In addition, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are estrogen receptor-negative, HER2(+), basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathologic variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this prosurvival pathway.
Regulatory idiotypes. T helper cells recognize a shared VH idiotope on phosphorylcholine-specific antibodies.
Authors: K Gleason, H Köhler
Journal: The Journal of Experimental Medicine (1982)

Priming of BALB/c mice with phosphorylcholine-hemocyanin (PC-Hy) induces T helper cells that are detected in splenic fragment cultures responding to immunization with trinitrophenylated PC-binding myeloma proteins, TEPC 15 (TNP-T15) and MOPC 167 (TNP-M167). Trinitrophenylation did not alter the binding site, idiotype, or isotype of the antibodies as demonstrated by binding studies. To assay idiotype-recognizing helper cells, Ly-2.2-depleted T cells from PC-Hy-primed donor mice were transferred to syngeneic athymic mice. Splenic anti-trinitrophenol fragment cultures were prepared from the nude recipients, and the response to TNP-T15 and TNP-M167 was measured by enzyme-linked immunosorbent assay. The number of responding fragments is dependent on the number of transferred primed T cells. The homing efficiency of 51Cr-labeled helper cells into the spleen of nude recipients was determined. The frequencies of T helper cells taken from PC-Hy-primed donors required for a B cell response to TNP-T15 or TNP-M167 were indistinguishable. The fine specificity of the anti-PC idiotype-recognizing T helper cells was studied by adding hapten (PC) or unconjugated myeloma proteins to fragment cultures as inhibitors at the time of immunization. PC and PC-bovine serum albumin, as well as T15 and M167, inhibited the helper function in vitro. Furthermore, free heavy chains of T15 and M167 partially inhibited T help, but free light chains of both idiotypes had no effect. These findings collectively show that T helper cells, induced by priming with antigen, recognize a shared idiotypic determination on T15 and M167 that is part of the PC binding site. The heavy chains of T15 and M167 appears to be the major structural component of this determinant. Evidently, T helper cells can recognize a shared determinant that is present on idiotypically different myeloma proteins. This determinant appears to be conserved throughout evolutionary and somatic mutations. The role of this shared, binding site-related idiotypic determinant as a regulatory idiotype in T-B cell interaction is discussed.
Addition of Either Lonidamine or Granulocyte Colony-Stimulating Factor Does Not Improve Survival in Early Breast Cancer Patients Treated With High-Dose Epirubicin and Cyclophosphamide
Authors: Paola Papaldo, Massimo Lopez, Enrico Cortesi, Eugenio Cammilluzzi, Mauro Antimi, Edmondo Terzoli, Giuseppe Lepidini, Patrizia Vici, Carlo Barone, Gianluigi Ferretti, Serena Di Cosimo, Cecilia Nisticò, Paolo Carlini, Francesca Conti, Luigi Di Lauro, Claudio Botti, Carlo Vitucci, Alessandra Fabi, Diana Giannarelli, Paolo Marolla
Journal: Journal of Clinical Oncology (2003)

Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity.From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients).Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non-G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non-G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively).EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.
Interleukin-10 Therapy—Review of a New Approach
Authors: K. Asadullah, W. Sterry, H. D. Volk
Journal: Pharmacological Reviews (2003)

Interleukin (IL)-10 is an important immunoregulatory cytokine produced by many cell populations. Its main biological function seems to be the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. However, very recent data suggest IL-10 also mediates immunostimulatory properties that help to eliminate infectious and noninfectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, in vitro and animal experiments suggest a major impact of IL-10 in inflammatory, malignant, and autoimmune diseases. So IL-10 overexpression was found in certain tumors as melanoma and several lymphomas and is considered to promote further tumor development. Systemic IL-10 release is a powerful tool of the central nervous system to prevent hyperinflammatory processes by activation of the neuro-endocrine axis following acute stress reactions. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been produced and is currently being tested in clinical trials. This includes rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and chronic hepatitis C. The results are heterogeneous. They give new insight into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.
Impaired Carotid Viscoelastic Properties in Women With Polycystic Ovaries
Authors: Kalpana Lakhani, Alexander M. Seifalian, Paul Hardiman
Journal: Circulation (2002)

Background — The purpose of this study was to assess the elastic properties of the carotid arteries in women with polycystic ovarian syndrome, asymptomatic women with polycystic ovaries, and healthy controls. Methods and Results — We recruited the following 60 subjects: 20 symptomatic women with polycystic ovaries attending the reproductive endocrinology clinics, 20 asymptomatic women with polycystic ovaries attending the family planning clinic, and 20 staff volunteers as healthy controls with normal ovaries on transvaginal scan. Compliance and stiffness index were assessed in the common and internal carotid arteries using duplex ultrasound equipped with an echo-locked arterial wall–tracking system. Compliance was significantly lower in the common carotid artery in symptomatic and asymptomatic women with polycystic ovaries than in the controls (10.7, 14.1, and 19.2 %mm Hg −1 ×10 −2 , respectively). The arterial stiffness index was correspondingly increased (12.3, 10.2, and 6.7, respectively). Similar results were obtained in the internal carotid artery for compliance (10.1, 11.0, and 16.9 %mm Hg −1 ×10 −2 , respectively) and stiffness index (14.8, 16.2, and 8.7, respectively). Conclusions — The results of this study provide additional evidence of vascular dysfunction in women with polycystic ovaries and are compatible with the hypothesis that they are at increased risk from coronary artery disease and stroke.
Randomised trial of α-tocopherol and β-carotene supplements on incidence of major coronary events in men with previous myocardial infarction
Authors: Janne M Rapola, Jarmo Virtamo, Samuli Ripatti, Jussi K Huttunen, Demetrius Albanes, Philip R Taylor, Olli P Heinonen
Journal: The Lancet (1997)
PET Evidence That Loxapine Is an Equipotent Blocker of 5-HT<sub>2</sub>and D<sub>2</sub>Receptors: Implications for the Therapeutics of Schizophrenia
Authors: Shitij Kapur, Robert Zipursky, Gary Remington, Corey Jones, Gordon McKay, Sylvain Houle
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses. METHOD: Ten patients who were taking loxapine (10–100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively. RESULTS: The D2 receptor occupancy ranged from 43% to 90% 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors. CONCLUSIONS: Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antispychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires >80% 5-HT2 occupancy in conjunction with <80% D2 occupancy. (Am J Psychiatry 1997; 154:1525–1529)
miR-199a-5p Silencing Regulates the Unfolded Protein Response in Chronic Obstructive Pulmonary Disease and α<sub>1</sub>-Antitrypsin Deficiency
Authors: Tidi Hassan, Tomás P. Carroll, Patrick G. Buckley, Robert Cummins, Shane J. O’Neill, Noel G. McElvaney, Catherine M. Greene
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Retention of abnormal α1-antitrypsin (AAT) activates the unfolded protein response in AAT-deficient monocytes. The regulatory role of microRNAs (miRNAs) in unfolded protein responses and chronic obstructive pulmonary disease pathogenesis has not been investigated.To investigate miRNA expression and function in MM and ZZ monocytes and identify miRNA(s) regulating the unfolded protein response.Peripheral blood monocytes were isolated from asymptomatic and symptomatic MM and ZZ individuals for miRNA expression profiling and pyrosequencing analysis. miRNA/gene and protein expression was measured with quantitative polymerase chain reaction and Western blotting. Overexpression and inhibition studies were performed with pre-miR or anti-miR, respectively. Luciferase reporter genes were used to elucidate direct miRNA-target interactions. Inflammatory cytokines were detected using the Meso Scale Discovery Plex assays.Forty-three miRNAs were differentially expressed, with miR-199a-5p most highly up-regulated in asymptomatic ZZ versus MM monocytes. miR-199a-2 promoter hypermethylation inhibits miR-199a-5p expression and was increased in symptomatic MM and ZZ monocytes compared with asymptomatic counterparts. GRP78, activating transcription factor 6, p50, and p65 were increased in symptomatic versus asymptomatic ZZ monocytes. Reciprocal down- or up-regulation of these markers was observed after miRNA modulation. Direct miR-199a-5p targeting of activating transcription factor 6, p50, and p65 by miR-199a-5p was demonstrated using luciferase reporter systems. Overexpression of miR-199a-5p also decreased other arms of the UPR and expression of cytokines that are not putative targets.miR-199a-5p is a key regulator of the unfolded protein response in AAT-deficient monocytes, and epigenetic silencing of its expression regulates this process in chronic obstructive pulmonary disease.
Reflex Blood Pressure Control during Acute Myocardial Ischemia in the Conscious Dog
Authors: D. FRED PETERSON, VERNON S. BISHOP
Journal: Circulation Research (1974)

Occlusions of the left circumflex coronary artery were performed before and after surgical denervation of sinoaortic baroreceptors in conscious, resting dogs. The removal of baroreceptors dramatically compromised arterial blood pressure maintenance. Mean pressure fell 9.1 mm Hg before denervation and 33.0 mm Hg after denervation. Aortic flow was reduced somewhat more without baroreceptors, and calculated total peripheral resistance fell 15% at the peak of occlusion in denervated dogs compared with a 2% increase in intact dogs. Flow studies indicated that femoral resistance was maintained or increased under the influence of active arterial baroreceptors but that femoral resistance fell dramatically in their absence. Renal resistance fell during coronary occlusion whether or not arterial baroreceptors were functional. Under both conditions, renal flow was maintained near its resting level. Results of this study suggest an important function in the maintenance of perfusion pressure by arterial baroreceptors during left circumflex coronary artery occlusion. The elimination of the arterial baroreceptors unmasked a dilatory response that reduced total peripheral resistance and, consequently, arterial blood pressure. Vessels which supply skeletal muscle and skin collectively were critically involved, but flow to the kidneys did not appear to play an important role.
HLA associations in sarcoidosis: a study of two ethnic groups.
Authors: J Gardner, H G Kennedy, A Hamblin, E Jones
Journal: Thorax (1984)

We report results of HLA-A, B, C, and DR typing in groups of white Caucasians of English descent and black West Indians of African descent with sarcoidosis. In the English patients we found a significantly increased frequency of Cw7, which was not found in the West Indian patients. Our results also suggest that DR3 and, in particular, inheritance of the B8/Cw7/DR3 haplotype is associated with good prognosis in English patients with sarcoidosis. There was no association between any HLA antigen and prognosis in the West Indian patients in this study.
Understanding help seeking behaviour among male offenders: qualitative interview study
Authors: Amanda Howerton, Richard Byng, John Campbell, David Hess, Christabel Owens, Peter Aitken
Journal: BMJ (2007)

<b>Objective </b> To explore the factors that influence help seeking for mental distress by offenders. <b>Design </b> Qualitative study based on in-depth interviews with prisoners before and after release. <b>Setting </b> One category B local prison in southern England. <b>Participants </b> 35 male offenders aged 18-52, a quarter of whom had been flagged as being at risk of self harm. <b>Results </b> Most respondents reported that they would not seek help from a general practitioner or other healthcare professional if experiencing mental distress. When followed up after release, none had sought medical help despite the fact that many had considerable emotional problems. Many participants were hesitant to seek help because they feared being given a formal diagnosis of mental illness. Some of these men feared the stigma that such a diagnosis would bring, whereas others feared that a diagnosis would mean having to confront the problem. Lack of trust emerged as the most prominent theme in prisoners9 discourse about not seeking help from health professionals. Distrust towards the “system” and authority figures in general was linked to adverse childhood experiences. Distrust directed specifically at healthcare professionals was often expressed as specific negative beliefs: many perceived that health professionals (most often doctors) “just don9t care,” “just want to medicate,” and treat patients “superficially.” Those men who would consider going to a general practitioner reported positive previous experiences of being respected and listened to. <b>Conclusions </b> Distrust is a major barrier to accessing health care among offenders. Like most people, the respondents in this study wanted to feel listened to, acknowledged, and treated as individuals by health professionals. By ensuring that a positive precedent is set, particularly for sceptical groups such as ex-prisoners, general practitioners and prison doctors may be able to encourage future help seeking. Information specifically designed for prisoners is needed to help to de-stigmatise mental illness, and preparation for release should include provision of information about access to health and social services. Awareness training for health professionals is recommended: trust might be fostered in this population by seemingly trivial gestures that indicate respect.
Effect of electronic health records in ambulatory care: retrospective, serial, cross sectional study
Authors: Terhilda Garrido, Laura Jamieson, Yvonne Zhou, Andrew Wiesenthal, Louise Liang
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To evaluate the effect of implementing comprehensive, integrated electronic health record systems on use and quality of ambulatory care <b>Design</b> Retrospective, serial, cross sectional study. <b>Setting</b> Colorado and Northwest regions of Kaiser Permanente, a US integrated healthcare delivery system. <b>Population</b> 367 795 members in the Colorado region and 449 728 members in the Northwest region. <b>Intervention</b> Implementation of electronic health record systems. <b>Main outcome measures</b> Total number of office visits and use of primary care, specialty care, clinical laboratory, radiology services, and telephone contact. Health Plan Employer Data and Information Set to assess quality. <b>Results</b> Two years after electronic health records were fully implemented, age adjusted rates of office visits fell by 9% in both regions. Age adjusted primary care visits decreased by 11% in both regions and specialty care visits decreased by 5% in Colorado and 6% in the Northwest. All these decreases were significant (P &lt; 0.0001). The percentage of members making ≥ 3 visits a year decreased by 10% in Colorado and 11% in the Northwest, and the percentage of members with ≤ 2 visits a year increased. In the Northwest, scheduled telephone contact increased from a baseline of 1.26 per member per year to 2.09 after two years. Use of clinical laboratory and radiology services did not change conclusively. Intermediate measures of quality of health care remained unchanged or improved slightly. <b>Conclusions</b> Readily available, comprehensive, integrated clinical information reduced use of ambulatory care while maintaining quality and allowed doctors to replace some office visits with telephone contacts. Shifting patterns of use suggest reduced numbers of ambulatory care visits that are inappropriate or marginally productive.
Release of compartment-specific enzymes from neonatal rat heart cell cultures during anoxia and reoxygenation
Authors: J C ALTONA, A VAN DER LAARSE, C H F B. VAN TRESLONG
Journal: Cardiovascular Research (1984)

The effects of anoxia and substrate deprivation on the extent of the release of several intracellular marker enzymes and DNA were studied using monolayer cultures of neonatal rat heart cells. After varying periods of anoxia, in a number of experiments followed by 1 h of reoxygenation and substrate repletion, the cells were analysed for cytoplasmic, lysosomal, and mitochondrial enzymes, and for nuclear DNA. Cellular enzyme activity and DNA content at any time during incubation were compared with the remaining activity of α-hydroxybutyrate dehydrogenase (HBDH), a cytoplasmic enzyme. The study demonstrates that the ultimate extent of enzyme depletion induced by anoxia with or without reoxygenation, is high (>80%) for cytoplasmic enzymes, is intermediate for sarcolemmal and lysosomal enzymes, and enzyme associated with the mitochondrial outer membrane (about 50%) and small (<10%) for enzymes associated with the mitochondrial inner membrane, and for nuclear DNA.
Automatic Control of Pressure Support for Ventilator Weaning in Surgical Intensive Care Patients
Authors: Dirk Schädler, Christoph Engel, Gunnar Elke, Sven Pulletz, Nils Haake, Inéz Frerichs, Günther Zick, Jens Scholz, Norbert Weiler
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Despite its ability to reduce overall ventilation time, protocol-guided weaning from mechanical ventilation is not routinely used in daily clinical practice. Clinical implementation of weaning protocols could be facilitated by integration of knowledge-based, closed-loop controlled protocols into respirators.To determine whether automated weaning decreases overall ventilation time compared with weaning based on a standardized written protocol in an unselected surgical patient population.In this prospective controlled trial patients ventilated for longer than 9 hours were randomly allocated to receive either weaning with automatic control of pressure support ventilation (automated-weaning group) or weaning based on a standardized written protocol (control group) using the same ventilation mode. The primary end point of the study was overall ventilation time.Overall ventilation time (median [25th and 75th percentile]) did not significantly differ between the automated-weaning (31 [19-101] h; n = 150) and control groups (39 [20-118] h; n = 150; P = 0.178). Patients who underwent cardiac surgery (n = 132) exhibited significantly shorter overall ventilation times in the automated-weaning (24 [18-57] h) than in the control group (35 [20-93] h; P = 0.035). The automated-weaning group exhibited shorter ventilation times until the first spontaneous breathing trial (1 [0-15] vs. 9 [1-51] h; P = 0.001) and a trend toward fewer tracheostomies (17 vs. 28; P = 0.075).Overall ventilation times did not significantly differ between weaning using automatic control of pressure support ventilation and weaning based on a standardized written protocol. Patients after cardiac surgery may benefit from automated weaning. Implementation of additional control variables besides the level of pressure support may further improve automated-weaning systems. Clinical trial registered with www.clinicaltrials.gov (NCT 00445289).