tbuckley/cabot-search huggingface dataset:
Brain Structural Alterations Induced by Fetal Exposure to Cocaine Persist Into Adolescence and Affect Behavior
Authors: Joseph T. Coyle
Journal: JAMA Psychiatry (2013)

Thirty years ago, an epidemic of crack cocaine abuse swept the country and had particularly devastating effects on poor individuals andminorities.Thisheavily addictive formof smokedcocaineensnaredmanyyoungwomenwhobecamepregnant.At the time, several clinical reports from small cohorts of cocaine-exposed infants suggestedsevereadverseneurobehavioraloutcomes, leading to the designation“crackbabies.”Nevertheless, thoughtful clinicians raised concerns about facile inferences that cocaine alone caused this phenotype.1,2 They noted a number of other well-established risk factors for these adverse outcomes that could be difficult to disentangle from exposure to cocaine including concurrent use of tobaccoandalcohol, knownbehavioral teratogens,poorperinatal care, and other adverse consequences of poverty such as poor diet. Cocainecauses its rewardingeffectsby inhibitionofthedopaminetransporter, which activates reward circuits in the forebrain.3 However, it is alsoan inhibitorof thenorepinephrine transporter aswell as the serotonintransporter, therebypotentiatingtheeffectsof theseother 2neurotransmitters. These “biogenic amine”neurotransmitter systems, the cell bodies of which are located in the midbrainbrainstem and compose the reticular core, are among the earliest neural systemstodevelop in thebrain.4Preclinical researchhasdemonstrated that during fetal brain development they play important roles inmodulatingneurogenesis, neuronalmigration, neuronal differentiation,andsynaptogenesis.5Thus, it isnotsurprising thatstudies in fetal rodents have demonstrated that cocaine causes a persistentdisruption indopaminesignaling,corticalGABAergic function, and pyramidal neuron dendritic structure in the prefrontal cortex, a dopamine-rich region.6 Other studies have shown that inhibition of serotonin transport in the fetal braindisrupts the formationof the so-called barrel fields in the rodent primary sensory cortex, a cortiJAMAPEDIATRICS
Isolation and culture of biliary epithelial cells.
Authors: R Joplin
Journal: Gut (1994)

At one time it was thought that biliary epithelial cells simply formed the lining to the tubular conduits which constitute the biliary tract. Development of in vitro systems for culturing biliary epithelial cells has enabled functional studies which increasingly show that this is far from true, and that biliary epithelial cells do have important functional roles. Disruption of these functions may be involved in the generation of pathology. Most functional studies to date have utilised cells isolated from rat liver. Increasingly, variations are being found between human and animal cells both in terms of function and phenotype. The relevance of animal cells in the study of human disease therefore remains obscure. Human biliary tract disease has to date been studied almost exclusively by examination of histological sections. The development of improved methods for isolating highly pure biliary epithelial cells from human liver provides a new technology with which to investigate directly the dynamics of human biliary epithelial cell biology and pathobiology. It is predicted that further progress will now be made in dissecting the biology and physiology of human biliary epithelium.
Somatic <i>ERCC2</i> Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma
Authors: Eliezer M. Van Allen, Kent W. Mouw, Philip Kim, Gopa Iyer, Nikhil Wagle, Hikmat Al-Ahmadie, Cong Zhu, Irina Ostrovnaya, Gregory V. Kryukov, Kevin W. O'Connor, John Sfakianos, Ilana Garcia-Grossman, Jaegil Kim, Elizabeth A. Guancial, Richard Bambury, Samira Bahl, Namrata Gupta, Deborah Farlow, Angela Qu, Sabina Signoretti, Justine A. Barletta, Victor Reuter, Jesse Boehm, Michael Lawrence, Gad Getz, Philip Kantoff, Bernard H. Bochner, Toni K. Choueiri, Dean F. Bajorin, David B. Solit, Stacey Gabriel, Alan D'Andrea, Levi A. Garraway, Jonathan E. Rosenberg
Journal: Cancer Discovery (2014)

Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis "responders," 25 pT2+ "nonresponders") to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders (q < 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma.Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro. Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy.
Importance of ablating all potential right atrial flutter circuits in postcardiac surgery patients
Authors: Atul Verma, Nassir F. Marrouche, Niranjan Seshadri, Robert A. Schweikert, Mandeep Bhargava, J.David Burkhardt, Fethi Kilicaslan, Jennifer Cummings, Walid Saliba, Andrea Natale
Journal: Journal of the American College of Cardiology (2004)
111Indium autologous leucocytes in inflammatory bowel disease.
Authors: S H Saverymuttu, A M Peters, J P Lavender, H J Hodgson, V S Chadwick
Journal: Gut (1983)

A non-invasive method of imaging and assessing inflammatory bowel disease is described. 111Indium labelled leucocyte scans were performed on 33 patients with a wide variety of inflammatory bowel diseases and 25 control patients. All patients with moderate or severe inflammatory bowel disease had positive scans with localisation of abnormal activity corresponding to the sites assessed to be diseased by radiology in either small or large bowel. No false positives were recorded in the control patients. Faecal excretion of 111In labelled leucocytes was increased in patients with inflammatory bowel disease according to disease severity and correlated with disease activity assessed by serum C-reactive protein levels (r = 0.74, p less than 0.001) or in those patients with Crohn9s disease by Crohn9s Disease Activity Index (r = 0.78, p less than 0.001). These data suggest that 111In labelled leucocytes may be used to provide a safe, non-invasive method of imaging diseased bowel and objectively assessing disease activity.
Relative mortality from overdose of antidepressants
Authors: J. A Henry, C. A Alexander, E. K Sener
Journal: BMJ (1995)

<h3>Abstract</h3> <b>Objective</b>: To compare the fatal toxicities of antidepressant drugs in 1987–92. <b>Design</b>: Retrospective epidemiological review of prescription data of the Department of Health, Scottish Office Home and Health Department, and Welsh Health Common Services Authority (excluding data from most private general practices and most hospitals), and mortality data from the Office of Population Censuses and Surveys and General Register Office in Scotland. <b>Setting</b>: General practice, England, Scotland, and Wales. <b>Main outcome measures</b>: Deaths per million prescriptions and deaths per defined daily dose. <b>Results</b>: 81.6% (1310/1606) of deaths from antidepressant overdose were due to two drugs, amitriptyline and dothiepin. The overall average of deaths per million prescriptions was 30.1. The overall rate for tricyclic drugs was 34.14 (95% confidence interval 32.47 to 38.86; P&lt;0.001), monoamine oxidase inhibitors 13.48 (6.93 to 22.19; P&lt;0.001), atypical drugs 6.19 (4.04 to 8.80; P&lt;0.001), and selective serotonin reuptake inhibitors 2.02 (0.64 to 4.17; P&lt;0.001). The numbers of deaths per million prescriptions of amoxapine, dothiepin, and amitriptyline were significantly higher than expected, while nine drugs had a significantly lower number of deaths per million prescriptions than expected. Analysis of deaths per defined daily dose showed a similar pattern. <b>Conclusions</b>: Safety in overdose should be considered in risk-benefit and cost-benefit considerations of antidepressants. A switch in prescribing, from drugs with a high number of deaths per million prescriptions to drugs with a low number, could reduce the numbers of deaths from overdose. Although this form of suicide prevention can be implemented easily and immediately, its introduction needs to be considered against the higher costs of some of the newer drugs. <h3>Key messages</h3> Key messages Antidepressant drugs such as the selective serotonin reuptake inhibitors and lofepramine have low toxicity in overdose Deaths from overdose can be prevented by switching prescribing from older, tricyclic drugs; such a move may contribute to government targets for reducing suicide Choice of a first line antidepressant should be based on several factors, including adverse effect profile, compliance, overdose safety, and cost, and the antidepressant should be appropriate to the patient and his or her clinical condition Patients with evidence of suicidal ideation should be given special consideration—admission to hospital may be indicated
CD1d-Restricted Natural Killer T Cells Can Down-regulate Tumor Immunosurveillance Independent of Interleukin-4 Receptor-Signal Transducer and Activator of Transcription 6 or Transforming Growth Factor-β
Authors: Masaki Terabe, Chand Khanna, Seuli Bose, Fraia Melchionda, Arnulfo Mendoza, Crystal L. Mackall, Lee J. Helman, Jay A. Berzofsky
Journal: Cancer Research (2006)

Abstract It has been shown previously that the suppression of tumor immunosurveillance may be a mechanism by which tumors resist immune detection and elimination. In this study, we evaluated the role of the immunoregulatory natural killer T (NKT) cells in the biology of immunosurveillance of osteosarcoma. The K7M2 mouse osteosarcoma cell line was implanted orthotopically into wild-type and NKT cell–deficient CD1d knockout (KO) BALB/c mice, and mice were monitored for growth of primary tumors. Further, we examined the role of CD4+ and/or CD8+ cells by depleting the cells in vivo and measuring CTL activity in vitro. We also asked the role of interleukin (IL)-4 receptor α (IL-4Rα)-signal transducer and activator of transcription 6 (STAT6) signaling, including IL-13, and transforming growth factor β (TGF-β) by using gene-disrupted mice or treating mice with cytokine antagonists. We were surprised to find a high rate of rejection of osteosarcoma primary tumors in 88% (14 of 16) of CD1d KO mice compared with syngeneic wild-type BALB/c mice that showed rejection of tumor in &amp;lt;24% of mice. Further studies suggested that the rejection of tumor in CD1d KO mice was dependent on CD8+ lymphocytes. Distinct from other murine tumor models, the negative regulation induced by CD1d-restricted NKT cells was not dependent on IL-4Rα-STAT6 signaling, including IL-13, or on TGF-β. These data suggest that a novel CD1d-restricted NKT cell–mediated mechanism for tumor immunosuppression is active in the K7M2 osteosarcoma model and that NKT cells can regulate immunosurveillance through more than one pathway. (Cancer Res 2006; 66(7): 3869-75)
Cancer and the Microenvironment
Authors: Shmuel Yaccoby, Michele J. Wezeman, Aminah Henderson, Michele Cottler-Fox, Qing Yi, Bart Barlogie, Joshua Epstein
Journal: Cancer Research (2004)

Abstract We have investigated the interaction between tumor cells and specific cells in their microenvironment using myeloma as a model. The role of myeloma-induced osteoclastogenesis in the disease was studied ex vivo. Myeloma plasma cells freshly purified from patients’ bone marrow attracted committed osteoclast (OC) precursors (n = 9; P &amp;lt; 0.01) and in 22 experiments directly induced their differentiation to multinucleated, bone-resorbing OCs (P &amp;lt; 0.00002) in a receptor activator of nuclear factor-κB ligand-mediated mechanism that was inhibited by the receptor activator of nuclear factor-κB (RANK-Fc) in 13 experiments by 71 ± 12% (P &amp;lt; 0.008). In contrast, myeloma cells did not induce differentiation of peripheral blood mononuclear cells. Myeloma plasma cells cocultured with OCs retained their viability and proliferative activity for &amp;gt;13 weeks. After 14 days in coculture, the plasma cells from 29 patients had higher viability (P &amp;lt; 2 × 10−6), fewer apoptotic cells (P &amp;lt; 4 × 10−15), and a higher bromodeoxyuridine labeling index (P &amp;lt; 0.0006) than controls. Physical contact between OCs and myeloma cells was required for these effects to take place. No differences were observed between OCs from healthy donors and those from myeloma patients. Blocking interleukin 6 activity, while reducing survival of myeloma cells, had no effect on their proliferative activity. These results support data obtained from animal models and clinical observations on the essential role of the microenvironment in tumor sustenance and progression.
Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone
Authors: R Rao, RK Gregson, AC Jones, EA Miles, MJ Campbell, JO Warner
Journal: European Respiratory Journal (1999)

Inhaled steroids are frequently used in childhood asthma, but concerns based on limited objective evidence remain, regarding long-term side-effects. In this study the systemic effects of standard doses of inhaled steroids in childhood asthma were assessed, comparing beclomethasone dipropionate (BDP) with fluticasone propionate (FP). The study was prospective, randomized and double-blind. Twenty-three steroid-naive children with moderately severe asthma, aged 5-10 yrs, were allocated either BDP (400 microg x day(-1) or FP (200 microg x day(-1)) using a metered-dose inhaler with a spacer. Asthma control was assessed at regular intervals over 20 months. Fasting morning blood and overnight urine samples were collected for estimation of serum cortisol, serum 1-carboxyterminal telopeptide (ICTP), serum osteocalcin and urine deoxypyridinoline (DPD). Bone mineral density (BMD) was measured at each visit. None of the markers of bone turnover showed any change during the study period. BMD increased at normal rates with age. Serum cortisol significantly decreased on BDP, but not on FP. A significant difference in growth rates was found between the groups, with a slower rate of growth towards the end of the observation period in the BDP group. In conclusion when taken in a relatively modest dose over a period of time, beclomethasone dipropionate had significant effects on the hypothalamic-pituitary-adrenal axis and statural growth in childhood asthma. These systemic effects were not seen with an equipotent dose of fluticasone propionate.
Interactions between MUC1 and p120 Catenin Regulate Dynamic Features of Cell Adhesion, Motility, and Metastasis
Authors: Xiang Liu, Chunhui Yi, Yunfei Wen, Prakash Radhakrishnan, Jarrod R. Tremayne, Thongtan Dao, Keith R. Johnson, Michael A. Hollingsworth
Journal: Cancer Research (2013)

Abstract The mechanisms by which MUC1 and p120 catenin contribute to progression of cancers from early transformation to metastasis are poorly understood. Here we show that p120 catenin ARM domains 1, 3–5, and 8 mediate interactions between p120 catenin and MUC1, and that these interactions modulate dynamic properties of cell adhesion, motility, and metastasis of pancreatic cancer cells. We also show that different isoforms of p120 catenin, when coexpressed with MUC1, create cells that exhibit distinct patterns of motility in culture (motility independent of cell adhesion, motility within a monolayer while exchanging contacts with other cells, and unified motility while maintaining static epithelial contacts) and patterns of metastasis. The results provide new insight into the dynamic interplay between cell adhesion and motility and the relationship of these to the metastatic process. Cancer Res; 74(5); 1609–20. ©2013 AACR.
Cranial Computed Tomography Interpretation in Acute Stroke
Authors: David L. Schriger, Mary Kalafut, Sidney Starkman, Michelle Krueger, Jeffrey L. Saver
Journal: JAMA (1998)

Context.—Intracranial hemorrhage must be excluded prior to administration of thrombolytic agents in acute stroke.Objective.—To evaluate physician accuracy in cranial computed tomography scan interpretation for determining eligibility for thrombolytic therapy in acute stroke.Design.—Administration of randomly selected, randomly ordered series of 15 computed tomography scans from a pool of 54 scans that demonstrated intracerebral hemorrhage, acute infarction, intracerebral calcifications (impostor for hemorrhage), old cerebral infarction (impostor for acute infarction), and normal findings.Participants.—A convenience sample of 38 emergency physicians, 29 neurologists, and 36 general radiologists.Main Outcome Measures.—Physician determination of eligibility for thrombolytic therapy based on computed tomography scan interpretation.Results.—Average correct score by all physicians on all computed tomography scans was 77% (95% confidence interval, 74%-80%). Of 569 computed tomography readings by emergency physicians, 67% were correct; of 435 readings by neurologists, 83% were correct; and of 540 readings by radiologists, 83% were correct. Overall sensitivity for detecting hemorrhage was 82% (95% confidence interval, 78%-85%); 17% of emergency physicians, 40% of neurologists, and 52% of radiologists achieved 100% sensitivity for identification of hemorrhage.Conclusion.—Physicians in this study did not uniformly achieve a level of sensitivity for identification of intracerebral hemorrhage sufficient to permit safe selection of candidates for thrombolytic therapy.
Increased Expression of the E3-Ubiquitin Ligase Receptor Subunit βTRCP1 Relates to Constitutive Nuclear Factor-κB Activation and Chemoresistance in Pancreatic Carcinoma Cells
Authors: Susanne Müerköster, Alexander Arlt, Bence Sipos, Maike Witt, Maike Großmann, Günter Klöppel, Holger Kalthoff, Ulrich R. Fölsch, Heiner Schäfer
Journal: Cancer Research (2005)

Abstract The permanent activation of the transcription factor nuclear factor-κB (NF-κB) in pancreatic cancer cells is associated with a profound resistance towards chemotherapy. In the present study, we show that chemoresistant pancreatic cancer cell lines exhibiting constitutive NF-κB activity (i.e., PancTu-1, BxPc3, and Capan-1) express significantly elevated levels of the E3-ubiquitin ligase receptor subunit βTRCP1, compared with pancreatic carcinoma cell lines lacking constitutive NF-κB activity and chemoresistance (i.e., PT45-P1 and T3M4). If transfected with βTRCP1, PT45-P1 cells exhibit an elevated NF-κB activity and become less sensitive towards anticancer drug treatment (i.e., etoposide). Conversely, blockade of βTRCP1 expression in PancTu-1 cells by transfection with a vector-expressed small interfering RNA reduces NF-κB activation and chemoresistance. In PancTu-1 cells, βTRCP1 expression is inhibited, at least in part, by the interleukin-1 (IL-1) receptor(I) antagonist, whereas stimulation of PT45-P1 cells with IL-1β resulted in an increased expression of βTRCP1, and transfection of this cell line with βTRCP1 induced IL-1β secretion in a NF-κB–dependent fashion. Thus, via its close and mutual link to IL-1β secretion, βTRCP1 expression might substantially contribute to the persistent, IL-1β–dependent activation of NF-κB in pancreatic carcinoma cells. In support of this, βTRCP1 expression is detectable at considerable levels in a great number of pancreatic ductal adenocarcinoma specimens, along with an intense staining for activated NF-κB. Altogether, our findings of the elevated βTRCP1 expression in pancreatic carcinoma cells pinpoint to another important mediator of constitutive NF-κB activation and thereby of chemoresistance.
The relationship between cardiac output and posthyperventilation hyperpnoea in patients with essential hypertension
Authors: S Bellofiore, LS Malatino, MA Sapienza, I Bellanuova, A Cataliotti, GU Di Maria
Journal: European Respiratory Journal (1998)

Posthyperventilation hyperpnoea (PHVH) is the progressive decline in minute ventilation (V'E) that follows abrupt cessation of voluntary hyperventilation. It has been hypothesized that the increase in cardiac output (CO) during hyperventilation could contribute to the duration of PHVH. This hypothesis was tested by measuring the duration of PHVH in patients with essential hypertension, in whom the increase in CO as a result of various stimuli is less pronounced. Twenty male hypertensives (mean arterial blood pressure+/-SEM: 178/ 107+/-3/1 mmHg), and 12 age-matched male healthy subjects were studied. The study consisted of three periods: control (5 min), voluntary hyperventilation (2 min), and recovery (3 min). V'E, CO, end-tidal CO2 and O2 tensions were measured, and the time constant (tau) of the V'E decay during recovery calculated. The V'E decay was faster in hypertensives (tau: 0-8.4 s) than in healthy subjects (tau: 12-59 s; p<0.01). During voluntary hyperventilation, CO increased to a lesser extent in hypertensives (6.8+0.7 L.min(-1)) than in healthy subjects (12.9+/-1.1 L.min(-1); p<0.01). In hypertensives, changes in CO during voluntary hyperventilation were significantly related to tau (r=0.646; n=20; p=0.002). The less pronounced rise in cardiac output during hyperventilation in hypertensives could account for the shorter duration of posthyperventilation hyperpnoea.
Role of beta 1 and beta 2 integrins in the adhesion of human CD34hi stem cells to bone marrow stroma.
Authors: J Teixidó, M E Hemler, J S Greenberger, P Anklesaria
Journal: Journal of Clinical Investigation (1992)

Hematopoietic stem cell interaction with elements of the underlying stroma is essential for sustained normal hematopoiesis. Here we have determined that adhesion receptors in the integrin family play a role in promoting adhesion of human hematopoietic stem cells to cultured human marrow stromal cells. Enriched CD34hi progenitor cells expressed VLA-4, VLA-5, and at least one or more beta 2 integrins. Homogeneous marrow stromal cell monolayers capable of supporting proliferation of cocultivated CD34hi cells expressed VCAM-1 and fibronectin (ligands for VLA-4 and VLA-5) as well as ICAM-1 (ligand for LFA-1 and Mac-1). Adhesion-blocking experiments indicated that VLA-4/VCAM-1, VLA-5/fibronectin, and beta 2-integrin/ICAM-1 pathways all are important for CD34hi cell attachment to stromal cells. Consistent with this suggestion, IL-1 stimulation of stromal cells caused both increased VCAM-1 and ICAM-1 expression and increased attachment by CD34hi bone marrow cells. In addition, CD34hi cells utilized VLA-4 to adhere to purified VCAM-1 and employed VLA-5 (and to a lesser extent VLA-4) to adhere to purified fibronectin. Together these results suggest that CD34hi stem cells may utilize multiple integrin-mediated adhesion pathways to localize within specialized microenvironmental niches created by marrow stromal cells.