tbuckley/cabot-search huggingface dataset:
Laser captured hepatocytes show association of butyrylcholinesterase gene loss and fibrosis progression in hepatitis C-infected drug users
Authors: Supriya Munshaw, Hyon S. Hwang, Michael Torbenson, Jeffrey Quinn, Kasper D. Hansen, Jacquie Astemborski, Shruti H. Mehta, Stuart C. Ray, David L. Thomas, Ashwin Balagopal
Journal: Hepatology (2012)

Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with precirrhosis liver fibrosis (Ishak fibrosis 3-5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in precirrhosis fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase ( BCHE ), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity was already decreased at study inception in 19 fibrosis progressors compared with 20 fibrosis nonprogressors ( P &lt; 0.05). Nonprogressors also had decreased BCHE activity over time compared with initial values, but these evolved a median (range) 8.6 (7.8-11.4) years after the study period inception ( P &lt; 0.05). Laser captured portal tracts were enriched for immune related genes when compared with hepatocytes but precirrhosis livers lost this enrichment. Conclusion : Chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users. (HEPATOLOGY 2012)
MP raises new allegations against Andrew Wakefield
Authors: Annabel Ferriman
Journal: BMJ (2004)

Dr Andrew Wakefield, the researcher who is the leading proponent of a link between autism and the measles, mumps, and rubella vaccine ( Lancet 1998;351: 637), was accused last week of conducting investigations on children without the proper approval of his hospital's ethics committee. The ethics committee of the Royal Free Hospital, London, where Dr Wakefield worked, was also criticised for the procedures it adopted.

Dr Evan Harris, Liberal Democrat MP for Oxford West and Abingdon, who sits on both the BMA's ethics committee and the House of Commons Science and Technology Committee, made the allegations during an adjournment debate in the House of Commons ( House of Commons Official Report (Hansard) 2004 March 15: cols 128-36).

Speaking about the work done at the Royal Free Hospital by the inflammatory bowel disease group between 1995 and 1998, Dr Harris said: “There is very clear evidence pointing towards unethical conduct by the researchers—or by one or some of them—and equally strong evidence of failure and incompetence by the research ethics committee.”

He said that documents …
Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism
Authors: William F. Bosron, Ting-Kai Li
Journal: Hepatology (1986)

It is now widely accepted that the various pharmacologic and addictive consequences of alcohol consumption are related to the tissue concentration of ethanol or its metabolic products. The oxidative metabolism of ethanol in liver is principally catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes exist in multiple molecular forms, and genetic models have been proposed to account for the multiplicity of isoenzymes. Alcohol dehydrogenase subunits are encoded at five different gene loci, and genetic polymorphism occurs at two alcohol dehydrogenase loci. Variant isoenzymes produced at the two polymorphic alcohol dehydrogenase loci account for the differences in enzyme electrophoretic patterns observed among individuals. Some of these variant isoenzymes exhibit widely different kinetic properties, and this may account for the 2- to 3-fold variation in alcohol elimination rate among individuals. Since the protein sequence of several of the alcohol dehydrogenase subunits has been determined and several of the alcohol dehydrogenase genes has been cloned, some of the structural changes which give rise to differences in catalytic and electrophoretic properties are now known. Genetic polymorphism also occurs at the aldehyde dehydrogenase gene locus which encodes the mitochondrial low K m for acetaldehyde aldehyde dehydrogenase isoenzyme. The variant isoenzyme exhibits little or no catalytic activity. Individuals with this “null” variant have higher than normal blood acetaldehyde levels and exhibit an alcohol-flush reaction which appears to be a deterrent to heavy drinking and alcoholism. Since epidemiological surveys have demonstrated genetic predisposition to alcohol abuse and alcoholism, it is reasonable to suppose that the polymorphism of either alcohol dehydrogenase or aldehyde dehydrogenase might be one of the underlying biological factors contributing to the inherited nature of alcoholism.
Comparable long‐term outcomes after reduced‐intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high‐risk acute lymphoblastic leukemia in complete remission
Authors: Ki‐Seong Eom, Seung‐Hwan Shin, Jae‐Ho Yoon, Seung‐Ah Yahng, Sung‐Eun Lee, Byung‐Sik Cho, Yoo‐Jin Kim, Hee‐Je Kim, Chang‐Ki Min, Dong‐Wook Kim, Jong‐Wook Lee, Woo‐Sung Min, Chong‐Won Park, Seok Lee
Journal: American Journal of Hematology (2013)

The role of reduced-intensity conditioning (RIC) in adult acute lymphoblastic leukemia (ALL) remains unclear because of the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of selection criteria for transplantation. We compared long-term outcomes of 60 consecutive RIC transplants (fludarabine plus melphalan) with 120 myeloablative conditioning (MAC) transplants (total body irradiation plus cyclophosphamide) for adult high-risk ALL in first or second complete remission. All transplants received a uniform strategy of pretransplant chemotherapy and GVHD prophylaxis. Compared to MAC transplants, RIC transplants had older age (46 years vs. 33 years, P < 0.001) and higher proportions of transplantation using peripheral blood (93.3% vs. 13.3%; P < 0.001) but otherwise showed similar characteristics. After a median follow-up of 67 months, RIC transplants showed comparable nonrelapse mortality (21.2% vs. 24.3%) and disease-free survival (50.8% vs. 54.9%) to MAC transplants, although relapse risk was higher (34.2% vs. 26.4%; HR, 2.07; P = 0.019) in multivariate analysis. Other independent factors associated with better outcomes were the presence of chronic GVHD and transplantation in first complete remission. Interestingly, the negative impact of RIC on relapse risk was seen only for Philadelphia-positive ALL transplants (32.7% vs. 19.6%; HR, 3.46; P = 0.020), while no difference was found between RIC and MAC for Philadelphia-negative ALL transplants (35.0% vs. 32.1%; HR, 1.39; P = 0.429). RIC can be considered as a reasonable choice for providing a sufficient long-term graft-versus-leukemia effect for adult high-risk ALL patients ineligible for MAC.
An isotype-specific trans-acting factor is defective in a mutant B cell line that expresses HLA-DQ, but not -DR or -DP.
Authors: S J Ono, V Bazil, M Sugawara, J L Strominger
Journal: The Journal of Experimental Medicine (1991)

The B lymphoblastoid cell line clone 13 (a subclone of the mutant cell line P3JHR-1) has been found to express high levels of HLA-DQ; by contrast, HLA-DR and -DP antigens are not expressed and cannot be induced by interferon gamma. Northern blot analysis using gene-specific probes indicated that the lack of surface expression of the DR and DP antigens is due to a marked decrease in the levels of steady-state RNA for both the alpha and beta chains. Southern blots demonstrated that none of the transcriptionally repressed genes are grossly deleted. Preparations of interspecific transient heterokaryons between clone 13 and the class II antigen-positive murine B cell lymphoma, A20, resulted in reactivation of the DRA gene and surface expression of both the DR and DP molecules. The efficiency of the DRA promoter relative to the DQB promoter is markedly and specifically diminished in clone 13 (P3JHR-1) as compared with the parental cell line, Jijoye, as assayed both by transient expression of appropriate chloramphenicol acetyltransferase gene (CAT) constructs and by in vitro transcription analysis. These data clearly demonstrate the existence of an isotype-specific trans-acting factor, and provide direct evidence that the highly homologous class II genes have distinct regulatory mechanisms.
High-Dose Ketoconazole for Treatment of Fungal Infections of the Central Nervous System
Authors: PHILIP C. CRAVEN
Journal: Annals of Internal Medicine (1983)

Mortality and complication rates remain unacceptably high with conventional intravenous and intrathecal therapy for patients with coccidioidal meningitis and intracerebral fungal lesions. We studied the ventricular and lumbar cerebrospinal fluid penetration of ketoconazole and the responses to therapy in two patients receiving ketoconazole orally, 800 mg daily, and amphotericin B intraventricularly for meningeal and extrameningeal coccidioidomycosis. Five patients received only 1200 mg of ketoconazole: one had uncomplicated coccidioidal meningitis, three had obstructive hydrocephalus due to coccidioidal meningitis, and one had a histoplasmal brain abscess. Ketoconazole concentrations in ventricular and lumbar fluid ranged from 0.05 to 1.65 µg/mL 4 and 8 hours after the dose. The mean penetration of ketoconazole (± SD) was 1.9% ± 0.8% for ventricular fluid and 5.4% ± 2.6% for lumbar fluid. Ketoconazole concentrations in cerebrospinal fluid varied directly with those in serum and with cerebrospinal fluid protein content. The encouraging clinical responses, convenience, safety, and the consistent penetration of ketoconazole into obstructed and nonobstructed cerebrospinal fluid support the use of these regimens as alternatives to conventional therapy.
Paraneoplastic pemphigus in two patients with B-cell non-Hodgkin's lymphoma: Significant responses to cyclophosphamide and prednisolone
Authors: Mark S. Hertzberg, Mark Schifter, John Sullivan, Karen Stapleton
Journal: American Journal of Hematology (2000)

To the Editor: Semenzato et al. proposed new criteria for large granular lymphocyte (LGL) leukemia because patients with low levels of GL were similar to those with levels greater than 2,000 GL/l [1].LGL leukemia is a GL proliferative disease often accompanied by pure red cell aplasia (PRCA).T-cell LGL leukemia is a clonal disease, and the phenotype of leukemic cells is CD3 + 4 -8 + .PRCA with thymoma is often associated with peripheral T cell expansion.We previously reported a case of PRCA with thymoma in which the T-cell receptor ␤ of both the thymus and peripheral mononuclear cells was rearranged [2].Thymoma and PRCA may be caused by T-cell clonal expansion, leukemia.We examined four patients with PRCA and thymoma (Table I), one of which was previously reported.Three of the four showed CD3 + 4 -8 + lymphocytosis and two exhibited T-cell receptor ␤ rearrangement of peripheral mononuclear cells.Patient 2 showed low levels of lymphocytes and the mononuclear cell's CD4/8 ratio of patient 3 was greater than 1.Due to the low levels of abnormal cells and low sensitivity of Southern blot analysis, we could not confirm the clonality of these two cases.According to treatment of PRCA with thymoma, the response rate of thymectomy was 12% [3].This limited effectiveness of thymectomy indicated that thymoma did not play a causative role in PRCA.Loughran reported 129 patients with LGL leukemia [4] and Oshimi et al. examined 33 patients [5].Neither study noted a complication of thymoma.PRCA with thymoma had been considered a distinct clinical entity from LGL leukemia.The old diagnostic criteria for LGL leukemia was "greater than 2,000 GL/l."The normal value of GL is 223 ± 99 l [4].Three of the 4 patients with PRCA and thymoma demonstrated levels greater than the mean + 3 SD (Table I).However, it is unknown whether or not a distinction between 'PRCA with thymoma' and 'PRCA with LGL leukemia' exists.Patients with LGL leukemia showed an indolent clinical course, and immunosuppressive therapy with cyclosporin A or low-dose cyclophosphamide was effective for the clinical symptoms.In contrast, patients with PRCA with thymoma were treated with more aggressive therapy such as surgical resection, intensive chemotherapy, or radiation.As the effectiveness of surgical resection for PRCA with thymoma is limited, PRCA with thymoma should be initially treated with immunosuppressive therapy.
Abstract 4605: Neurotrophin system expression in human lung cancer stem cells
Authors: Rita Mancini
Journal: Cancer Research (2012)

Abstract The availability of in vitro and in vivo systems which reproduce the natural heterogeneity of spontaneous human cancers is of critical importance to assess the potential of new combination treatments and to establish better correlations between molecular signatures and response to therapy. We have focused our attention on the subset of non small cell lung cancers (NSCLC) classified as Lung Adenocarcinomas (AdenoCa) which account for approximately 40% of lung cancer cases and have recently reported that Malignant Pleural Effusions (MPEs) represent an excellent source to culture a wide variety of Lung AdenoCa cells from different donors (Mancini et al, PlosOne, 2011). Reproducible protocols for rapid cancer cell isolation from MPEs and growth in adherent and spheroid conditions have been established in our lab. In order to avoid long periods of adaptations in cell culture that may lead to the selection of subpopulation of cells with particular growth advantages all samples are banked at early passages, on average one month following MPE collection. Furthermore we have observed that these cells can achieve efficient tumor engraftment in recipient NOD/SCID mice, also upon inoculation of small number of cells, thus suggesting indirectly the presence of tumor initiating cells. We believe to have a set up solid system for the study of AdenoCa biology. Recently, we have started to study the expression of neurotrophins (NTs) in cultured lung adenocarcinoma cells from malignant pleural effusion. Using enzyme-linked immunosorbent assays in cancer stem cells and adherent cells from the same patients we have detected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their levels are higher as compared with adhesion and spheroid cells. We have documented, using molecular biology and immunocytochemistry, a different expression of the NTs and their cognate receptors, in lung cancer stem cells in comparison with differentiated cancer cells. Furthermore, the expression on these peptides resembles the previously documented pattern demonstrated in human embryonic stem cells. These data further support the possible role of NTs in cancer cell behavior. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4605. doi:1538-7445.AM2012-4605
TENDON TRANSPLANTATION IN DROP-WRIST DUE TO NERVOUS INJURY
Authors: V. Pennell
Journal: BMJ (1919)

3=114Z i cj .9~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. . .w patient, and may even cause death (Breinl and Priestley's case).3. Antimony should not be given for longer periods than necessary, and therefore it is important that some definite test should be evolved which will indicate when the infection of kala-azar has disappeared and tlle patient is cured.4. If antimony is finally proved to destroy the Schi8to- soma haernatobiu4m, then a similar test to determine when this destruction has taken place is required.5. In all cases where antimonium tartaratum is given intravenously the patient should be confined to bed on the day of the injection and kept there till the day after, and should be carefully watchied throughout the course, any indications of gastric or constitutional dis.turbances at once contraindicating further injections.6.Not more than two injections a week bhould be given, andl the salt should not be given in too concentrated a fc n.REFERENcES.
THE FUNCTION OF NEUROPSYCHIATRY IN THE ARMY
Authors: ROY D. HALLORAN, MALCOLM J. FARRELL
Journal: American Journal of Psychiatry (1943)

The special and prominent place that neuropsychiatry occupies in the Army has been discussed. The problems confronting this specialty have been considered, together with the contributions that can be and have been made. Much of the progress in this field was given momentum by the last war. Neuropsychiatrists have again an exceptional opportunity to collect valuable data from many sources which will further enrich neuropsychiatric understanding and literature if they will seize the unexcelled opportunity within their grasp. At the same time they will contribute in fullest measure to a successful conclusion of the greatest military effort in the world's history.
Prediction, explanation, and the role of generative models in language processing
Authors: Thomas A. Farmer, Meredith Brown, Michael K. Tanenhaus
Journal: Behavioral and Brain Sciences (2013)

Abstract We propose, following Clark, that generative models also play a central role in the perception and interpretation of linguistic signals. The data explanation approach provides a rationale for the role of prediction in language processing and unifies a number of phenomena, including multiple-cue integration, adaptation effects, and cortical responses to violations of linguistic expectations.
P226 Inhalation characteristics with spiromax<sup>®</sup>and turbuhaler<sup>®</sup>dry powder inhalers (dpi) in healthy adults and patients with asthma or chronic obstructive pulmonary disease (copd): before and after enhanced training: Abstract P226 Table 1.
Authors: H Chrystyn, W Azouz, P Chetcuti, H Hosker, D Saralaya
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> Acceleration of inhaled flow from a DPI is important to facilitate de-aggregation of the metered dose and to ensure delivery of an appropriate dose. Patients need to inhale as fast as possible from the beginning of their inhalation manoeuvre and continue inhaling until their lungs are full.<sup>1</sup> This study investigated inhalation characteristics when patients and healthy adults (HA) inhale through placebo Spiromax<sup>®</sup> and placebo Turbuhaler<sup>®</sup> DPIs and assessed the impact of enhanced DPI technique training. <h3>Methods</h3> This was a randomised, open-label, crossover study involving children (6–11 years old, [CA]), adolescents (12–17 years old [AA]) and adults with asthma [ADULT], COPD patients and HA. Study participants were trained to use the Spiromax and Turbuhaler DPIs according to the Patient Information Leaflets. Inhalation characteristics were measured. Each participant received enhanced training using an In-Check Dial™ to measure inspiratory flow (IF). Participants were encouraged to increase their IF by inhaling more quickly. Inhalation characteristics were measured in the same way as before enhanced training. <h3>Results</h3> Before enhanced training,peak inspiratory flow (PIF) and maximum change in pressure (∆P) were significantly higher with Spiromax versus Turbuhaler (p &lt; 0.05; all patient groups). There were also trends towards slightly higher inspiratory acceleration (ACC) with Spiromax. Table 1 shows the pre-training inhalation characteristics. Enhanced training significantly improved PIF, ACC and ∆P (p &lt; 0.05) in all subjects and in both inhalers except ∆P with Spiromax in patients with COPD. Percentage improvements in ∆P and ACC are shown in Table 1. Significantly greater improvements (p &lt; 0.05) were seen with Spiromax versus Turbuhaler (post training) for PIF (all groups), ∆P in AA, ADULT and patients with COPD, and for ACC in ADULT and COPD patients. <h3>Conclusions</h3> Patients achieved faster IF and greater positive change in pressure with Spiromax versus Turbuhaler. Enhanced training with a focus on maximising inspiratory effort produced significant improvement in inhalation parameters with both devices, and significantly greater improvements in these parameters with Spiromax versus Turbuhaler in adult patients. <h3>References</h3> Laube BL, <i>et al</i>. <i>Eur Respir J</i> 2011;37:1308–31.
High Mobility Group Box2 Promoter-controlled Suicide Gene Expression Enables Targeted Glioblastoma Treatment
Authors: Poonam Balani, Jerome Boulaire, Ying Zhao, Jieming Zeng, Jiakai Lin, Shu Wang
Journal: Molecular Therapy (2009)

Achievement of specific tumor cell targeting remains a challenge for glioma gene therapy. We observed that the human high mobility group box2 (HMGB2) gene had a low level of expression in normal human brain tissues, but was significantly upregulated in glioblastoma tissues. With progressive truncation of a 5′-upstream sequence of the HMGB2 gene, we identified a 0.5-kb fragment displaying a high transcriptional activity in glioblastoma cells, but a low activity in normal brain cells. To test the feasibility of using the HMGB2 promoter sequence in targeted cancer therapy, we constructed a baculoviral vector expressing the herpes simplex virus thymidine kinase (HSVtk) gene driven by the HMGB2 promoter. Transduction with the viral vector induced cell death in glioblastoma cell lines in the presence of ganciclovir (GCV), but did not affect the survival of human astrocytes and neurons. In a mouse xenograft model, intratumor injection of the baculoviral vector suppressed the growth of human glioblastoma cells and prolonged the survival of tumor-bearing mice. Our results suggest that the novel 5′ sequence of HMGB2 gene has a potential to be used as an efficient, tumor-selective promoter in targeted vectors for glioblastoma gene therapy. Achievement of specific tumor cell targeting remains a challenge for glioma gene therapy. We observed that the human high mobility group box2 (HMGB2) gene had a low level of expression in normal human brain tissues, but was significantly upregulated in glioblastoma tissues. With progressive truncation of a 5′-upstream sequence of the HMGB2 gene, we identified a 0.5-kb fragment displaying a high transcriptional activity in glioblastoma cells, but a low activity in normal brain cells. To test the feasibility of using the HMGB2 promoter sequence in targeted cancer therapy, we constructed a baculoviral vector expressing the herpes simplex virus thymidine kinase (HSVtk) gene driven by the HMGB2 promoter. Transduction with the viral vector induced cell death in glioblastoma cell lines in the presence of ganciclovir (GCV), but did not affect the survival of human astrocytes and neurons. In a mouse xenograft model, intratumor injection of the baculoviral vector suppressed the growth of human glioblastoma cells and prolonged the survival of tumor-bearing mice. Our results suggest that the novel 5′ sequence of HMGB2 gene has a potential to be used as an efficient, tumor-selective promoter in targeted vectors for glioblastoma gene therapy.