tbuckley/cabot-search huggingface dataset:
Abstract LB-71: Carcinogenic significance of integrated hepatitis b viral factors and its genotype in hepatocarcinogenesis.
Authors: Soma Banerjee, Somenath Datta, Shrabasti Roychoudhury, Debanjali Dasgupta, Amit Ghosh, Gaurav Roy, Simanti Datta, Abhijit Chowdhury
Journal: Cancer Research (2013)

Abstract Integration of Hepatitis B Virus (HBV) is one of the major causes underlying Hepatocellular carcinoma (HCC) development. Recent studies revealed that altered expression of multiple cellular genes due to multiple random integration of viral factors lead to development of HCC. The present study aims to identify the carcinogenic significance of integrated HBV genome and its genotype in HCC development. Host-Viral Junctions were determined in HCC (T) /adjacent tissues (NT) and cirrhotic (-HCC) tissues by sequencing of Alu PCR product followed by sequence blast. Host gene expression was checked by real time PCR. Competition between two coexisting genotypes was studied by replication assay using genotype specific PCR from media and viral core particle isolated from genotype specific plasmid transfected HepG2 cell line. Similarly, each viral genotype mediated DNA damage (γH2aX foci by confocal microscopy), ROS generation (DCFDA quantitation by Facs analysis and ER stress marker GRP78 luciferase assay), homologous recombination efficiency were also compared. HBV integration was observed in 66.7% of T (8/12), 33.3% (4/12) NT and 75% (6/8) cirrhotic tissue samples in 18, 4 and 8 different locations respectively. These viral integration analysis within or close to several host genes, such as genes involved in differentiation, signaling, stress response, cell cycle, telomere regulations (8/30, 26.7%) etc and most of them showed altered expression. Interestingly, C-terminal truncated HBX which lost its growth suppressive domain were observed more in T (5/8, 62.5%) than NT (2/4, 50%) tissue samples. Most importantly, upon genotype analysis of each five clones in serum and tissue showed genotype C preferentially integrated in coexistence of both C and D genotype as “free virus” in tissue but D genotype observed in circulation. Genotype specific PCR from HBV/C &amp; D cotransfected media showed that in presence of HBV/C, D replicates better than C but HBV/C with high recombination frequency generates more DNA damage and facilitate viral integration. Thus random integration of HBV in host chromosome causes alterations in oncogenic gene expression and these alterations presumably lead to clonal selection of hepatocyte that acquires a growth advantage and proceeds towards HCC. Genotype of HBV is an important determining factor for HBV integration and liver inury. Citation Format: Soma Banerjee, Somenath Datta, Shrabasti Roychoudhury, Debanjali Dasgupta, Amit Ghosh, Gaurav Roy, Simanti Datta, Abhijit Chowdhury. Carcinogenic significance of integrated hepatitis b viral factors and its genotype in hepatocarcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-71. doi:10.1158/1538-7445.AM2013-LB-71
Glycine Receptor Autoimmune Spectrum With Stiff-Man Syndrome Phenotype
Authors: Andrew McKeon, Eugenia Martinez-Hernandez, Eric Lancaster, Joseph Y. Matsumoto, Robert J. Harvey, Kathleen M. McEvoy, Sean J. Pittock, Vanda A. Lennon, Josep Dalmau
Journal: JAMA Neurology (2012)

To determine whether glycine receptor α1 subunit-specific autoantibodies (GlyRα1-IgG) occur in a broader spectrum of brainstem and spinal hyperexcitability disorders than the progressive encephalomyelitis with rigidity and myoclonus phenotype recognized to date, and to ascertain disease specificity.Retrospective, case-control study.Mayo Clinic, Rochester, Minnesota, and University of Barcelona, Spain.Eighty-one patients with stiff-man syndrome phenotype, 80 neurologic control subjects, and 20 healthy control subjects.Glycine receptor α1-transfected cells to test serum or cerebrospinal fluid from cases and control subjects.Frequency of GlyRα1-IgG positivity among stiff-man syndrome phenotype cases and control subjects. Comparison of GlyRα1-IgG seropositive and seronegative cases.Seropositive cases (12% of cases) included 9 with stiff-man syndrome (4 classic; 5 variant; 66% were glutamic acid decarboxylase 65-IgG positive) and 1 with progressive encephalomyelitis with rigidity and myoclonus. Immunotherapy responses were noted more frequently in GlyRα1-IgG-positive cases (6 of 7 improved) than in seronegative cases (7 of 25 improved; P= .02). The single seropositive control patient had steroid-responsive vision loss and optic atrophy with inflammatory cerebrospinal fluid.Glycine receptor α1-IgG aids identification of autoimmune brainstem/spinal cord hyperexcitability disorders and may extend to the glycinergic visual system.
Abstract P6-04-17: The irreversible c-Jun N-terminal kinase (JNK) inhibitor, JNK-IN-8, sensitizes basal-like breast cancer cells to lapatinib
Authors: ND Ebelt, CL Van Den Berg
Journal: Cancer Research (2013)

Abstract Basal-like breast cancers represent 15-20% of breast cancers diagnosed each year. These tumors appear earlier in life and have the worst prognosis due to high prevalence of metastasis. Endocrine and molecularly targeted therapies such as trastuzumab or lapatinib are ineffective against this tumor subtype. A high frequency of p53 mutations, low BRCA1 expression along with high epidermal growth factor receptor (EGFR) expression provide some insight into what types of targeted therapies may be useful for basal-like tumors in the future. We have recently shown that JNK2 mediates the expression of p53 and BRCA1 in response to EGFR activation to promote epithelial to mesenchymal transition and metastasis. Further, high JNK2 expression is associated with poorer survival in patients with basal-like breast cancer. These findings suggest that the JNK pathway may be a promising target for basal-type breast cancer treatment. Commonly used competitive ATP inhibitors of JNK have suffered from lack of specificity for JNK. However, the Gray laboratory recently developed highly specific covalent inhibitors of JNK (Zhang, et al. 2012). The agent showing the best properties is JNK-IN-8. Our data show that treatment of human and mouse basal-like, breast cancer cell lines with JNK-IN-8 sensitizes them to lapatinib. Single agents had minor affects on cell viability and cell cycle regulation, but combination treatment led to G2/M arrest and endoreduplication along with synergistic apoptotic responses. Further, the expression and electrophoretic mobility of mitotic arrest deficient 2 (MAD2) (a protein mediating chromosomal segregation) decreased after combination treatment which could explain the chromosomal duplication abnormalities observed. Combination treatment using lapatinib and JNK-IN-8 modulates extracellular signal-regulated kinase (ERK) phosphorylation unlike either drug alone suggesting that both JNK and ERK target G2/M check point proteins, and when perturbed, sensitize basal-type breast cancer cells to targeted therapies. We conclude that use of specific JNK inhibitors in tumors that are resistant to lapatinib, or perhaps trastuzumab, may sensitize them to treatments with these drugs, and may also prevent resistance to these drugs in tumors that were initially responsive. Considering that JNKs are nodes in receptor tyrosine kinase and many other signaling pathways, JNK-IN-8 treatment may improve the efficacy of other targeted therapies as well. Zhang, T. et al. “Discovery of potent and selective covalent inhibitors of JNK”. Chem Biol. 2012 Jan 27;19(1):140-54. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-17.
Percutaneous Transluminal Septal Myocardial Ablation in Hypertrophic Obstructive Cardiomyopathy
Authors: Lothar Faber, Hubert Seggewiss, Ulrich Gleichmann
Journal: Circulation (1998)

Background —Percutaneous transluminal septal myocardial ablation (PTSMA) has been introduced as an alternative procedure for reducing the left ventricular outflow tract gradient (LVOTG) in hypertrophic obstructive cardiomyopathy. We report on the acute and mid-term results in 91 symptomatic patients with respect to intraprocedural myocardial contrast echocardiography (MCE). Methods and Results —PTSMA was intended for 46 women and 45 men (54.1±15.5 years). In 2 patients, the intervention could not be completed. In the first 30 patients the target vessel was determined by probatory balloon occlusion alone and in the remainder by additional intraprocedural MCE. Resting LVOTG was reduced from 73.8±35.4 to 16.6±18.1 and nostextrasystolic LVOTG from 149.3±42.5 to 61.9±43.0 mm Hg ( P &lt;0.0001 each). In 10 (11%) patients, permanent DDD pacemaker implantation was necessary. Two (2%) patients died, 1 from ventricular fibrillation associated with treatment for chronic obstructive pulmonary disease after 9 days and 1 from fulminant pulmonary embolism after 2 days. After 3 months, mean New York Heart Association class was reduced from 2.8±0.6 to 1.1±1.0 ( P &lt;0.0001). The LVOTG remained reduced to 14.6±25.5 mm Hg at rest and 49.1±48.7 mm Hg ( P &lt;0.0001 each). Four patients underwent successful repeat PTSMA. Determination of the target vessel by MCE was associated with a higher rate of acute (92% vs 70%; P &lt;0.01) and mid-term (94% vs 64%; P &lt;0.01) success. Conclusions —PTSMA is a promising nonsurgical technique for reduction of symptoms and LVOTG in hypertrophic obstructive cardiomyopathy. MCE has been shown to be a useful addition to probatory balloon occlusion for target vessel selection. Prospective, long-term observations of larger populations and a comparison with the established forms of therapy are necessary to determine the definitive significance of PTSMA.
Macrophages sense and kill bacteria through carbon monoxide–dependent inflammasome activation
Authors: Barbara Wegiel, Rasmus Larsen, David Gallo, Beek Yoke Chin, Clair Harris, Praveen Mannam, Elzbieta Kaczmarek, Patty J. Lee, Brian S. Zuckerbraun, Richard Flavell, Miguel P. Soares, Leo E. Otterbein
Journal: Journal of Clinical Investigation (2014)

Microbial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood. The gasotransmitter carbon monoxide (CO) is generated by the stress-responsive enzyme heme oxygenase-1 (HO-1, encoded by Hmox1), which is highly induced in macrophages in response to bacterial infection. HO-1 deficiency results in inadequate pathogen clearance, exaggerated tissue damage, and increased mortality. Here, we determined that macrophage-generated CO promotes ATP production and release by bacteria, which then activates the Nacht, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome, intensifying bacterial killing. Bacterial killing defects in HO-1–deficient murine macrophages were restored by administration of CO. Moreover, increased CO levels enhanced the bacterial clearance capacity of human macrophages and WT murine macrophages. CO-dependent bacterial clearance required the NALP3 inflammasome, as CO did not increase bacterial killing in macrophages isolated from NALP3-deficient or caspase-1–deficient mice. IL-1β cleavage and secretion were impaired in HO-1–deficient macrophages, and CO-dependent processing of IL-1β required the presence of bacteria-derived ATP. We found that bacteria remained viable to generate and release ATP in response to CO. The ATP then bound to macrophage nucleotide P2 receptors, resulting in activation of the NALP3/IL-1β inflammasome to amplify bacterial phagocytosis by macrophages. Taken together, our results indicate that macrophage-derived CO permits efficient and coordinated regulation of the host innate response to invading microbes.
Environmental exposure to volatile organic compounds among workers in Mexico City as assessed by personal monitors and blood concentrations.
Authors: I Romieu, M Ramirez, F Meneses, D Ashley, S Lemire, S Colome, K Fung, M Hernandez-Avila
Journal: Environmental Health Perspectives (1999)

Benzene, an important component in gasoline, is a widely distributed environmental contaminant that has been linked to known health effects in animals and humans, including leukemia. In Mexico City, environmental benzene levels, which may be elevated because of the heavy traffic and the poor emission control devices of older vehicles, may pose a health risk to the population. To assess the potential risk, portable passive monitors and blood concentrations were used to survey three different occupational groups in Mexico City. Passive monitors measured the personal exposure of 45 workers to benzene, ethylbenzene, toluene, o-xylene and m-/p-xylene during a work shift. Blood concentrations of the above volatile organic compounds (VOCs), methyl tert-butyl ether, and styrene were measured at the beginning and the end of a work shift. Passive monitors showed significantly higher (p > 0.0001) benzene exposure levels among service station attendants (median = 330 microg/m3; range 130-770) as compared to street vendors (median = 62 microg/m3; range 49-180) and office workers (median = 44 microg/m3, range 32-67). Baseline blood benzene levels (BBLs) for these groups were higher than those reported for similar populations from Western countries (median = 0.63 microg/L, n = 24 for service station attendants; median = 0.30 microg/L, n = 6 for street vendors; and median = 0.17 microgr;g/L, n = 7 for office workers). Nonsmoking office workers who were nonoccupationally exposed to VOCs had BBLs that were more than five times higher than those observed in a nonsmoking U.S. population. BBLs of participants did not increase during the work shift, suggesting that because the participants were chronically exposed to benzene, complex pharmacokinetic mechanisms were involved. Our results highlight the need for more complete studies to assess the potential benefits of setting environmental standards for benzene and other VOCs in Mexico.
Properties of the carcinoma-associated antigen MH 99/KS 1/4 in normal and transformed human keratinocytes: regulation of synthesis, molecular cross-linking and ultrastructural localization
Authors: M.P. SCHON, M. SCHON, C. EBERHARD KLEIN, R. KAUFMANN, F. HERZBERG, R. SCHMIDT, C.E. ORFANOS
Journal: British Journal of Dermatology (1995)

A 38-kDa cell-surface glycoprotein defined by monoclonal antibody MH 99 is markedly increased in many epithelial tumours. In normal human skin, it is a characteristic marker for germ-cell phenotypic tissues. Although the gene encoding the MH 99 antigen has recently been cloned, and several histological and biochemical studies have been performed, the biological function of this interesting antigen still remains unknown. In the present study, we examined the synthesis of MH 99 in keratinocyte populations showing different in vitro differentiation capacity. Normal keratinocytes, spontaneously immortalized keratinocytes (cell line HaCaT), three SV-40-transformed keratinocyte lines (130, 425, and HaSV), and two squamous cell carcinoma lines (SCL-1 and SCL-2), were compared. Radioimmunoprecipitation revealed the highest levels of synthesis in cell populations with the least differentiation. This was paralleled by an increase of MH 99 synthesis in normal keratinocytes cultured in low concentrations of Ca2+ and by an increase of MH 99 synthesis during subculture of normal keratinocytes. Both phenomena were paralleled by an opposite behaviour of a differentiation marker. Molecular cross-linking and subsequent immunoprecipitation led to a decrease of the MH 99 signal, but an increase of a high molecular weight protein signal was seen. After cleavage of the crosslinker, the MH 99 signal reappeared, whereas the signal of the large protein remained unchanged. Thus, the MH 99 antigen may be associated with a high molecular weight protein on the cell surface, supporting the suggestion of a receptor-like function. Phosphorylation of the molecule could not be detected. Immunoelectron microscopy revealed homogeneous distribution on the cell surface, but cells of the same culture exhibited clear differences in their MH 99 expression. A concept for MH 99 regulation in normal and transformed human keratinocyte populations in vitro is proposed, showing that the synthesis of MH 99 is inversely correlated with cell differentiation. The association with a high molecular weight protein supports the suggestion that the MH 99 antigen interacts with other molecules.
Germany pushes for more organ donation
Authors: A. Tuffs
Journal: BMJ (2011)

All German citizens who apply for identity cards, driving licences, and health insurance cards will have to declare their wishes concerning organ donation under a new law being prepared by the German parliament.

It is hoped that the new law will boost the number of donated organs in Germany, which lags behind other European countries, such as Spain and Austria. Figures from the Council of Europe for 2009 show that the number of deceased donors …
Inhibition of leukemic cell proliferation by factor(s) released from irradiated lymphocytes of B‐chronic lymphocytic leukemia patients
Authors: Hanna Bessler, Ida Notti, Amos M. Cohen, Baruch Klein, Meir Djaldetti
Journal: American Journal of Hematology (1994)

An attempt was made to clarify the mechanism by which splenic irradiation in patients with B-chronic lymphocytic leukemia (B-CLL) can induce a reduction in lymph node size. For this purpose peripheral blood lymphocytes from B-CLL patients were exposed to cobalt irradiation and were cultured for 1-8 days. The effect of the supernatants on the proliferation capacity of normal and malignant human cells was examined. A suppression of phytohemagglutinin (PHA)-induced proliferation of autologous and heterologous B-CLL lymphocytes was observed, whereas there was no effect on the proliferation of lymphocytes obtained from healthy volunteers. In addition, supernatants of irradiated B-CLL lymphocytes inhibited thymidine incorporation into blasts derived from patients with acute leukemia and the lymphoblastoid cell line Daudi, but they did not exert any effect on normal cells obtained from human embryonic liver. These results suggest the secretion of some factor(s) by irradiated B-CLL lymphocytes, which may inhibit the proliferation of malignant cells but has no effect on normal cells.
THE WASSERMANN REACTION IN DIABETES MELLITUS WITH SPECIAL REFERENCE TO ITS RELATION TO ACIDOSIS
Authors: JOHN H. RICHARDS
Journal: JAMA (1913)

<h3>INTRODUCTION</h3> On account of the non-specific antigen employed, the question is ever present whether conditions other than syphilis will give positive Wassermann reactions. Such conditions have been reported from time to time. As early as 1908 Eichelberg<sup>1</sup>reported positive reactions in a series of scarlet fever cases. Marchildon<sup>2</sup>reported positive results in one case of appendicitis, one case of cancer and two cases of typhoid. Weil and Braun<sup>3</sup>reported positive results in cases of sepsis, cancer, typhoid, phthisis, typhus and diabetes. Wechselmann and Meier<sup>4</sup>and many others have reported positive results in leprosy. Boehm<sup>5</sup>and Reinhard<sup>5</sup>reported cases of malaria and beriberi with positive Wassermann reactions. Halberstaedter, Mueller and Reiche<sup>6</sup>have reported positive results in measles (nine cases), in varicella (five cases) and in pertussis (14 cases). Treuber<sup>7</sup>has reported one case of lymphosarcomatosis in which was found a positive Wassermann reaction. Semon
Therapeutic Plasma Exchange
Authors: Kenneth H. Shumak, Gail A. Rock
Journal: New England Journal of Medicine (1984)

THE acceptance of the Renaissance concept that an illness could be helped by bloodletting was tempered by the adverse effects of blood loss. Indeed, Louis XIII and George Washington were probably killed by this therapy.1 , 2 The selective removal of plasma (plasmapheresis) was first carried out early in this century by Fleig3 and Abel et al.,4 but there was little enthusiasm for its clinical use, because the manual removal of large amounts of plasma was cumbersome and time-consuming. In 1960 Schwab and Fahey reported that plasmapheresis is unquestionably beneficial to patients with Waldenström's macroglobulinemia and manifestations of hyperviscosity5; manual plasmapheresis . . .
Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial
Authors: Wolfgang Kern, Torsten Haferlach, Claudia Schoch, Helmut Löffler, Winfried Gassmann, Achim Heinecke, Maria Christina Sauerland, Wolfgang Berdel, Thomas Büchner, Wolfgang Hiddemann
Journal: Blood (2002)
P95 Assessment of F/HN-pseudotyped Lentivirus as a Clinically Relevant Vector For Lung Gene Therapy
Authors: U Griesenbach, M Inoue, C Meng, R Farley, M Chan, NK Newman, A Brum, J You, A Kerton, A Shoemark, AC Boyd, JC Davies, TE Higgins, DR Gill, SC Hyde, JA Innes, DJ Porteous, M Hasegawa, EWFW Alton
Journal: Thorax (2012)

<h3>Rational</h3> Our ongoing efforts to improve pulmonary gene transfer thereby enabling gene therapy for the treatment of lung diseases such as cystic fibrosis (CF) has led to the development of a lentiviral vector (SIV) pseudotyped with the Sendai virus envelope proteins F and HN. <h3>Objectives</h3> Here, we begin to place this vector onto a translational pathway to the clinic, by addressing some key milestones that have to be achieved. <h3>Main results</h3> These include: (1) a single dose produces lung expression for the life-time of the mouse (approximately 2 years), (2) only brief contact time is needed to achieve transduction, (3) repeated daily administration leads to a dose-related increase in gene expression, (4) repeated monthly administration to mouse lower airways is feasible without loss of gene expression, (5) there is no evidence of chronic toxicity during a 2 year study period, (6) F/HN-SIV transduction generates persistent gene expression in human differentiated airway cultures, and human lung slices and transduces freshly obtained primary human airway epithelial cells. <h3>Conclusions</h3> The data support F/HN-pseudotyped SIV as a promising vector for pulmonary gene therapy for a number of diseases including CF and we are now undertaking the necessary refinements to progress this vector into clinical trials.
Effect of Repaglinide Addition to NPH Insulin Monotherapy on Glycemic Control in Patients With Type 2 Diabetes
Authors: Daniel Antonio de Luis, Rocío Aller, Luis Cuellar, Concepción Terroba, Hilda Ovalle, Olatz Izaola, Enrique Romero
Journal: Diabetes Care (2001)

Repaglinide is a new type of oral hypoglycemic agent. Its rapid absorption, short metabolic half-time (1 h), and novel insulin release profile are all characteristics desired for treating elderly people with type 2 diabetes. The aim of this study was to investigate the efficacy and safety of repaglinide in combination with NPH insulin in subjects with type 2 diabetes on insulin monotherapy with suboptimal glycemic control.

The prospective, no-blind study was performed in our clinical research unit. We selected 27 (7 men and 20 women) type 2 diabetic patients who were nonsmokers and whose glycemic control was unsatisfactory (HbA1c >7.1%) with two doses of NPH insulin for >6 months. Additional inclusion criteria were age 45–75 years (mean 65 ± 9.6) and BMI >21 kg/m2 (mean 27.2 ± 3.9). For the purpose of this study, we followed the American Diabetes Association’s standards for medical care, which considers an HbA1c level  7.1% as unsatisfactory glycemic control. All subjects were required to be able to comply with the protocol and to carry out home blood glucose …