tbuckley/cabot-search huggingface dataset:
The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma
Authors: C Hellerbrand, T Amann, J Schlegel, P Wild, F Bataille, T Spruss, A Hartmann, A-K Bosserhoff
Journal: Gut (2007)

Melanoma inhibitory activity 2 (MIA2) is a novel gene of the MIA gene family. The selective expression of MIA2 in hepatocytes is controlled by hepatocyte nuclear factor (HNF) 1 binding sites in the MIA2 promotor. In contrast, in most hepatocellular carcinomas (HCC) MIA2 expression is down-regulated or lost.In this study we examined the regulation and functional role of MIA2 in hepatocancerogenesis.In HCC cell lines and tissues HNF-1 expression was lower than in primary human hepatocytes (PHH) and corresponding non-tumorous tissue, respectively, and correlated significantly with the down-regulation of MIA2 expression. Re-expression of HNF-1 in HCC cells reinduced MIA2 in HCC cells to similar levels as found in PHH. Further, MIA2 was re-expressed in HCC cell lines by stable transfection, and the generated cell clones revealed a strongly reduced invasive potential and proliferation rate in vitro. In line with these findings treatment of HCC cells with recombinant MIA2 inhibited proliferation and invasion. In nude mice MIA2 re-expressing HCC cells grew significantly slower and revealed a less invasive growth pattern. Immunohistochemical analysis of a tissue microarray containing HCC and corresponding non-cancerous liver tissue of 85 patients confirmed reduced MIA2 expression in HCC. Furthermore, MIA2 negative HCC tissue showed a significantly higher Ki67 labelling index and loss of MIA2 expression correlated significantly with more advanced tumour stages.This study presents MIA2 as an inhibitor of HCC growth and invasion both in vitro and in vivo, and consequently, as a tumour suppressor of HCC. Further, our findings indicate a novel mechanism, how loss of HNF-1 expression in HCC affects tumorigenicity via down-regulation of MIA2.
A comparative study of the effects of certain halogenated benzimidazole ribosides on RNA synthesis, cell proliferation, and interferon production.
Authors: I Tamm, P B Sehgal
Journal: The Journal of Experimental Medicine (1977)

5-(or 6-)Bromo-4,5-(or 5,7-)dichloro-1-beta-D-ribofuranosylbenzimidazole, 5,6-dibromo-1-beta-D-ribofuranosylbenzimidazole, and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole show closely similar structure-activity relationships with respect to inhibition of cellular RNA synthesis, cellular proliferation, and influenza virus multiplication, and also with respect to enhancement of interferon production. The activities ofth ese compounds are ranked 20:2.5:1. The log dose-response curves constructed for inhibiton of FS-4 cell RNA synthesis show similar slopes and a leveling off at 60-70% inhibition of RNA synthesis at the highest concentrations of each compound tested. This evidence suggests that these three derivatives act through the same mechanism. It has been shown previously that the dichloro compound selectively inhibits nuclear heterogenous RNA and messenger RNA synthesis. The concentrations of the benzimidazole ribosides at which the rate of proliferation of human fibroblasts (FS-4) is reduced by 50% are as follows: monobromodichloro: 1.7 muM (0.68 mug/ml); dibromo: 12 muM (4.9 mug/ml); dichloro: 38 muM (12 mug/ml). All compounds reduce the exponential rate of cell proliferation in a dose-dependent manner. The inhibition of cell growth is reversible upon removal of the compounds from the medium. Protocols based on any one of the three halobenzimidazole ribosides give interferon yields from poly(I)-poly(C)-induced FS-4 cells which are comparable to the high yields obtained with the conventional cycloheximide-actinomycin D protocol. The enhancement of interferon yield depends on blocking of the synthesis of RNA which is involved in the shutoff of interferon production.
β-Blockers Restore Calcium Release Channel Function and Improve Cardiac Muscle Performance in Human Heart Failure
Authors: Steven Reiken, Xander H.T. Wehrens, John A. Vest, Alessandro Barbone, Stefan Klotz, Donna Mancini, Daniel Burkhoff, Andrew R. Marks
Journal: Circulation (2003)

Background— Chronic β-adrenergic receptor (β-AR) blockade improves cardiac contractility and prolongs survival in patients with heart failure; however, the mechanisms underlying these favorable responses are poorly understood. Stress-induced activation of the sympathetic nervous system results in protein kinase A (PKA)-mediated phosphorylation of the calcium (Ca 2+ ) release channel/cardiac ryanodine receptor (RyR2), required for cardiac excitation-contraction (EC) coupling, activating the RyR2 channel, and increasing cardiac contractility. The hyperadrenergic state of heart failure results in leaky RyR2 channels attributable to PKA hyperphosphorylation and depletion of the stabilizing FK506 binding protein, FKBP12.6. We tested the hypothesis that improved cardiac muscle function attributable to β-AR blockade is associated with restoration of normal RyR2 channel function in patients with heart failure. Methods and Results— We assessed the effects of β-AR blockade on left ventricular volume using isolated perfused hearts and β-agonist responsiveness using muscle strips from patients undergoing transplantation. Twenty-four human hearts were examined, 10 from patients with heart failure treated with β-AR blockers (carvedilol, metoprolol, or atenolol), 9 from patients with heart failure without β-AR blocker treatment, and 5 normal hearts. RyR2 PKA phosphorylation was determined by back-phosphorylation, FKBP12.6 in the RyR2 macromolecular complex was determined by coimmunoprecipitation, and channel function was assayed using planar lipid bilayers. β-AR blockers reduced left ventricular volume (reverse remodeling) and restored β-agonist response in cardiac muscle from patients with heart failure. Improved cardiac muscle function was associated with restoration of normal FKBP12.6 levels in the RyR2 macromolecular complex and RyR2 channel function. Conclusions— Improved cardiac muscle function during β-AR blockade is associated with improved cardiac Ca 2+ release channel function in patients with heart failure.
Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas
Authors: Elizabeth M Swisher, Rachel M Gonzalez, Toshiyasu Taniguchi, Rochelle L Garcia, Tom Walsh, Barbara A Goff, Piri Welcsh
Journal: Molecular Cancer (2009)

DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure. Of 115 primary sporadic ovarian carcinomas, 39 (34%) had low BRCA1 protein and 49 (42%) had low BRCA2 expression. BRCA1 and BRCA2 protein expression were highly concordant (p < 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary neoplasms. BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards). In paired specimens, BRCA1 protein expression increased in 13/21 (62%) and BRCA2 protein expression increased in 15/21 (71%) of recurrent carcinomas with low or intermediate protein in the paired primary. In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%). Similar frequencies of MLH1, BRCA1, and FANCF promoter methylation occurred in primary carcinomas without previous chemotherapy, after neoadjuvant chemotherapy, or in recurrent neoplasms. Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival. Recurrent ovarian carcinomas commonly have increased BRCA1 and/or BRCA2 protein expression post chemotherapy exposure which could mediate resistance to platinum based therapies. However, alterations in expression of these proteins after chemotherapy are not commonly mediated by promoter methylation, and other regulatory mechanisms are likely to contribute to these alterations.
Electromechanical Characterization of Chronic Myocardial Infarction in the Canine Coronary Occlusion Model
Authors: Lior Gepstein, Alexander Goldin, Jonathan Lessick, Gal Hayam, Shlomo Shpun, Yitzhak Schwartz, Guil Hakim, Rona Shofty, Aharon Turgeman, Dina Kirshenbaum, Shlomo A. Ben-Haim
Journal: Circulation (1998)

Background —Defining the presence, extent, and nature of the dysfunctional myocardial tissue remains a cornerstone in diagnostic cardiology. A nonfluoroscopic, catheter-based mapping technique that can spatially associate endocardial mechanical and electrical data was used to quantify electromechanical changes in the canine chronic infarction model. Methods and Results —We mapped the left ventricular (LV) electromechanical regional properties in 11 dogs with chronic infarction (4 weeks after LAD ligation) and 6 controls. By sampling the location of a special catheter throughout the cardiac cycle at multiple endocardial sites and simultaneously recording local electrograms from the catheter tip, the dynamic 3-dimensional electromechanical map of the LV was reconstructed. Average endocardial local shortening (LS, measured at end systole and normalized to end diastole) and intracardiac bipolar electrogram amplitude were quantified at 13 LV regions. Endocardial LS was significantly lower at the infarcted area (1.2±0.9% [mean±SEM], P &lt;0.01) compared with the noninfarcted regions (7.2±1.1% to 13.5±1.5%) and with the same area in controls (15.5±1.2%, P &lt;0.01). Average bipolar amplitude was also significantly lower at the infarcted zone (2.3±0.2 mV, P &lt;0.01) compared with the same region in controls (10.3±1.3 mV) and with the noninfarcted regions (4.0±0.7 to 10.2±1.5 mV, P &lt;0.01) in the infarcted group. In addition, the electrical maps could accurately delineate both the location and extent of the infarct, as demonstrated by the high correlation with pathology (Pearson’s correlation coefficient=0.90) and by the precise identification of the infarct border. Conclusions —Chronic myocardial infarcted tissue can be characterized and quantified by abnormal regional mechanical and electrical functions. The unique ability to assess the regional ventricular electromechanical properties in various myocardial disease states may become a powerful tool in both clinical and research cardiology.
Sympathetic 2-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload
Authors: R. Gilsbach, J. Schneider, A. Lother, S. Schickinger, J. Leemhuis, L. Hein
Journal: Cardiovascular Research (2010)

α2-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release from sympathetic neurons. Despite detailed knowledge about subtype-specific functions of α2-receptors, the relative contributions of sympathetic vs. non-sympathetic receptors involved in these cardiovascular effects have not been identified. The aim of this study was to define the physiological and pharmacological role of α2A-adrenoceptors in adrenergic vs. non-adrenergic cells at baseline and during sympathetic stress. Transgenic mice expressing α2A-adrenoceptors under control of the dopamine β-hydroxylase (Dbh) promoter were generated and crossed with mice carrying a constitutive deletion in the α2A- and α2C-adrenoceptor genes. α2AC-deficient mice showed increased norepinephrine plasma levels, cardiac hypertrophy, and fibrosis at baseline. Expression of the Dbh-α2A transgene in sympathetic neurons prevented these effects. In contrast, Dbh-α2A receptors mediated only a minor part of the bradycardic and hypotensive effects of the α2-agonist medetomidine. After chronic pressure overload as induced by transverse aortic constriction in mice, the Dbh-α2A transgene did not reduce norepinephrine spillover, cardiac dysfunction, hypertrophy, or fibrosis. In isolated wild-type atria, α2-agonist-induced inhibition of [3H]norepinephrine release was significantly desensitized after pressure overload. In primary sympathetic neurons from Dbh-α2A transgenic mice, norepinephrine and medetomidine induced endocytosis of α2A-adrenoceptors into neurite processes. α2A-Adrenoceptors expressed in adrenergic cells are essential feedback inhibitors of sympathetic norepinephrine release to prevent cardiac hypertrophy and fibrosis at baseline. However, these receptors are desensitized by chronic pressure overload which in turn may contribute to the pathogenesis of this condition.
Mast cell deficiency in <i>KitW-sh</i> mice does not impair antibody-mediated arthritis
Authors: Joseph S. Zhou, Wei Xing, Daniel S. Friend, K. Frank Austen, Howard R. Katz
Journal: The Journal of Experimental Medicine (2007)

We previously reported that joint swelling, synovial thickening, and cartilage matrix depletion induced by the injection of anti-collagen monoclonal antibodies and lipopolysaccharide (LPS) in BALB/c mice are increased in the absence of inhibitory leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4; formerly gp49B1) in a neutrophil-dependent manner. Because both mast cells and neutrophils express LILRB4, we sought a mast cell requirement with mast cell–deficient mouse strains, but unexpectedly obtained full arthritis in KitW-sh mice and full resistance in KitW/KitW-v mice. KitW-sh mice were indeed mast cell deficient as assessed by histology and the absence of IgE/mast cell–dependent passive cutaneous anaphylaxis in the ear and joint as well as passive systemic anaphylaxis. Deletion of LILRB4 in KitW-sh mice exacerbated anti-collagen/LPS-induced joint swelling that was abolished by neutrophil depletion, establishing a counterregulatory role for LILRB4 in the absence of mast cells. Whereas blood neutrophil levels and LPS-elicited tissue neutrophilia were equal in KitW-sh and Kit+ mice, both were impaired in KitW/KitW-v mice. Although both strains are mast cell deficient and protected from IgE-mediated anaphylactic reactions, their dramatically different responses to autoantibody-mediated, neutrophil-dependent immune complex arthritis suggest that other host differences determine the extent of mast cell involvement. Thus, a conclusion for an absolute mast cell role in a pathobiologic process requires evidence from both strains.
School education and allergic sensitization in adults
Authors: T. Schäfer, S. Ruhdorfer, L. Weigl, D. Wessner, J. Heinrich, H. ‐ E. Wichmann, J. Ring
Journal: Allergy (2001)

Background: There is evidence of an association between socioeconomic status (SES) and atopy mainly from studies in children which investigated atopic diseases and parental SES. We determined the association of allergic sensitization, as measured by skin prick test (SPT) and allergen‐specific IgE (RAST), and SES in a population‐based study in adults. Methods: Within a population‐based, nested, case‐control study, a standardized interview was performed and allergic sensitization to common aeroallergens was determined by SPT and RAST. Results: A total of 1537 adults (50.4% female, age: median 50.0, range 28‐78 years) were investigated, half of whom (50.2%) exhibited at least one positive RAST result according to the study design. SPT reactivity was 37.3% in this group and was estimated to be 26.1% in the representative study base of 4178 adults. Within increasing categories of school graduation (none; after 8, 10, 13, and &gt;13 years), the prevalence of SPT (20.5%, 31.3%, 44.0%, 44.2%, 48.1%; P trend &lt;0.0001) and RAST reactivity (35.0%, 48.0%, 52.3%, 48.4%, 58.4%; P trend=0.004) increased continuously. Similar results were obtained when testing this association on the level of single allergens. After control for age, sex, and parental history of atopic diseases, all but the first odds ratios for SPT remained significant (first category=reference, 2.06, 3.21, 3.88, 3.96). The same model for RAST reactivity revealed a similar result with effect estimate for the last category being significant (first category=reference, 1.89, 2.08, 2.10, 2.81). Conclusions: Allergic sensitization (SPT and RAST) to common aeroallergens in adults follows a significant and linear association with school education.
Breast Cancer Follow-Up and Management After Primary Treatment: American Society of Clinical Oncology Clinical Practice Guideline Update
Authors: James L. Khatcheressian, Patricia Hurley, Elissa Bantug, Laura J. Esserman, Eva Grunfeld, Francine Halberg, Alexander Hantel, N. Lynn Henry, Hyman B. Muss, Thomas J. Smith, Victor G. Vogel, Antonio C. Wolff, Mark R. Somerfield, Nancy E. Davidson
Journal: Journal of Clinical Oncology (2012)

To provide recommendations on the follow-up and management of patients with breast cancer who have completed primary therapy with curative intent.To update the 2006 guideline of the American Society of Clinical Oncology (ASCO), a systematic review of the literature published from March 2006 through March 2012 was completed using MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed the evidence to determine whether the recommendations were in need of updating.There were 14 new publications that met inclusion criteria: nine systematic reviews (three included meta-analyses) and five randomized controlled trials. After its review and analysis of the evidence, the Update Committee concluded that no revisions to the existing ASCO recommendations were warranted.Regular history, physical examination, and mammography are recommended for breast cancer follow-up. Physical examinations should be performed every 3 to 6 months for the first 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. For women who have undergone breast-conserving surgery, a post-treatment mammogram should be obtained 1 year after the initial mammogram and at least 6 months after completion of radiation therapy. Thereafter, unless otherwise indicated, a yearly mammographic evaluation should be performed. The use of complete blood counts, chemistry panels, bone scans, chest radiographs, liver ultrasounds, pelvic ultrasounds, computed tomography scans, [(18)F]fluorodeoxyglucose-positron emission tomography scans, magnetic resonance imaging, and/or tumor markers (carcinoembryonic antigen, CA 15-3, and CA 27.29) is not recommended for routine follow-up in an otherwise asymptomatic patient with no specific findings on clinical examination.
Quantified Tumor T1 Is a Generic Early-Response Imaging Biomarker for Chemotherapy Reflecting Cell Viability
Authors: Paul M.J. McSheehy, Claudia Weidensteiner, Catherine Cannet, Stephane Ferretti, Didier Laurent, Stephan Ruetz, Michael Stumm, Peter R. Allegrini
Journal: Clinical Cancer Research (2009)

Identification of a generic response biomarker by comparison of chemotherapeutics with different action mechanisms on several noninvasive biomarkers in experimental tumor models.The spin-lattice relaxation time of water protons (T(1)) was quantified using an inversion recovery-TrueFISP magnetic resonance imaging method in eight different experimental tumor models before and after treatment at several different time points with five different chemotherapeutics. Effects on T(1) were compared with other minimally invasive biomarkers including vascular parameters, apparent diffusion coefficient, and interstitial fluid pressure, and were correlated with efficacy at the endpoint and histologic parameters.In all cases, successful chemotherapy significantly lowered tumor T(1) compared with vehicle and the fractional change in T(1) (DeltaT(1)) correlated with the eventual change in tumor size (range: r(2) = 0.21, P < 0.05 to r(2) = 0.73, P < 0.0001), except for models specifically resistant to that drug. In RIF-1 tumors, interstitial fluid pressure was decreased, but apparent diffusion coefficient and permeability increased in response to the microtubule stabilizer patupilone and 5-fluorouracil. Although DeltaT(1) was small (maximum of -20%), the variability was very low (5%) compared with other magnetic resonance imaging methods (24-48%). Analyses ex vivo showed unchanged necrosis, increased apoptosis, and decreased %Ki67 and total choline, but only Ki67 and choline correlated with DeltaT(1). Correlation of Ki67 and DeltaT(1) were observed in other models using patupilone, paclitaxel, a VEGF-R inhibitor, and the mammalian target of rapamycin inhibitor everolimus.These results suggest that a decrease in tumor T(1) reflects hypocellularity and is a generic marker of response. The speed and robustness of the method should facilitate its use in clinical trials.
THE AMYGDALAE AND BEHAVIOR
Authors: JULES H. MASSERMAN, MELVIN LEVITT, THOMAS MCAVOY, ARTHUR KLING, CURTIS PECHTEL
Journal: American Journal of Psychiatry (1958)

The individual and social behavior of 15 cats and 18 rhesus monkeys was recorded and analyzed during a control period of from 3 to 15 months, during which the animals were also trained to solve increasingly complicated problems. Adaptational conflicts were used to induce persistent experimental neuroses in 3 kittens, 2 cats, 3 young monkeys and 8 adult ones. The amygdalae were then totally ablated, with some injury to the surrounding areas, in 6 of the cats and all of the monkeys; in the remaining 9 cats only the lateral or the medial amygdalae were removed. Postoperatively, the cats exhibited: 1. no general amnesia for previous learning; 2. only mild amelioration of neurotic behavior; 3. moderate motor restlessness; 4. variable sexual drive including a phase of hypererotism; 5. markedly altered interactions with other cats and humans; 6. slowed re-learning due to low motivation and erratic or perseverative performance on both simple and complex tasks; and 7. severe disorganization of adaptive behavior after short periods of isolation and inactivity. The adult neurotic animals were: 8. markedly amenable to therapy although the kittens very low resistance to the re-induction of were only mildly so; whereas 9. all showed neuroses. In comparison, the monkeys showed 1. an initial increase in oral activity; 2. extensive amnesia for previous learning, coupled with 3. limited diminution of neurotic symptoms in the young animals as contrasted with almost complete amelioration in the adults; 4. the ability to regain preoperative performance levels on learned problems, although the retraining period was lengthened by altered motivation, restlessness in the testing apparatus, and precipitate or inflexible responses; 5. tolerance of the proximity of or handling by a single human, contrasted with 6. fear responses to other animals or when more than one human was present; 7. increased inter-animal aggression, possibly related to 8. hypersexuality; and 9. diminished resistance to the re-induction of neuroses. The theoretical implications of these finding were briefly considered.