tbuckley/cabot-search huggingface dataset:
Mutation Frequencies and Spectra in DNA Polymerase η–Deficient Mice
Authors: Rita A. Busuttil, Qingcong Lin, Peter J. Stambrook, Raju Kucherlapati, Jan Vijg
Journal: Cancer Research (2008)

Abstract The low-fidelity polymerase η (polη) is required for bypass of UV-induced pyrimidine dimers inserting adenine nucleotides opposite these lesions. Mutations in the polη gene are responsible for the genetic defect in xeroderma pigmentosum variant patients. To study if the lack of polη significantly elevates spontaneous mutation frequency in various organs and tissues of the mouse, we crossed polη-deficient mice with transgenic mice harboring a chromosomally integrated lacZ-plasmid reporter construct. In cultured embryonic fibroblasts from the lacZ-polη−/− mice, 2.5 J/m2 UV irradiation induced ∼5-fold more mutations than in cells from lacZ control mice, in which an ∼3-fold increase in mutation frequency was found compared with the normal level. Whereas untreated cells harbored mainly 1-bp deletions, UV induced both transitions and transversions, with the latter type more highly represented in the polη-null cells than in the controls. No difference in mutation induction between the polη-null cells and the wild-type cells was observed after treatment with N-ethyl-N-nitrosourea. Having shown the validity of the lacZ model to accurately identify polη-associated mutagenesis, we then determined the mutant frequency at the lacZ locus in liver, spleen, and small intestine of 12-month-old animals. No differences were found between polη-null, heterozygous, or littermate control mice. We conclude that the polη defect is specific for UV damage and has no effect on in vivo mutagenesis in mice. [Cancer Res 2008;68(7):2081–4]
Wired for Reproduction: Organization and Development of Sexually Dimorphic Circuits in the Mammalian Forebrain
Authors: Richard B. Simerly
Journal: Annual Review of Neuroscience (2002)

▪ Abstract Mammalian reproduction depends on the coordinated expression of behavior with precisely timed physiological events that are fundamentally different in males and females. An improved understanding of the neuroanatomical relationships between sexually dimorphic parts of the forebrain has contributed to a significant paradigm shift in how functional neural systems are approached experimentally. This review focuses on the organization of interconnected limbic-hypothalamic pathways that participate in the neural control of reproduction and summarizes what is known about the developmental neurobiology of these pathways. Sex steroid hormones such as estrogen and testosterone have much in common with neurotrophins and regulate cell death, neuronal migration, neurogenesis, and neurotransmitter plasticity. In addition, these hormones direct formation of sexually dimorphic circuits by influencing axonal guidance and synaptogenesis. The signaling events underlying the developmental activities of sex steroids involve interactions between nuclear hormone receptors and other transcriptional regulators, as well as interactions at multiple levels with neurotrophin and neurotransmitter signal transduction pathways.
Limitations of stereotactic biopsy in the initial management of gliomas
Authors: Robert J. Jackson, Gregory N. Fuller, Dima Abi-Said, Frederick F. Lang, Ziya L. Gokaslan, Wei Ming Shi, David M. Wildrick, Raymond Sawaya
Journal: Neuro-Oncology (2001)

Stereotactic biopsy is often performed for diagnostic purposes before treating patients whose imaging studies highly suggest glioma. Indications cited for biopsy include diagnosis and/or the "inoperability" of the tumor. This study questions the routine use of stereotactic biopsy in the initial management of gliomas. At The University of Texas M. D. Anderson Cancer Center, we retrospectively reviewed a consecutive series of 81 patients whose imaging studies suggested glioma and who underwent stereotactic biopsy followed by craniotomy/resection (within 60 days) between 1993 and 1998. All relevant clinical and imaging information was reviewed, including computerized volumetric analysis of the tumors based on pre- and postoperative MRI. Stereotactic biopsy was performed at institutions other than M. D. Anderson in 78 (96%) of 81 patients. The majority of tumors were located either in eloquent brain (36 of 81 = 44%) or near-eloquent brain (41 of 81 = 51%), and this frequently was the rationale cited for performing stereotactic biopsy. Gross total resection (>95%) was achieved in 46 (57%) of 81 patients, with a median extent of resection of 96% for this series. Diagnoses based on biopsy or resection in the same patient differed in 40 (49%) of 82 cases. This discrepancy was reduced to 30 (38%) of 80 cases when the biopsy slides were reviewed preoperatively by each of three neuropathologists at M. D. Anderson. Major neurologic complications occurred in 10 (12.3%) of 81 surgical patients and 3 (3.7%) of 81 patients undergoing biopsy. Surgical morbidity was probably higher in our series than it would be for glioma patients in general because our patients represent a highly selected subset of glioma patients whose tumors present a technical challenge to remove. Stereotactic biopsy is frequently inaccurate in providing a correct diagnosis and is associated with additional risk and cost. If stereotactic biopsy is performed, expert neuropathology consultation should be sought.
Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice
Authors: H Yoshiji
Journal: Gut (2005)

Orchestration of two major classes of angiogenic factors-namely, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2)-has been shown to play a pivotal role in tumour angiogenesis, including hepatocellular carcinoma (HCC). However, few studies have focused on the direct interaction of these factors on in vivo tumour development and angiogenesis.To examine the interaction between both factors in murine HCC.We examined the combination effect of VEGF and Ang-2 overexpression by means of a combination of a retroviral tetracycline (tet) regulated gene manipulating system in vivo, by providing tet in the drinking water, and a conventional plasmid gene expression system.Neither Ang-2 nor VEGF overexpression induced proliferation of HCC cells in vitro. In vivo, although overexpression of Ang-2 did not increase tumour development, simultaneous expression of Ang-2 and VEGF synergistically augmented tumour growth and angiogenesis in murine HCC. Ang-2 plus VEGF induced tumour development was markedly attenuated by treatment with neutralising monoclonal antibodies against VEGF receptors. Ang-2 plus VEGF overexpression significantly increased the activities of matrix metalloproteinase (MMP)-2 and MMP-9 in the tumour. Suppression of intratumoral VEGF almost completely abolished this augmentation of MMPs.These results suggest that Ang-2 synergistically augments VEGF mediated HCC development and angiogenesis. This proangiogenic activity was exerted only in the presence of VEGF, at least partly mediated via induction of MMP-2 and MMP-9 in the tumour.
Complete Pathologic Response After Preoperative Chemotherapy for Colorectal Liver Metastases: Myth or Reality?
Authors: René Adam, Dennis A. Wicherts, Robbert J. de Haas, Thomas Aloia, Francis Lévi, Bernard Paule, Catherine Guettier, Francis Kunstlinger, Valérie Delvart, Daniel Azoulay, Denis Castaing
Journal: Journal of Clinical Oncology (2008)

Purpose Complete clinical response (CCR) of colorectal liver metastases (CLM) following chemotherapy is of limited predictive value for complete pathologic response (CPR) and cure of the disease. The objective of this study was to determine predictive factors of CPR as well as its impact on survival. Patients and Methods From January 1985 to July 2006, 767 consecutive patients with CLM underwent liver resection after systemic chemotherapy. Patients with CPR were compared with patients without CPR. Results Twenty-nine of 767 (4%) patients had CPR, and none of these 29 patients had CCR. Patients with CPR (mean age, 54 years) had a mean number of 3.3 metastases at diagnosis (mean size, 29.3 mm). Objective response and stable disease were observed in 79% and 21% of cases, respectively. Postoperative mortality rate was 0%. After a median follow-up of 52.2 months (range, 1.1 to 193.0 months), overall 5-year survival was 76% for patients with CPR compared with 45% for patients without CPR (P = .004). Independent predictive factors for CPR were: age ≤ 60 years, size of metastases ≤ 3 cm at diagnosis, carcinoembryonic antigen (CEA) level at diagnosis ≤ 30 ng/mL, and objective response following chemotherapy. The probability of CPR ranged from 0.2% when all factors were absent to 30.9% when all were present. Conclusion CPR was observed in 4% of patients with CLM treated with preoperative chemotherapy. However, CPR may occur in almost one-third of objective responders age ≤ 60 years with metastases ≤ 3 cm and low CEA values. CPR is associated with uncommon high survival rates.
Short term effects of corticosteroid pulse treatment on disease activity and the wellbeing of patients with active rheumatoid arthritis
Authors: J W G Jacobs
Journal: Annals of the Rheumatic Diseases (2001)

To investigate the short term effects of corticosteroid pulse treatment (CPT) on disease activity, functional ability, and psychological wellbeing of patients with active rheumatoid arthritis (RA).Of 66 consecutive patients with active RA admitted for CPT, erythrocyte sedimentation rate, C reactive protein level, haemoglobin concentration, platelet count, duration of early morning stiffness, a joint score, and grip strength were assessed before and after CPT. Additionally, a health status questionnaire was administered. Effects of CPT were expressed as before to after intervention effect sizes and, to place them in perspective, compared with the (long term) effect sizes of disease modifying antirheumatic drug (DMARD) treatment in a historical contrast group of patients with early RA.Statistically significant improvement from baseline in disease activity, physical functioning, and psychological wellbeing after CPT was seen, with moderate to large effect sizes, resembling the effects seen after DMARD treatment. Neither depression nor psychosis occurred during and after CPT.Qualitatively and quantitatively the short term effects of CPT in patients with active established RA on various dimensions of health status resemble the long term effects of conventional DMARD treatment in patients with early RA. Psychological disorders do not seem to be common short term side effects of CPT in patients with active RA.
G Protein Modulation of Voltage-Gated Calcium Channels
Authors: Annette C. Dolphin
Journal: Pharmacological Reviews (2003)

Calcium influx into any cell requires fine tuning to guarantee the correct balance between activation of calcium-dependent processes, such as muscle contraction and neurotransmitter release, and calcium-induced cell damage. G protein-coupled receptors play a critical role in negative feedback to modulate the activity of the CaV2 subfamily of the voltage-dependent calcium channels, which are largely situated on neuronal and neuro-endocrine cells. The basis for the specificity of the relationships among membrane receptors, G proteins, and effector calcium channels will be discussed, as well as the mechanism by which G protein-mediated inhibition is thought to occur. The inhibition requires free G beta gamma dimers, and the cytoplasmic linker between domains I and II of the CaV2 alpha 1 subunits binds G beta gamma dimers, whereas the intracellular N terminus of CaV2 alpha 1 subunits provides essential determinants for G protein modulation. Evidence suggests a key role for the beta subunits of calcium channels in the process of G protein modulation, and the role of a class of proteins termed "regulators of G protein signaling" will also be described.
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
Authors: S Vincent Rajkumar, Meletios A Dimopoulos, Antonio Palumbo, Joan Blade, Giampaolo Merlini, María-Victoria Mateos, Shaji Kumar, Jens Hillengass, Efstathios Kastritis, Paul Richardson, Ola Landgren, Bruno Paiva, Angela Dispenzieri, Brendan Weiss, Xavier LeLeu, Sonja Zweegman, Sagar Lonial, Laura Rosinol, Elena Zamagni, Sundar Jagannath, Orhan Sezer, Sigurdur Y Kristinsson, Jo Caers, Saad Z Usmani, Juan José Lahuerta, Hans Erik Johnsen, Meral Beksac, Michele Cavo, Hartmut Goldschmidt, Evangelos Terpos, Robert A Kyle, Kenneth C Anderson, Brian G M Durie, Jesus F San Miguel
Journal: The Lancet Oncology (2014)
Methacholine-induced volume dependence of respiratory resistance in preschool children
Authors: F Marchal, N Loos, P Monin, R Peslin
Journal: European Respiratory Journal (1999)

Enhanced negative volume dependence of airway resistance is associated with bronchoconstriction in tracheostomized paralysed open-chest animals. Significant upper airways responses may be associated with bronchoconstriction and could thereby alter the pattern of volume dependence in spontaneously breathing subjects. The aim of the study was to test whether volume dependence of respiratory resistance (Rrs) could be demonstrated in preschool children undergoing routine methacholine challenge. The volume dependence of respiratory oscillation resistance at 12 and 20 Hz (Rrs,12 and Rrs,20) was examined in eight 4-5.5-yr-old children showing a positive response to methacholine. Multiple linear regression analysis was also used to account for flow dependence during tidal breathing (Rrs,12 or Rrs,20=K1+K2 inverted question markV' inverted question mark+K3V). Rrs,12 and Rrs,20 yielded similar results. Negative volume dependence was present at baseline and significantly enhanced by methacholine (p&lt;0.01). For instance, the mean+/-SD inspiratory K3 at 20 Hz was 4.1+/-1.3 hPa x s x L(-2) at baseline and -15.0+/-4.3 hPa x s x L(-2) after methacholine, in which case it was also larger on expiration than on inspiration (p&lt;0.05), possibly as a result of upper airway responses. A significant increase in the negative volume dependence of respiratory resistance may thus be shown in preschool children in response to methacholine. The volume dependence (K3) during inspiration may be particularly useful in detecting bronchoconstriction, because it is less likely to be affected by upper airway mechanisms than during expiration.
Tryptophan rich diet as a new approach to study the serotoninergic enteropancreatic axis.
Authors: B Goke, G Richter, V Keim, R Arnold
Journal: Gut (1987)

The influence of a tryptophan enriched diet (L-tryptophan added as 1% of total diet), fed over 10 days, on the rat duodenum and pancreas was studied by immunohistology, measurements of serotonin and tryptophan tissue concentrations by HPLC, and incubations of pancreatic lobules. Ingestion of a tryptophan enriched diet resulted in increased contents of tryptophan and serotonin in the duodenum that was not accompanied by a significant change of the serotonin cell density. Neither basal nor CCK-stimulated amylase release from isolated pancreatic lobules was altered after tryptophan enriched food. Although serotonin could be extracted from the pancreas, no increase in serotonin concentration was detected after ingestion of the tryptophan diet. A 'serotonin loading' diet may be a useful tool to study the significance of amines produced by gut endocrine cells in respects to enteropancreatic connections.
Visual Object Recognition
Authors: Nikos K. Logothetis, David L. Sheinberg
Journal: Annual Review of Neuroscience (1996)

Visual object recognition is of fundamental importance to most animals. The diversity of tasks that any biological recognition system must solve suggests that object recognition is not a single, general purpose process. In this review, we consider evidence from the fields of psychology, neuropsychology, and neurophysiology, all of which supports the idea that there are multiple systems for recognition. Data from normal adults, infants, animals, and brain damaged patients reveal a major distinction between the classification of objects at a basic category level and the identification of individual objects from a homogeneous object class. An additional distinction between object representations used for visual perception and those used for visually guided movements provides further support for a multiplicity of visual recognition systems. Recent evidence from psychophysical and neurophysiological studies indicates that one system may represent objects by combinations of multiple views, or aspects, and another may represent objects by structural primitives and their spatial interrelationships.
Comment on Pepino et al. Sucralose Affects Glycemic and Hormonal Responses to an Oral Glucose Load. Diabetes Care 2013;36:2530–2535
Authors: V. Lee Grotz, Jeremy D. Jokinen
Journal: Diabetes Care (2014)

We are interested in the recent publication by Pepino et al. (1), given that the body of evidence supports the safe use of sucralose.

Pepino et al. was a small, nonblinded, randomized, cross-over study in a select group of mostly female (15/17), predominantly African American (13/17), relatively young (mean age 35 years), morbidly obese (BMI 42.3 ± 1.6 kg/m2), insulin-sensitive subjects. The study evaluated the response to a 75-g oral glucose tolerance test (OGTT) conducted 10 min after consumption of 60 mL of either distilled water or an aqueous 2 mmol/L sucralose solution. OGTTs were conducted about 1 week apart in the morning after a self-reported overnight fast.

While a statistically significant difference in peak plasma glucose …
Synovial synoviolin in relation to response to TNF blockade in patients with rheumatoid arthritis and psoriatic arthritis
Authors: R Klaasen, C A Wijbrandts, A W van Kuijk, D Pots, D M Gerlag, P P Tak
Journal: Annals of the Rheumatic Diseases (2012)

Recently, synoviolin, a novel E3 ubiquitin ligase, was identified in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and synovial tissue, where it may contribute to the dysregulated proliferation and apoptosis seen in RA.1 2 Synoviolin expression is also associated with arthritis development in mice.1 The exact mechanism of synoviolin regulation and expression remains to be elucidated, but recently a role for tumour necrosis factor α (TNFα) and interleukin 1b was suggested as these cytokines increased the expression of synoviolin in RA FLS.3 Another interesting observation is that high level sustained expression of synoviolin in whole peripheral blood was related to decreased clinical response in RA patients treated with TNF blockade.4 Therefore, we investigated synoviolin expression in synovium and its relationship to later response to TNF blockade in patients with RA compared with psoriatic arthritis (PsA) and osteoarthritis (OA).

Synovial tissue samples were obtained …
Cocultures of adult ventricular myocytes with stellate ganglia or intrinsic cardiac neurones from guinea pigs: spontaneous activity and pharmacological properties
Authors: M Horackova, M H Huang, J A Armour, D A Hopkins, C Mapplebeck
Journal: Cardiovascular Research (1993)

The aim was to develop long term primary cocultures of adult ventricular myocytes with autonomic neurones dissociated from stellate or intrinsic cardiac ganglia. This was to provide an experimental model for the investigation of the regulatory role of autonomic neurones with respect to cardiac myocyte function.Ventricular myocytes and stellate and intrinsic cardiac neurones were enzymatically dissociated from adult male guinea pigs and plated together on 13 mm cover slips; the cultures were maintained in an incubator for two to 10 weeks. The electrical properties of cultured myocytes and neurones were investigated by means of a conventional microelectrode technique and the spontaneous contractile activity of the myocytes was recorded by a video system. The electrical, contractile, and pharmacological properties of myocyte-neuronal networks were investigated by superfusing the cultures with various neuromodulators and blockers.The electrical properties of the cultured myocytes and neurones were similar to those reported in other in vitro studies. Innervated and non-innervated cardiomyocyte cultures responded differently, however, to various pharmacological interventions. Spontaneous contractions were attenuated by tetrodotoxin (4 x 10(-7) M), beta adrenergic blockade, and nicotinic blockade more in cocultures than in cardiac myocyte cultures alone. On the other hand, the beta agonist isoproterenol increased the spontaneous beating in both types of cocultures more than in myocytes alone. The effects of the muscarinic agonist bethanechol and the muscarinic blocker atropine were not significantly different in innervated and non-innervated cultures. Nicotine induced either an increase or decrease in contractile rates of both cocultures and did not affect non-innervated myocyte cultures.Cocultures of myocytes and autonomic neurones alter the responses of myocytes relative to cultures without neurones. The results suggest that functional contacts can be established between adult myocytes and dissociated neurones in primary cultures. Contractile rates of such myocyte cultures are influenced by the presence of neurones. Neurones innervating these cultures were modified by beta adrenergic, muscarinic, and nicotinic agents.
Copy-neutral loss of heterozygosity and chromosome gains and losses are frequent in gastrointestinal stromal tumors
Authors: Nelson Lourenço, Zofia Hélias-Rodzewicz, Jean-Baptiste Bachet, Sabrina Brahimi-Adouane, Fabrice Jardin, Jeanne Tran van Nhieu, Frédérique Peschaud, Emmanuel Martin, Alain Beauchet, Frédéric Chibon, Jean-François Emile
Journal: Molecular Cancer (2014)

A KIT gain of function mutation is present in 70% of gastrointestinal stromal tumors (GISTs) and the wild-type (WT) allele is deleted in 5 to 15% of these cases. The WT KIT is probably deleted during GIST progression. We aimed to identify the mechanism of WT KIT loss and to determine whether other genes are involved or affected. Whole-genome SNP array analyses were performed in 22 GISTs with KIT exon 11 mutations, including 11 with WT loss, to investigate the mechanisms of WT allele deletion. CGH arrays and FISH were performed in some cases. Common genetic events were identified by SNP data analysis. The 9p21.3 locus was studied by multiplex quantification of genomic DNA. Chromosome instability involving the whole chromosome/chromosome arm (whole C/CA) was detected in 21/22 cases. The GISTs segregated in two groups based on their chromosome number: polyGISTs had numerous whole C/CA gains (mean 23, range [9 to 43]/3.11 [1 to 5]), whereas biGISTs had fewer aberrations. Whole C/CA losses were also frequent and found in both groups. There were numerous copy-neutral losses of heterozygosity (cnLOH) of whole C/CA in both polyGIST (7/9) and biGIST (9/13) groups. cnLOH were frequent on 4q, 11p, 11q, 1p, 2q, 3p and 10, and never involved 12p, 12q, 20p, 20q or 19q. Other genetic alterations included segmental chromosome abnormalities, complete bi-allelic deletions (homozygous deletions) and, more rarely, amplifications. Nine of 11 GISTs with homozygous KIT exon 11 mutations had cnLOH of chromosome 4. The cnLOH of whole C/CA is a frequent genetic alteration in GISTs and is closely associated with homozygous mutations of KIT and WT allele deletion.