tbuckley/cabot-search huggingface dataset:
Differentiation of adult rat cardiac myocytes in cell culture.
Authors: L B Bugaisky, R Zak
Journal: Circulation Research (1989)

Cardiac myocytes isolated from adult rat hearts were grown on laminin coated culture dishes for more than a month. During this time, the cells underwent a morphological transformation which has also been referred to by others as cell remodeling (Guo J-X, Jacobson SL, Brown DL: Cell Mot Cytoskeleton 1986;6:291-304). This results in a change in myocyte morphology from its typical in vivo cylindrical shape to one which is more pleiomorphic. Despite the long-term change in morphology, myocytes expressed for differing lengths of time several aspects of the adult phenotype as evidenced by the following: 1) maintenance of cylindrical shape and/or evident cross-striations for the first 24-48 hours in culture, 2) reappearance of cross-striations during the second week in culture, 3) little or no spontaneous contractility for the first 4 days in culture, 4) expression of only the V1 isoform of myosin for at least 7 days, and 5) altered myosin isoform expression in response to changes in environmental conditions. These factors taken together suggest that in culture the adult cardiac myocyte remains a highly differentiated cell (as opposed to possible dedifferentiation) and maintains many of its previous in vivo characteristics. Such highly differentiated adult cells should be suitable as an in vitro system for studying the direct cellular effects of factors which regulate growth and differentiation of the in vivo heart.
Identification of gases responsible for the odour of human flatus and evaluation of a device purported to reduce this odour
Authors: F L Suarez, J Springfield, M D Levitt
Journal: Gut (1998)

Background/Aims —While the social significance of flatus derives mainly from its odour, previous studies have focused on the non-odoriferous components of rectal gas. The aims of the present study were to determine the role of sulphur-containing gases in flatus odour and test the efficacy of a device purported to reduce this odour. Methods —Flatus was quantitatively collected via rectal tube from 16 healthy subjects who ingested pinto beans and lactulose to enhance flatus output. The concentrations of sulphur-containing gases in each passage were correlated with odour intensity assessed by two judges. Odour intensity was also determined after treatment of flatus samples with zinc acetate, which binds sulphydryl compounds (hydrogen sulphide and methanethiol), or activated charcoal. Utilising gas-tight Mylar pantaloons, the ability of a charcoal lined cushion to adsorb sulphur-containing gases instilled at the anus of eight subjects was assessed. Results —The main sulphur-containing flatus component was hydrogen sulphide (1.06 (0.2) μmol/l), followed by methanethiol (0.21 (0.04) μmol/l) and dimethyl sulphide (0.08 (0.01) μmol/l) (means (SEM)). Malodour significantly correlated with hydrogen sulphide concentration (p⩽0.001). Zinc acetate reduced sulphur gas content but did not totally eliminate odour, while activated charcoal removed virtually all odour. The cushion adsorbed more than 90% of the sulphur gases. Conclusion —Sulphur-containing gases are the major, but not the only, malodorous components of human flatus. The charcoal lined cushion effectively limits the escape of these sulphur-containing gases into the environment.
Lifestyle and Metformin Interventions Have a Durable Effect to Lower CRP and tPA Levels in the Diabetes Prevention Program Except in Those Who Develop Diabetes
Authors: Ronald B. Goldberg, Marinella G. Temprosa, Kieren J. Mather, Trevor J. Orchard, Abbas E. Kitabchi, Karol E. Watson
Journal: Diabetes Care (2014)

We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes.The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS).CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response.Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels.
Myostatin, the cardiac chalone of insulin-like growth factor-1
Authors: V GAUSSIN, C DEPRE
Journal: Cardiovascular Research (2005)

See article by Shyu et al. [2] (pages 405–414) in this issue. 

In the 1960s, Bullough introduced the concept of chalones, inhibitors of cell growth that provide a negative feedback mechanism to control the size of a specific tissue [1]. In a very elegant study in this issue, Shu et al. [2] demonstrate that myostatin represents a chalone of the insulin-like growth factor-1 (IGF-1) pathway in the heart.

The IGF-1 signaling pathway, as summarized in Fig. 1A, represents an important physiological mechanism of cardiac cell growth that is initiated upon binding of IGF-1 to a tyrosine–kinase receptor (IGFR) very similar to the insulin receptor. When activated, the IGFR phosphorylates the insulin receptor substrate-1 (IRS-1). Tyrosine phosphorylated IRS-1 is a docking protein for the phosphatidylinositol 3-kinase (PI3K), which in turn activates the protein kinase Akt. IGFR can also bind adapter proteins such as Sos-2, which activates the proto-oncogene Ras and thereby the MAP kinases ERK1 and ERK2 (or p42/p44 MAP kinases). As illustrated in Fig. 1A, these two signaling pathways mediate most of the effects of IGF-1 in the heart, which are very reminiscent of the effects of insulin. ERK1/2 stimulates cell growth through activation of specific transcription factors (such as Elk-1 or GATA), whereas Akt stimulates glucose metabolism and cell growth [3] and prevents apoptosis [4].



Fig. 1 
Summary of the IGF-1 signaling pathway (panel A) and … 



*Corresponding author. Tel.: +1 973 972 3926; fax: +1 973 972 7489. Email address: deprech{at}umdnj.edu
Computational tools for the study of allergens
Authors: V. Brusic, N. Petrovsky, S. M. Gendel, M. Millot, O. Gigonzac, S. J. Stelman
Journal: Allergy (2003)

Allergy is a major cause of morbidity worldwide. The number of characterized allergens and related information is increasing rapidly creating demands for advanced information storage, retrieval and analysis. Bioinformatics provides useful tools for analysing allergens and these are complementary to traditional laboratory techniques for the study of allergens. Specific applications include structural analysis of allergens, identification of B‐ and T‐cell epitopes, assessment of allergenicity and cross‐reactivity, and genome analysis. In this paper, the most important bioinformatic tools and methods with relevance to the study of allergy have been reviewed.
On the binding of tumor necrosis factor (TNF) to heparin and the release in vivo of the TNF-binding protein I by heparin.
Authors: M Lantz, H Thysell, E Nilsson, I Olsson
Journal: Journal of Clinical Investigation (1991)

Tumor necrosis factor (TNF), a protein released by activated macrophages, is a central mediator of the host response to infection and inflammation. The TNF-binding protein I (TNF-BP-I) is a soluble fragment of the p60 transmembrane TNF receptor and an antagonist to TNF. The level of serum TNF-BP-I was found to be increased in patients with renal insufficiency as a result of a decrease in the glomerular filtration rate. During hemodialysis of patients with renal failure there was a rapid but transient increase in serum TNF-BP-I. This increase was found to be caused by heparin given before dialysis and a similar dose-dependent response to heparin was observed also in healthy individuals. The finding of a repeated release of TNF-BP-I into the circulation with intermittent injections of heparin indicates that TNF-BP-I is present both in a storage pool and in a circulating pool. The mechanism for the heparin-mediated release of TNF-BP-I was not explained; TNF-BP did not show affinity for heparin. On the other hand, TNF was found to have affinity for heparin and it could also be dissociated from heparin by TNF-BP-I. It is suggested that heparin-like molecules of the extracellular matrix can retain TNF in physical proximity with target cells and restrict the actions of TNF and protect against systemic harmful manifestations.
Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781
Authors: Carmen A. Banuelos, Judit P. Banáth, Susan H. MacPhail, Jin Zhao, Tarren Reitsema, Peggy L. Olive
Journal: Clinical Cancer Research (2007)

Abstract Purpose: PCI-24781 is a novel broad spectrum histone deacetylase inhibitor that is currently in phase I clinical trials. The ability of PCI-24781 to act as a radiation sensitizer and the mechanisms of radiosensitization were examined. Experimental Design: Exponentially growing human SiHa cervical and WiDr colon carcinoma cells were exposed to 0.1 to 10 μmol/L PCI-24781 in vitro for 2 to 20 h before irradiation and 0 to 4 h after irradiation. Single cells and sorted populations were analyzed for histone acetylation, H2AX phosphorylation, cell cycle distribution, apoptotic fraction, and clonogenic survival. Results: PCI-24781 treatment for 4 h increased histone H3 acetylation and produced a modest increase in γH2AX but negligible cell killing or radiosensitization. Treatment for 24 h resulted in up to 80% cell kill and depletion of cells in S phase. Toxicity reached maximum levels at a drug concentration of ∼1 μmol/L, and cells in G1 phase at the end of treatment were preferentially spared. A similar dose-modifying factor (DMF0.1 = 1.5) was observed for SiHa cells exposed for 24 h at 0.1 to 3 μmol/L, and more radioresistant WiDr cells showed less sensitization (DMF0.1 = 1.2). Limited radiosensitization and less killing were observed in noncycling human fibroblasts. Cell sorting experiments confirmed that depletion of S-phase cells was not a major mechanism of radiosensitization and that inner noncycling cells of SiHa spheroids could be sensitized by nontoxic doses. PCI-24781 pretreatment increased the fraction of cells with γH2AX foci 24 h after irradation but did not affect the initial rate of loss of radiation-induced γH2AX or the rate of rejoining of DNA double-strand breaks. Conclusions: PCI-24781 shows promise as a radiosensitizing agent that may compromise the accuracy of repair of radiation damage.
Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline
Authors: Natasha B. Leighl, Natasha Rekhtman, William A. Biermann, James Huang, Mari Mino-Kenudson, Suresh S. Ramalingam, Howard West, Sara Whitlock, Mark R. Somerfield
Journal: Journal of Clinical Oncology (2014)

Purpose The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) guideline on molecular testing for the selection of patients with lung cancer for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors was considered for endorsement. Methods American Society of Clinical Oncology (ASCO) staff reviewed the CAP/IASLC/AMP guideline for developmental rigor; an ASCO ad hoc review panel of experts reviewed the guideline content. Results The ASCO panel concurred that the recommendations are clear, thorough, and based on the most relevant scientific evidence in this content area and present options that will be acceptable to patients. The CAP/IASLC/AMP guideline comprises 37 recommendations (evidence grade A or B), expert consensus opinions, or suggestions that address the following five principal questions: (1) When should molecular testing be performed? (2) How should EGFR testing be performed? (3) How should ALK testing be performed? (4) Should other genes be routinely tested in lung adenocarcinoma? (5) How should molecular testing be implemented and operationalized? Conclusion The ASCO review panel endorses the CAP/IASLC/AMP guideline. This guideline represents an important advance toward standardization of EGFR and ALK testing practices and is of major clinical relevance in advancing the care of patients with lung cancer. In the Discussion section, the ASCO review panel highlights three evolving areas: advances in ALK testing methodology, considerations for selecting appropriate populations for molecular testing, and emergence of other targetable molecular alterations.
HSPA12B and repairing the heart: beauty in simplicity
Authors: Fouad A. Zouein, Mazen Kurdi, George W. Booz
Journal: Cardiovascular Research (2013)

This editorial refers to ‘HSPA12B attenuates cardiac dysfunction and remodelling after myocardial infarction through an eNOS-dependent mechanism’ by J. Li et al ., pp. 671–681, this issue. 

HSPA12B is a member of a newly identified subfamily of the Hsp70 family of heat shock proteins and is predominately expressed in endothelial cells.1,2 Blood pressure may play a role in its expression, as HSPA12B is expressed in endothelial cells in heart, adipose tissue, brain, kidney, and lung, but not in liver sinusoidal endothelial cells.1 In the heart and brain, vessels of all sizes express HSPA12B, whereas in lung and adipose tissue, expression is largely in capillaries. The cell-restricted expression of HSPA12B, which is otherwise not a feature of heat shock proteins, alone presages its importance to endothelial cell function and indeed studies have established that HSPA12B is required for angiogenesis, specifically in the processes of adhesion, migration, and tube formation.1,2 Endothelial cell HSPA12B expression seems to be dynamic and is increased in confluent HUVEC cultures kept in medium containing endothelial cell-specific growth factors, by heat shock, and during tubule formation.1–3 Protein levels are likely regulated by a post-transcriptional mechanism as well.1 Twenty-two putative client proteins have been identified for HSPA12B, including AKAP12 (A-kinase-anchoring protein 12) and hPODXL (human podocalyxin-like), both of which are implicated in cell adhesion, and aryl hydrocarbon receptor nuclear translocator (ARNT).1

HSPA12B also has protective actions in endothelial cells. Transgenic mice overexpressing the human hspa12b gene (including the endothelial cell-specific promoter) were found to be remarkably protected …
<i>Introduction Biologique a lêtude de Ia Neurologie et de Ia Psychopathologie Integration et Désintégration de la Function.</i>By C. V. Monaxow<i>et</i>R. Mourgue. (<i>Paris: Librairie Félix Alcan, 1928.</i>)
Authors: John Notkin
Journal: American Journal of Psychiatry (1931)
Increases in the number of brain metastases detected at frame-fixed, thin-slice MRI for gamma knife surgery planning
Authors: A. Nagai, Y. Shibamoto, Y. Mori, C. Hashizume, M. Hagiwara, T. Kobayashi
Journal: Neuro-Oncology (2010)

For gamma knife planning, 2.4-mm-slice MRIs are taken under rigid frame fixation, so tiny tumors become visible. This study evaluated differences in the numbers of brain metastases between conventional contrast-enhanced MRI (6 ± 1 mm slice thickness) taken before patient referral and contrast-enhanced MRI for gamma knife planning. The numbers of metastases on the 2 images were counted by at least 2 oncologists. For gamma knife planning, spoiled gradient-recalled echo images were obtained after 0.1 mmol/kg gadolinium administration using a 1.5-T system. Images from 1045 patients with an interval between the 2 MRI studies of 6 weeks or less were analyzed. Increases in the number of metastases were found in 33.7% of the 1045 patients, whereas the number was identical in 62.3%. In 4.0%, the number decreased, indicating overdiagnosis at conventional MRI. These proportions did not differ significantly by the interval before gamma knife. An increase from single to multiple metastases was found in 16.0%. Meningeal dissemination was newly diagnosed in 2.3%. On planning images, the proportions of patients with 1, 2, 3, and 4 or more lesions were 37.6%, 19.3%, 9.3%, and 33.8%, respectively. In cases of colorectal cancer and hepatoma, the proportions of patients with a single metastasis (32 of 61 [52%] and 5 of 6 [83%], respectively) were higher than that of patients with other malignancies. In about one-third of the patients, an increased number of metastases were found on the thin-slice images. This should be kept in mind when deciding the treatment strategy for brain metastases.
Model Describing the Relationship Between Pharmacokinetics and Hematologic Toxicity of the Epirubicin-Docetaxel Regimen in Breast Cancer Patients
Authors: M. Sandström, H. Lindman, P. Nygren, E. Lidbrink, J. Bergh, M.O. Karlsson
Journal: Journal of Clinical Oncology (2004)

Purpose The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients. Patients and Methods Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m 2 . Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m 2 ) or reduced (minimum, 40/50 mg/m 2 ). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment. Results In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data. Conclusion The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.
Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia
Authors: Jonathan M. Gall, Zhiyong Wang, Ramon G. Bonegio, Andrea Havasi, Marc Liesa, Pradheep Vemula, Steven C. Borkan
Journal: Journal of the American Society of Nephrology (2014)

Proximal tubule (PT) cells are critical targets of acute ischemic injury. Elimination of the mitochondrial fusion protein mitofusin 2 (Mfn2) sensitizes PT cells to apoptosis in vitro. However, the role of PT Mfn2 in ischemic AKI in vivo is unknown. To test its role, we evaluated the effects of conditional KO of PT Mfn2 (cKO-PT-Mfn2) on animal survival after transient bilateral renal ischemia associated with severe AKI. Forty-eight hours after ischemia, 28% of control mice survived compared with 86% of cKO-PT-Mfn2 animals (P<0.001 versus control). Although no significant differences in histologic injury score, apoptosis, or necrosis were detected between genotypes, cKO-PT-Mfn2 kidneys exhibited a 3.5-fold increase in cell proliferation restricted to the intrarenal region with Mfn2 deletion. To identify the signals responsible for increased proliferation, primary PT cells with Mfn2 deficiency were subjected to stress by ATP depletion in vitro. Compared with normal Mfn2 expression, Mfn2 deficiency significantly increased PT cell proliferation and persistently activated extracellular signal–regulated kinase 1/2 (ERK1/2) during recovery from stress. Furthermore, stress and Mfn2 deficiency decreased the interaction between Mfn2 and Ras detected by immunoprecipitation, and purified Mfn2 dose-dependently decreased Ras activity in a cell-free assay. Ischemia in vivo also reduced the Mfn2-RAS interaction and increased both RAS and p-ERK1/2 activity in the renal cortical homogenates of cKO-PT-Mfn2 mice. Our results suggest that, in contrast to its proapoptotic effects in vitro, selective PT Mfn2 deficiency accelerates recovery of renal function and enhances animal survival after ischemic AKI in vivo, partly by increasing Ras-ERK–mediated cell proliferation.
Prognostic Significance of Basal-Like Phenotype and Fascin Expression in Node-Negative Invasive Breast Carcinomas
Authors: Socorro María Rodríguez-Pinilla, David Sarrió, Emiliano Honrado, David Hardisson, Francisco Calero, Javier Benitez, José Palacios
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Basal-like phenotype tumors are frequently found among BRCA1 germ-line mutated breast carcinomas. They are biologically aggressive and have a tendency towards visceral metastasis when untreated. Nevertheless, it has been suggested that they respond to chemotherapy better than other types of tumors. Fascin expression has been associated with lung metastasis in breast cancer. The aim of this study was to determine whether basal-like phenotype and fascin were related in both sporadic and familial tumors and with prognosis in node-negative sporadic breast cancers. Experimental design: 230 nonfamilial and 28 hereditary node-negative invasive breast carcinomas were immunohistochemically analyzed using tissue microarrays. Tumors that were estrogen receptor/HER2 negative and cytokeratin 5/6 and/or epidermal growth factor receptor positive were considered to have a basal-like phenotype. Results: A basal-like phenotype was found in 11.9% of sporadic cancers. Among patients not receiving adjuvant chemotherapy, a basal-like phenotype was associated with poor prognosis (P = 0.001, log-rank test) whereas no such association was found in patients receiving it. Tumors with a basal-like phenotype showed local recurrence (17.4%) or visceral metastasis (13%) but not bone metastasis (P = 0.001). Fascin expression was observed in 25.1% of sporadic invasive breast carcinomas and was associated with the basal-like phenotype, but not with prognosis or recurrence pattern. Fascin was expressed in 83.3% and 16.7% BRCA1- and BRCA2-associated carcinomas, respectively (P = 0.048). Conclusions: Basal-like tumors had a tendency towards visceral metastasis and their prognosis was dependent on the use of postoperative chemotherapy. Although fascin expression was associated with the basal-like phenotype, it was not associated with their metastatic behavior. Fascin expression is frequent in BRCA1-associated tumors.