tbuckley/cabot-search huggingface dataset:
Chemokine (C-C Motif) Ligand 2 Mediates the Prometastatic Effect of Dysadherin in Human Breast Cancer Cells
Authors: Jeong-Seok Nam, Mi-Jin Kang, Adam M. Suchar, Takeshi Shimamura, Ethan A. Kohn, Aleksandra M. Michalowska, V. Craig Jordan, Setsuo Hirohashi, Lalage M. Wakefield
Journal: Cancer Research (2006)

Abstract Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-κB pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo. This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer. (Cancer Res 2006; 66(14): 7176-84)
Alterations in Expression of Cadherin&amp;ndash;6 and E&amp;ndash;Cadherin during Kidney Development and in Renal Cell Carcinoma
Authors: Toru Shimazui, Jeannette Oosterwijk-Wakka, Hideyuki Akaza, Pierre Paul Bringuier, Emiel Ruijter, Frans M.J. Debruyne, Jack A. Schalken, Egbert Oosterwijk
Journal: European Urology (2000)
A new method for isolating the nonidentical protein subunits of human plasma α-lipoprotein
Authors: Daniel Rudman, Luis A. Garcia, Carolyn H. Howard
Journal: Journal of Clinical Investigation (1970)

Human plasma alpha lipoprotein (αLP) was totally delipidated by gel filtration on Sephadex LH-20 in a medium of 2 butanol:acetic acid:H2O, 4:1:5. The resulting alpha protein (αP) exhibited two major bands, labeled C and D, on acrylamide-gel electrophoresis in 5.0 M urea at pH 8.8 or 4.0. Minor bands labeled A and B, also present, were shown to be aggregates of C which form when the latter is lyophilized. The C and D components were isolated in pure form from αP (prepared by LH-20 chromatography of αLP) by gel filtration of this protein on Sephadex G-200 in a medium of 1.0 N acetic acid: the C component emerged with a distribution coefficient (Kd) of 0.4, and the D component with a coefficient of 0.7. From each 100 mg of αP, 68 mg of C and 22 mg of D were isolated. 3 mg of a minor fraction with Kd 0.1, containing A and B components as well as C, were also obtained. D but not C reacts with rabbit antiserum to human αLP. C and D differ substantially in content of arginine, histidine, ½-cystine, isoleucine, and tryptophan.
Induced Deletion of the <i>N-Cadherin</i> Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure
Authors: Igor Kostetskii, Jifen Li, Yanming Xiong, Rong Zhou, Victor A. Ferrari, Vickas V. Patel, Jeffery D. Molkentin, Glenn L. Radice
Journal: Circulation Research (2005)

The structural integrity of the heart is maintained by the end-to-end connection between the myocytes called the intercalated disc. The intercalated disc contains different junctional complexes that enable the myocardium to function as a syncytium. One of the junctional complexes, the zonula adherens or adherens junction, consists of the cell adhesion molecule, N-cadherin, which mediates strong homophilic cell–cell adhesion via linkage to the actin cytoskeleton. To determine the function of N-cadherin in the working myocardium, we generated a conditional knockout containing loxP sites flanking exon 1 of the N-cadherin ( Cdh2 ) gene. Using a cardiac-specific tamoxifen-inducible Cre transgene, N-cadherin was deleted in the adult myocardium. Loss of N-cadherin resulted in disassembly of the intercalated disc structure, including adherens junctions and desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired cardiac function, with most animals dying within two months after tamoxifen administration. Decreased sarcomere length and increased Z-line thickness were observed in the mutant hearts consistent with loss of muscle tension because N-cadherin was no longer available to anchor myofibrils at the plasma membrane. Ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous ventricular tachycardia, confirming that the deaths were arrhythmic in nature. A significant decrease in the gap junction protein, connexin 43, was observed in the N-cadherin–depleted hearts. This animal model provides the first demonstration of the hierarchical relationship of the structural components of the intercalated disc in the working myocardium, thus establishing N-cadherin’s paramount importance in maintaining the structural integrity of the heart.
Baroreflex control of renal sympathetic nerve activity is preserved in heart failure despite reduced arterial baroreceptor sensitivity.
Authors: M E Dibner-Dunlap, M D Thames
Journal: Circulation Research (1989)

The purpose of this study was to determine if arterial baroreflex control of sympathetic nerve traffic is impaired in heart failure. We recorded renal nerve activity during changes in arterial pressure while simultaneously recording from aortic baroreceptor afferent fibers in 10 dogs with heart failure induced by rapid ventricular pacing and in 10 sham animals. Sensitivity of the aortic baroreceptors (percent change in nerve activity per millimeters mercury change in mean arterial pressure) was reduced in the heart failure group (heart failure, 2.3 +/- 0.3; sham, 3.6 +/- 0.4, p = 0.02). Despite the reduced sensitivity of aortic baroreceptors in heart failure, there was no difference in the baroreflex gain of renal nerve activity (heart failure, -5.5 +/- 1.4; sham, -5.8 +/- 1.3, p = NS). These values tended to decrease in both groups after vagotomy. The relation between baroreceptor input and renal sympathetic output, or central baroreflex gain (percent change in renal nerve activity divided by percent change in aortic nerve activity) was similar in both groups before vagotomy (heart failure, -2.4 +/- 0.6; sham, -2.3 +/- 0.5, p = NS). Vagotomy reduced central gain in the sham group (-0.9 +/- 0.1, p = 0.03) but not in the heart failure group (-1.7 +/- 0.5, p = NS), suggesting that the contribution of vagal afferents in the baroreflex arc is reduced in heart failure. Baroreflex control of R-R interval was attenuated in heart failure when assessed by blood pressure elevation but not reduction, indicating abnormal parasympathetic but preserved cardiac sympathetic mechanisms in heart failure. Thus, dogs with heart failure exhibit reduced sensitivity of aortic baroreceptors but preserved baroreflex control of renal nerve activity. Reduced baroreceptor sensitivity with preservation of baroreflex control of sympathetic nerve activity may contribute to the sympathoexcitatory state known to exist in heart failure.
Antibiotic prescription strategies for acute sore throat: a prospective observational cohort study
Authors: Paul Little, Beth Stuart, F D Richard Hobbs, Chris C Butler, Alastair D Hay, Brendan Delaney, John Campbell, Sue Broomfield, Paula Barratt, Kerenza Hood, Hazel Everitt, Mark Mullee, Ian Williamson, David Mant, Michael Moore
Journal: The Lancet Infectious Diseases (2014)
Evaluation of a Diagnostic Algorithm for Hereditary Hemochromatosis in 3,500 Patients With Diabetes
Authors: Jan-Uwe Hahn, Michael Steiner, Sabine Bochnig, Hartmut Schmidt, Peter Schuff-Werner, Wolfgang Kerner
Journal: Diabetes Care (2006)

Hereditary hemochromatosis may lead to hepatic cirrhosis, cardiomyopathy, diabetes, arthritis, and impotence (1, 2). In the Caucasian population, HFE gene mutations (C282Y and H63D) are present in the majority of patients demonstrating phenotypic expression (3–6). Conversely, the clinical penetrance in mutation carriers is low (7).

In the precirrhotic stage, ∼20% of hemochromatosic patients demonstrate hyperglycemia, with the prevalence increasing to >70% in the presence of liver cirrhosis (8). Two mechanisms contribute to the development of hyperglycemia and diabetes. Liver iron overload leads to insulin resistance, and the pancreatic β-cell iron accumulation results in cell damage and diminished insulin secretion (1). The prevalence of genotypic and phenotypic hemochromatosis is higher in diabetic versus nondiabetic populations (9–11).

In an attempt to distinguish patients with hemochromatosis-associated secondary diabetes from other forms of diabetes, we applied a screening program to diabetic patients aged ≥40 years. The present report summarizes …
The Growth Arrest Function of the Human Oncoprotein Mouse Double Minute-2 Is Disabled by Downstream Mutation in Cancer Cells
Authors: Ruizhe Zhou, Rebecca Frum, Sumitra Deb, Swati P. Deb
Journal: Cancer Research (2005)

We have reported earlier that ectopic expression of mouse double minute-2 (MDM2) induces G1 arrest in normal cells. To explain occasional overexpression of MDM2 in cancer cells, we searched for deletion or substitution mutation in the growth suppressor domains of MDM2 in several breast cancer cell lines that overexpress the oncoprotein. Our results suggest the absence of alteration (deletion or substitution) in the open reading frame of MDM2 transcripts in such cells. Because the breast cancer cell line MCF-7 overexpresses MDM2, we isolated the full-length MDM2 transcript from this cell line. The MDM2 cDNA synthesized from transcripts isolated from MCF-7 cells induced inhibition of G1 to S phase transition in normal human diploid cells such as WI38, suggesting that the genetic alterations in breast cancer cells that overexpress MDM2 disable the growth arrest function of the oncoprotein. Consistently, overexpression of full-length MDM2 in MCF-7 cells over its high endogenous level did not inhibit G1-S transition efficiently. Although MDM2 overexpression was accompanied by CDK4 overexpression or absence of cdk4 inhibitor p16 in most breast cancer cells, we found remarkably high levels of cyclin A rather than cyclin E in these cells. Ectopic expression of cyclin A released MDM2-mediated inhibition of G1-S transition in normal human diploid WI38 cells. We propose that cancer cells expressing high levels of cyclin A escape MDM2-mediated G1 arrest, which may account for a selective growth advantage over normal cells.
Syx, a RhoA Guanine Exchange Factor, Is Essential for Angiogenesis In Vivo
Authors: Maija K. Garnaas, Karen L. Moodie, Miao-liang Liu, Ganesh V. Samant, Keguo Li, Ruth Marx, Jay M. Baraban, Arie Horowitz, Ramani Ramchandran
Journal: Circulation Research (2008)

Rho GTPases play an important and versatile role in several biological processes. In this study, we identified the zebrafish ortholog of the mammalian Rho A guanine exchange factor, synectin-binding guanine exchange factor (Syx), and determined its in vivo function in the zebrafish and the mouse. We found that Syx is expressed specifically in the vasculature of these organisms. Loss-of-function studies in the zebrafish and mouse point to a specific role for Syx in angiogenic sprouting in the developing vascular bed. Importantly, vasculogenesis and angioblast differentiation steps were unaffected in syx knockdown zebrafish embryos, and the vascular sprouting defects were partially rescued by the mouse ortholog. Syx knockdown in vitro impairs vascular endothelial growth factor-A-induced endothelial cell migration and angiogenesis. We have also uncovered a potential mechanism of endothelial sprout guidance in which angiomotin, a component of endothelial cell junctions, plays an additive role with Syx in directing endothelial sprouts. These results identify Syx as an essential contributor to angiogenesis in vivo.
Regional Cortical Thinning in Subjects With Violent Antisocial Personality Disorder or Schizophrenia
Authors: Veena M. Narayan, Katherine L. Narr, Veena Kumari, Roger P. Woods, Paul M. Thompson, Arthur W. Toga, Tonmoy Sharma
Journal: American Journal of Psychiatry (2007)

Violent behavior is associated with antisocial personality disorder and to a lesser extent with schizophrenia. Neuroimaging studies have suggested that several biological systems are disturbed in schizophrenia, and structural changes in frontal and temporal lobe regions are reported in both antisocial personality disorder and schizophrenia. The neural substrates that underlie violent behavior specifically and their structural analogs, however, remain poorly understood. Nor is it known whether a common biological basis exists for aggressive, impulsive, and violent behavior across these clinical populations. To explore the correlates of violence with brain structure in antisocial personality disorder and schizophrenia, the authors used magnetic resonance imaging data to investigate for the first time, to the authors' knowledge, regional differences in cortical thickness in violent and nonviolent individuals with schizophrenia and/or antisocial personality disorder and in healthy comparison subjects. Subject groups included right-handed men closely matched for demographic variables (total number of subjects=56). Violence was associated with cortical thinning in the medial inferior frontal and lateral sensory motor cortex, particularly in the right hemisphere, and surrounding association areas (Brodmann's areas 10, 11, 12, and 32). Only violent subjects with antisocial personality disorder exhibited cortical thinning in inferior mesial frontal cortices. The biological underpinnings of violent behavior may therefore vary between these two violent subject groups in which the medial frontal cortex is compromised in antisocial personality disorder exclusively, but laminar abnormalities in sensorimotor cortices may relate to violent behavior in both antisocial personality disorder and schizophrenia.
Depression Severity and Drug Injection HIV Risk Behaviors
Authors: Michael D. Stein, David A. Solomon, Debra S. Herman, Bradley J. Anderson, Ivan Miller
Journal: American Journal of Psychiatry (2003)

This study examined the association of depression severity and drug injection HIV risk behavior among injection drug users.Injection drug users who met the DSM-IV criteria for major depressive disorder, dysthymia, or substance-induced mood disorder lasting at least 3 months were asked how often they used "needles or syringes that someone else had used" (injection risk behavior) in the past 90 days. Depression severity was measured by using the Modified Hamilton Rating Scale for Depression.Of the 109 subjects, 63% were male, 82% were Caucasian, and 10% were HIV positive. The subjects' mean modified Hamilton depression scale score was 21.0 (SD=3.9). The mean number of reported instances of injection risk behavior (needle sharing) in the past 90 days was 57.5 (SD=134.7). In a logistic regression analysis in which the effects of age, race, gender, number of days on which injection drugs were used (injection days), and average number of injections per injection day were controlled, depression severity was associated with injection risk (odds ratio=1.5; 95% confidence interval=1.1-2.3).Greater severity of depression is associated with greater frequency of injection risk behavior among depressed injection drug users. Risk reduction programs that target depressed injection drug users need to be designed.
Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study
Authors: Andrew N Phillips, Clifford Leen, Alan Wilson, Jane Anderson, David Dunn, Achim Schwenk, Chloe Orkin, Teresa Hill, Martin Fisher, John Walsh, Deenan Pillay, Loveleen Bansi, Brian Gazzard, Philippa Easterbrook, Richard Gilson, Margaret Johnson, Caroline A Sabin
Journal: The Lancet (2007)
Lineage-Specific Transcriptional Profiles of Symbiodinium spp. Unaltered by Heat Stress in a Coral Host
Authors: Daniel J. Barshis, Jason T. Ladner, Thomas A. Oliver, Stephen R. Palumbi
Journal: Molecular Biology and Evolution (2014)

Dinoflagellates of the genus Symbiodinium form an endosymbiosis with reef building corals, in which photosynthetically derived nutrients comprise the majority of the coral energy budget. An extraordinary amount of functional and genetic diversity is contained within the coral-associated Symbiodinium, with some phylotypes (i.e., genotypic groupings), conferring enhanced stress tolerance to host corals. Recent advances in DNA sequencing technologies have enabled transcriptome-wide profiling of the stress response of the cnidarian coral host; however, a comprehensive understanding of the molecular response to stress of coral-associated Symbiodinium, as well as differences among physiologically susceptible and tolerant types, remains largely unexplored. Here, we examine the transcriptome-wide response to heat stress via RNA-Seq of two types of Symbiodinium, the putatively thermotolerant type D2 and the more susceptible type C3K, resident within the same coral host species, Acropora hyacinthus. Contrary to previous findings with coral hosts, we find no detectable change in gene expression across the dinoflagellate transcriptome after 3 days of elevated thermal exposure, despite physical evidence of symbiosis breakdown. However, hundreds of genes identified as orthologs between the C and D types exhibited significant expression differences within treatments (i.e., attributable solely to type, not heat exposure). These include many genes related to known thermotolerance mechanisms including heat shock proteins and chloroplast membrane components. Additionally, both the between-treatment similarities and between-type differences remained pervasive after 12-18 months of common garden acclimation and in mixed Symbiodinium assemblages within the same coral host colony.
Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death
Authors: N. Lowri Thomas, Christopher H. George, F. Anthony Lai
Journal: Cardiovascular Research (2004)

Objectives: Point mutations in the cardiac ryanodine receptor (RyR2) mediate abnormal intracellular Ca2+ release and are associated with stress-induced ventricular tachycardia (VT), leading to sudden cardiac death (SCD). Although the precise molecular basis of RyR2 dysfunction in SCD remains controversial, there is consensus that the mutations characterised to date all exhibit gain-of-function Ca2+ release properties following cell stimulation. We investigated the functional impact of a distinct set of SCD-linked RyR2 mutations (L433P, N2386I, R176Q/T2504M) on intracellular Ca2+ handling. Methods: We expressed full-length recombinant human wild-type (WT) and SCD-linked RyR2 mutations in human embryonic kidney (HEK) cells, and profiled the spatial and amplitude characteristics of caffeine-evoked Ca2+ release through homo-tetrameric channels in living cells using rapid confocal laser scanning microscopy. Results: Analysis of the precise mode of Ca2+ release in HEK cells expressing RyR2 mutants demonstrated profound differences when compared with WT channels. The SCD-linked RyR2 mutations characterised in this study exhibited heterogeneous Ca2+ release profiles, including the novel observation that one of the mutants, (L433P), exhibited a marked reduction in sensitivity to channel activation. However, all SCD-linked RyR2 mutations characterised in this study resulted in an increased duration of elevated cytoplasmic Ca2+ levels following channel activation. Conclusions: Our live cell-based data demonstrates functional heterogeneity of Ca2+ release through SCD-linked RyR2 mutants, suggesting that the mechanistic basis of RyR2 dysfunction in SCD may be more complex than previously anticipated. These findings may have profound consequences for the therapeutic modulation of RyR2 in stress-induced VT and SCD.
High-Fiber Cereal Reduces Postprandial Insulin Responses in Hyperinsulinemic but not Normoinsulinemic Subjects
Authors: Thomas M.S. Wolever, Janice E. Campbell, Daniela Geleva, G. Harvey Anderson
Journal: Diabetes Care (2004)

OBJECTIVE—The objective of this study was to compare the plasma glucose and insulin responses elicited by two ready-to-eat breakfast cereals (one being high and the other being low in cereal fiber) and to see if the differences in response depended on subjects’ fasting plasma insulin. RESEARCH DESIGN AND METHODS—Nondiabetic men (n = 77) were studied on two occasions after 10- to 14-h overnight fasts. They consumed 25 g of available carbohydrate from high- or low-fiber breakfast cereals in random order with blood taken at intervals for 2 h. Data from the 42 men with high fasting plasma insulin (FPI) on screening (&amp;gt;40 pmol/l) were compared with those from the 35 men with normal FPI (≤40 pmol/l). RESULTS—Hyperinsulinemic men had significantly higher waist circumference and BMI, lower HDL cholesterol, and a trend toward higher triglycerides (P = 0.07) than control subjects. In all 77 subjects, the incremental area under the glucose response curve (AUC) after high-fiber cereal was 11.8 ± 5.5% (P = 0.036) less than after low-fiber cereal with the reductions being equivalent in the hyperinsulinemic (12.6 ± 8.3%) and control (10.9 ± 9.1%) groups. However, insulin peak rise was reduced by the high-fiber cereal only in hyperinsulinemic men (351 ± 29 vs. 485 ± 55 pmol/l) but not in control subjects (211 ± 20 vs. 220 ± 20 pmol/l; cereal × group interaction P = 0.044). Insulin AUC after the high-fiber cereal, expressed as a percentage of that after low-fiber cereal, was negatively related to FPI (P = 0.009) but not to age, BMI, or waist circumference. CONCLUSIONS—The high-fiber cereal reduced glucose responses to the same extent in normal and hyperinsulinemic men, but reduced insulin responses only in hyperinsulinemic subjects.
A Law Enforcement Training Program in a Mental Health Center Catchment Area
Authors: EDWARD J. ROLDE, ELLSWORTH FERSCH, FRANCIS J. KELLY, SUSAN FRANK, MAURICE GUBERMAN
Journal: American Journal of Psychiatry (1973)

To increase understanding, communication, and cooperation between law enforcement officers and mental health workers in handling juveniles, the authors devised a training program and obtained the participation of ten law enforcement agencies. They made their presentations relevant to the local situation, used the expertise of the officers to good advantage, and focused on the pressure placed on the individual officer to perform his duties in the style of his department. The program was well received and influenced not only individual behavior but the policies of the participating organizations.