tbuckley/cabot-search huggingface dataset:
Identification of the First Specific Inhibitor of p90 Ribosomal S6 Kinase (RSK) Reveals an Unexpected Role for RSK in Cancer Cell Proliferation
Authors: Jeffrey A. Smith, Celeste E. Poteet-Smith, Yaming Xu, Timothy M. Errington, Sidney M. Hecht, Deborah A. Lannigan
Journal: Cancer Research (2005)

Abstract p90 ribosomal S6 kinase (RSK) is an important downstream effector of mitogen-activated protein kinase, but its biological functions are not well understood. We have now identified the first small-molecule, RSK-specific inhibitor, which we isolated from the tropical plant Forsteronia refracta. We have named this novel inhibitor SL0101. SL0101 shows remarkable specificity for RSK. The major determinant of SL0101-binding specificity is the unique ATP-interacting sequence in the amino-terminal kinase domain of RSK. SL0101 inhibits proliferation of the human breast cancer cell line MCF-7, producing a cell cycle block in G1 phase with an efficacy paralleling its ability to inhibit RSK in intact cells. RNA interference of RSK expression confirmed that RSK regulates MCF-7 proliferation. Interestingly, SL0101 does not alter proliferation of a normal human breast cell line MCF-10A, although SL0101 inhibits RSK in these cells. We show that RSK is overexpressed in ∼50% of human breast cancer tissue samples, suggesting that regulation of RSK has been compromised. Thus, we show that RSK has an unexpected role in proliferation of transformed cells and may be a useful new target for chemotherapeutic agents. SL0101 will provide a powerful new tool to dissect the molecular functions of RSK in cancer cells.
Identification of a novel FLCN interacting protein, FNIP2
Authors: Hisashi Hasumi, Masaya Baba, Seung-Beom Hong, Yukiko Hasumi, W. Marston Linehan, Laura Schmidt
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1787 

Birt-Hogg-Dube syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts and renal neoplasia, is caused by germline mutations in the BHD(FLCN) gene that encodes a novel tumor suppressor protein, folliculin(FLCN). FLCN interacts with a novel protein FNIP1 and 5’-AMP-activated protein kinase (AMPK). Through bioinformatic searches, we found that KIAA1450 had high homology to FNIP1 and this strong similarity prompted us to consider its involvement in BHD syndrome. Due to the homology to FNIP1, we have designated KIAA1450 as FLCN interacting protein 2(FNIP2). To investigate an interaction between FLCN and FNIP2, HEK293 cells expressing HA-tagged FNIP2 in a doxycycline-dependent manner were lysed and immunoprecipitated with anti-HA antibody followed by western blotting to identify co-immunoprecipitated endogenous FLCN and AMPK subunits. Endogenous FLCN and all of the AMPK subunits (α,β and γ) were co-immunoprecipitated with HA-FNIP2. We could also detect the interaction of endogenous FLCN and FNIP2 using anti-FLCN and anti-FNIP2 antibodies. Furthermore, HA-FLCN and FNIP2-Flag transfected into MCF7 cells colocalized in the cytoplasm in a reticular pattern as seen by immunofluorescence microscopy. To see a direct interaction between FLCN and FNIP2 and to determine the FNIP2 binding domain in FLCN, we performed an in vitro binding assay with full length GST-FLCN or GST-FLCN deletion mutants, and in vitro translated 35S- labeled FNIP2. Full length GST-FLCN bound to FNIP2 and N-terminal GST-FLCN deletion mutants that retained the C-terminus were also able to bind FNIP2. However C-terminally deleted GST-FLCN mutants could not bind FNIP2. Interestingly, the majority of BHD mutations found in BHD patients were predicted to alter the reading frame and prematurely truncate FLCN protein. The loss of FLCN binding to FNIP2 caused by C-terminal deletion suggests that the interaction between FLCN and FNIP2 is physiologically important. We have identified a novel FLCN interacting protein, FNIP2. Although its function is unknown, FNIP2 as well as FNIP1 may play an important role in the development of chromophobe renal cell carcinoma and oncocytoma, the most common renal tumors found in BHD patients. Funded by NCI Contract N01-CO-12400.
Abstract 12641: Endothelial Cell Hspa12B Plays a Cardioprotective Role in Sepsis Induced Cardiac Dysfunction via the Release of MicroRNA Containing Exosomes
Authors: Xia Zhang, Xiaohui Wang, Tuanzhu Ha, Li Liu, Race Kao, John Kalbfleisch, David Williams, Chuanfu Li
Journal: Circulation (2014)

Heat shock protein A12B (HSPA12B) is predominately expressed in endothelial cells and has been reported to contribute to angiogenesis. We hypothesized that HSPA12B plays a protective role in sepsis-induced cardiac dysfunction. Endothelial HSPA12B -/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgical operation served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 hour after CLP. In WT septic mice, ejection fraction (EF%) and fractional shortening (%FS) were significantly reduced by 34.8% and 43.1% (p&lt;0.05), compared with control. HSPA12B -/- septic mice showed even greater decrements in EF% and FS% values (19.9% and 22.5%), when compared with WT septic mice. Serum levels of TNFα and IL-6 were higher in HSPA12B -/- septic mice than in WT septic mice. The expression of ICAM1 and VCAM1 in the myocardium of HSPA12B -/- septic mice was greater than in WT septic mice. Exosomes play an important role in cell-cell communication. In vitro data showed that exosomes isolated from the serum of HSPA12B -/- septic mice induced increased levels of TNFα and IL-6, NF-κB binding activity and TRAF6 ubiquitination in macrophages, when compared with WT septic exosomes. HSPA12B -/- septic exosomes contained significantly less microRNA-146a, which negatively regulates NF-κB signaling, when compared with WT septic exosomes. Endothelial cells (HUVEC) treated with HSPA12B -/- septic exosomes showed decreased expression of tight junction proteins (ZO-1and Occludin) and miR-126, which regulates the expression of adhesion molecules, when compared with WT septic exosomes treatment. In addition, the amounts of miR-146a and miR-126 in the exosomes from the serum of HSPA12B -/- septic mice were less than in the exosomes from WT septic mice. This is the first report that endothelial cell HSPA12B attenuates cardiac dysfunction in sepsis via secretion of exosomes and microRNA expression. We conclude that endothelial HSPA12B plays a cardioprotective role in sepsis via microRNA containing exosomes.
Absence of Late-Replicating X-Chromosome in a Female Patient With Acute Myeloid Leukemia and the 8;21 Translocation&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: G Levan, F Mitelman
Journal: JNCI Journal of the National Cancer Institute (1979)

Autoradiography was used to demonstrate that the x-chromosome of the 45,X,-X,t(8;21) stemline of a female patient with acute myeloid leukemia (AML) was the active X-chromosome. This suggested that in patients housing AML with the 8;21 translocation, the loss of the inactive X-chromosome in females and of the Y in males (which is known to occur in nearly half of the patients) entails selective advantage to the stemline.
Effects of Treating Depression and Low Perceived Social Support on Clinical Events After Myocardial Infarction
Authors: Lisa F Berkman, James Blumenthal, Matthew Burg, Robert M Carney, Diane Catellier, Marie J Cowan, Susan M Czajkowski, Robert DeBusk, James Hosking, Allan Jaffe, Peter G Kaufmann, Pamela Mitchell, James Norman, Lynda H Powell, James M Raczynski, Neil Schneiderman
Journal: JAMA (2003)

Depression and low perceived social support (LPSS) after myocardial infarction (MI) are associated with higher morbidity and mortality, but little is known about whether this excess risk can be reduced through treatment.To determine whether mortality and recurrent infarction are reduced by treatment of depression and LPSS with cognitive behavior therapy (CBT), supplemented with a selective serotonin reuptake inhibitor (SSRI) antidepressant when indicated, in patients enrolled within 28 days after MI.Randomized clinical trial conducted from October 1996 to April 2001 in 2481 MI patients (1084 women, 1397 men) enrolled from 8 clinical centers. Major or minor depression was diagnosed by modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and severity by the 17-item Hamilton Rating Scale for Depression (HRSD); LPSS was determined by the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Social Support Instrument (ESSI). Random allocation was to usual medical care or CBT-based psychosocial intervention.Cognitive behavior therapy was initiated at a median of 17 days after the index MI for a median of 11 individual sessions throughout 6 months, plus group therapy when feasible, with SSRIs for patients scoring higher than 24 on the HRSD or having a less than 50% reduction in Beck Depression Inventory scores after 5 weeks.Composite primary end point of death or recurrent MI; secondary outcomes included change in HRSD (for depression) or ESSI scores (for LPSS) at 6 months.Improvement in psychosocial outcomes at 6 months favored treatment: mean (SD) change in HRSD score, -10.1 (7.8) in the depression and psychosocial intervention group vs -8.4 (7.7) in the depression and usual care group (P<.001); mean (SD) change in ESSI score, 5.1 (5.9) in the LPSS and psychosocial intervention group vs 3.4 (6.0) in the LPSS and usual care group (P<.001). After an average follow-up of 29 months, there was no significant difference in event-free survival between usual care (75.9%) and psychosocial intervention (75.8%). There were also no differences in survival between the psychosocial intervention and usual care arms in any of the 3 psychosocial risk groups (depression, LPSS, and depression and LPSS patients).The intervention did not increase event-free survival. The intervention improved depression and social isolation, although the relative improvement in the psychosocial intervention group compared with the usual care group was less than expected due to substantial improvement in usual care patients.
Genesis and evolution of behavioral disorders: from infancy to early adult life
Authors: Alexander Thomas, Stella Chess
Journal: American Journal of Psychiatry (1984)

The New York Longitudinal Study has followed the behavioral development of 133 subjects from early infancy to early adult life. Special attention has been given to the systematic clinical evaluation and follow-up of all subjects presenting any evidence of behavior disorder. The authors present incidence and outcome data, define the concept of temperament, and briefly discuss conceptual issues and empirical findings. They found the "goodness of fit" (consonance between the individual and the environment) concept useful in tracing developmental sequences. The authors summarize quantitative analyses identifying significant group correlations between antecedent variables and early adult outcome and suggest a tentative classification of the idiosyncratic factors also evident in the clinical course of individual subjects, with case illustrations.
2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation
Authors: Valentin Fuster, Lars E. Rydén, Davis S. Cannom, Harry J. Crijns, Anne B. Curtis, Kenneth A. Ellenbogen, Jonathan L. Halperin, G. Neal Kay, Jean-Yves Le Huezey, James E. Lowe, S. Bertil Olsson, Eric N. Prystowsky, Juan Luis Tamargo, L. Samuel Wann
Journal: Journal of the American College of Cardiology (2011)
Response to Comment on Hughes et al. An Early Pregnancy HbA1c ≥5.9% (41 mmol/mol) Is Optimal for Detecting Diabetes and Identifies Women at Increased Risk of Adverse Pregnancy Outcomes. Diabetes Care 2014;37:2953–2959
Authors: Ruth C.E. Hughes, M. Peter Moore, Joanna E. Gullam, Janet Rowan
Journal: Diabetes Care (2015)

We appreciate the opportunity to respond to the comments made by Anderson et al. (1) on our recent article (2). We agree, as highlighted under our study limitations, that the low participation rate in the oral glucose tolerance test (OGTT) could affect the validity of the HbA1c sensitivity and specificity calculations. As women with lower HbA1c (particularly <5.6% [38 mmol/mol]) were least likely to consent to an early OGTT, it is possible that the optimal HbA1c threshold for identifying women with undiagnosed preexisting diabetes (not gestational diabetes mellitus [GDM]) is in fact lower than 5.9% (41 mmol/mol) and we invite others …
Abstract 303: Did the Difficult Airway Influence Outcome After Out-of-Hospital Cardiac Arrest? A German Register-Based Study
Authors: Jan Wnent, Rüdiger Franz, Rolf Lefering, Jörg Walther, Stephan Seewald, Matthias Fischer, Tanja Jantzen, Martin Messelken, Andreas Bohn, Jan-Thorsten Gräsner
Journal: Circulation (2014)

Background: [[Unable to Display Character:  ]]Airway management during resuscitation is pivotal for treating hypoxia. For securing the airway endotracheal intubation is the gold standard. The German Resuscitation Registry analysis investigates the influence of airway management on primary outcomes after out-of-hospital cardiac arrest, in a physician-based two tired emergency medical system. The German Resuscitation Registry was founded in 2007. It is a voluntary registry and covers a population about 20 mio inhibitants. Up to May 2014 45.000 cases are included in the registry.

Methods: [[Unable to Display Character:  ]]A total of 8.512 patients recorded in the German Resuscitation Registry (2007-2011) were analyzed. The Return of Spontaneous Circulation After Cardiac Arrest (RACA)(2) score was used to compare observed return of spontaneous circulation (ROSC) rates with the ROSC predicted by the score and to analyze factors influencing the primary outcome. Patients were classified into three groups: difficult intubation, impossible intubation, and a control group with normal airways.

Results: [[Unable to Display Character:  ]]The observed ROSC matched the predicted ROSC in the groups with difficult airways and normal airways. The impossible intubation group had lower ROSC rates (31.3% vs. 40.5%,(P < 0.05)). Impossible intubation was more frequent in men (OR 0.44; 95% CI, 0.28-0.70), young patients (OR 0.46; 95% CI, 0.27-0.79) and those with trauma (OR 0.45; 95% CI, 0.21-0.99). Fewer impossible intubations were reported when the emergency physicians were anesthesiologists (OR 1.54; 95% CI, 1.05-2.27). If a supraglottic airway device was not used, the observed ROSC (18.0%; 95% CI, 7.4%-28.6%) was poorer than predicted (38.2%). In the difficult intubation group the observed ROSC rate was 44.1% in comparison to the predicted ROSC rate of 41.3% (n.s.).

Conclusions: [[Unable to Display Character:  ]]Outcomes after resuscitation are poorer when endotracheal intubation is not possible. Predictive factors for impossible intubation are male gender, younger age, and trauma. Supraglottic airway devices should be used at an early stage whenever these negative factors are present. Training in airway management as well as team training is essential in advanced life support.
Growth Hormone in Chronic Heart Failure
Authors: Philipp Dreifuss
Journal: Circulation (1998)

To the Editor:Anker et al 1 ' 2 reported on the hormonal changes in chronic heart failure (CHF) and their importance for cardiac cachexia.The authors found a trend for increased human growth hormone (hGH) in cachectic patients but similar levels of hGH in noncachectic patients compared with control subjects.No significant differences between patients and the control group were seen for insulin-like growth factor-1 (IGF-1).Nevertheless, the IGF-1/hGH ratio was approximately four times higher in noncachectic CHF patients and control subjects than in cachectic subjects.The authors suggest the presence of hGH-resistance in CHF because the increase in hGH in the cachectic patients was not accompanied by an increase in IGF-1.With respect to the metabolic hGH-IGF-1-status in CHF, the published data so far are controversial.An exploratory pilot research in nine patients with CHF caused by dilated cardiomyopathy (DCM) and New York Heart Association functional class of dyspnea III-IV investigated hGH metabolism in severe CHF. 3 The study group was compared with a control group matched for age, sex, and body mass index.Patients with CHF had markedly depressed levels of IGF-1, whereas hGH had not been measured.Another metabolic study by Giustina et al 4 in patients with severe CHF caused by DCM (NYHA functional class of dyspnea III-IV) showed an impaired spontaneous hGH secretion, but Anand et al 5 found hGH to be greatly increased in untreated patients with severe CHF.Therefore CHF appears to be associated with a perturbation of the hGH/IGF-1 axis, leading to a state of functional IGF-1 deficiency. 6This can be viewed as a state of maladaptation, with the consequence that falling IGF-1 levels either systemic, or locally generated within the myocardium, cause a deleterious effect on myocardial function.The mechanism of the perturbation in the hGH/IGF-1 axis (systemic/local) is unclear; possible mechanisms include reduced hGH secretion from the pituitary or hGH resistance.Perturbation of this axis-either primary, as a result of hGH deficiency, or secondary, as a maladaptive response to CHF-may be responsible for the exacerbation of myocardial dysfunction.Furthermore, it must be mentioned that DCM is the cause of CHF in which subcutaneous recombinant hGH (r-hGH) is likely to effectively counteract the pathogenetic defect of the disease. 7" 9 That is why subcutaneous r-hGH in conjunction with the widely accepted drugs for CHF, for example, angiotensin-converting enzyme inhibitors, diuretics, nitrates, calcium antagonists, and digoxin, could become an alternative to cardiac transplantation, as there is a worldwide shortage of donor organs. 10 Further in vivo and in vitro studies with r-hGH in failing myocardial tissue are necessary and awaited.
Abstract 1207: Ambient Ultrafine Particulate Matter Enhances Atherosclerosis in apoE Null Animals
Authors: Jesus A Araujo, Ke-Wei Gong, Berenice Barajas, Michael Kleinman, Jack Harkema, Constantinos Sioutas, Aldons J Lusis, Andre Nel
Journal: Circulation (2006)

Epidemiological studies suggest that exposure to ambient particulate matter (PM) constitutes a risk factor for atherosclerosis. Exposure to fine PM (particles with aerodynamic diameter < 2.5 μm, PM...
Abstract 4022: Control of Cardiovascular Risk Factors in Peripheral Arterial Disease Patients in the REduction in Atherothrombosis for Continued Health (REACH) Registry
Authors: Patrice Cacoub, M T Abola, Iris Baumgartner, Deepak L Bhatt, Mark A Creager, Chiau-Suong Liau, Shinya Goto, Joachim Rother, Alan T Hirsch
Journal: Circulation (2006)
Neurobiological mechanisms of panic anxiety: biochemical and behavioral correlates of yohimbine-induced panic attacks
Authors: Dennis S. Charney, Scott W. Woods, Wayne K. Goodman, George R. Heninger
Journal: American Journal of Psychiatry (1987)

The effects of yohimbine, an alpha 2-adrenergic receptor antagonist, on anxiety, blood pressure, heart rate, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and cortisol were determined in 20 healthy subjects and 68 patients who had agoraphobia with panic attacks or panic disorder. Yohimbine produced panic attacks meeting DSM-III criteria in 37 patients and one healthy subject. The patients reporting yohimbine-induced panic attacks had significantly larger increases in plasma MHPG, cortisol, systolic blood pressure, and heart rate than the healthy subjects. These findings support the hypothesis relating high noradrenergic neuronal activity to the pathophysiology of panic attacks in a subgroup of panic disorder patients.
Factors associated with first course chemotherapy among older patients with newly diagnosed non-Hodgkin's lymphoma: National SEER-Medicare study
Authors: M. D. Voelker, E. A. Chrischilles, K. B. Wright, B. K. Link, T.-R. Park, D. J. Delgado
Journal: Journal of Clinical Oncology (2004)

6118 Background: Chemotherapy (CT) is indicated for some non-Hodgkin's lymphoma (NHL) patients (pts) with initial diagnosis. We describe clinical and nonclinical factors associated with receipt of first course CT. Methods: Using the National Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified newly diagnosed NHL pts (1991–1999), age ≥66 years, with continuous non-HMO Medicare part A and B benefits. First course CT was defined as a claim within 5 months of diagnosis (Dx) and whether cyclophosphamide with either doxorubicin or mitoxantrone (CH/CN) was given was determined. Univariate and multivariate analyses were performed using Pearson's Chi-Square test and SAS logistic regression methods. Results: Of 35,063 pts with NHL, 15,014 met inclusion criteria, and 7536 (50%) received CT (63% CH/CN). Among all 15,014 pts, factors multivariately associated (p≤0.05) with receiving CT were: diffuse large cell (DLC) histology, advanced (adv) stage, younger age, white race, Charlson comorbidity index (CCI) =0, no renal disease, no anemia, no radiation therapy, SEER site and Dx year. The largest associations were for DLC vs follicular histology (Odds Ratio (OR)=3.3, 95%CI: 2.9, 3.6) and age 66–70 years vs ≥86 years (OR=4.7, 95%CI: 4.1, 5.4). Among 2457 adv stage pts with DLC histology, 1660 (68%) received any CT, of whom 1154 (70%) received CH/CN. On multivariate analysis, older pts and those with CCI>0 or anemia were significantly (p≤0.05) less likely to receive CT. Multivariately, receipt of CH/CN was significantly (p≤0.05) less likely with advancing age, CCI>0, anemia, heart disease, and radiation therapy. SEER site and Dx year were independently associated with receiving CH/CN. Of particular interest was the rate (only 68%) of CT use in adv stage DLC lymphoma. Conclusions: Nonclinical factors (younger age, white race, Dx year and SEER site) and clinical factors (DLC histology, adv stage, no radiation therapy and less comorbidity) were independently associated with receiving first course CT in this population-based study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc. Amgen, Inc. Amgen, Inc.