tbuckley/cabot-search huggingface dataset:
Crucial Role for Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase-II in Regulating Diastolic Stress of Normal and Failing Hearts via Titin Phosphorylation
Authors: Nazha Hamdani, Judith Krysiak, Michael M. Kreusser, Stefan Neef, Cristobal G. dos Remedios, Lars S. Maier, Markus Krüger, Johannes Backs, Wolfgang A. Linke
Journal: Circulation Research (2013)

Myocardial diastolic stiffness and cardiomyocyte passive force (F(passive)) depend in part on titin isoform composition and phosphorylation. Ca(2+)/calmodulin-dependent protein kinase-II (CaMKII) phosphorylates ion channels, Ca(2+)-handling proteins, and chromatin-modifying enzymes in the heart, but has not been known to target titin.To elucidate whether CaMKII phosphorylates titin and modulates F(passive) in normal and failing myocardium.Titin phosphorylation was assessed in CaMKIIδ/γ double-knockout (DKO) mouse, transgenic CaMKIIδC-overexpressing mouse, and human hearts, by Pro-Q-Diamond/Sypro-Ruby staining, autoradiography, and immunoblotting using phosphoserine-specific titin-antibodies. CaMKII-dependent site-specific titin phosphorylation was quantified in vivo by mass spectrometry using stable isotope labeling by amino acids in cell culture mouse heart mixed with wild-type (WT) or DKO heart. F(passive) of single permeabilized cardiomyocytes was recorded before and after CaMKII-administration. All-titin phosphorylation was reduced by >50% in DKO but increased by up to ≈100% in transgenic versus WT hearts. Conserved CaMKII-dependent phosphosites were identified within the PEVK-domain of titin by quantitative mass spectrometry and confirmed in recombinant human PEVK-fragments. CaMKII also phosphorylated the cardiac titin N2B-unique sequence. Phosphorylation at specific PEVK/titin N2B-unique sequence sites was decreased in DKO and amplified in transgenic versus WT hearts. F(passive) was elevated in DKO and reduced in transgenic compared with WT cardiomyocytes. CaMKII-administration lowered F(passive) of WT and DKO cardiomyocytes, an effect blunted by titin antibody pretreatment. Human end-stage failing hearts revealed higher CaMKII expression/activity and phosphorylation at PEVK/titin N2B-unique sequence sites than nonfailing donor hearts.CaMKII phosphorylates the titin springs at conserved serines/threonines, thereby lowering F(passive). Deranged CaMKII-dependent titin phosphorylation occurs in heart failure and contributes to altered diastolic stress.
Networks as complex dynamic systems: Applications to clinical and developmental psychology and psychopathology
Authors: Paul L. C. van Geert, Henderien W. Steenbeek
Journal: Behavioral and Brain Sciences (2010)

Cramer et al.'s article is an example of the fruitful application of complex dynamic systems theory. We extend their approach with examples from our own work on development and developmental psychopathology and address three issues: (1) the level of aggregation of the network, (2) the required research methodology, and (3) the clinical and educational application of dynamic network thinking.
Constitutive Expression of Interleukin (IL)-4 In Vivo Causes Autoimmune-type Disorders in Mice
Authors: Klaus J. Erb, Beate Rüger, Maja von Brevern, Bernhard Ryffel, Annelise Schimpl, Karen Rivett
Journal: The Journal of Experimental Medicine (1997)

The transgenic (tg) expression of interleukin (IL)-4 under the control of a major histocompatibility complex (MHC) class I promoter leads to B cell hyperactivity in mice, characterized by increased B cell surface MHC class II and CD23 expression, elevated responsiveness of the B cells to polyclonal ex vivo stimulation, and increased immunoglobulin (Ig)G1 and IgE serum levels. Tg mice develop anemia, glomerulonephritis with complement and immune deposition in the glomeruli, and show increased production of autoantibodies. Treatment of IL-4 tg mice with anti-IL-4 neutralizing antibodies protected the mice from disease development, showing that IL-4 was responsible for the observed disorders. Deletion of superantigen responsive autoreactive T cells in the IL-4 tg mice was normal and treatment of mutant mice with deleting anti-CD4 antibodies failed to ablate the onset of autoimmune-like disease, suggesting that CD4+ T cells were not the primary cause of the disorders. Furthermore, the deletion of B cells reacting against MHC class I molecules was also normal in the IL-4 tg mice. Therefore the most likely explanation for the increased production of autoantibodies and the autoimmunelike disorders is that IL-4 acts directly on autoreactive B cells by expanding them in a polyclonal manner. Taken together our results show that inappropriate multi-organ expression of IL-4 in vivo leads to autoimmune-type disease in mice.
Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications
Authors: Suyun Huang
Journal: Clinical Cancer Research (2007)

Numerous cytokines, growth factors, and oncogenic proteins activate signal transducer and activator of transcription 3 (Stat3), which has been recognized as one of the common pathways in cancer cells. Stat3 signaling affects the expression and function of a variety of genes that are critical to cell survival, cell proliferation, invasion, angiogenesis, and immune evasion. Evidently, the Stat3 signaling pathway regulates cancer metastasis and constitutes a potential preventive and therapeutic target for cancer metastasis.
THROMBOPOIETIN: UNDERSTANDING AND MANIPULATING PLATELET PRODUCTION
Authors: K. Kaushansky, MD
Journal: Annual Review of Medicine (1997)

▪ Abstract Until recently, platelet production was the least understood aspect of blood cell development. This gap in our understanding resulted from the scarcity of megakaryocytes, the marrow precursor of blood platelets, and from confusion surrounding the cytokines and hormones that support their development. The recent cloning and characterization of thrombopoietin (TPO) has profoundly changed our udnerstanding of platelet production. Using in vitro assay systems, several groups have shown that TPO supports the proliferation of megakaryocytic progenitor cells and their differentiation into mature platelet-producing cells. Moreover, and somewhat surprisingly, TPO also acts in synergy with other pluripotent cytokines on the hematopoietic stem cell to augment development of erythroid and myeloid progenitors. These in vitro effects correlate well with the in vivo biology of the hormone. When administered to normal animals, TPO expands the numbers of hematopoietic progenitors of all lineages and greatly accelerates platelet production. Moreover, when TPO or its receptor is genetically eliminated, progenitor cell levels of all lineages are reduced, and platelet production is profoundly impaired. In animals administered cytoreductive therapy, the use of TPO is associated with accelerated hematopoietic recovery, not only of megakaryocytes and platelets, but also of erythrocytes and leukocytes. It, thus, is hoped that TPO may play an important role in reducing the myelosuppressive complications of naturally occurring and iatrogenic states of marrow failure.
Outcome measures in acne vulgaris: systematic review
Authors: H. Barratt, F. Hamilton, J. Car, C. Lyons, A. Layton, A. Majeed
Journal: British Journal of Dermatology (2008)

Summary Background Clinical trials require valid and reliable outcome measures to facilitate the interpretation and communication of results, and the secondary use of data for systematic reviews. There are numerous tools available to assess the severity of acne vulgaris in clinical trials, and extensive debate about the merits of these. Objectives To review the literature about investigator-assessed outcome measures used in clinical trials for acne vulgaris; and to evaluate the measurement properties of these tools. Methods A systematic literature review was conducted of articles outlining and evaluating investigator-assessed outcome measures for acne. Results Thirty-one papers met the criteria for inclusion in the literature review, including nine papers proposing a novel means of assessing acne, and five evaluating existing outcome measures. Variable attempts had been made to evaluate these tools. Conclusions The array of evaluation tools used in acne trials prohibits good secondary analysis of trial data, and complicates the interpretation of study results, potentially compromising clinical care. Existing outcome measures need to be assessed further and agreement reached about which should be used more widely. Other innovative methods of assessing acne should also be explored.
Mutant V600E <i>BRAF</i> Increases Hypoxia Inducible Factor-1α Expression in Melanoma
Authors: Suresh M. Kumar, Hong Yu, Robin Edwards, Lianjun Chen, Steven Kazianis, Patricia Brafford, Geza Acs, Meenhard Herlyn, Xiaowei Xu
Journal: Cancer Research (2007)

Abstract Mutations in the BRAF serine/threonine kinase gene are frequently found in cutaneous melanomas. Activation of hypoxia inducible factor-1α (HIF-1α) in response to both hypoxic stress and oncogenic signals has important implications in cancer development and progression. Here, we report that mutant BRAFV600E increases HIF-1α expression in melanoma cells. Our microarray profiling data in 35 melanoma and melanocyte cell lines showed that HIF-1α gene expression was significantly increased in melanomas harboring BRAFV600E mutation. Stable suppression of mutant BRAFV600E or both wild-type and mutant BRAFV600E by RNA interference in melanoma cells resulted in significantly decreased HIF-1α expression. Knockdown of mutant BRAFV600E induced significant reduction of cell survival and proliferation under hypoxic conditions, whereas knockdown of both wild-type and mutant BRAFV600E resulted in further reduction. The effects of BRAF knockdown can be rescued by reintroducing BRAFV600E into tumor cells. Transfection of BRAFV600E into melanoma cells with wild-type BRAF induced significantly more hypoxic tolerance. Knockdown of HIF-1α in melanoma cells resulted in decreased cell survival under hypoxic conditions. Pharmacologic inhibition of BRAF by BAY 43-9006 also resulted in decreased HIF-1α expression. Although HIF-1α translational rate was not changed, the protein was less stable in BRAF knockdown cells. In additional, von Hippel-Lindau protein expression was significantly increased in BRAF knockdown cells. Our data show for the first time that BRAFV600E mutation increases HIF-1α expression and melanoma cell survival under hypoxic conditions and suggest that effects of the oncogenic V600E BRAF mutation may be partially mediated through the HIF-1α pathway. [Cancer Res 2007;67(7):3177–84]
Making Eosinophils Through Subtle Shifts in Transcription Factor Expression
Authors: Kelly McNagny, Thomas Graf
Journal: The Journal of Experimental Medicine (2002)

More than a century after eosinophil granulocytes were baptized by Paul Ehrlich their role in defense mechanisms against parasitic infections and in allergic reactions has been firmly established ([1][1]). In contrast to the wealth of functional knowledge about these cells, their developmental
CD98hc (SLC3A2) Loss Protects Against Ras-Driven Tumorigenesis by Modulating Integrin-Mediated Mechanotransduction
Authors: Soline Estrach, Sin-Ae Lee, Etienne Boulter, Sabrina Pisano, Aurélia Errante, Floriane S. Tissot, Laurence Cailleteau, Catherine Pons, Mark H. Ginsberg, Chloé C. Féral
Journal: Cancer Research (2014)

CD98hc (SLC3A2) is the heavy chain component of the dimeric transmembrane glycoprotein CD98, which comprises the large neutral amino acid transporter LAT1 (SLC7A5) in cells. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor prognosis clinically, but its exact contributions to tumorigenesis are uncertain. In this study, we showed that genetic deficiency of CD98hc protects against Ras-driven skin carcinogenesis. Deleting CD98hc after tumor induction was also sufficient to cause regression of existing tumors. Investigations into the basis for these effects defined two new functions of CD98hc that contribute to epithelial cancer beyond an intrinsic effect of CD98hc on tumor cell proliferation. First, CD98hc increased the stiffness of the tumor microenvironment. Second, CD98hc amplified the capacity of cells to respond to matrix rigidity, an essential factor in tumor development. Mechanistically, CD98hc mediated this stiffness sensing by increasing Rho kinase (ROCK) activity, resulting in increased transcription mediated by YAP/TAZ, a nuclear relay for mechanical signals. Our results suggest that CD98hc contributes to carcinogenesis by amplifying a positive feedback loop, which increases both extracellular matrix stiffness and resulting cellular responses. This work supports a rationale to explore the use of CD98hc inhibitors as cancer therapeutics.
Effects of Basic Nuclear Proteins on Cardiac Muscle Function
Authors: ARNOLD SCHWARTZ, ARLINE H. LASETER, GARY G. FERGUSON
Journal: Circulation Research (1965)

A method for the preparation of semipurified basic proteins from cardiac muscle was presented. At low ionic strengths (below 0.05) and in the presence of Mg ++ , these compounds, as well as purified histones from a variety of tissues, inhibited the Mg ++ - ATP ase activity of cardiac and skeletal muscle actomyosin or myofibrillar suspensions. Under similar conditions, a retardation of superprecipitation occurred. At high ionic strengths (above 0.06) the histones stimulated the Mg ++ - ATP ase. In the presence of Ca ++ , and at all ionic strengths studied, the histones elicited a marked stimulation of actomyosin ATP ase. Administration of histones to anesthetized, open-chest guinea pigs, caused a significant depression of the force of contraction of the hearts. These data suggest a possible involvement of basic nuclear proteins in cardiac activity.
Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults
Authors: Timothy M. Hughes, Lewis H. Kuller, Emma J. M. Barinas-Mitchell, Eric M. McDade, William E. Klunk, Ann D. Cohen, Chester A. Mathis, Steven T. DeKosky, Julie C. Price, Oscar L. Lopez
Journal: JAMA Neurology (2014)

Recent studies show that cerebral β-amyloid (Aβ) deposition is associated with blood pressure and measures of arterial stiffness in nondemented individuals.To examine the association between measures of arterial stiffness and change in Aβ deposition over time.Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography using the Pittsburgh compound B twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer at the time closest to the second positron emission tomography scan. All measures were performed under standardized conditions. Pulse wave velocity (PWV) was measured in the central (carotid-femoral and heart-femoral PWV), peripheral (femoral-ankle PWV), and mixed (brachial-ankle PWV) vascular beds.The change in Aβ deposition over 2 years was calculated from the 81 individuals with repeat Aβ-positron emission tomography.The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time. Each standard deviation increase in central stiffness (carotid-femoral PWV, P = .001; heart-femoral PWV, P = .004) was linked with increases in Aβ deposition over 2 years.This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.
Toward precision medicine in glioblastoma: the promise and the challenges
Authors: Michael D. Prados, Sara A. Byron, Nhan L. Tran, Joanna J. Phillips, Annette M. Molinaro, Keith L. Ligon, Patrick Y. Wen, John G. Kuhn, Ingo K. Mellinghoff, John F. de Groot, Howard Colman, Timothy F. Cloughesy, Susan M. Chang, Timothy C. Ryken, Waibhav D. Tembe, Jeffrey A. Kiefer, Michael E. Berens, David W. Craig, John D. Carpten, Jeffrey M. Trent
Journal: Neuro-Oncology (2015)

Integrated sequencing strategies have provided a broader understanding of the genomic landscape and molecular classifications of multiple cancer types and have identified various therapeutic opportunities across cancer subsets. Despite pivotal advances in the characterization of genomic alterations in glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. In this review, we highlight potential reasons why targeting single alterations has yielded limited clinical efficacy in glioblastoma, focusing on issues of tumor heterogeneity and pharmacokinetic failure. We outline strategies to address these challenges in applying precision medicine to glioblastoma and the rationale for applying targeted combination therapy approaches that match genomic alterations with compounds accessible to the central nervous system.
Differences in disability as measured by the Health Assessment Questionnaire between patients with and without digital ulcers in systemic sclerosis: a post hoc analysis of pooled data from two randomised controlled trials in digital ulcers using bosentan: Table 1
Authors: Caleb Zelenietz, Janet Pope
Journal: Annals of the Rheumatic Diseases (2010)

Digital ulcers (DUs) cause significant morbidity in systemic sclerosis (SSc), occurring in 50% of patients with the disease.1 Patients report the impact of Raynaud's phenomenon and DU as worse than lung and gastrointestinal problems associated with SSc.2 The Health Assessment Questionnaire (HAQ)3 score is higher in patients with SSc with DU than in those without DU.4 A subset of the Health Assessment Questionnaire Disability Index (HAQ-DI) has been used for determining hand function,5 which is associated with work disability in patients with SSc.6 The purpose of this study was to determine if the HAQ score improved when a DU healed and if it worsened when a DU occurred.

Data were obtained from Actelion Pharmaceuticals Ltd for this post hoc analysis. All patients participating in the RAndomised Placebo-controlled Investigation of Digital ulcers …
Angiotensin-Converting Enzyme Inhibitors
Authors: Nancy J. Brown, Douglas E. Vaughan
Journal: Circulation (1998)

Abstract —ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT 1 receptor antagonists.
Surgical treatment of emphysematous bullae: late outcome.
Authors: M G Pearson, C Ogilvie
Journal: Thorax (1983)

From 1967 to 1972 12 patients were operated on for emphysematous bullae in the Liverpool regional cardiothoracic centre. The patient with the poorest lung function died in the immediate postoperative period but the remainder survived for more than five years. All but one of the survivors showed evidence of benefit three to six months after surgery and all those not retired returned to full-time employment for at least five years. Nine patients were reviewed 5-10 years after surgery. These all reported a gradual return of dyspnoea, which was matched by a falling one-second forced expiratory volume (FEV1) (mean fall 82 ml a year); but five were still maintaining some of their postoperative improvement. When mean preoperative lung function values were compared with the values obtained 5-10 years later there was still a significant improvement in forced vital capacity; but FEV1, residual volume, transfer coefficient, and arterial oxygen and carbon dioxide tensions were unchanged. Chest radiographs showed no new bullae or (except in one case) any increase in size of pre-existing bullae. We conclude that the removal of large emphysematous bullae did not hasten the progress of the underlying emphysema and that in most patients some benefit lasted for more than five years after the operation. Patients treated by lobectomy fared at least as well as those treated by bullectomy alone. It may be relevant to the relatively good progress of patients in this series that only three had suffered from chronic bronchitis before operation or smoked after operation, all but two had bullae occupying half or more of one hemithorax, and none had hypercapnia.
Reduced miR-128 in Breast Tumor–Initiating Cells Induces Chemotherapeutic Resistance via Bmi-1 and ABCC5
Authors: Yinghua Zhu, Fengyan Yu, Yu Jiao, Juan Feng, Wei Tang, Herui Yao, Chang Gong, Jianing Chen, Fengxi Su, Yan Zhang, Erwei Song
Journal: Clinical Cancer Research (2011)

Tumor-initiating cells are resistant to chemotherapy, but how microRNAs play a role in regulating drug resistance of breast tumor-initiating cells (BT-IC) needs to be clarified.
Decrease of serum paraoxonase activity in chronic renal failure.
Authors: T F Dantoine, J Debord, J P Charmes, L Merle, P Marquet, G Lachatre, C Leroux-Robert
Journal: Journal of the American Society of Nephrology (1998)

Paraoxonase is an esterase that hydrolyzes organophosphate compounds. The enzyme is associated with HDL and could protect LDL against peroxidation, which suggests a possible involvement of paraoxonase in the antiatherogenic properties of HDL. Paraoxonase activity has been shown to be low in patients with myocardial infarction, diabetes mellitus, or familial hypercholesterolemia. Because cardiovascular disease is the main cause of death in chronic renal failure, serum paraoxonase activity was measured by spectrophotometry using three synthetic substrates (phenyl acetate, paraoxon, and 4-nitrophenyl acetate) in 305 patients with kidney disease, including 47 patients with non-end-stage chronic renal failure, 104 patients treated with hemodialysis, 22 patients treated with peritoneal dialysis, and 132 renal transplant patients. Patients were compared with two groups of aged-matched control subjects (total number = 195). Especially with 4-nitrophenyl acetate, paraoxonase activity was lower in patients with some degree of renal insufficiency (chronic renal failure [P < 0.05], chronic hemodialysis [P < 10(-4)], chronic peritoneal dialysis [P < 10(-4)]) than in control subjects. In transplant patients, paraoxonase activity was not found to be different from that in control subjects. The decrease of paraoxonase activity and thus the reduction of its antiatherogenic properties in renal failure could be an essential factor of premature vascular aging, especially when dialysis is used. Renal transplantation seems to restore paraoxonase activity.