tbuckley/cabot-search huggingface dataset:
Leukemia Inhibitory Factor Activates Cardiac L-Type Ca <sup>2+</sup> Channels via Phosphorylation of Serine 1829 in the Rabbit Ca <sub>v</sub> 1.2 Subunit
Authors: Eiichi Takahashi, Keiichi Fukuda, Shunichiro Miyoshi, Mitsushige Murata, Takahiro Kato, Makoto Ita, Tsutomu Tanabe, Satoshi Ogawa
Journal: Circulation Research (2004)

We have previously reported that leukemia inhibitory factor (LIF) gradually increased cardiac L-type Ca2+ channel current (I(CaL)), which peaked at 15 minutes in both adult and neonatal rat cardiomyocytes, and this increase was blocked by the mitogen-activated protein kinase kinase inhibitor PD98059. This study investigated the molecular basis of LIF-induced augmentation of I(CaL) in rodent cardiomyocytes. LIF induced phosphorylation of a serine residue in the alpha(1c) subunit (Ca(v)1.2) of L-type Ca2+ channels in cultured rat cardiomyocytes, and this phosphorylation was inhibited by PD98059. When constructs encoding either a wild-type or a carboxyl-terminal-truncated rabbit Ca(v)1.2 subunit were transfected into HEK293 cells, LIF induced phosphorylation of the resultant wild-type protein but not the mutant protein. Cotransfection of constitutively active mitogen-activated protein kinase kinase also resulted in phosphorylation of the Ca(v)1.2 subunit in the absence of LIF stimulation. In in-gel kinase assays, extracellular signal-regulated kinase phosphorylated a glutathione S-transferase fusion protein of the carboxyl-terminal region of Ca(v)1.2 (residues 1700 through 1923), which contains the consensus sequence Pro-Leu-Ser-Pro. A point mutation within this consensus sequence, which results in a substitution of alanine for serine at residue 1829 (S1829A), was sufficient to abolish the LIF-induced phosphorylation. LIF increased I(CaL) in HEK cells transfected with wild-type Ca(v)1.2 but not with the mutated version. These results provide direct evidence that LIF phosphorylates the serine residue at position 1829 of the Ca(v)1.2 subunit via the actions of extracellular signal-regulated kinase and that this phosphorylation increases I(CaL) in cardiomyocytes.
Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST)
Authors: Edward F McKone, Drucy Borowitz, Pavel Drevinek, Matthias Griese, Michael W Konstan, Claire Wainwright, Felix Ratjen, Isabelle Sermet-Gaudelus, Barry Plant, Anne Munck, Ying Jiang, Geoffrey Gilmartin, Jane C Davies
Journal: The Lancet Respiratory Medicine (2014)
Synergistic role of micronemal proteins in Toxoplasma gondii virulence
Authors: Odile Cérède, Jean François Dubremetz, Martine Soête, Didier Deslée, Henri Vial, Daniel Bout, Maryse Lebrun
Journal: The Journal of Experimental Medicine (2005)

Apicomplexan parasites invade cells by a unique mechanism involving discharge of secretory vesicles called micronemes. Microneme proteins (MICs) include transmembrane and soluble proteins expressing different adhesive domains. Although the transmembrane protein TRAP and its homologues are thought to bridge cell surface receptors and the parasite submembranous motor, little is known about the function of other MICs. We have addressed the role of MIC1 and MIC3, two soluble adhesins of Toxoplasma gondii, in invasion and virulence. Single deletion of the MIC1 gene decreased invasion in fibroblasts, whereas MIC3 deletion had no effect either alone or in the mic1KO context. Individual disruption of MIC1 or MIC3 genes slightly reduced virulence in the mouse, whereas doubly depleted parasites were severely impaired in virulence and conferred protection against subsequent challenge. Single substitution of two critical amino acids in the chitin binding–like (CBL) domain of MIC3 abolished MIC3 binding to cells and generated the attenuated virulence phenotype. Our findings identify the CBL domain of MIC3 as a key player in toxoplasmosis and reveal the synergistic role of MICs in virulence, supporting the idea that parasites have evolved multiple ligand–receptor interactions to ensure invasion of different cells types during the course of infection.
Activation of CXCR2 by Extracellular Matrix Degradation Product Acetylated Pro-Gly-Pro Has Therapeutic Effects against Sepsis
Authors: Sang Doo Kim, Ha Young Lee, Jae Woong Shim, Hak Jung Kim, Young Hyun Yoo, Joon Seong Park, Suk-Hwan Baek, Brian A. Zabel, Yoe-Sik Bae
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Rationale: Acetylated Pro-Gly-Pro (Ac-PGP) is an endogenous degradation product of extracellular collagen that binds to leukocyte-expressed chemoattractant receptor CXCR2. Although certain agents that block CXCR2-mediated signaling protect against experimental sepsis, the roles of Ac-PGP and CXCR2 in sepsis are unclear.Objectives: To investigate the role of Ac-PGP and its receptor, CXCR2, in murine models of cecal ligation and puncture (CLP)–induced polymicrobial sepsis and organ injury.Methods: The impact of in vivo Ac-PGP treatment on animal survival after induction of experimental sepsis was assessed. Vital organ inflammation and immune cell apoptosis were evaluated by histology, and the modulation of proinflammatory cytokine production and bactericidal activity by Ac-PGP in mouse and human blood leukocytes was measured.Measurements and Main Results: The activation of CXCR2 by tripeptide agonist Ac-PGP dramatically improved survival in three experimental sepsis models. Ac-PGP elicited bactericidal activity via the generation of hydrogen peroxide, inhibited lung inflammation, and reduced immune cell apoptosis. Fluorescein isothiocyanate–labeled PGP bound directly to CXCR2, and the protective effect of Ac-PGP in sepsis was abolished in CXCR2-deficient mice. Ac-PGP treatment enhanced the production of type 1 cytokines (IFN-γ and IL-12) but inhibited the production of proinflammatory cytokines (tumor necrosis factor [TNF]-α, IL-1β, and IL-6) in vivo. In vitro, Ac-PGP directly increased IFN-γ production and decreased the LPS-stimulated production of TNF-α by mouse splenocytes and human leukocytes. Furthermore, direct treatment of LPS-stimulated splenocytes with IFN-γ resulted in diminished secretion of TNF-α and IL-6.Conclusions: CXCR2 and Ac-PGP are thus novel target and starting molecules, respectively, for the development of therapeutic agents against sepsis.
Impact of childhood vitiligo on adult life
Authors: M.W. Linthorst Homan, J. de Korte, M.A. Grootenhuis, J.D. Bos, M.A.G. Sprangers, J.P.W. van der Veen
Journal: British Journal of Dermatology (2008)

The onset of vitiligo occurs before the age of 20 years in 50% of patients. Having a chronic disease in childhood can impede a child's health-related quality of life (HRQL).Firstly, to compare the social and psychosexual development and current HRQL of young adult patients with childhood vitiligo with those of a group of healthy controls. Secondly, to compare these outcomes in patients reporting negative childhood experiences with those of patients not reporting negative childhood experiences.Eligible patients were mailed questionnaires on (i) sociodemographic and clinical characteristics, (ii) social and psychosexual development, (iii) generic and dermatology-specific HRQL, (iv) presence of negative childhood experiences related to vitiligo, (v) specification of these negative experiences and (vi) patients' recommendations for further care.A total of 232 patients with vitiligo completed the questionnaires. Social and psychosexual development and generic HRQL in young adult patients with childhood vitiligo were not different from those of healthy controls. However, patients reporting negative childhood experiences reported significantly more problems in social development than those not reporting negative experiences. Furthermore, negative childhood experiences were significantly associated with more HRQL impairment in early adulthood.Reporting negative experiences from childhood vitiligo appears to be associated with HRQL impairment in young adults with vitiligo.
Immediate triggering of 4-1BB co-stimulation during initiation of tumor-infiltrating lymphocyte (TIL) expansion from melanoma tumors accelerates CD8+ T-cell outgrowth and tumor specificity
Authors: Jessica Chacon, Shari Pilon-Thomas, Amod Sarnaik, Patrick Hwu, Laszlo Radvanyi
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TIL) has emerged as a powerful salvage therapy option for patients with metastatic melanoma, even those that have progressed on anti-CTLA-4 and anti-PD-1 protocols. The expansion of TIL enriched in effector-memory CD8+
Echocardiographic Predictors of Outcome in Eisenmenger Syndrome
Authors: Pamela Moceri, Konstantinos Dimopoulos, Emmanouil Liodakis, Ioannis Germanakis, Aleksander Kempny, Gerhard-Paul Diller, Lorna Swan, Stephen J. Wort, Philip S. Marino, Michael A. Gatzoulis, Wei Li
Journal: Circulation (2012)

Background— Eisenmenger syndrome differs significantly from other types of pulmonary arterial hypertension in its physiology and prognosis. We sought to assess the relationship between the echocardiographic characteristics of patients with Eisenmenger syndrome and mortality. Methods and Results— Clinical and echocardiographic variables were assessed in 181 consecutive patients with Eisenmenger syndrome, excluding those with complex congenital heart disease. Patients' mean age was 39.1±12.8 years, 59 (32.6%) were male, 122 (67.4%) were in functional class III or higher, and 74 (40.9%) were on advanced therapies. Mean oxygen saturation at rest was 85.1±7.8%, and median B-type natriuretic peptide was 55.4 ng/L. Over a median follow-up of 16.4 months, 19 patients died; the strongest predictors of mortality were tricuspid annular plane systolic excursion and peak systolic velocity, myocardial performance (expressed as total isovolumic time and ratio of systolic to diastolic duration), and elevated central venous pressure (expressed as right atrial [RA] area, RA pressure, and ratio of RA to left atrial area), even after we accounted for advanced therapies. A composite score based on the strongest echocardiographic predictors of outcome, including 1 point for each of the following: tricuspid annular plane systolic excursion &lt;15 mm, ratio of right ventricular effective systolic to diastolic duration ≥1.5, RA area ≥25 cm 2 , ratio of RA to left atrial area ≥1.5, was highly predictive of clinical outcome (area under the curve 0.90±0.01), with no improvement when B-type natriuretic peptide and resting saturations were added into the model. Conclusions— Echocardiographic parameters of right ventricular function and RA area predict mortality in Eisenmenger patients. A new composite echocardiographic score, described herewith, may be incorporated into the noninvasive, periodic assessment of these patients.
Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4
Authors: Hilmar M Warenius, Jeremy D Kilburn, Jon W Essex, Richard I Maurer, Jeremy P Blaydes, Usha Agarwala, Laurence A Seabra
Journal: Molecular Cancer (2011)

Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, CDK4 gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of CDK2 and CDK6; and o verexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor. A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy. These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4.
MicroRNA-223 delivered by platelet-derived microvesicles promotes lung cancer cell invasion via targeting tumor suppressor EPB41L3
Authors: Hongwei Liang, Xin Yan, Yi Pan, Yongsheng Wang, Nan Wang, Limin Li, Yuan Liu, Xi Chen, Chen-Yu Zhang, Hongwei Gu, Ke Zen
Journal: Molecular Cancer (2015)

Patients with hematogenous metastatic lung cancer displayed significantly increased platelet count and aggregation compared to lung cancer patients without hematogenous metastasis. The mechanism underlying the correlation between the lung cancer hematogenous metastasis and platelet activation remains unknown. In the present study, we explored the role of microRNA-223 (miR-223) derived from platelets in modulating lung cancer cell invasion. Our results demonstrated that platelets from NSCLC patients contain higher level of miR-223 than that from healthy subjects. The concentration of miR-223 in the platelet-secreted microvesicles (P-MVs) from NSCLC patients was also increased compared to that from healthy subjects. Incubation of human lung cancer A549 cells with P-MVs resulted in rapid delivery of miR-223 into A549 cells, in which platelet miR-223 targeted EPB41L3 and thus promoted A549 cell invasion. The effect of P-MVs on reducing EPB41L3 in A549 cells but promoting tumor cell invasion could be largely abolished by depletion of miR-223 via transfection with miR-223 antagomir. The role of EPB41L3 in inhibiting A549 cell invasion was further validated by directly downregulating EPB41L3 via transfecting cells with EPB41L3 siRNA or miR-223 mimic. Our study demonstrates for the first time that platelet-secreted miR-223 via P-MVs can promote lung cancer cell invasion via targeting tumor suppressor EPB41L3.
Casein Kinase 1ϵ Promotes Cell Proliferation by Regulating mRNA Translation
Authors: Sejeong Shin, Laura Wolgamott, Philippe P. Roux, Sang-Oh Yoon
Journal: Cancer Research (2013)

Deregulation of translation initiation factors contributes to many pathogenic conditions, including cancer. Here, we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1ε (CK1ε) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the translation initiation complex eIF4F, is downregulated by binding the negative-acting factor 4E-BP1. We found that genetic or pharmacologic inhibition of CK1ε attenuated 4E-BP1 phosphorylation, thereby increasing 4E-BP1 binding to eIF4E and inhibiting mRNA translation. Mechanistic investigations showed that CK1ε interacted with and phosphorylated 4E-BP1 at two novel sites T41 and T50, which were essential for 4E-BP1 inactivation along with increased mRNA translation and cell proliferation. In summary, our work identified CK1ε as a pivotal regulator of mRNA translation and cell proliferation that acts by inhibiting 4E-BP1 function. As CK1ε is highly expressed in breast tumors, these findings offer an initial rationale to explore CK1ε blockade as a therapeutic strategy to treat cancers driven by deregulated mRNA translation.
SNAI1 Is Required for Tumor Growth and Lymph Node Metastasis of Human Breast Carcinoma MDA-MB-231 Cells
Authors: David Olmeda, Gema Moreno-Bueno, Juana M. Flores, Angels Fabra, Francisco Portillo, Amparo Cano
Journal: Cancer Research (2007)

Abstract The transcription factor, SNAI1 (Snail), has recently been proposed as an important mediator of tumor invasion because of its role in E-cadherin down-regulation and induction of epithelial-mesenchymal transition. In human breast cancer, the expression of SNAI1 and/or the homologous SNAI2 (Slug) has been associated with E-cadherin repression, local or distant metastasis, tumor recurrence, or poor prognosis in different tumor series. However, the specific contribution of either factor to breast tumor progression is still unclear. We have analyzed the role of SNAI1 in human breast cancer by loss of function studies and provide evidence of a major role for SNAI1 in both primary tumor growth and metastasis of human breast carcinoma MDA-MB-231 cells. Specific silencing of SNAI1 by short hairpin RNA induces a decrease in mesenchymal and proinvasive markers (MMP9, ID1, SPARC) in MDA-MB-231 cells, concomitant with reduced in vitro invasive behavior. More importantly, stable SNAI1 silencing in MDA-MB-231 cells leads to a dramatic reduction of in vivo tumor incidence and growth rate. Tumors induced by MDA-MB-231-SNAI1–silenced cells show extensive necrotic regions and a significant decrease in invasive and angiogenic markers. Moreover, SNAI1 silencing increases the sensitivity of MDA-MB-231 cells to chemotherapeutics relevant in breast cancer treatments, gemcitabine and docetaxel. Remarkably, analysis of cell lines derived from lymph node metastasis indicates that SNAI1 expression is required for metastatic dissemination. [Cancer Res 2007;67(24):11721–31]
Thyrotoxicosis Masked by Diabetic Ketoacidosis
Authors: Makoto Kunishige, Etsuko Sekimoto, Machiko Komatsu, Yoshimi Bando, Hisanori Uehara, Keisuke Izumi
Journal: Diabetes Care (2001)

A 48-year-old man had been treated at our hospital for type 2 diabetes and Graves' disease. He was diagnosed with diabetic ketoacidosis (DKA) twice during previous visits. He was prescribed methimazole (10 mg/day) and insulin, but his drug compliance was poor. He had not visited our hospital since 3 September 1998, when his HbAlc level was 11.6% (normal 4.3-5.8) and his thyroid function tests revealed euthyroidism. He had stopped taking medication 30 December 1998, and he was admitted to our hospital on 6 January 1999, with general fatigue, a sore throat, and excessive thirst. He appeared drowsy, and he presented with Kussmaul respirations, irregular tachycardia, dry skin, injected …
Relative nutritional value of whole protein, hydrolysed protein and free amino acids in man.
Authors: K J Moriarty, J E Hegarty, P D Fairclough, M J Kelly, M L Clark, A M Dawson
Journal: Gut (1985)

To compare their effects on nitrogen balance, diets containing either lactalbumin whole protein, its peptide-rich enzymic hydrolysate or an equivalent mixture of free amino acids as the sole source of dietary nitrogen were fed to two healthy subjects, each studied for 38 days on two separate occasions. The nitrogen intake (47 mg/kg body wt/day) induced a state of negative nitrogen balance, stimulating nitrogen conservation. Net daily nitrogen balance (mean +/- SD) in subject 1 was -0.23 +/- 0.72 g (amino acids) vs + 0.05 +/- 0.52 g (protein) and -0.21 +/- 0.58 g (amino acids) vs -0.05 +/- 0.57 g (hydrolysate), and in subject 2, -0.19 +/- 0.60 g (amino acids) vs -0.16 +/- 0.51 g (protein) and -0.42 +/- 0.35 g (amino acids) vs -0.62 +/- 0.34 g (hydrolysate). Analysis of these results by the cumulative sum technique showed no significant differences in the effect of the three nitrogen sources on nitrogen balance. This study indicates that there is no nutritional evidence to support the current practice of prescribing expensive enteral diets containing peptides or amino acids rather than the much cheaper whole protein to patients with normal gastrointestinal function.
Longitudinal Analysis of Fibroblast Growth Factor Expression After Transplantation and Association With Severity of Cardiac Allograft Vasculopathy
Authors: Geraldine G. Miller, Stacy F. Davis, James B. Atkinson, Donald B. Chomsky, Pedro Pedroso, V. Seenu Reddy, Davis C. Drinkwater, Xiao-Ming Zhao, Richard N. Pierson
Journal: Circulation (1999)

Vascular smooth muscle cell growth factors are postulated to contribute to cardiac allograft vasculopathy (CAV). Few data quantitatively address the timing, location, or stimuli for growth factor expression and relationship to CAV.Acidic fibroblast growth factor (aFGF) mRNA expression was determined in serial endomyocardial biopsies during the first year after transplantation. Patients with high levels of aFGF mRNA and elevations after the early posttransplant period had significantly more severe CAV than patients with low aFGF and no late elevations.Parenchymal aFGF expression varies between patients and in the same patient over time and correlates with development of CAV.
Wound Healing in the Kidney
Authors: Raimund Hirschberg
Journal: Journal of the American Society of Nephrology (2004)

The degree of renal interstitial fibrosis, i.e. , the poorly organized accumulation of extracellular matrix (ECM) proteins such as collagens (types I, III, and IV), fibronectin, laminins, and others, has emerged as the pathohistologic entity that correlates better with the degree of renal filtration
Immune Cell Activation by Bacterial Cpg-DNA through Myeloid Differentiation Marker 88 and Tumor Necrosis Factor Receptor–Associated Factor (Traf)6
Authors: Hans Häcker, Ramunas M. Vabulas, Osamu Takeuchi, Katsuaki Hoshino, Shizuo Akira, Hermann Wagner
Journal: The Journal of Experimental Medicine (2000)

Transition of immature antigen presenting cells (APCs) to the state of professional APCs is essential for initiation of cell-mediated immune responses to pathogens. Signal transduction via molecules of the Toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) pathway is critical for activation of APCs either by pathogen-derived pattern ligands like lipopolysaccharides (LPS) or by CD40 ligation through T helper cells. The capacity of bacterial DNA (CpG-DNA) to induce APCs to differentiate into professional APCs represents an interesting discovery. However, the signaling pathways involved are poorly understood. Here we show that CpG-DNA activates the TLR/IL-1R signaling pathway via the molecules myeloid differentiation marker 88 (MyD88) and tumor necrosis factor receptor–associated factor 6 (TRAF6), leading to activation of kinases of the IκB kinase complex and the c-jun NH2-terminal kinases. Moreover, cells of TLR2- and TLR4-deficient mice are activated by CpG-DNA, whereas cells of MyD88-deficient mice do not respond. The data suggest that CpG-DNA initiates signaling via the TLR/IL-1R pathway in APCs in a manner similar to LPS and to T helper cell–mediated CD40 ligation. Activation of the TLR/IL-1R signaling pathway by foreign bacterial DNA may be one way to initiate innate defense mechanisms against infectious pathogens in vivo.
OFF-PUMP CABG ATTENUATES MORBIDITY AND MORTALITY FOR PATIENTS AT EXTREMES OF BODY MASS INDEX
Authors: William B. Keeling, Patrick Kilgo, Michael E. Halkos, John D. Puskas, Omar M. Lattouf, Robert A. Guyton, Vinod H. Thourani
Journal: Journal of the American College of Cardiology (2011)