tbuckley/cabot-search huggingface dataset:
Partially Phosphorylated T Cell Receptor ζ Molecules Can Inhibit T Cell Activation
Authors: Ellen N. Kersh, Gilbert J. Kersh, Paul M. Allen
Journal: The Journal of Experimental Medicine (1999)

The T cell receptor complex (TCR) ζ chain is constitutively tyrosine phosphorylated specifically at two of the six ζ immunoreceptor tyrosine-based activation motif (ITAM) tyrosine residues in resting peripheral T cells. Further phosphorylation of ζ is induced by both agonist and antagonist ligands of the TCR, with agonists inducing complete phosphorylation of the ζ ITAM tyrosines. After antagonist stimulation, ζ phosphorylation is incomplete and generates discrete forms of partially phosphorylated ITAMs. Here, we mutate specific tyrosines in chimeric human CD8-ζ molecules to reflect phosphorylation in resting T cells as well as phosphorylation induced by agonist and antagonist ligands. We demonstrate that such partially phosphorylated TCR-ζ species can inhibit IL-2 production in T cell hybridomas and proliferation in T cell clones. This reveals a previously unrecognized, inhibitory function of partially phosphorylated ITAMs. These findings support the concept that TCR antagonism can arise through the generation of an inhibitory signal within the TCR complex and that constitutive ζ phosphorylation in resting T cells is an inhibitory signaling environment.
Prevalence of anti-HCV antibodies in kidney allograft recipients with chronic B or non A non B hepatitis or without liver dysfunction
Authors: F. Lunel, D. Jeannot, M. Perrin, F. Luciani, P. Grippon, J.F. Cadranel, A. Devillechabrolle, C. Jacobs, C. Chatclain, P. Opolon
Journal: Journal of Hepatology (1990)
Redox Regulation of Soluble Epoxide Hydrolase by 15-Deoxy-Δ-Prostaglandin J <sub>2</sub> Controls Coronary Hypoxic Vasodilation
Authors: Rebecca L. Charles, Joseph R. Burgoyne, Manuel Mayr, Steven M. Weldon, Norbert Hubner, Hua Dong, Christophe Morisseau, Bruce D. Hammock, Aimee Landar, Philip Eaton
Journal: Circulation Research (2010)

15-Deoxy-Δ-prostaglandin (15d-PG)J(2) is an electrophilic oxidant that dilates the coronary vasculature. This lipid can adduct to redox active protein thiols to induce oxidative posttranslational modifications that modulate protein and tissue function.To investigate the role of oxidative protein modifications in 15d-PGJ(2)-mediated coronary vasodilation and define the distal signaling pathways leading to enhanced perfusion.Proteomic screening with biotinylated 15d-PGJ(2) identified novel vascular targets to which it adducts, most notably soluble epoxide hydrolase (sEH). 15d-PGJ(2) inhibited sEH by specifically adducting to a highly conserved thiol (Cys521) adjacent to the catalytic center of the hydrolase. Indeed a Cys521Ser sEH "redox-dead" mutant was resistant to 15d-PGJ(2)-induced hydrolase inhibition. 15d-PGJ(2) dilated coronary vessels and a role for hydrolase inhibition was supported by 2 structurally different sEH antagonists each independently inducing vasorelaxation. Furthermore, 15d-PGJ(2) and sEH antagonists also increased coronary effluent epoxyeicosatrienoic acids consistent with their vasodilatory actions. Indeed 14,15-EET alone induced relaxation and 15d-PGJ(2)-mediated vasodilation was blocked by the EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE). Additionally, the coronary vasculature of sEH-null mice was basally dilated compared to wild-type controls and failed to vasodilate in response to 15d-PGJ(2). Coronary vasodilation to hypoxia in wild-types was accompanied by 15d-PGJ(2) adduction to and inhibition of sEH. Consistent with the importance of hydrolase inhibition, sEH-null mice failed to vasodilate during hypoxia.This represents a new paradigm for the regulation of sEH by an endogenous lipid, which is integral to the fundamental physiological response of coronary hypoxic vasodilation.
Stress injury of the lunate in tennis players: a case series and related biomechanical considerations
Authors: Javier Maquirriain, Juan P Ghisi
Journal: British Journal of Sports Medicine (2007)

Objective: To investigate clinical and imaging differential diagnosis and tennis stroke biomechanics potentially involved in lunate stress injury pathogenesis. Methods: The present report describes five competitive tennis players with overuse-related dorsal wrist pain assessed by magnetic resonance imaging. Results: Magnetic resonance imaging revealed the presence of lunate stress injury. All players were treated conservatively, with symptom resolution and complete functional recovery achieved at 14 weeks. Conclusions: Lunate stress injuries should be considered in the differential diagnosis of overuse-related dorsal wrist pain in tennis players.
Halogenated Benzimidazole Carboxamides Target Integrin α4β1 on T-Cell and B-Cell Lymphomas
Authors: Richard D. Carpenter, Arutselvan Natarajan, Edmond Y. Lau, Mirela Andrei, Danielle M. Solano, Felice C. Lightstone, Sally J. DeNardo, Kit S. Lam, Mark J. Kurth
Journal: Cancer Research (2010)

Integrin alpha(4)beta(1) is an attractive but poorly understood target for selective diagnosis and treatment of T-cell and B-cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships, and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin alpha(4)beta(1) antagonists. We documented tumor uptake of derivatives labeled with (125)I in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin alpha(4)beta(1) predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high-affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic ((18)F) or radiotherapeutic ((131)I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies.
The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb
Authors: Tharinda W Rajapaksha, William A Eimer, Thomas C Bozza, Robert Vassar
Journal: Molecular Neurodegeneration (2011)

Abstract Background The β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), is a prime therapeutic target for lowering cerebral β-amyloid (Aβ) levels in Alzheimer's disease (AD). Clinical development of BACE1 inhibitors is being intensely pursued. However, little is known about the physiological functions of BACE1, and the possibility exists that BACE1 inhibition may cause mechanism-based side effects. Indeed, BACE1 -/- mice exhibit a complex neurological phenotype. Interestingly, BACE1 co-localizes with presynaptic neuronal markers, indicating a role in axons and/or terminals. Moreover, recent studies suggest axon guidance molecules are potential BACE1 substrates. Here, we used a genetic approach to investigate the function of BACE1 in axon guidance of olfactory sensory neurons (OSNs), a well-studied model of axon targeting in vivo . Results We bred BACE1 -/- mice with gene-targeted mice in which GFP is expressed from the loci of two odorant-receptors (ORs), MOR23 and M72, and olfactory marker protein (OMP) to produce offspring that were heterozygous for MOR23-GFP, M72-GFP, or OMP-GFP and were either BACE1 +/+ or BACE1 -/- . BACE1 -/- mice had olfactory bulbs (OBs) that were smaller and weighed less than OBs of BACE1 +/+ mice. In wild-type mice, BACE1 was present in OSN axon terminals in OB glomeruli. In whole-mount preparations and tissue sections, many OB glomeruli from OMP-GFP; BACE1 -/- mice were malformed compared to wild-type glomeruli. MOR23-GFP; BACE1 -/- mice had an irregular MOR23 glomerulus that was innervated by randomly oriented, poorly fasciculated OSN axons compared to BACE1 +/+ mice. Most importantly, M72-GFP; BACE1 -/- mice exhibited M72 OSN axons that were mis-targeted to ectopic glomeruli, indicating impaired axon guidance in BACE1 -/- mice. Conclusions Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in axon guidance. OSNs continually undergo regeneration and hence require ongoing axon guidance. Neurogenesis and the regeneration of neurons and axons occur in other adult populations of peripheral and central neurons that also require axon guidance throughout life. Therefore, BACE1 inhibitors under development for the treatment of AD may potentially cause axon targeting defects in these neuronal populations as well.
Moraxella catarrhalis induces ERK- and NF- B-dependent COX-2 and prostaglandin E2 in lung epithelium
Authors: P. D. N'Guessan, B. Temmesfeld-Wollbrück, J. Zahlten, J. Eitel, S. Zabel, B. Schmeck, B. Opitz, S. Hippenstiel, N. Suttorp, H. Slevogt
Journal: European Respiratory Journal (2007)

Moraxella catarrhalis is a major cause of infectious exacerbations of chronic obstructive lung disease. Cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E 2 (PGE 2 ), are considered to be important regulators of lung function. The present authors tested the hypothesis that M. catarrhalis induces COX-2-dependent PGE 2 production in pulmonary epithelial cells. In the present study, the authors demonstrate that M. catarrhalis specifically induces COX-2 expression and subsequent PGE 2 release in pulmonary epithelial cells. Furthermore, the prostanoid receptor subtypes EP2 and EP4 were also upregulated in these cells. The M. catarrhalis -specific ubiquitous cell surface protein A1 was important for the induction of COX-2 and PGE 2 . Moreover, M. catarrhalis -induced COX-2 and PGE 2 expression was dependent on extracellular signal-regulated kinase 1/2-driven activation of nuclear factor-κB, but not on the activation of p38 mitogen-activated protein kinase. In conclusion, the present data suggest that ubiquitous cell surface protein A1 of Moraxella catarrhalis , extracellular signal-regulated kinase 1/2 and nuclear factor-κB control cyclooxygenase-2 expression and subsequent prostaglandin E 2 release by lung epithelial cells. Moraxella catarrhalis -induced prostaglandin E 2 expression might counteract lung inflammation promoting colonisation of the respiratory tract in chronic obstructive pulmonary disease patients.
GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment
Authors: Klaus Podar, Laurence P. Catley, Yu-Tzu Tai, Reshma Shringarpure, Pedro Carvalho, Toshiaki Hayashi, Renate Burger, Robert L. Schlossman, Paul G. Richardson, Lini N. Pandite, Rakesh Kumar, Teru Hideshima, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2003)
A Model for Personalized in Vivo Analysis of Human Immune Responsiveness
Authors: Hannes Kalscheuer, Nichole Danzl, Takashi Onoe, Ted Faust, Robert Winchester, Robin Goland, Ellen Greenberg, Thomas R. Spitzer, David G. Savage, Hiroyuki Tahara, Goda Choi, Yong-Guang Yang, Megan Sykes
Journal: Science Translational Medicine (2012)

Personalized humanized mice can model intrinsic defects in human immune disease.
Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy
Authors: Xiaodan Ren, Cory Hogaboam, Audra Carpenter, Lisa Colletti
Journal: Journal of Clinical Investigation (2003)

Stem cell factor (SCF) is a molecule with known proliferative effects on hematopoietic cells. More recent studies suggest that this molecule may also have effects on cellular differentiation and proliferation in other types of cells. The current investigations demonstrate that there is a large reservoir of SCF in the liver, that hepatic SCF levels change dramatically following partial hepatectomy in mice, and that SCF blockade, either by administration of anti-SCF antibodies or by using genetically altered, SCF-deficient mice, inhibits hepatocyte proliferation after partial hepatectomy; if SCF is replaced in the genetically SCF-deficient mice after partial hepatectomy, hepatocyte proliferation is restored to that seen in WT animals. Furthermore, SCF administration to IL-6 knockout mice also restores hepatocyte proliferation to normal. In vitro studies using primary mouse hepatocytes demonstrate that SCF causes hepatocyte proliferation and is induced by IL-6 and that treatment with anti-SCF antibodies inhibits IL-6-induced hepatocyte proliferation. Further in vivo studies in IL-6 knockout mice demonstrate that SCF administration to these animals increases p-stat3 levels, suggesting that the SCF-induced increase in hepatocyte proliferation in this system is stat3-mediated.
Granulomatous involvement of the liver in patients with AIDS.
Authors: M S Orenstein, A Tavitian, B Yonk, H P Dincsoy, J Zerega, S K Iyer, E W Straus
Journal: Gut (1985)

During a one month period liver biopsy was carried out on eight patients with established acquired immune deficiency syndrome (AIDS) and two suspected of having AIDS to evaluate raised liver enzymes or unexplained fever and weight loss. Each of the 10 patients were found to have hepatic granulomas. Appropriate staining techniques showed acid-fast bacilli in seven of the liver specimens. One specimen contained numerous Cryptococcal organisms. Two biopsies showed granulomas but no organisms. Liver biopsy was found to be a high yield and rapid diagnostic procedure in patients with AIDS. Our results suggest that hepatic mycobacterial infection may be more common in the syndrome than previously recognised and that liver biopsy specimens should be examined routinely for the presence of acid-fast bacilli.
The Tumor Suppressor Gene <i>hCDC4</i> Is Frequently Mutated in Human T-Cell Acute Lymphoblastic Leukemia with Functional Consequences for Notch Signaling
Authors: Alena Malyukova, Takeaki Dohda, Natalie von der Lehr, Shahab Akhondi, Martin Corcoran, Mats Heyman, Charles Spruck, Dan Grandér, Urban Lendahl, Olle Sangfelt
Journal: Cancer Research (2007)

Abstract Notch signaling is of crucial importance in normal T-cell development and Notch 1 is frequently mutated in T-cell acute lymphoblastic leukemias (T-ALL), leading to aberrantly high Notch signaling. In this report, we determine whether T-ALL mutations occur not only in Notch1 but also in the F-box protein hCdc4 (Sel-10, Ago, or Fbxw7), a negative regulator of Notch1. We show that the hCDC4 gene is mutated in leukemic cells from more than 30% of patients with pediatric T-ALL and derived cell lines. Most hCDC4 mutations found were missense substitutions at critical arginine residues (Arg465, Arg479, and Arg505) localized in the substrate-binding region of hCdc4. Cells inactivated for hCdc4 and T-ALL cells containing hCDC4 mutations exhibited an increased Notch1 protein half-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent proteolysis of Notch1. Furthermore, restoration of wild-type but not mutant hCdc4 in HCT 116 hCDC4-negative cells led to an increased Notch1 ubiquitylation and decreased Notch1 signaling. These results show that hCdc4 mutations interfere with normal Notch1 regulation in vivo. Finally, we found that mutations in hCDC4 and NOTCH1 can occur in the same cancers and that patients carrying hCDC4 and/or NOTCH1 mutations have a favorable overall survival. Collectively, these data show that mutation of hCDC4 is a frequent event in T-ALL and suggest that hCDC4 mutations and gain-of-function mutations in NOTCH1 might synergize in contributing to the development of pediatric T-ALL leukemogenesis. [Cancer Res 2007;67(12):5611–6]
Neurophysiology of the cough reflex
Authors: JG Widdicombe
Journal: European Respiratory Journal (1995)

Cough is due to activation of sensory receptors in the larynx and lower respiratory tract, sending impulses to the brainstem. The central organization of cough is poorly understood. The afferent pathways for cough are from receptors in and under the epithelium of the airways. These receptors are rapidly adapting, with thin myelinated fibres in the vagus nerves, which can be directly stimulated by tussive agents. Activation of C-fibre receptors in the airway releases sensory neuropeptides. These cause neurogenic inflammation and may activate rapidly adapting receptors to cause cough. The central connections of the C-fibre receptors inhibit cough. Thus, the sensitivity of the cough reflex and its pattern of response is due to a complex interaction between C-fibre receptors and rapidly adapting receptors, with peripheral and central nervous interactions. How these mechanisms apply to clinical cough in patients is at present poorly understood, but is beginning to be clarified.
A Novel Androgen Receptor Splice Variant Is Up-regulated during Prostate Cancer Progression and Promotes Androgen Depletion–Resistant Growth
Authors: Zhiyong Guo, Xi Yang, Feng Sun, Richeng Jiang, Douglas E. Linn, Hege Chen, Hegang Chen, Xiangtian Kong, Jonathan Melamed, Clifford G. Tepper, Hsing-Jien Kung, Angela M.H. Brodie, Joanne Edwards, Yun Qiu
Journal: Cancer Research (2009)

Abstract The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer Res 2009;69(6):2305–13]
Characteristics of Prolonged Ca <sup>2+</sup> Release Events Associated With the Nuclei in Adult Cardiac Myocytes
Authors: Zhaokang Yang, Derek S. Steele
Journal: Circulation Research (2004)

Confocal microscopy was used to study the properties of nuclear Ca2+ regulation in adult ventricular myocytes. Prolonged nuclear Ca2+ release (PNCR) events were identified in both intact and permeabilized rat myocytes. PNCR occurred spontaneously and was restricted to localized regions at the ends of the elongated nuclei. Typically, PNCR took the form of a rapid rise in [Ca2+] followed by a maintained plateau. The mean duration of PNCR (1.78+/-0.19 seconds) was markedly greater than the half decay time for cytosolic Ca2+ sparks (31.2+/-0.56 ms) obtained under the same conditions. The PNCR width at half maximum amplitude (5.0+/-0.2 microm) was also significantly greater than that of cytosolic Ca2+ sparks (2.6+/-0.05 microm) obtained under the same conditions. Experiments involving the use of syto-11 to accurately locate the nuclei demonstrated that PNCR originates from the nuclear envelope or a closely associated structure. The spatial spread of PNCR was asymmetrical, with greater diffusion of Ca2+ toward the center of the nucleus than the cytosol. Both PNCR and Ca2+ sparks were abolished by interventions that deplete SR Ca2+ stores or inhibit RYR activation. Experiments on intact, electrically stimulated cells revealed that diffusion of Ca2+ from the ends of the nucleus toward the center is a prominent feature of the nucleoplasmic Ca2+ transient. The possibility that recruitment of Ca2+ release sites involved in PNCR might influence the temporal and spatial characteristics of the nucleoplasmic [Ca2+] transient is considered.
Payment for Immunosuppression After Organ Transplantation
Authors: B L Kasiske, D Cohen, M R Lucey, J F Neylan
Journal: JAMA (2000)

Dramatic improvements in organ transplantation have meant that a growing number of patients must take expensive immunosuppressive medications for the rest of their lives. Currently, Medicare covers most transplantation procedures in the United States, but ends coverage for outpatient immunosuppressive medications after 36 months. Evidence suggests that at least some patients have reduced immunosuppression and their transplants fail because they cannot afford these medication costs. In the years since the advent of effective immunosuppressive therapy, the US Congress has struggled with this issue, and in 1999 temporarily extended medication coverage for eligible patients (based on age and disability) by 8 months. However, a more permanent solution is needed. We advocate that Medicare should cover the cost of all immunosuppressive therapy for all solid organ transplant recipients who cannot afford to pay. A number of potentially cost-effective approaches could be taken, but, in any case, something must be done to ensure that transplants do not fail because recipients cannot pay for immunosuppression.
Angioplasty for Acute Coronary Syndromes
Authors: A N Tenaglia, R S Stack
Journal: Annual Review of Medicine (1993)

The acute ischemic syndromes (unstable angina and acute myocardial infarction) are often treated with percutaneous transluminal coronary angioplasty. Angioplasty should be considered in patients with unstable angina refractory to medical therapy and in those with evidence for ischemia after medical stabilization. Direct or primary angioplasty is indicated in patients with acute myocardial infarction with contraindications to thrombolytic therapy and is a reasonable alternative even in those eligible for thrombotytics. While there is no role for immediate angioplasty of a patent infarct-related artery following thrombolysis, rescue angioplasty of persistently occluded arteries may be beneficial, although further studies are needed.