tbuckley/cabot-search huggingface dataset:
The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
Authors: Xinming Su, Desiree H. Floyd, Alun Hughes, Jingyu Xiang, Jochen G. Schneider, Ozge Uluckan, Emanuela Heller, Hongju Deng, Wei Zou, Clarissa S. Craft, Kaiming Wu, Angela C. Hirbe, Dorota Grabowska, Mark C. Eagleton, Sarah Townsley, Lynne Collins, David Piwnica-Worms, Thomas H. Steinberg, Deborah V. Novack, Pamela B. Conley, Michelle A. Hurchla, Michael Rogers, Katherine N. Weilbaecher
Journal: Journal of Clinical Investigation (2012)

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.
Morelloflavone, a Biflavonoid, Inhibits Tumor Angiogenesis by Targeting Rho GTPases and Extracellular Signal-Regulated Kinase Signaling Pathways
Authors: Xiufeng Pang, Tingfang Yi, Zhengfang Yi, Sung Gook Cho, Weijing Qu, Decha Pinkaew, Ken Fujise, Mingyao Liu
Journal: Cancer Research (2009)

Abstract Morelloflavone, a biflavonoid extracted from Garcinia dulcis, has shown antioxidative, antiviral, and anti-inflammatory properties. However, the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date. In this study, we postulated that morelloflavone might have the ability to inhibit angiogenesis, the pivotal step in tumor growth, invasiveness, and metastasis. We showed that morelloflavone could inhibit vascular endothelial growth factor (VEGF)–induced cell proliferation, migration, invasion, and capillary-like tube formation of primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the mouse aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay. Furthermore, morelloflavone inhibited tumor growth and tumor angiogenesis of prostate cancer cells (PC-3) in xenograft mouse tumor model in vivo, suggesting that morelloflavone inhibited tumorigenesis by targeting angiogenesis. To understand the underlying mechanism of morelloflavone on the inhibitory effect of tumor growth and angiogenesis, we showed that morelloflavone could inhibit the activation of both RhoA and Rac1 GTPases but have little effect on the activation of Cdc42 GTPase. Additionally, morelloflavone inhibited the phosphorylation and activation of Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathway kinases without affecting VEGF receptor 2 activity. Together, our results indicate that morelloflavone exerts antiangiogenic action by targeting the activation of Rho-GTPases and ERK signaling pathways. These findings are the first to reveal the novel functions of morelloflavone in tumor angiogenesis and its molecular basis for the anticancer action. [Cancer Res 2009;69(2):518–25]
Arthrogenic muscle response to a simulated ankle joint effusion
Authors: R M Palmieri, C D Ingersoll, M A Hoffman, M L Cordova, D A Porter, J E Edwards, J P Babington, B A Krause, M B Stone
Journal: British Journal of Sports Medicine (2004)

Arthrogenic muscle inhibition (AMI) is a continuing reflex reaction of the musculature surrounding a joint after distension or damage to the structures of that joint. This phenomenon has been well documented after knee joint injury and has been generalised to occur at other joints of the human body, yet minimal research has been conducted in this regard. The response of the muscles crossing the ankle/foot complex after ankle injury and effusion is not well understood. AMI may occur after an ankle sprain contributing to residual dysfunction.To determine if AMI is present in the soleus, peroneus longus, and tibialis anterior musculature after a simulated ankle joint effusion.Eight neurologically sound volunteers (mean (SD) age 23 (4) years, height 171 (6) cm, mass 73 (10) kg) participated. Maximum H-reflex and maximum M-wave measurements were collected using surface electromyography after delivery of a percutaneous stimulus to the sciatic nerve before its bifurcation into the common peroneal and posterior tibial nerves.The H-reflex and M-wave measurements in all muscles increased (p< or =0.05) after the simulated ankle joint effusion.Simulated ankle joint effusion results in facilitation of the soleus, peroneus longus, and tibialis anterior motoneurone pools. This may occur to stabilise the foot/ankle complex in order to maintain posture and/or locomotion.
Congenital hepatic fibrosis with congenital heart disease. A family study with ultrastructural features of the liver.
Authors: Y Naveh, N Roguin, R Ludatscher, L Auslaender, A Schramek, M Aharon
Journal: Gut (1980)

A family with congenital hepatic fibrosis (CHF) and congenital heart disease (CHD) is presented. The consanguineous healthy parents gave birth to 12 children of whom 10 survived. One son had CHF and CHD, one daughter had CHF and a second daughter had CHD. Three other siblings probably had small a ventricular septal defect and another one probably had mild pulmonary valve stenosis. Development of portal hypertension and hypersplenism necessitated performing shunt operation on both siblings suffering from congenital hepatic fibrosis. Ultrastructural findings were giant mitochondria with large laminar inclusions in hepatocytes, and excess of villi and whorls of membranes and collagen fibrils between hepatocytes.
Decreased muscle PPAR concentrations: a mechanism underlying skeletal muscle abnormalities in COPD?
Authors: S. A. Sathyapala, P. Kemp, M. I. Polkey
Journal: European Respiratory Journal (2007)

Peripheral muscle weakness is a common and serious complication of chronic obstructive pulmonary disease (COPD), which precedes loss of fat-free mass and is an independent predictor of mortality in patients with Global Initiative for COPD grade III or IV disease 1. Current treatment options for muscle weakness are limited to exercise and supplemental feeding for cachectic patients. However, this approach is not effective in all individuals and the development of drugs that could be used as adjunctive therapies in the treatment of muscle weakness is hindered by a lack of knowledge of the molecular mechanisms responsible for the muscle dysfunction.

Two types of muscle abnormality are observed in the quadriceps muscle of patients with moderate and severe COPD. Atrophy occurs, particularly of the anaerobic type-IIx fibres, and is manifest as a loss of muscle strength. In addition, loss of muscle oxidative capacity arises from the depletion of aerobic type-I fibres and a reduction in mitochondria and oxidative enzymes within both type-I and -IIa fibres, resulting in decreased muscle endurance. At present, it is unclear whether these two processes are linked, for example whether atrophy of type-IIx fibres drives a switch of type-I to type-II fibres, or whether these processes occur independently. Animal studies have identified an array of pathways that could be involved in the development of muscle atrophy or loss of oxidative capacity. Some of these may be more relevant in animal models than in human disease. For example, some pathways that have been studied may be more involved in muscle development rather than a response to external stimuli, let alone the complex array of stimuli which may be present in COPD. In addition, there may be redundancy in the system so that multiple pathways have to be disrupted before skeletal muscle dysfunction arises. To date, few candidate …
Deep Sequencing Identifies <i>IDH1</i> R132S Mutation in Adult Medulloblastoma
Authors: Matija Snuderl, Joanna Triscott, Paul A. Northcott, Helen A. Shih, Esther Kong, Hayley Robinson, Sandra E. Dunn, A. John Iafrate, Stephen Yip
Journal: Journal of Clinical Oncology (2014)
Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis
Authors: Yoshinari Miyamoto, Dongquan Shi, Masahiro Nakajima, Kouichi Ozaki, Akihiro Sudo, Akihiro Kotani, Atsumasa Uchida, Toshihiro Tanaka, Naoshi Fukui, Tatsuhiko Tsunoda, Atsushi Takahashi, Yusuke Nakamura, Qing Jiang, Shiro Ikegawa
Journal: Nature Genetics (2008)
Pituitary Tumor Transforming Gene Binding Factor: A New Gene in Breast Cancer
Authors: Rachel J. Watkins, Martin L. Read, Vicki E. Smith, Neil Sharma, Gary M. Reynolds, Laura Buckley, Craig Doig, Moray J. Campbell, Greg Lewy, Margaret C. Eggo, Laurence S. Loubiere, Jayne A. Franklyn, Kristien Boelaert, Christopher J. McCabe
Journal: Cancer Research (2010)

Pituitary tumor transforming gene (PTTG) binding factor (PBF; PTTG1IP) is a relatively uncharacterized oncoprotein whose function remains obscure. Because of the presence of putative estrogen response elements (ERE) in its promoter, we assessed PBF regulation by estrogen. PBF mRNA and protein expression were induced by both diethylstilbestrol and 17beta-estradiol in estrogen receptor alpha (ERalpha)-positive MCF-7 cells. Detailed analysis of the PBF promoter showed that the region -399 to -291 relative to the translational start site contains variable repeats of an 18-bp sequence housing a putative ERE half-site (gcccctcGGTCAcgcctc). Sequencing the PBF promoter from 122 normal subjects revealed that subjects may be homozygous or heterozygous for between 1 and 6 repeats of the ERE. Chromatin immunoprecipitation and oligonucleotide pull-down assays revealed ERalpha binding to the PBF promoter. PBF expression was low or absent in normal breast tissue but was highly expressed in breast cancers. Subjects with greater numbers of ERE repeats showed higher PBF mRNA expression, and PBF protein expression positively correlated with ERalpha status. Cell invasion assays revealed that PBF induces invasion through Matrigel, an action that could be abrogated both by siRNA treatment and specific mutation. Furthermore, PBF is a secreted protein, and loss of secretion prevents PBF inducing cell invasion. Given that PBF is a potent transforming gene, we propose that estrogen treatment in postmenopausal women may upregulate PBF expression, leading to PBF secretion and increased cell invasion. Furthermore, the number of ERE half-sites in the PBF promoter may significantly alter the response to estrogen treatment in individual subjects.
Diabetic Endothelin B Receptor–Deficient Rats Develop Severe Hypertension and Progressive Renal Failure
Authors: Thiemo Pfab, Christa Tho[Combining Diaeresis]ne-Reineke, Franziska Theilig, Ines Lange, Henning Witt, Christiane Maser-Gluth, Michael Bader, Johannes-Peter Stasch, Patricia Ruiz, Sebastian Bachmann, Masashi Yanagisawa, Berthold Hocher
Journal: Journal of the American Society of Nephrology (2006)

The endothelin (ET) system has been implicated in the pathogenesis of diabetic nephropathy. The role of the ET-B receptor (ETBR) is still unclear. The effect of ETBR deficiency on the progression of diabetic nephropathy in a streptozotocin model was analyzed in four groups: (1) Homozygous ETBR-deficient (ETBRd) diabetic rats, (2) ETBRd rats, (3) diabetic controls, and (4) wild-type controls. BP and kidney function were measured for 10 wk, followed by biochemical and histologic analysis of the kidneys. The study demonstrates that ETBRd diabetic rats on a normal-sodium diet develop severe hypertension, albuminuria, and a mild reduction of creatinine clearance. The strong BP rise seems not to be caused by activation of the renin-angiotensin-aldosterone system or by suppression of the nitric oxide system. Elevated plasma ET-1, possibly reflecting a reduced ETBR-dependent clearance, seems to cause the severe hypertension via the ETA receptor. The results do not support the hypothesis that a reduction of ETBR activity inhibits the progression of diabetic nephropathy. The study demonstrates for the first time that the combination of diabetes and ETBR deficiency causes severe low-renin hypertension with progressive renal failure.
Cyclic Variation of Intracellular Calcium
Authors: Edward G. Lakatta, Victor A. Maltsev, Konstantin Y. Bogdanov, Michael D. Stern, Tatiana M. Vinogradova
Journal: Circulation Research (2003)

While a diversity of cell types and distribution within the sinoatrial node and cell-cell interactions add complexity to a complete elucidation of the heart's pacemaker function, it has become clear that cyclic variation of submembrane [Ca2+] and activation of the Na+-Ca2+ exchanger during diastolic depolarization (DD) act in concert with ion channels to confer on sinoatrial node cells (SANCs) their status of dominance with respect to pacemaker function. Studies using confocal microscopy indicate that subsarcolemmal Ca2+ release via ryanodine receptors occurs not only in response to the action potential (AP) upstroke, but also during the DD, and this is augmented by beta-adrenergic receptor (beta-AR) stimulation. Spontaneous APs simulated by mathematical SANC models beat at a faster rate when this subsarcolemmal Ca2+ waveform measured under beta-AR stimulation is introduced into the modeling scheme. Thus, in future investigation of pacemaker functioning in health, disease, and disease therapies the "bar ought to be raised" to embrace the impact of cyclic variation in submembrane [Ca2+] on pacemaker function. The full text of this article is available at http://www.circresaha.org.
RELATIONSHIP BETWEEN AORTIC DIAMETER AND MAJOR ADVERSE EVENTS IN TYPE B AORTIC DISSECTION &amp;ndash; RESULTS FROM THE KAISER PERMANENTE REGISTRY OF AORTIC DISSECTIONS
Authors: Somjot Singh Brar, Kevin Izquierdo, Jaqueline Schwartz, Cuong Lam, Aman Saw, Albert Shen, Raymond Chen, Thomas A. Pfeffer, Michael Jorgensen, Steven Khan, William Gray, Vicken Aharonian, Prakash Mansukhani
Journal: Journal of the American College of Cardiology (2012)
Enhanced drug-loading and therapeutic efficacy of hydrotropic oligomer-conjugated glycol chitosan nanoparticles for tumor-targeted paclitaxel delivery
Authors: Heebeom Koo, Kyung Hyun Min, Sang Cheon Lee, Jae Hyung Park, Kinam Park, Seo Young Jeong, Kuiwon Choi, Ick Chan Kwon, Kwangmeyung Kim
Journal: Journal of Controlled Release (2013)
DNA Aβ42 Vaccination as Possible Alternative Immunotherapy for Alzheimer Disease
Authors: Roger N. Rosenberg, Doris Lambracht-Washington
Journal: JAMA Neurology (2013)

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Inhibitor of Growth 4 Suppresses Cell Spreading and Cell Migration by Interacting with a Novel Binding Partner, Liprin α1
Authors: Jiang-Cheng Shen, Motoko Unoki, Damien Ythier, Alain Duperray, Lyuba Varticovski, Kensuke Kumamoto, Remy Pedeux, Curtis C. Harris
Journal: Cancer Research (2007)

Inhibitor of growth 4 (ING4) is a candidate tumor suppressor that plays a major role in gene regulation, cell cycle control, apoptosis, and angiogenesis. ING4 expression is down-regulated in glioblastoma cells and head and neck squamous cell carcinoma. Here, we identified liprin alpha1/PPFIA1, a cytoplasmic protein necessary for focal adhesion formation and axon guidance, as a novel interacting protein with ING4. ING4 and liprin alpha1 colocalized at lamellipodia in the vicinity of vinculin. Overexpressed ING4 suppressed cell spreading and cell migration. In contrast, overexpressed liprin alpha1 enhanced cell spreading and cell migration. Knockdown of endogenous ING4 with RNA interference induced cell motility, whereas knockdown of endogenous liprin alpha1 suppressed cell motility. ING4 also suppressed cell motility that was enhanced by liprin alpha1. However, ING4 did not further suppress cell motility when liprin alpha1 was suppressed with RNA interference, suggesting a functional and mechanistic interdependence between these proteins. In addition to its nuclear functions, cytoplasmic ING4 interacts with liprin alpha1 to regulate cell migration and, with its known antiangiogenic function, may prevent invasion and metastasis.
Matrix metalloproteinases and TIMP‐1 production by peripheral blood granulocytes from COPD patients and asthmatics
Authors: D. Cataldo, C. Munaut, A. Noël, F. Frankenne, P. Bartsch, J. M. Foidart, R. Louis
Journal: Allergy (2001)

Both asthmatic and COPD patients were found to have increased amounts of granulocytes and matrix metalloproteinase‐9 (MMP‐9) in their sputum. The present study was conducted to investigate whether the elevated amounts of MMP‐9 and TIMP‐1 found in such patients' airways may be linked to an enhanced secretion by granulocytes. Blood granulocytes from asthmatics ( n =10), COPD patients ( n =11), and healthy controls ( n =11) were isolated and cultured under basal conditions or after stimulation by phorbol 12‐myristate 13‐acetate (PMA) or N ‐formyl‐ l ‐methionyl‐ l ‐leucyl‐ l ‐phenylalanine (fMLP). MMP‐9 activity was detected by zymography while MMP‐8 and TIMP‐1 levels were measured by ELISA. In zymography, pro‐ and activated forms of MMP‐9 were present in each group (healthy subjects, asthmatics, and COPD patients). Spontaneous release was not different between the three groups. Stimulation by fMLP and PMA increased to a similar extent the release of MMP‐9 by granulocytes in all the three groups. TIMP‐1 levels were also increased after stimulation by PMA and fMLP only in healthy subjects and COPD patients. MMP‐8 levels were barely detectable. We conclude that circulating granulocytes from COPD patients and asthmatics do not display an abnormal secretion of MMP‐9, and that granulocytes from asthmatics have an impaired ability to release TIMP‐1 upon stimulation.
CHARACTERISTICS OF A STRAIN OF LYMPHOCYTIC CHORIOMENINGITIS VIRUS ENCOUNTERED AS A CONTAMINANT IN TISSUE CULTURES OF RABIES VIRUS
Authors: J. Casals-Ariet, L. T. Webster
Journal: The Journal of Experimental Medicine (1940)

A strain of lymphocytic choriomeningitis virus has been encountered, which grows readily in mouse embryo, serum, Tyrode culture media. Its origin is not definitely known but appears to be either the mouse brain tissue or, more probably, the monkey serum. This strain gives clear cut results on filtration tests through Elford membranes, establishing the size of the virus, according to formula, as 33 to 50 mµ. The strain shows a high and uniform virulence in W-Swiss mice. This appears to be due in part, at least, to the age and strain of mice employed for passage and titration. The strain has been found to be more virulent in young than in old mice, especially following intraperitoneal inoculation. Finally, the strain, when given as a vaccine intraperitoneally in amounts as small as 160 intracerebral lethal doses, induces an immunity against subsequent intracerebral inoculations of as much as 10,000 lethal doses.
Effect of a structurally modified human granulocyte colony stimulating factor, G-CSFa, on leukopenia in mice and monkeys
Authors: Yongping Jiang, Wenhong Jiang, Yuchang Qiu, Wei Dai
Journal: Journal of Hematology & Oncology (2011)

Granulocyte colony stimulating factor (G-CSF) regulates survival, proliferation, and differentiation of neutrophilic granulocyte precursors, Recombinant G-CSF has been used for the treatment of congenital and therapy-induced neutropenia and stem cell mobilization. Due to its intrinsic instability, recombinant G-CSF needs to be excessively and/or frequently administered to patients in order to maintain a plasma concentration high enough to achieve therapeutic effects. Therefore, there is a need for the development of G-CSF derivatives that are more stable and active in vivo.Using site-direct mutagenesis and recombinant DNA technology, a structurally modified derivative of human G-CSF termed G-CSFa was obtained. G-CSFa contains alanine 17 (instead of cysteine 17 as in wild-type G-CSF) as well as four additional amino acids including methionine, arginine, glycine, and serine at the amino-terminus. Purified recombinant G-CSFa was tested for its in vitro activity using cell-based assays and in vivo activity using both murine and primate animal models.In vitro studies demonstrated that G-CSFa, expressed in and purified from E. coli, induced a much higher proliferation rate than that of wild-type G-CSF at the same concentrations. In vivo studies showed that G-CSFa significantly increased the number of peripheral blood leukocytes in cesium-137 irradiated mice or monkeys with neutropenia after administration of cyclophosphamide. In addition, G-CSFa increased neutrophil counts to a higher level in monkeys with a concomitant slower declining rate than that of G-CSF, indicating a longer half-life of G-CSFa. Bone marrow smear analysis also confirmed that G-CSFa was more potent than G-CSF in the induction of granulopoiesis in bone marrows of myelo-suppressed monkeys.G-CSFa, a structurally modified form of G-CSF, is more potent in stimulating proliferation and differentiation of myeloid cells of the granulocytic lineage than the wild-type counterpart both in vitro and in vivo. G-CSFa can be explored for the development of a new generation of recombinant therapeutic drug for leukopenia.