tbuckley/cabot-search huggingface dataset:
Expression and function of toll-like receptors in peripheral blood mononuclear cells of patients with polymyalgia rheumatica and giant cell arteritis
Authors: L. Alvarez Rodriguez, M. Lopez-Hoyos, C. Mata, A. Fontalba, J. Calvo Alen, M. J. Marin, J. L. Fernandez-Luna, J. Aguero Balbin, M. Aranzamendi Zaldunbide, R. Blanco, V. M. Martinez-Taboada
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To investigate the expression and function of the Toll-like receptor (TLR) family in peripheral blood mononuclear cells (PBMCs) of patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). <h3>Methods</h3> The authors analysed 70 patients with PMR, 20 with GCA, and 24 healthy controls (HC). TLR expression was assessed by flow cytometry. TLR function was assessed by stimulating PBMCs with specific ligands. <h3>Results</h3> A significantly increased expression of TLR7 in PBMCs of patients with active disease compared with HC was found. Despite increased expression of TLR7, circulating monocytes from patients showed a significantly lower in vitro response to TLR7 agonists. No amino acid substitutions predicted to be functionally damaging were found in TLR7. A normal response to specific TLR7 agonists in patients in complete remission eliminated a genetic defect. TLR expression and function were also affected to some degree in other diseases characterised by a strong acute phase response. <h3>Conclusion</h3> These data suggest activation of TLR7 during the active phase of PMR and GCA which resolves with complete disease remission. Whether this finding is the consequence of the marked inflammatory process in these disorders or activation by natural ligands remains to be explored.
The Effect of CXCL12 Processing on CD34+ Cell Migration in Myeloproliferative Neoplasms
Authors: Sool Yeon Cho, Mingjiang Xu, John Roboz, Min Lu, John Mascarenhas, Ronald Hoffman
Journal: Cancer Research (2010)

Abstract Primary myelofibrosis (PMF) and polycythemia vera (PV) are chronic myeloproliferative neoplasms. PMF and, to a lesser degree, PV are characterized by constitutive mobilization of hematopoietic stem cells (HSC) and progenitor cells (HPC) into the peripheral blood (PB). The interaction between the chemokine CXCL12 and its receptor CXCR4 plays a pivotal role in determining the trafficking of CD34+ cells between the bone marrow (BM) and the PB. PMF, but not PV, is associated with downregulation of CXCR4 by CD34+ cells due to epigenetic events. Both PV and PMF patients have elevated levels of immunoreactive forms of CXCL12 in the BM and PB. Using electrospray mass spectrometry, the PB and BM plasma of PV and PMF patients was shown to contain reduced amounts of intact CXCL12 but significant amounts of several truncated forms of CXCL12, which are lacking in normal PB and BM plasma. These truncated forms of CXCL12 are the product of the action of several serine proteases, including dipeptidyl peptidase-IV, neutrophil elastase, matrix metalloproteinase-2 (MMP-2), MMP-9, and cathepsin G. Unlike CXCL12, these truncates either lack the ability to act as a chemoattractant for CD34+ cells and/or act as an antagonist to the action of CXCL12. These data suggest that proteolytic degradation of CXCL12 is characteristic of both PV and PMF and that the resulting truncated forms of CXCL12, in addition to the reduced expression of CXCR4 by CD34+ cells, lead to a profound mobilization of HSC/HPC in PMF. Cancer Res; 70(8); 3402–10. ©2010 AACR.
Inhibitors of suppressive histone modification promote direct reprogramming of fibroblasts to cardiomyocyte-like cells
Authors: Hiroyuki Hirai, Nobuaki Kikyo
Journal: Cardiovascular Research (2014)

We recently reported that the combination of Gata4, Hand2, Tbx5, and the fusion gene MM3 between Mef2c and the transactivation domain of MyoD (MM3-GHT) produces 18 times as many clusters of beating cells (induced cardiomyocyte-like cells or iCMs) as the wild-type combination (M-GHT).1 In the current study, we added the chemicals GSK126 and UNC0638 to MM3-GHT to examine whether depletion of suppressive histone markers further increases the efficiency of making iCMs. GSK126 inhibits Enhancer of Zeste Homolog 2 (Ezh2), which induces di- and trimethylation of Lys27 on histone H3 (H3K27me2 and H3K27me3, respectively) as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2).2 UNC0638 inhibits two closely related enzymes, G9a and GLP, which form a heterodimer in vivo and mediate mono- and dimethylation of Lys9 on histone H3 (H3K9me and H3K9me2) and methylation of non-histone substrates such as p53.3 H3K27me3 and H3K9me2 are typically associated with suppressed genes although the underlying mechanisms have not been fully characterized.

We prepared fibroblasts from the heads of Day 13.5 mouse embryos and incubated them with 1 μM GSK126 for 2 days to verify a decrease of H3K27me3 (see Supplementary material online, Figure S1 A ). To test the effect of GSK126 on reprogramming, fibroblasts were transduced with MM3-GHT on Day −1 and 0, and GSK126 was added to the culture medium at different time points ( Figure 1 A ). The most effective schedule was to add GSK126 from Day 1 to 4, resulting in 2.1 times as many iCM clusters as negative control without GSK126 ( Figure 1A , encircled and Supplementary material online, Figure S1 B ). Ca2+ oscillations in the cells were monitored using a transgene encoding the Ca2+ indicator protein GCaMP5, which emits stronger green fluorescence in the presence of …
Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study
Authors: Akira Kawai, Nobuhito Araki, Hideshi Sugiura, Takafumi Ueda, Tsukasa Yonemoto, Mitsuru Takahashi, Hideo Morioka, Hiroaki Hiraga, Toru Hiruma, Toshiyuki Kunisada, Akihiko Matsumine, Takanori Tanase, Tadashi Hasegawa, Shunji Takahashi
Journal: The Lancet Oncology (2015)
Borna disease virus-specific T cells protect against or cause immunopathological Borna disease.
Authors: J A Richt, A Schmeel, K Frese, K M Carbone, O Narayan, R Rott
Journal: The Journal of Experimental Medicine (1994)

In this report we show that passive immunization of Lewis rats with viable CD4+, Borna disease virus (BDV)-specific T cells before infection with BDV resulted in protection against BD, whereas inoculation of these T cells after BDV infection induced clinical disease with more rapid onset than seen in BDV control animals. The protective as well as encephalitogenic effector functions of BDV-specific CD4+ T cells were mediated only by viable BDV-specific T cells. The protective situation was obtained by passive transfer of BDV-specific T cells into animals inoculated later with virus, whereas the immunopathological situation was observed when virus-specific T cells developed normally or after adoptive transfer, and appeared on the scene after considerable virus replication in the brain.
Regulation of glomerular filtration and proximal tubule reabsorption.
Authors: F G Knox, None Cuche J-L, C E Ott, J A Diaz-Buxo, G Marchand
Journal: Circulation Research (1975)

In this review current hypotheses for the regulation of filtration rate and the subsequent reabsorption of that filtrate by the proximal tubule are discussed. In the rat the filtration rate is highly plasma flow dependent because of the phenomenon of filtration equilibrium. On the other hand, in man and dog filtration rate is much less dependent on renal plasma flow. In these species glomerular capillary pressure rather than glomerular plasma flow may be the primary determinant of filtration. Three hypotheses for the autoregulation of glomerular filtration are discussed. Of these the myogenic theory, which holds that increases in perfusion pressure result in an intrinsic contraction of the smooth muscle in the walls of the afferent arterioles, remains the best, if not completely adequate, explanation for the phenomenon. The role of a macula densa feedback mechanism is controversial, although data are presented which strongly militate against this hypothesis. Similarly, the prostaglandins, although important in determining vascular resistance, probably do not mediate autoregulation. Two prevalent hypotheses for the regulation of fluid reabsorption by the proximal tubule, the physical factor hypothesis and the humoral hypothesis, are discussed. Data presented indicate that peritubule Starling forces have a marked effect on isotonic reabsorption by the proximal tubule in the presence of volume expansion and enhanced backleak into the proximal tubule lumen. However, in hydropenia and diminished backleak, changes in peritubule capillary Starling forces have little effect on proximal sodium reabsorption. Thus, the physical factor mechanism is a rather insensitive regulator of proximal reabsorption in the absence of volume expansion. Hormones known to regulate sodium transport per se, such as aldosterone, have no effect on sodium reabsorption by the proximal tubule. In contrast, those hormones primarily regulating anion reabsorption in the proximal tubule, such as parathyroid hormone, have significant effects on fluid reabsorption. Thus, the humoral regulation of anion reabsorption has secondary effects on proximal sodium reabsorption.
Dual Targeting of the Akt/mTOR Signaling Pathway Inhibits Castration-Resistant Prostate Cancer in a Genetically Engineered Mouse Model
Authors: Nicolas Floc'h, Carolyn Waugh Kinkade, Takashi Kobayashi, Alvaro Aytes, Celine Lefebvre, Antonina Mitrofanova, Robert D. Cardiff, Andrea Califano, Michael M. Shen, Cory Abate-Shen
Journal: Cancer Research (2012)

Although the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer (CRPC) and, therefore, it remains fatal. In this study, we investigate a new therapeutic approach for treatment of CRPC, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting CRPC in preclinical studies in vivo using a refined genetically engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2 feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (Rb) pathway. Our findings suggest that dual targeting of the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of CRPC, particularly for patients with deregulated Rb pathway activity.
Interleukin-4 and Transforming Growth Factor-Beta Single Nucleotide Genes Polymorphisms Confer Susceptibility To Atopic Dermatitis
Authors: Nima Rezaei, Zahra Aryan, Nasrin Behniafard, Elham Farhadi, Soheila Sotoudeh, Mojdeh Khaledi, Maryam Mahmoudi, Asghar Aghamohammadi, Ali Akbar Amirzargar, Mohammad Gharagozlou
Journal: Journal of Allergy and Clinical Immunology (2014)
The DIRS1 Group of Retrotransposons
Authors: Timothy J. D. Goodwin, Russell T. M. Poulter
Journal: Molecular Biology and Evolution (2001)

Only three retrotransposons of the DIRS1 group have previously been described: DIRS1 from the slime mold Dictyostelium discoideum, PAT from the nematode Panagrellus redivivus, and Prt1 from the zygomycetous fungus Phycomyces blakesleeanus. Analyses of the reverse transcriptase sequences encoded by these elements suggest that they are related to the long terminal repeat (LTR) retroelements, such as the Ty3/gypsy retrotransposons and the vertebrate retroviruses. The DIRS1-group elements, however, have several unusual structural features which distinguish them from typical LTR elements: (1) they lack the capacity to encode DDE-type integrases or aspartic proteases; (2) they have open reading frames (ORFs) of unknown function; (3) they integrate without creating duplications of their target sites; and (4) although they are bordered by terminal repeats, these sequences differ from typical LTRs in that they are either inverted repeats or "split" direct repeats. Because of the small number of DIRS1-like elements described, and the unusual structures of these elements, little is known about their evolution, distribution, and replication mechanisms. Here, we report the identification of several new DIRS1-like retrotransposons, including elements from nematodes, sea urchins, fish, and amphibia. We also present evidence for the existence of DIRS1-like sequences in the human genome. In addition, we show that the lack of DDE-type integrase genes from elements of the DIRS1 group is explained by the finding that the previously uncharacterized ORFs of these elements encode proteins related to the site-specific recombinase of bacteriophage lambda. The presence of lambda-recombinase-like genes in DIRS1 elements also accounts for the lack of target-site duplications for these elements and may be related to the unusual structures of their terminal repeats.
European Commission proposes rules for cross border health care
Authors: R. Watson
Journal: BMJ (2008)

The European Commission has tabled draft legislation setting out rules whereby patients who choose to receive medical treatment in another European Union country would be reimbursed by their national health authority.

The proposal follows several judgments over the past decade by the European Court of Justice confirming that individuals have the right to be reimbursed for health care they receive abroad, subject to certain conditions. However, uncertainty over the exact way the right should be exercised and the effects that an increase in demand would have on countries’ health …
Early versus On-Demand Nasoenteric Tube Feeding in Acute Pancreatitis
Authors: Olaf J. Bakker, Sandra van Brunschot, Hjalmar C. van Santvoort, Marc G. Besselink, Thomas L. Bollen, Marja A. Boermeester, Cornelis H. Dejong, Harry van Goor, Koop Bosscha, Usama Ahmed Ali, Stefan Bouwense, Wilhelmina M. van Grevenstein, Joos Heisterkamp, Alexander P. Houdijk, Jeroen M. Jansen, Thom M. Karsten, Eric R. Manusama, Vincent B. Nieuwenhuijs, Alexander F. Schaapherder, George P. van der Schelling, Matthijs P. Schwartz, B.W. Marcel Spanier, Adriaan Tan, Juda Vecht, Bas L. Weusten, Ben J. Witteman, Louis M. Akkermans, Marco J. Bruno, Marcel G. Dijkgraaf, Bert van Ramshorst, Hein G. Gooszen
Journal: New England Journal of Medicine (2014)

Early enteral feeding through a nasoenteric feeding tube is often used in patients with severe acute pancreatitis to prevent gut-derived infections, but evidence to support this strategy is limited. We conducted a multicenter, randomized trial comparing early nasoenteric tube feeding with an oral diet at 72 hours after presentation to the emergency department in patients with acute pancreatitis.
c-Fos as a Proapoptotic Agent in TRAIL-Induced Apoptosis in Prostate Cancer Cells
Authors: Xiaoping Zhang, Liang Zhang, Hongmei Yang, Xu Huang, Hasan Otu, Towia A. Libermann, William C. DeWolf, Roya Khosravi-Far, Aria F. Olumi
Journal: Cancer Research (2007)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic molecule c-FLIP(L). c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels. Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a cancer cell will undergo cell death after TRAIL treatment. Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therapies.
Increased sheep lung vascular permeability caused by Escherichia coli endotoxin.
Authors: K L Brigham, R Bowers, J Haynes
Journal: Circulation Research (1979)

We infused Escherichia coli endotoxin, 0.07-1.33 microgram/kg, intravenously into chronically instrumented unanesthetized sheep and measured pulmonary arterial and left atrial pressures, lung lymph flow, lymph and blood plasma protein concentrations, and arterial blood gases. Endotoxin caused a biphasic reaction: an early phase of pulmonary hypertension and a long late phase of steady state increased pulmonary vascular permeability during which pulmonary arterial and left atrial pressures were not increased significantly and lung lymph flow was 5 times the baseline value. Lymph: plasma total protein concentration ratio during the late phase (0.76 +/- 0.04) was significantly (P less than 0.05) higher than during baseline (0.66 +/- 0.03). The lymph response was reproducible. Lung lymph clearance of endogenous proteins with molecular radii (r) 35.5 to 96 A was increased during the steady state late phase of the reaction, but, as during baseline, clearance decreased as r increased. The endotoxin reaction was similar to the reaction to infusing whole Pseudomonas bacteria, except that endotoxin had less effect on pressures during the steady state response and caused a relatively larger increase in lymph clearance of large proteins. We conclude that E. coli endotoxin in sheep causes a long period of increased lung vascular permeability and may have a greater effect on large solute pathways across microvessels than do Pseudomonas bacteria.
Global Climate Change and Infectious Diseases
Authors: Emily K. Shuman
Journal: New England Journal of Medicine (2010)

Climate change is occurring as a result of warming of the earth's atmosphere due to human activity generating excess amounts of greenhouse gases. Because of its potential impact on the hydrologic cycle and severe weather events, climate change is expected to have an enormous effect on human health, including on the burden and distribution of many infectious diseases. The infectious diseases that will be most affected by climate change include those that are spread by insect vectors and by contaminated water. The burden of adverse health effects due to these infectious diseases will fall primarily on developing countries, while it is the developed countries that are primarily responsible for climate change. It is up to governments and individuals to take the lead in halting climate change, and we must increase our understanding of the ecology of infectious diseases in order to protect vulnerable populations.
Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-Renewal and Erythroid Differentiation
Authors: Jan Jacob Schuringa, Ki Young Chung, Giovanni Morrone, Malcolm A.S. Moore
Journal: The Journal of Experimental Medicine (2004)

Activation of the transcription factor signal transducer and activator of transcription (STAT)5 is involved in various aspects of hematopoiesis, affecting cell proliferation, differentiation, and cell survival. Constitutive activation of STAT5 has also been associated with leukemic transformation. We overexpressed the constitutively active mutant STAT5A(1*6) in human cord blood CD34+ cells and evaluated the effects on the hematopoietic potential of stem cells in a variety of in vitro and in vivo systems. The observed phenotypic changes were correlated with differential gene expression patterns induced by STAT5A(1*6). Our data indicate that a persistent activation of STAT5A in human hematopoietic stem and progenitor cells results in their enhanced self-renewal and diverts differentiation to the erythroid lineage.
A Novel Peptide Specifically Binding to Interleukin-6 Receptor (gp80) Inhibits Angiogenesis and Tumor Growth
Authors: Jen-Liang Su, Kuo-Pao Lai, Chi-An Chen, Ching-Yao Yang, Pei-Sheng Chen, Chiao-Chia Chang, Chia-Hung Chou, Chi-Lun Hu, Min-Liang Kuo, Chang-Yao Hsieh, Lin-Hung Wei
Journal: Cancer Research (2005)

Abstract Experimental and clinical findings support the essential role of interleukin (IL)-6 in the pathogenesis of various human cancers and provide a rationale for targeted therapeutic investigations. A novel peptide, S7, which selectively binds to IL-6 receptor (IL-6R) α chain (gp80) and broadly inhibits IL-6-mediated events, was identified using phage display library screening. The synthetic S7 peptide specifically bound to soluble IL-6R as well as cognate human IL-6Rα, resulting in a dose-dependent blockade of the interaction between IL-6 and IL-6Rα. S7 peptide prevents IL-6–mediated survival signaling and sensitizes cervical cancer cells to chemotherapeutic compounds in vitro. The in vitro analysis of antiangiogenic activity showed that S7 peptide substantially inhibits IL-6–induced vascular endothelial growth factor-A expression and angiogenesis in different cancer cell lines. Furthermore, S7 peptide was bioavailable in vivo, leading to a significant suppression of IL-6–induced vascular endothelial growth factor–mediated cervical tumor growth in severe combined immunodeficient mice. These observations show the feasibility of targeting IL-6/IL-6R interaction using the small peptide and highlight its potential in the clinical applications.
Organization and implementation of mass medical rescue after an earthquake
Authors: Yan-Ling Zhang
Journal: Military Medical Research (2014)

On May 12, 2008, an 8.0-magnitude earthquake occurred in Wenchuan, Sichuan Province. In this disaster, 69,000 people were killed, 18,000 people were reported missing, and 37,000 people were injured, including more than 10,000 who were seriously injured. Trauma was the most commonly observed type of injury, with fractures accounting for 74% of all injury cases. On April 14, 2010, a 7.1-magnitude earthquake occurred in Yushu of Qinghai Province. In this disaster, 2,698 people were killed, 270 people were reported missing, and 11,000 people were injured, including more than 3,100 who were seriously injured. Fracture injury accounted for 58.4% of all injury cases. After each earthquake, the Chinese Army Medical Services responded promptly, according to the previously established guidelines, and sent out elite forces to the disaster areas, with the objectives of organizing, coordinating and participating in an efficient and evidence-based medical rescue effort. After the Wenchuan earthquake, 397 mobile medical service teams including 7,061 health workers were sent to the disaster areas. A total of 69,000 casualties were treated, and 22,000 surgeries were performed. After the Yushu earthquake, 25 mobile medical service teams involving 2,025 health workers were sent. They performed 1,635 surgeries and created an astounding outcome of "zero deaths" in the aftermath of the earthquake during their treatment of casualties in a high-altitude region. Within a week after each earthquake, the military teams rescued approximately 60% of the total number of rescued casualties and evacuated approximately 80% of the total number of evacuated sick or wounded victims, playing a critical role and making invaluable contributions to earthquake relief. The experience and lessons learned from the rescue efforts of the Chinese military after the two earthquakes have highlighted several key aspects in emergency medical rescue: (1) medical rescue theories must be updated; (2) military-civilian cooperation must be stressed; (3) professional rescue forces must be strengthened; (4) supporting facilities must be improved; and (5) international exchanges and cooperation must be deepened.