tbuckley/cabot-search huggingface dataset:
Reporting of radiographic methods in randomised controlled trials assessing structural outcomes in rheumatoid arthritis
Authors: G. Baron, I. Boutron, B. Giraudeau, P. Ravaud
Journal: Annals of the Rheumatic Diseases (2006)

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2<sup>d</sup>) donor to BALB/c (H-2<sup>d</sup>) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti–PD-1, anti–PD-L1, or anti–PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17<sup>+</sup>IFN-γ<sup>+</sup> T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17<sup>+</sup>IFN-γ<sup>+</sup> T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1<sup>−/−</sup> recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.
Rapid Genetic Diversification and High Fitness Penalties Associated with Pathogenicity Evolution in a Plant Virus
Authors: A. Fraile, I. Pagan, G. Anastasio, E. Saez, F. Garcia-Arenal
Journal: Molecular Biology and Evolution (2010)

Under the gene-for-gene model of host–pathogen coevolution, recognition of pathogen avirulence factors by host resistance factors triggers host defenses and limits infection. Theory predicts that the evolution of higher levels of pathogenicity will be associated with fitness penalties and that the cost of higher pathogenicity must be much smaller than that of not infecting the host. The analysis of pathogenicity costs is of academic and applied relevance, as these are determinants for the success of resistance genes bred into crops for disease control. However, most previous attempts of addressing this issue in plant pathogens yielded conflicting and inconclusive results. We have analyzed the costs of pathogenicity in pepper-infecting tobamoviruses defined by their ability to infect pepper plants with different alleles at the resistance locus L. We provide conclusive evidence of pathogenicity-associated costs by comparison of pathotype frequency with the fraction of the crop carrying the various resistance alleles, by timescaled phylogenies, and by temporal analyses of population dynamics and selection pressures using nucleotide sequences. In addition, experimental estimates of relative fitness under controlled conditions also provided evidence of high pathogenicity costs. These high pathogenicity costs may reflect intrinsic properties of plant virus genomes and should be considered in future models of host–parasite coevolution.
Preferential covalent binding of acetaldehyde to the α-chain of purified rat liver tubulin
Authors: Richard B. Jennett, Michael F. Sorrell, Abbas Saffari-fard, James L. Ockner, Dean J. Tuma
Journal: Hepatology (1989)

Hepatic ethanol oxidation generates the reactive intermediate acetaldehyde, which binds to proteins. Previous work, using bovine brain tubulin as a model protein, has shown that acetaldehyde preferentially formed stable adducts on the α-chain of the heterodimeric molecule. This binding resulted in functional impairment of the tubulin/microtubule system as evidenced by a decreased ability of adducted tubulin to form microtubules. Since tubulin/microtubules are believed to be very important cytoskeletal components of the hepatocyte and results with brain tubulin were interesting, our goal was to extend these studies to liver tubulin. We purified tubulin from rat liver by a polymerization-based cycle method followed by phosphocellulose chromatography. We then characterized the covalent binding of [ 14 C]acetaldehyde to liver tubulin. Naturally forming and cyanoborohydride-stimulated stable adducts formed linearly with liver tubulin in a manner almost identical to that with brain tubulin. We also found that the α-chain of the native heterodimeric liver tubulin molecule was the preferred site of adduct formation at low acetaldehyde to protein ratios. These results confirm and extend our previous findings with the brain tubulin model and further suggest that the α-chain of tubulin may be a preferential site for acetaldehyde-adduct formation during ethanol oxidation in the liver.
Adjunctive treatment with quetiapine for major depressive disorder: are the benefits of treatment worth the risks?
Authors: T. Pringsheim, D. Gardner, S. B. Patten
Journal: BMJ (2015)

Quetiapine was approved in 2009 and 2010 for the adjunctive treatment of major depressive disorder (MDD) in several countries worldwide, including the European Union, Canada, the United States, and Australia. These approvals followed three industry sponsored trials of quetiapine versus placebo added to an antidepressant for depression in adults who had an inadequate response to at least six weeks of antidepressant treatment. All three trials showed statistically significant improvements in symptoms of depression compared with placebo.1

Pharmacoepidemiological studies in the United States and Canada have shown a shift in practice over the past decade in the use of antipsychotic drugs in the management of MDD. The US National Ambulatory Medical Care Survey found that the percentage of office visits in which a non-psychotic depression was diagnosed that included adjunctive antipsychotic treatment increased from 4.6% (95% confidence interval 2.9% to 6.3%) in 1999-2000 to 12.5% (9.7% to 15.3%) in 2009-10.2 Quetiapine was the most frequently used antipsychotic drug for augmentation from 2007 to 2010. US data have also shown declining rates of psychotherapy among antidepressant users as the percentage of patients receiving antipsychotic drugs has increased.3 Over the past decade, Canada has seen a large and preferential increase in the use of quetiapine, which has been the most commonly prescribed antipsychotic since 2007. In 2005, 3.2 prescriptions for quetiapine by family physicians were dispensed per 100 Canadians; by 2012 this had increased to 12.0 per 100.4 Mood disorders were the most common diagnoses associated with quetiapine prescriptions.

With an estimated global point prevalence of 4.4%,5 MDD is a frequently encountered problem in clinical practice. Approximately 33% of people in the STAR*D sample (a prospective study of 3671 people with MDD) entered remission after initial selective serotonin reuptake inhibitor treatment; this increased to 50% after a switch …
Increased Risk of Paroxysmal Atrial Fibrillation Episodes Associated with Acute Increases in Ambient Air Pollution
Authors: David Q. Rich, Murray A. Mittleman, Mark S. Link, Joel Schwartz, Heike Luttmann-Gibson, Paul J. Catalano, Frank E. Speizer, Diane R. Gold, Douglas W. Dockery
Journal: Environmental Health Perspectives (2005)

We reported previously that 24-hr moving average ambient air pollution concentrations were positively associated with ventricular arrhythmias detected by implantable cardioverter defibrillators (ICDs). ICDs also detect paroxysmal atrial fibrillation episodes (PAF) that result in rapid ventricular rates. In this same cohort of ICD patients, we assessed the association between ambient air pollution and episodes of PAF.We performed a case-crossover study.Patients who lived in the Boston, Massachusetts, metropolitan area and who had ICDs implanted between June 1995 and December 1999 (n=203) were followed until July 2002.We used conditional logistic regression to explore the association between community air pollution and 91 electrophysiologist-confirmed episodes of PAF among 29 subjects.We found a statistically significant positive association between episodes of PAF and increased ozone concentration (22 ppb) in the hour before the arrhythmia (odds ratio=2.08; 95% confidence interval=1.22, 3.54; p=0.001). The risk estimate for a longer (24-hr) moving average was smaller, thus suggesting an immediate effect. Positive but not statistically significant risks were associated with fine particles, nitrogen dioxide, and black carbon.Increased ambient O3 pollution was associated with increased risk of episodes of rapid ventricular response due to PAF, thereby suggesting that community air pollution may be a precipitant of these events.
The human RECQ1 helicase is highly expressed in glioblastoma and plays an important role in tumor cell proliferation
Authors: Ramiro Mendoza-Maldonado, Valentina Faoro, Sailesh Bajpai, Matteo Berti, Federico Odreman, Marco Vindigni, Tamara Ius, Abdollah Ghasemian, Serena Bonin, Miran Skrap, Giorgio Stanta, Alessandro Vindigni
Journal: Molecular Cancer (2011)

RecQ helicases play an essential role in the maintenance of genome stability. In humans, loss of RecQ helicase function is linked with predisposition to cancer and/or premature ageing. Current data show that the specific depletion of the human RECQ1 helicase leads to mitotic catastrophe in cancer cells and inhibition of tumor growth in mice. Here, we show that RECQ1 is highly expressed in various types of solid tumors. However, only in the case of brain gliomas, the high expression of RECQ1 in glioblastoma tissues is paralleled by a lower expression in the control samples due to the poor expression of RECQ1 in non-dividing tissues. This conclusion is validated by immunohistochemical analysis of a tissue microarray containing 63 primary glioblastomas and 19 perilesional tissue samples, as control. We also show that acute depletion of RECQ1 by RNAi results in a significant reduction of cellular proliferation, perturbation of S-phase progression, and spontaneous γ-H2AX foci formation in T98G and U-87 glioblastoma cells. Moreover, RECQ1 depleted T98G and U-87 cells are hypersensitive to HU or temozolomide treatment. Collectively, these results indicate that RECQ1 has a unique and important role in the maintenance of genome integrity. Our results also suggest that RECQ1 might represent a new suitable target for anti cancer therapies aimed to arrest cell proliferation in brain gliomas.
Trop-2 Promotes Prostate Cancer Metastasis By Modulating β1 Integrin Functions
Authors: Marco Trerotola, Danielle L. Jernigan, Qin Liu, Javed Siddiqui, Alessandro Fatatis, Lucia R. Languino
Journal: Cancer Research (2013)

Abstract The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β1 integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on fibronectin, a phenomenon dependent on β1 integrins. Mechanistically, we demonstrate that Trop-2 and the α5β1 integrin associate through their extracellular domains, causing relocalization of α5β1 and the β1-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific as this molecule does not modulate migration on vitronectin, does not associate with the major vitronectin receptor, αvβ3 integrin, and does not affect localization of αvβ3 integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we show that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that β1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2. Cancer Res; 73(10); 3155–67. ©2013 AACR.
Action of Hypoxia on the Pulmonary Vasculature
Authors: CARMEN RIVERA-ESTRADA, PAUL W. SALTZMAN, DONALD SINGER, LOUIS N. KATZ
Journal: Circulation Research (1958)

The hemodynamic effects of acute hypoxia upon the pulmonary circulation were studied in dogs. The most striking changes were observed on the venous side of the circuit, consisting of a rise in venous (and arterial wedge) pressure greater than that in the pulmonary artery and an increase in the pressure gradient between the venules and the left atrium. These alterations are discussed and interpreted in an attempt to further clarify the response of the pulmonary circulation to hypoxia. It is suggested that there is arteriolar dilatation associated with increased postcapillary vascular resistance.
Genotype-restricted growth and aging patterns in hematopoietic stem cell populations of allophenic mice.
Authors: G Van Zant, B P Holland, P W Eldridge, J J Chen
Journal: The Journal of Experimental Medicine (1990)

We have studied contributions to hematopoiesis of genetically distinct stem cell populations in allophenic mice. Chimeras were made by aggregating embryos of inbred strains known to differ with respect to stem cell population kinetics. One partner strain (DBA/2) has previously been shown to normally have a stem cell (CFU-S) population of which 24% are in S-phase of the cell cycle, whereas the homologous population of the other partner strain (C57BL/6) was characterized by having only 2.6% in cycle (7). Contributions of the chimeric stem cell population to mature blood cell pools were studied throughout the life of the mice and intrinsic differences in stem cell function and aging were reflected in dynamic patterns of blood cell composition. The DBA/2 stem cell population was eclipsed by stem cells of the C57BL/6 genotype and, after 1.5-3 yr, the hemato-lymphoid composition of 22 of 27 mice studied for this long had shifted by at least 25 percentage points toward the C57BL/6 genotype. 8 of the 27 had hematolymphoid populations solely of C57BL/6 origin. To test whether or not a population of stem cells with an inherently higher cycling rate (DBA/2) might have a competitive advantage during repopulation, we engrafted allophenic marrow into lethally irradiated (C57BL/6 x DBA/2)F1 recipients. DBA/2 hematopoiesis was predominant early, far outstripping its representation in the marrow graft. Perhaps as a consequence of inherently greater DBA/2 stem cell proliferation, the populations of developmentally more restricted precursor populations (CFU-E, BFU-E, CFU-GM, CFU-GEMM) showed an overwhelming DBA/2 bias in the first 2-3 mo after engraftment. However, as in the allophenic mice themselves during the aging process, the C57BL/6 genotypic representation was ascendant over the subsequent months. The shift toward C57BL/6 genotype was first documented in the marrow and spleen precursor cell populations and was subsequently reflected in the circulating, mature blood cells. Bone marrow-derived stromal cell cultures from engrafted mice were studied and genotypic analyses showed donor representation in stromal cell populations that reflected donor hematopoietic contributions in the same recipient. Results from these studies involving two in vivo settings (allophenic mice and engraftment by allophenic marrow) are consistent with the notion that a cell autonomous difference in stem cell proliferation confers on one population a competitive repopulating advantage, but at the expense of longevity.
Combining Radiotherapy with APO010 in Cancer Treatment
Authors: Inge Verbrugge, Esther H.J. Wissink, Rogier W. Rooswinkel, Johan Jongsma, Nicola Beltraminelli, Marc Dupuis, Jannie Borst, Marcel Verheij
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Various proapoptotic agents are currently being explored to improve the outcome of radiotherapy. We have evaluated whether APO010—a novel recombinant ligand of the Fas/CD95 death receptor—enhanced the cytotoxic effect of radiation on lymphoid and solid tumor cell types. Experimental Design: A Bcl-2–overexpressing T-leukemic cell line (Jurkat), a colon carcinoma cell line (HCT116), and a mesothelioma cell line were used as model systems in vitro and in a subcutaneous transplant setting in immunodeficient mice. Sensitivity to single and combined treatment was read out by apoptosis hallmarks and clonogenic survival in vitro, and by tumor growth delay using bioluminescence and palpation in vivo. Results: Whereas the three cell lines resisted apoptosis induction by irradiation and APO010 alone, combined treatment greatly enhanced their apoptotic response. In clonogenic survival assays, APO010 reduced the outgrowth of Jurkat-Bcl-2 and HCT116 cells and sensitized the mesothelioma cell line to radiation. In vivo, systemic treatment with APO010 alone caused tumor growth delay in Jurkat-Bcl-2 and HCT116 cells. However, APO010 did not improve the efficacy of radiotherapy in any of the model systems at the selected single dose, which had moderate and reversible systemic toxicity. Conclusions: Although APO010 and radiation had a clear combined cytotoxic effect on tumor cells in vitro, a combined therapeutic effect was not achieved on the same cells subcutaneously grafted in mice, at APO010 doses approximating the maximally tolerable level. These findings suggest that it will be difficult to identify a therapeutic window for this combined modality approach in a clinical setting.
A Novel Nanoparticle Drug Delivery System: The Anti-inflammatory Activity of Curcumin Is Enhanced When Encapsulated in Exosomes
Authors: Dongmei Sun, Xiaoying Zhuang, Xiaoyu Xiang, Yuelong Liu, Shuangyin Zhang, Cunren Liu, Stephen Barnes, William Grizzle, Donald Miller, Huang-Ge Zhang
Journal: Molecular Therapy (2010)

Monocyte-derived myeloid cells play vital roles in inflammation-related autoimmune/inflammatory diseases and cancers. Here, we report that exosomes can deliver anti-inflammatory agents, such as curcumin, to activated myeloid cells in vivo. This technology provides a means for anti-inflammatory drugs, such as curcumin, to target the inflammatory cells as well as to overcome unwanted off-target effects that limit their utility. Using exosomes as a delivery vehicle, we provide evidence that curcumin delivered by exosomes is more stable and more highly concentrated in the blood. We show that the target specificity is determined by exosomes, and the improvement of curcumin activity is achieved by directing curcumin to inflammatory cells associated with therapeutic, but not toxic, effects. Furthermore, we validate the therapeutic relevance of this technique in a lipopolysaccharide (LPS)-induced septic shock mouse model. We further show that exosomes, but not lipid alone, are required for the enhanced anti-inflammatory activity of curcumin. The specificity of using exosomes as a drug carrier creates opportunities for treatments of many inflammation-related diseases without significant side effects due to innocent bystander or off-target effects. Monocyte-derived myeloid cells play vital roles in inflammation-related autoimmune/inflammatory diseases and cancers. Here, we report that exosomes can deliver anti-inflammatory agents, such as curcumin, to activated myeloid cells in vivo. This technology provides a means for anti-inflammatory drugs, such as curcumin, to target the inflammatory cells as well as to overcome unwanted off-target effects that limit their utility. Using exosomes as a delivery vehicle, we provide evidence that curcumin delivered by exosomes is more stable and more highly concentrated in the blood. We show that the target specificity is determined by exosomes, and the improvement of curcumin activity is achieved by directing curcumin to inflammatory cells associated with therapeutic, but not toxic, effects. Furthermore, we validate the therapeutic relevance of this technique in a lipopolysaccharide (LPS)-induced septic shock mouse model. We further show that exosomes, but not lipid alone, are required for the enhanced anti-inflammatory activity of curcumin. The specificity of using exosomes as a drug carrier creates opportunities for treatments of many inflammation-related diseases without significant side effects due to innocent bystander or off-target effects.
Higher-primate phylogeny--why can't we decide?
Authors: R Holmquist, M M Miyamoto, M Goodman
Journal: Molecular Biology and Evolution (1988)

At present, no definitive agreement on either the correct branching order or differential rates of evolution among the higher primates exists, despite the accumulated integration of decades of morphological, immunological, protein and nucleic acid sequence data, and numerous reasonable theoretical models for the analysis, interpretation, and understanding of those data. Of the three distinct unrooted phylogenetic trees, that joining human with chimpanzee and the gorilla with the orangutan is currently favored, but the two alternatives that group humans with either gorillas or the orangutan rather than with chimpanzees also have support. This paper is a synthetic and critical review of the methodological literature and isolates some 20 specific reasons why uncertainty in the evolutionary understanding of our closest living relatives persists. Many of the difficulties are eliminated or ameliorated by Lake's new methods of phylogenetic invariants and operator metrics. In the companion paper these new methods are used to analyze both the nuclear and mitochondrial DNA of the higher primates.