tbuckley/cabot-search huggingface dataset:
Complete Columbian mammoth mitogenome suggests interbreeding with woolly mammoths
Authors: Jacob Enk, Alison Devault, Regis Debruyne, Christine E King, Todd Treangen, Dennis O'Rourke, Steven L Salzberg, Daniel Fisher, Ross MacPhee, Hendrik Poinar
Journal: Genome biology (2011)

Abstract Background Late Pleistocene North America hosted at least two divergent and ecologically distinct species of mammoth: the periglacial woolly mammoth ( Mammuthus primigenius ) and the subglacial Columbian mammoth ( Mammuthus columbi ). To date, mammoth genetic research has been entirely restricted to woolly mammoths, rendering their genetic evolution difficult to contextualize within broader Pleistocene paleoecology and biogeography. Here, we take an interspecific approach to clarifying mammoth phylogeny by targeting Columbian mammoth remains for mitogenomic sequencing. Results We sequenced the first complete mitochondrial genome of a classic Columbian mammoth, as well as the first complete mitochondrial genome of a North American woolly mammoth. Somewhat contrary to conventional paleontological models, which posit that the two species were highly divergent, the M. columbi mitogenome we obtained falls securely within a subclade of endemic North American M. primigenius . Conclusions Though limited, our data suggest that the two species interbred at some point in their evolutionary histories. One potential explanation is that woolly mammoth haplotypes entered Columbian mammoth populations via introgression at subglacial ecotones, a scenario with compelling parallels in extant elephants and consistent with certain regional paleontological observations. This highlights the need for multi-genomic data to sufficiently characterize mammoth evolutionary history. Our results demonstrate that the use of next-generation sequencing technologies holds promise in obtaining such data, even from non-cave, non-permafrost Pleistocene depositional contexts.
Monocytes or T cells in Crohn's disease: does IL-16 allow both to play at that game?
Authors: S SCHREIBER
Journal: Gut (2001)

See article on page 795 

Interleukin (IL)-16 was first described in 1982 under the name “lymphocyte chemoattractant factor”.1 Since its cloning in 1994,2 the complex structure and biological function of this cytokine has been extensively explored. In 1999, the IL-16 gene was localised to chromosome 15q26.33 but the role of genetic variants of this gene have yet to be explored in human disease.

IL-16 can be produced by a variety of inflammatory cells, including mast cells, eosinophils, mononuclear phagocytes, and CD4+ and CD8+ T cells.4 IL-16 is expressed as an 80 kDa precursor molecule,5 which is processed to active IL-16 by caspase 3.6 

Most interestingly, the main receptor for IL-16 appears to be the CD4 molecule (which identifies T helper cells but is also present on monocytes and other phagocytes). It is assumed that interaction with the CD4 molecule is the …
Inherited Susceptibility to Bleomycin-Induced Chromatid Breaks in Cultured Peripheral Blood Lymphocytes
Authors: J. Cloos, E. J. C. Nieuwenhuis, D. I. Boomsma, D. J. Kuik, M. L. T. van der Sterre, F. Arwert, G. B. Snow, B. J. M. Braakhuis
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes may reflect the way a person deals with carcinogenic challenges. This susceptibility (also referred to as mutagen sensitivity) has been found to be increased in patients with environmentally related cancers, including cancers of the head and neck, lung, and colon, and, in combination with carcinogenic exposure, this susceptibility can greatly influence cancer risk. The purpose of this study was to assess the heritability of mutagen sensitivity. METHODS: Heritability was determined by use of a maximum likelihood method that employed the FISHER package of pedigree analysis. Bleomycin-induced breaks per cell values for 135 healthy volunteers without cancer were determined. These individuals were from 53 different pedigrees and included 25 monozygotic twin pairs (n = 50), 14 pairs of dizygotes (twin pairs and siblings, n = 28), and 14 families selected on the basis of a first-degree relative who was successfully treated for head and neck cancer and who had no sign of recurrence for at least 1 year. All data were analyzed simultaneously, and different models of familial resemblance were fitted to the data. All P values are two-sided. Results: Our results showed no evidence for the influence of a shared family environment on bleomycin-induced chromatid breaks. Genetic influences, however, were statistically significant ( P = .036) and accounted for 75% of the total variance. CONCLUSIONS: The high heritability estimate of the susceptibility to bleomycin-induced chromatid breaks indicates a clear genetic basis. The findings of this study support the notion that a common genetic susceptibility to DNA damage—and thereby a susceptibility to cancer—may exist in the general population.
Inhibition of Copper-Zinc Superoxide Dismutase Induces Cell Growth, Hypertrophic Phenotype, and Apoptosis in Neonatal Rat Cardiac Myocytes In Vitro
Authors: Deborah A. Siwik, John D. Tzortzis, David R. Pimental, Donny L.-F. Chang, Patrick J. Pagano, Krishna Singh, Douglas B. Sawyer, Wilson S. Colucci
Journal: Circulation Research (1999)

Abstract —Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that inhibition of endogenous antioxidant enzymes can regulate the phenotype of cardiac myocytes. Neonatal rat ventricular myocytes in vitro were exposed to diethyldithiocarbamic acid (DDC), an inhibitor of cytosolic (Cu, Zn) and extracellular superoxide dismutase (SOD). DDC inhibited SOD activity and increased intracellular superoxide in a concentration-dependent manner. A low concentration (1 μmol/L) of DDC stimulated myocyte growth, as demonstrated by increases in protein synthesis, cellular protein, prepro–atrial natriuretic peptide, and c- fos mRNAs and decreased sarcoplasmic reticulum Ca 2+ ATPase mRNA. These actions were all inhibited by the superoxide scavenger Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid). Higher concentrations of DDC (100 μmol/L) stimulated myocyte apoptosis, as evidenced by DNA laddering, characteristic nuclear morphology, in situ terminal deoxynucleotidyl transferase–mediated nick end-labeling (TUNEL), and increased bax mRNA expression. DDC-stimulated apoptosis was inhibited by the SOD/catalase mimetic EUK-8. The growth and apoptotic effects of DDC were mimicked by superoxide generation with xanthine plus xanthine oxidase. Thus, increased intracellular superoxide resulting from inhibition of SOD causes activation of a growth program and apoptosis in cardiac myocytes. These findings support a role for oxidative stress in the pathogenesis of myocardial remodeling and failure.
Randomized Double-Blind Trial of Darbepoetin Alfa in Patients With Symptomatic Heart Failure and Anemia
Authors: Jalal K. Ghali, Inder S. Anand, William T. Abraham, Gregg C. Fonarow, Barry Greenberg, Henry Krum, Barry M. Massie, Scott M. Wasserman, Marie-Louise Trotman, Yan Sun, Beat Knusel, Paul Armstrong
Journal: Circulation (2008)

Substantial evidence suggests that anemia is an independent risk factor for worse outcomes in patients with heart failure (HF). The Study of Anemia in Heart Failure Trial (STAMINA-HeFT) is the largest multicenter, randomized, double-blind, placebo-controlled trial to date evaluating the effect of treating anemia in HF.Patients (N=319) with symptomatic HF, left ventricular ejection fraction < or = 40%, and hemoglobin > or = 9.0 g/dL and < or = 12.5 g/dL were randomized (double-blind) to placebo (N=157) or darbepoetin alfa (N=162) subcutaneously every 2 weeks for 1 year (target hemoglobin, 14.0+/-1.0 g/dL). The primary end point was change from baseline to week 27 in treadmill exercise time. Secondary end points were change from baseline in New York Heart Association class and quality of life at week 27. An additional prespecified efficacy analysis included the time to death by any cause or first HF-related hospitalization by 1 year. At baseline, the median (interquartile range) hemoglobin was 11.4 (10.9, 12.0) g/dL. At week 27, darbepoetin alfa treatment increased median (interquartile range) hemoglobin by 1.8 (1.1, 2.5) g/dL (placebo, 0.3 [-0.2, 1.0] g/dL; P<0.001). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14.0+/-1.0 g/dL during the study and experienced a hemoglobin increase of > or = 1.0 g/dL from baseline. By intent-to-treat analysis, darbepoetin alfa treatment did not significantly improve exercise duration, New York Heart Association class, or quality of life score compared with placebo. A nonsignificant trend was observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated patients compared with placebo (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10). Occurrences of adverse events were similar in both treatment groups.In this study of patients with symptomatic HF and anemia, treatment with darbepoetin alfa was not associated with significant clinical benefits. Darbepoetin alfa treatment was well tolerated and effectively raised hemoglobin. A trend of lower risk of morbidity and mortality was observed.
Inhibitor κB Kinase 2 Is a Myosin Light Chain Kinase in Vascular Smooth Muscle
Authors: Zhekang Ying, Jussara M. do Carmo, Lusha Xiang, Alexandre A. da Silva, Minjie Chen, Michael J. Ryan, Michael Ostrowski, Sanjay Rajagopalan, John E. Hall
Journal: Circulation Research (2013)

Myosin light chain (MLC) phosphorylation determines vascular contractile status. In addition to the classic Ca²⁺-dependent MLC kinase (MLCK), another unidentified kinase(s) also contributes to MLC phosphorylation in living cells. Inhibitor κB kinase 2 (IKK2)-deficient mouse embryonic fibroblasts demonstrate abnormal morphology and migration, suggesting that IKK2 may be involved in MLC phosphorylation.Therefore, we tested whether IKK2 is an MLCK in living cells and the role of IKK2 in mediating vasoconstriction and blood pressure regulation.In the present study, we showed that recombinant IKK2-phosphorylated MLC and intact myosin in vitro, and the kinetic parameters were comparable with those of the classic MLCK. Overexpression of IKK2 increased cellular MLC phosphorylation level, and pharmacological inhibition of IKK2 markedly decreased vascular smooth muscle cell MLC phosphorylation, suggesting that IKK2 is an MLCK in living cells. IKK2 inhibitors dose- and time-dependently attenuated vasoconstriction elicited by diverse agonists, suggesting the physiological importance of IKK2 as an MLCK. Vascular smooth muscle cell-specific IKK2-deficient mice had decreased aortic contractile responses, and reduced hypertensive responses to several vasoconstrictors, compared with wild-type mice, confirming the physiological importance of IKK2 as an MLCK.Our data provide a novel mechanism whereby IKK2 regulates MLC phosphorylation as an MLCK and, thus, vascular function and blood pressure.
TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation
Authors: Soo Young Lee, Sang Yull Lee, Yongwon Choi
Journal: The Journal of Experimental Medicine (1997)

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.
Endoscopic ultrasound combined with submucosal saline injection for differentiation of T1a and T1b esophageal squamous cell carcinoma: a novel technique
Authors: J.-J. Li, H.-B. Shan, M.-F. Gu, L. He, L.-J. He, L.-M. Chen, G.-Y. Luo, G.-L. Xu
Journal: Endoscopy (2013)

Endoscopic ultrasound (EUS) is the optimum method for investigation of early esophageal squamous cell carcinoma (ESCC). However, it is difficult to substage early ESCC as T1a or T1b. The aim of this study was to improve the staging accuracy of early ESCC by using EUS combined with submucosal saline injection (SSI). The study enrolled 15 patients with suspected early ESCC who were examined by EUS and subsequently by SSI combined with EUS. The patients then underwent endoscopic or surgical resection within 10 days. The accuracy of EUS staging (alone or following SSI) was evaluated and compared with the pathological results postoperatively. No severe complications of the SSI arose. EUS plus SSI easily distinguished the mucosa from the lesion and the submucosa because of the low-echoic saline-filled cushion in the submucosa. The accuracy of SSI combined with EUS for staging T1a or T1b was 86.7 %, which was better than that using EUS alone (60.0 %).
p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells.
Authors: M Woodrow, N A Clipstone, D Cantrell
Journal: The Journal of Experimental Medicine (1993)

In T lymphocytes, triggering of the T cell receptor (TCR) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells (NFAT), a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2. One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium. Calcium signals are important for NFAT induction, and recent studies have identified calcineurin, a calcium-calmodulin dependent serine-threonine phosphatase, as a prominent component of the calcium signaling pathway in T cells. A second important molecule in TCR signal transduction is the guanine nucleotide binding protein, p21ras, which is coupled to the TCR by a protein tyrosine kinase dependent mechanism. The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation. However, coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction. These data identify calcineurin and p21ras as cooperative partners in T cell activation.
An Electrocardiographic, Anatomic, and Metabolic Study of Zonal Myocardial Ischemia in Coronary Heart Disease
Authors: MICHAEL V. HERMAN, WILLIAM C. ELLIOTT, RICHARD GORLIN
Journal: Circulation (1967)

An integrated approach, utilizing cine coronary angiography, the standard 12-lead and post-exercise electrocardiograms, and regional myocardial lactate metabolism, is presented for detection of regional myocardial ischemia in patients with coronary heart disease. The normal electrocardiogram was of no predictive value and was present with extensive coronary disease and myocardial production of lactate. The abnormal electrocardiogram gave an accurate indication of a portion, but not all zones of ischemia. Multiple electrocardiographic abnormalities were invariably associated with severe coronary artery disease, although in most patients many more coronary lesions were present than electrocardiographic abnormalities. The regional lactate pattern was very helpful in localizing myocardial ischemia and significant coronary artery lesions. Regional lactate abnormalities may have a great practical value in the selection of patients for myocardial revascularization surgery and in their postoperative evaluation.
The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome
Authors: Laura Crisponi, Manila Deiana, Angela Loi, Francesca Chiappe, Manuela Uda, Patrizia Amati, Luigi Bisceglia, Leopoldo Zelante, Ramaiah Nagaraja, Susanna Porcu, M. Serafina Ristaldi, Rosalia Marzella, Mariano Rocchi, Marc Nicolino, Anne Lienhardt-Roussie, Annie Nivelon, Alain Verloes, David Schlessinger, Paolo Gasparini, Dominique Bonneau, Antonio Cao, Giuseppe Pilia
Journal: Nature Genetics (2001)
Selective attenuation of Toll-like receptor 2 signalling may explain the atheroprotective effect of sphingosine 1-phosphate
Authors: A. I. Duenas, M. Aceves, I. Fernandez-Pisonero, C. Gomez, A. Orduna, M. S. Crespo, C. Garcia-Rodriguez
Journal: Cardiovascular Research (2008)

Vascular inflammation is a major atherogenic factor and Toll-like receptor (TLR) 2 ligands, including bacterial and serum lipoproteins, seem to be involved in atherogenesis. On this basis, we analysed the effect of lipoproteins and different lipid components on TLR2-dependent signalling.In TLR2-transfected human embryonic kidney 293 cells and human monocytes, oxidized low-density lipoproteins inhibited nuclear factor (NF)-kappaB-driven transcriptional activity and chemokine gene expression in response to TLR2 ligands. Sphingosine 1-phosphate (S1P) and oxidized palmitoyl-arachidonoyl-phosphatidylcholine, but not lipoprotein-carried lysophospholipids, inhibited TLR2 activation. Silencing experiments in TLR2-transfected 293 cells showed that the S1P-mediated attenuation effect is mediated by S1P receptors type 1 and type 2. To address the physiological significance of these findings, additional experiments were performed in human peripheral blood monocytes and monocyte-derived macrophages. In both cell types, S1P selectively attenuated TLR2 signalling, as NF-kappaB and extracellular signal-regulated kinase activation, but not c-Jun amino terminal kinase phosphorylation, were inhibited by physiologically relevant concentrations of S1P. Moreover, the attenuation of TLR2 signalling was partially reverted by pharmacological inhibition of phosphoinositide 3-kinase (PI3K) and Ras pathways. In addition, S1P inhibited the chemokine gene expression elicited by TLR2, but not by TLR4 ligands.These findings disclose a cross-talk mechanism between lipoprotein components and TLR in which engagement of S1P receptors exert selective attenuation of TLR2-dependent activation via PI3K and Ras signalling. A corollary to these data is that the negative cross-talk of S1P receptors and TLR2 signalling might be involved in the atheroprotective effects of S1P.
Phase II Study of Pomegranate Juice for Men with Rising Prostate-Specific Antigen following Surgery or Radiation for Prostate Cancer
Authors: Allan J. Pantuck, John T. Leppert, Nazy Zomorodian, William Aronson, Jenny Hong, R. James Barnard, Navindra Seeram, Harley Liker, Hejing Wang, Robert Elashoff, David Heber, Michael Aviram, Louis Ignarro, Arie Belldegrun
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. Experimental Design: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA &amp;gt;0.2 and &amp;lt;5 ng/mL and Gleason score ≤7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels. Results: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P &amp;lt; 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P &amp;lt; 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption. Conclusions: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.
Differential Prognosis of Mcrc Patients Post-Progression to First Line Triplet Chemotherapy/Bevacizumab, Fir-B/Fox, According to Second Line Treatment and Kras Genotype
Authors: Gemma Bruera, Katia Cannita, Aldo Victor Giordano, Roberto Vicentini, Corrado Ficorella, Enrico Ricevuto
Journal: Annals of Oncology (2013)
Comparisons of Patient and Physician Expectations for Cancer Survivorship Care
Authors: Winson Y. Cheung, Bridget A. Neville, Danielle B. Cameron, E. Francis Cook, Craig C. Earle
Journal: Journal of Clinical Oncology (2009)

To compare expectations for cancer survivorship care between patients and their physicians and between primary care providers (PCPs) and oncologists.Survivors and their physicians were surveyed to evaluate for expectations regarding physician participation in primary cancer follow-up, screening for other cancers, general preventive health, and management of comorbidities.Of 992 eligible survivors and 607 physicians surveyed, 535 (54%) and 378 (62%) were assessable, respectively. Among physician respondents, 255 (67%) were PCPs and 123 (33%) were oncologists. Comparing patients with their oncologists, expectations were highly discrepant for screening for cancers other than the index one (agreement rate, 29%), with patients anticipating significantly more oncologist involvement. Between patients and their PCPs, expectations were most incongruent for primary cancer follow-up (agreement rate, 35%), with PCPs indicating they should contribute a much greater part to this aspect of care. Expectations between patients and their PCPs were generally more concordant than between patients and their oncologists. PCPs and oncologists showed high discordances in perceptions of their own roles for primary cancer follow-up, cancer screening, and general preventive health (agreement rates of 3%, 44%, and 51%, respectively). In the case of primary cancer follow-up, both PCPs and oncologists indicated they should carry substantial responsibility for this task.Patients and physicians have discordant expectations with respect to the roles of PCPs and oncologists in cancer survivorship care. Uncertainties around physician roles and responsibilities can lead to deficiencies in care, supporting the need to make survivorship care planning a standard component in cancer management.
Cutaneous fibrinolytic potential, tPA dependent, is reduced in Behçet's disease
Authors: T. LOTTI, M. MATUCCI-CERINIC
Journal: British Journal of Dermatology (1989)

We report our studies on the cutaneous and plasma fibrinolytic activities (FA) in nine patients with Behçet's disease (BD) as compared with nine normal controls. The euglobulin lysis time of the plasma and cutaneous fibrinolytic activity were determined in these patients. The studies showed that the plasma fibrinolytic activity was reduced in the patients with BD and there was impaired cutaneous fibrinolytic potential, tPA dependent, in those patients with venous and arterial thromboses.