tbuckley/cabot-search huggingface dataset:
Evaluation of Role of Natural Killer Cells in Radiation-Induced Leukemogenesis in Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Eliezer Gorelik, Boas Rosen, Diana Copeland, Brian Weatherly, Ronald B. Herberman
Journal: JNCI Journal of the National Cancer Institute (1984)

The relationship of the leukemogenic and natural killer (NK)-suppressive effects of fractionated doses of gamma-radiation in mice was studied. A/J mice were relatively resistant; CBA/J, BALB/c, and C57BL/6 were susceptible to both the NK-suppressive and leukemogenic effects, and young (1 mo old) C57BL/6 mice were more susceptible than were 2- and 3-month-old C57BL/6 mice to both effects. Age-dependent susceptibility to radiation-induced leukemogenesis also was observed in C57BL/6 (bg/bg) (beige) mice. No differences in incidence and latent period of lymphoma development were found between C57BL/6 (+/+) and beige mice. Bone marrow cells (BMC) from normal C57BL/6 donors reconstituted the NK reactivity of irradiated C57BL/6 (+/+) or beige recipients and inhibited leukemogenesis. Although BMC of beige donors did not reconstitute the NK reactivity of irradiated C57BL/6 (+/+) or beige recipients, these cells were as efficient for antileukemic protection as were BMC from C57BL/6 (+/+) mice. The bone marrow of irradiated mice contained preleukemia cells that produced leukemias when transplanted iv into recipients preirradiated with 400 R. Inoculation (iv) of spleen cells (SpC) from syngeneic nude mice plus preleukemia bone marrow cells (PBMC) were able to inhibit leukemia formation in the 400 R-irradiated recipients. SpC from beige mice, normal C57BL/6 (+/+) mice, or C57BL/6 (+/+) mice treated with anti-asialo GM1 serum had no influence on the development of leukemia after their transplantation with PBMC.
Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy
Authors: D.Y. Heng, M.J. MacKenzie, U.N. Vaishampayan, G.A. Bjarnason, J.J. Knox, M.H. Tan, L. Wood, Y. Wang, C. Kollmannsberger, S. North, F. Donskov, B.I. Rini, T.K. Choueiri
Journal: Annals of Oncology (2011)
FATAL INFECTION OF IRRADIATED WHITE MICE WITH EUROPEAN TYPHUS BY THE INTRA-ABDOMINAL ROUTE
Authors: P. Y. Liu, John C. Snyder, John F. Enders
Journal: The Journal of Experimental Medicine (1941)

A fatal infection of irradiated white mice with the Breinl strain of European typhus has been established and passed serially for 22 passages by the intra-abdominal route. Rickettsiae were abundant and easily demonstrable in the moribund or dead mice. The mortality of irradiated mice infected with passage material (peritoneal washings or blood) was nearly 100 per cent as contrasted to no mortality in the control mice given the same dose of x-ray (450 R) and the same volume of fluid intra-abdominally. (The observation period of control mice was arbitrarily limited to 14 days.) After eighteen passages in irradiated mice no increase in virulence for non-irradiated adult mice was detected. After passage in guinea pigs, the rickettsial infection deriving from the mouse passage material was identical with the Breinl strain as judged by fever, cross immunity tests, and brain lesions in sections.
Exercise tests and anxiety independently reflect physical quality of life in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension
Authors: Michael Halank, Franziska Einsle, Stephanie Christoph, Hinrich Bremer, Ralf Ewert, Heinrike Wilkens, Joachim Meyer, Hans-Juergen Seyfarth, Martin Kolditz, Gesine Wieder, Gert Hoeffken, Volker Koellner
Journal: European Respiratory Journal (2012)

Background:    Up to now, only few data existed evaluating quality of life in patients with PAH and/or CTEPH.   Question:   To describe the association between anxiety, depression, cardiopulmonary hemodynamics, and exercise parameters with physical quality of life (QoL).   Methods:   Patients with PAH and/or CTEPH performed a 6 minute walk test, cardiopulmonary exercise testing (CPET) and right heart catheterization and completed 3 QoL questionnaires (SF36, SRGQ and MacNew). Hospital Anxiety and Depression Scale (HADS) was used to assess psychological constructs like anxiety and depression.   Results:   63 PAH und 22 CTEPH patients were prospectively included. Peak oxygen uptake (VO2 peak) during CPET was 13±4 ml/min/kg and 6 minute walk distance (6MWD) was 325±127 m. After multivariate analysis anxiety showed an independent association with activity, impact, and total scores in SGRQ and with emotional, physical, social and total scores in MacNew and with mental score in SF36. There was an independent correlation between depression and physical, mental and symptom scores in SF-36. Peak VO2 showed an independent association with all above mentioned subscales in SGRQ and with physical and mental QoL in SF36, whereas 6MWD was associated with all above mentioned scores of the MacNew and the symptom score of SF36.   Conclusion:    Peak VO2 and 6MWD reflect quality of life in patients with PAH and/or CTEPH. In addition, anxiety and depression showed a strong association with mental and physical QoL underlining the need for awareness of these disorders.
Manipulating the Tumor Microenvironment <i>Ex Vivo</i> for Enhanced Expansion of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy
Authors: Jessica Ann Chacon, Amod A. Sarnaik, Jie Qing Chen, Caitlin Creasy, Charuta Kale, John Robinson, Jeffrey Weber, Patrick Hwu, Shari Pilon-Thomas, Laszlo Radvanyi
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8+ T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8+ T cells recently found to constitute the majority of tumor-specific T cells. Experimental Design: We used an agonistic anti–4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation. Results: We found that addition of an agonistic anti–4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8+ TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8+ T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8+ T cells with anti–4-1BB, suggesting that an ongoing HLA class I–mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8+ TIL outgrowth. Conclusions: Our results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. Clin Cancer Res; 21(3); 611–21. ©2014 AACR.
Potential effect of metabolic acidosis on beta 2-microglobulin generation
Authors: M Sonikian, J Gogusev, J Zingraff, S Loric, B Quednau, G Bessou, W Siffert, T B Drüeke, H P Reusch, F C Luft
Journal: Journal of the American Society of Nephrology (1996)

Beta 2-microglobulin (beta 2M) is responsible for dialysis-associated amyloidosis. Level of beta 2M in plasma increase during chronic renal failure; however, retention does not appear to be the sole mechanism responsible. The effect of metabolic acidosis on beta 2M production was examined. Thirty-six patients with stable chronic renal insufficiency, 12 uremic patients before their first dialysis, 8 hemodialysis patients who were assigned to acetate or bicarbonate dialysate and then crossed over to the alternative regimen, and 6 normal subjects given NH4Cl to initiate metabolic acidosis were studied. In vitro studies in the human myeloid cell line U 937 were also performed. beta 2M protein was measured with ELISA, beta 2M mRNA was measured with reverse transcription polymerase chain reaction, and the U 937 cells were studied at two pH levels with FACScan flow cytometry. The cells were exposed in vitro up to 60 min in a buffered incubation medium to either pH 5.10 or pH 7.34. An inverse correlation was found between beta 2M and bicarbonate concentrations in plasma in the stable chronic renal failure patients (r = -0.54; P < 0.05) and in the uremic patients before their first dialysis (r = -0.72; P < 0.05). In hemodialysis patients, blood pH and plasma bicarbonate values were lower (P < 0.05) and beta 2M concentrations in plasma were higher (P < 0.05) with acetate than with bicarbonate dialysate. In normal men, NH4Cl resulted in an increase (P < 0.05) in beta 2M mRNA expression in lymphocytes by an average factor of 1.5 (range, 1.1 to 1.8). In U 937 cells, the cell surface expression of beta 2M and HLA Class I heavy chain assembled with beta 2M decreased at low pH compared with normal pH. Concomitantly, an increase in beta 2M release into the supernatant was observed, possibly as the result of beta 2M dissociation from cell surface HLA Class I complex. The results suggest that metabolic acidosis may enhance cellular beta 2M generation and release.
Mechanisms of Coronary Microvascular Dilation Induced by the Activation of Pertussis Toxin–Sensitive G Proteins Are Vessel-Size Dependent
Authors: Tatsuya Komaru, Toshinori Tanikawa, Akihiko Sugimura, Toshinobu Kumagai, Kouichi Sato, Hiroshi Kanatsuka, Kunio Shirato
Journal: Circulation Research (1997)

G proteins are critically important mediators of many signal transduction systems. In the present study, we investigated the effect of direct activation of pertussis toxin (PTX)–sensitive G protein (G PTX ) on coronary arterial microvascular tone in 37 open-chest anesthetized dogs in vivo. Coronary arterial microvessels on the surface of the beating left ventricle were visualized by performing fluorescence coronary microangiography using an intravital microscope with a floating objective system. Microvessels were divided into two groups, small microvessels (inner diameter, ≤130 μm) and large microvessels (inner diameter, &gt;130 μm). Topically applied mastoparan (G protein activator, 10, 30, and 100 μmol/L) produced homogeneous microvascular dilation in a concentration-dependent manner (10 μmol/L, 7.9±2.0%; 30 μmol/L, 10.3±2.4%; and 100 μmol/L, 16.7±4.5% in small microvessels; 10 μmol/L, 5.3±1.2%; 30 μmol/L, 9.8±2.5%; and 100 μmol/L, 15.5±3.9% in large microvessels). These dilations were reversed to constriction by pretreatment with PTX (300 ng/mL, 2 hours) in both microvessel groups. Blockade of nitric oxide production by N ω -nitro- l -arginine (LNNA, 300 μmol/L) offset the mastoparan-induced dilation in large microvessels but not in small microvessels. Cosuperfusion of glibenclamide (10 μmol/L) with LNNA produced constriction of all sizes of microvessels in response to mastoparan, whereas charybdotoxin (10 nmol/L) did not affect the mastoparan effect. Pretreatment with glibenclamide alone reversed mastoparan dilation to constriction in small microvessels, whereas it only offset the dilation without producing constriction in large microvessels. We conclude that the activation of G PTX produces homogeneous coronary arterial microvascular dilation and that the underlining mechanisms of the dilation are vessel size dependent. The l -arginine–nitric oxide pathway mediates the dilation only in large microvessels, whereas ATP-sensitive K + channel activation plays a central role in the dilation of small microvessels when G PTX is directly activated. ATP-sensitive K + channels are also involved in the dilation of large microvessels in a synergistic fashion with nitric oxide production.
Ursolic Acid Inhibits Growth and Metastasis of Human Colorectal Cancer in an Orthotopic Nude Mouse Model by Targeting Multiple Cell Signaling Pathways: Chemosensitization with Capecitabine
Authors: Sahdeo Prasad, Vivek R. Yadav, Bokyung Sung, Simone Reuter, Ramaswamy Kannappan, Amit Deorukhkar, Parmeswaran Diagaradjane, Caimiao Wei, Veerabhadran Baladandayuthapani, Sunil Krishnan, Sushovan Guha, Bharat B. Aggarwal
Journal: Clinical Cancer Research (2012)

Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid, a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated.The effect of ursolic acid on proliferation of CRC cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and protein expression by Western blot. The effect of ursolic acid on the growth and chemosensitization was also examined in orthotopically implanted CRC in nude mice.We found that ursolic acid inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-κB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, and survivin), proliferative (cyclin D1), and metastatic (MMP-9, VEGF, and ICAM-1) proteins. When examined in an orthotopic nude mouse model, ursolic acid significantly inhibited tumor volume, ascites formation, and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that ursolic acid downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-κB, STAT3, and β-catenin. In addition, ursolic acid suppressed EGF receptor (EGFR) and induced p53 and p21 expression. We also observed bioavailability of ursolic acid in the serum and tissue of animals.Overall, our results show that ursolic acid can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through the suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis.
Early detection of COPD is important for lung cancer surveillance
Authors: Yasuo Sekine, Hideki Katsura, Eitetsu Koh, Kenzo Hiroshima, Takehiko Fujisawa
Journal: European Respiratory Journal (2011)

It is well known that chronic obstructive pulmonary disease (COPD) is a significant risk factor for lung cancer. Approximately 1% of COPD patients develop lung cancer every year, which may be associated with genetic susceptibility to cigarette smoke. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of nuclear factor-κB and signal transducer and activator of transcription 3 play crucial roles in the development of lung cancer from COPD. Low-dose computed tomography (LDCT) is an effective procedure for the early detection of lung cancer in high-risk patients. However, determining which patients should be screened for lung cancer in a primary care setting is difficult. In this article, we review the epidemiology and aetiology of lung cancer associated with COPD, verify the efficacy of lung cancer screening by LDCT, and discuss the importance of early detection of COPD for lung cancer surveillance. We propose that, for the prevention of both diseases, COPD screening in smokers should be initiated as early as possible, so they can stop smoking and so that candidates for an efficient lung cancer screening programme can be identified.
Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells
Authors: E. L. Kim, R. Wustenberg, A. Rubsam, C. Schmitz-Salue, G. Warnecke, E.-M. Bucker, N. Pettkus, D. Speidel, V. Rohde, W. Schulz-Schaeffer, W. Deppert, A. Giese
Journal: Neuro-Oncology (2010)

Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy.
Species Tree Inference Using a Mixture Model
Authors: Ikram Ullah, Pekka Parviainen, Jens Lagergren
Journal: Molecular Biology and Evolution (2015)

Species tree reconstruction has been a subject of substantial research due to its central role across biology and medicine. A species tree is often reconstructed using a set of gene trees or by directly using sequence data. In either of these cases, one of the main confounding phenomena is the discordance between a species tree and a gene tree due to evolutionary events such as duplications and losses. Probabilistic methods can resolve the discordance by coestimating gene trees and the species tree but this approach poses a scalability problem for larger data sets. We present MixTreEM-DLRS: A two-phase approach for reconstructing a species tree in the presence of gene duplications and losses. In the first phase, MixTreEM, a novel structural expectation maximization algorithm based on a mixture model is used to reconstruct a set of candidate species trees, given sequence data for monocopy gene families from the genomes under study. In the second phase, PrIME-DLRS, a method based on the DLRS model (Åkerborg O, Sennblad B, Arvestad L, Lagergren J. 2009. Simultaneous Bayesian gene tree reconstruction and reconciliation analysis. Proc Natl Acad Sci U S A. 106(14):5714–5719), is used for selecting the best species tree. PrIME-DLRS can handle multicopy gene families since DLRS, apart from modeling sequence evolution, models gene duplication and loss using a gene evolution model (Arvestad L, Lagergren J, Sennblad B. 2009. The gene evolution model and computing its associated probabilities. J ACM. 56(2):1–44). We evaluate MixTreEM-DLRS using synthetic and biological data, and compare its performance with a recent genome-scale species tree reconstruction method PHYLDOG (Boussau B, Szöllősi GJ, Duret L, Gouy M, Tannier E, Daubin V. 2013. Genome-scale coestimation of species and gene trees. Genome Res. 23(2):323–330) as well as with a fast parsimony-based algorithm Duptree (Wehe A, Bansal MS, Burleigh JG, Eulenstein O. 2008. Duptree: a program for large-scale phylogenetic analyses using gene tree parsimony. Bioinformatics 24(13):1540–1541). Our method is competitive with PHYLDOG in terms of accuracy and runs significantly faster and our method outperforms Duptree in accuracy. The analysis constituted by MixTreEM without DLRS may also be used for selecting the target species tree, yielding a fast and yet accurate algorithm for larger data sets. MixTreEM is freely available at http://prime.scilifelab.se/mixtreem/.
New lexicon and criteria for the diagnosis of Alzheimer's disease
Authors: Giorgio Giaccone, Thomas Arzberger, Irina Alafuzoff, Safa Al-Sarraj, Herbert Budka, Charles Duyckaerts, Peter Falkai, Isidro Ferrer, James W Ironside, Gábor G Kovács, David Meyronet, Piero Parchi, Efstratios Patsouris, Tamas Revesz, Peter Riederer, Annemieke Rozemuller, Andrea Schmitt, Bengt Winblad, Hans Kretzschmar
Journal: The Lancet Neurology (2011)
Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism
Authors: Jill L. Silverman, Daniel G. Smith, Stacey J. Sukoff Rizzo, Michael N. Karras, Sarah M. Turner, Seda S. Tolu, Dianne K. Bryce, Deborah L. Smith, Kari Fonseca, Robert H. Ring, Jacqueline N. Crawley
Journal: Science Translational Medicine (2012)

Autism-like behaviors in mice were reversed by a negative modulator of a metabotropic glutamate receptor, suggesting a treatment for symptoms of autism spectrum disorders.
Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with RA?
Authors: S L Hider
Journal: Annals of the Rheumatic Diseases (2003)

We read with interest the paper by Ranganathan et al proposing that pharmacogenetics may be a useful tool to help predict methotrexate (MTX) toxicity and efficacy in rheumatoid arthritis (RA).1

One aspect they highlight is the potential role of drug efflux mechanisms in contributing to the lack of response to MTX in some patients. It is important to note that although they discuss the drug efflux transporter P-glycoprotein (P-gp) as being of interest, the paper they cite in support of this view actually reports an experiment in which MTX resistance was mediated by a different drug transporter, multidrug resistance protein 1 (MRP1).2 A range of efflux transporters have been described, including P-gp, MRP, and breast cancer resistance protein (BCRP). Different drugs appear to be substrates for different efflux transporters.3 The drug transporter that mediates MTX resistance remains somewhat controversial.

Llorente et al studied 16 patients with RA and found higher P-glycoprotein (P-gp) levels in patients who were defined as being refractory to disease modifying drug treatment than in treatment responders.4 Similarly, Norris et al demonstrated increased P-gp expression in leukaemic cell lines resistant …
Filaggrin related antibodies among the aged
Authors: T Palosuo
Journal: Annals of the Rheumatic Diseases (2003)

The mean age at onset of new cases of rheumatoid arthritis (RA) has increased markedly. Because the prevalence of false positive rheumatoid factor reactions increases with advancing age, the diagnostic value of this test has limitations among the aged.To study the occurrence of two filaggrin related antibodies in an aged population.The study covered 300 subjects aged 78-88 years, one of whom had RA. The sera were tested with enzyme linked immunosorbent assays (ELISAs), using filaggrin purified from human skin and citrullinated cyclic peptide (CCP) as antigens.One patient with RA was positive for both antibodies. When the cut off level for positive reactions was set at the 98th centile of healthy blood donors, 24 (8%) of the other subjects were positive for antibodies against filaggrin, but only one against CCP.The test for anti-CCP antibody has better specificity than the test for antibodies against filaggrin among the aged.