tbuckley/cabot-search huggingface dataset:
Advanced glycation end products enhance osteoclast-induced bone resorption in cultured mouse unfractionated bone cells and in rats implanted subcutaneously with devitalized bone particles.
Authors: T Miyata, K Notoya, K Yoshida, K Horie, K Maeda, K Kurokawa, S Taketomi
Journal: Journal of the American Society of Nephrology (1997)

Advanced glycation end products (AGE) are formed in long-lived matrix proteins by a nonenzymatic reaction with sugar. The presence of AGE in beta 2-microglobulin-amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits, was recently demonstrated. This suggested a potential link of AGE in bone resorption and initiated this investigation of whether AGE enhance bone resorption. When mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, both AGE-modified beta 2-microglobulin and BSA increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts of those modified with the early glycation products did not. AGE proteins, however, did not increase the number of newly formed osteoclasts, even in the coculture of mouse bone marrow cells with osteoblastic cells isolated from mouse calvaria. Enhanced bone resorption was also observed when unfractionated bone cells were cultured on AGE-modified dentin slices. AGE-enhanced bone resorption was effectively inhibited by calcitonin and ipriflavone, both of which are inhibitors of bone resorption. AGE-enhanced bone resorption was further supported by in vivo evidence that rat bone particles-upon incubation with glucose for 60 days (AGE-bone particles)-when implanted subcutaneously in rats, were resorbed to a much greater extent than control bone particles upon parallel incubation without glucose. These findings suggest that AGE enhance osteoclast-induced bone resorption. Although the mechanism remains unknown, AGE are unlikely to promote differentiation of osteoclast progenitors into osteoclasts, suggesting that AGE activate osteoclasts or alter microenvironments favorable for bone resorption by osteoclasts. The modification of bone matrices with AGE might play a role in the remodeling of senescent bone matrix tissues, further implicating a pathological significance of AGE in dialysis-related amyloidosis or osteoporosis associated with diabetes and aging.
Mechanisms of Synergistic Antileukemic Interactions between Valproic Acid and Cytarabine in Pediatric Acute Myeloid Leukemia
Authors: Chengzhi Xie, Holly Edwards, Xuelian Xu, Hui Zhou, Steven A. Buck, Mark L. Stout, Qun Yu, Jeffrey E. Rubnitz, Larry H. Matherly, Jeffrey W. Taub, Yubin Ge
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To determine the possibility of synergistic antileukemic activity and the underlying molecular mechanisms associated with cytarabine combined with valproic acid (VPA; a histone deacetylase inhibitor and a Food and Drug Administration–licensed drug for treating both children and adults with epilepsy) in pediatric acute myeloid leukemia (AML). Experimental Design: The type and extent of antileukemic interactions between cytarabine and VPA in clinically relevant pediatric AML cell lines and diagnostic blasts from children with AML were determined by MTT assays and standard isobologram analyses. The effects of cytarabine and VPA on apoptosis and cell cycle distributions were determined by flow cytometry analysis and caspase enzymatic assays. The effects of the two agents on DNA damage and Bcl-2 family proteins were determined by Western blotting. Results: We showed synergistic antileukemic activities between cytarabine and VPA in four pediatric AML cell lines and nine diagnostic AML blast samples. t(8;21) AML blasts were significantly more sensitive to VPA and showed far greater sensitivities to combined cytarabine and VPA than non-t(8;21) AML cases. Cytarabine and VPA cooperatively induced DNA double-strand breaks, reflected in induction of γH2AX and apoptosis, accompanied by activation of caspase-9 and caspase-3. Further, VPA induced Bim expression and short hairpin RNA knockdown of Bim resulted in significantly decreased apoptosis induced by cytarabine and by cytarabine plus VPA. Conclusions: Our results establish global synergistic antileukemic activity of combined VPA and cytarabine in pediatric AML and provide compelling evidence to support the use of VPA in the treatment of children with this deadly disease. Clin Cancer Res; 16(22); 5499–510. ©2010 AACR.
Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications
Authors: Stefan Fröhling, Claudia Scholl, D. Gary Gilliland, Ross L. Levine
Journal: Journal of Clinical Oncology (2005)

Myeloid malignancies are clonal disorders that are characterized by acquired somatic mutation in hematopoietic progenitors. Recent advances in our understanding of the genetic basis of myeloid malignancies have provided important insights into the pathogenesis of acute myeloid leukemia (AML) and myeloproliferative diseases (MPD) and have led to the development of novel therapeutic approaches. In this review, we describe our current state of understanding of the genetic basis of AML and MPD, with a specific focus on pathogenetic and therapeutic significance. Specific examples discussed include RAS mutations, KIT mutations, FLT3 mutations, and core binding factor rearrangements in AML, and JAK2 mutations in polycythemia vera, essential thrombocytosis, and chronic idiopathic myelofibrosis.
Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs
Authors: D Cirstea, T Hideshima, L Santo, H Eda, Y Mishima, N Nemani, Y Hu, N Mimura, F Cottini, G Gorgun, H Ohguchi, R Suzuki, H Loferer, N C Munshi, K C Anderson, N Raje
Journal: Leukemia (2013)
Color memory penetrates early vision
Authors: James A. Schirillo
Journal: Behavioral and Brain Sciences (1999)

Pylyshyn's concentration on form perception to demonstrate that early vision is cognitively impenetrable neglects that color perception is also part of early vision. Thus, the finding of Duncker (1939), Bruner et al. (1951), and Delk and Fillenbaum (1965) that the expected color of objects affects how they are perceived challenges Pylyshyn's thesis.
Interferon (IFN) beta acts downstream of IFN-gamma-induced class II transactivator messenger RNA accumulation to block major histocompatibility complex class II gene expression and requires the 48-kD DNA-binding protein, ISGF3-gamma.
Authors: H T Lu, J L Riley, G T Babcock, M Huston, G R Stark, J M Boss, R M Ransohoff
Journal: The Journal of Experimental Medicine (1995)

Interferon (IFN) gamma, a cardinal proinflammatory cytokine, induces expression of the gene products of the class II locus of the major histocompatibility complex (MHC), whereas IFN-alpha or -beta suppresses MHC class II expression. The mechanism of IFN-beta-mediated MHC class II inhibition has been unclear. Recently, a novel factor termed class II transactivator (CIITA) has been identified as essential for IFN-gamma-induced MHC class II transcription. We studied the status of IFN-gamma-induced CIITA messenger RNA (mRNA) accumulation and CIITA-driven transactivation in IFN-beta-treated cells and used cell lines that had defined defects in the type I IFN response pathway to address the roles of IFN signaling components in the inhibition of MHC class II induction. IFN-beta treatment did not suppress IFN-gamma-induced accumulation of CIITA mRNA. After cells were stably transfected with CIITA, endogenous MHC class II genes were constitutively expressed, and MHC class II promoters, delivered by transfection, were actively transcribed in CIITA-expressing cells. Expression of these promoters was significantly impaired by pretreatment with IFN-beta. These results suggest that IFN-beta acts downstream of CIITA mRNA accumulation, and acts in part by reducing the functional competence of CIITA for transactivating MHC class II promoters. IFN stimulated gene factor 3 (ISGF3) gamma was essential for IFN-beta to mediate inhibition of MHC class II induction, regardless of whether MHC class II transcription was stimulated by IFN-gamma or directly by CIITA expression. Results of these experiments suggest that inhibition of MHC class II in IFN-beta-treated cells requires expression of gene(s) directed by the ISGF3-IFN-stimulated response element pathway, and that these gene product(s) may act by blocking CIITA-driven transcription of MHC class II promoters.
Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells.
Authors: M Eichelberger, W Allan, M Zijlstra, R Jaenisch, P C Doherty
Journal: The Journal of Experimental Medicine (1991)

Transgenic mice homozygous for a beta 2-microglobulin (beta 2-m) gene disruption and normal mice that had been treated with a CD8-specific mAb were infected intranasally with an H3N2 influenza A virus. Both groups of CD8T cell-deficient mice eliminated the virus from the infected respiratory tract. Potent CTL activity was detected in lung lavage populations taken from mice with intact CD8+ T cell function, with minimal levels of cytotoxicity being found for inflammatory cells obtained from the antibody-treated and beta 2-m mutant mice. We therefore conclude that cells infected with an influenza A virus can be cleared from the respiratory tract of mice lacking both functional class I major histocompatibility complex (MHC) glycoproteins and class I MHC-restricted, CD8+ effector T cells.
Elastic fibres: histological correlation with orcein and a new monoclonal antibody, HB8
Authors: J.F. DAWSON, J.BROCHIER †, D. SCHMITT, S.SAELAND †, J. THIVOLET
Journal: British Journal of Dermatology (2006)

HB8 is a new monoclonal antibody, prepared against human lymphocytes, which has been found to react with elastic fibres, possibly the microfibrillar component. Samples of normal human and animal skin and human skin from various pathological conditions were subjected to immunolabelling with HB8, and alternate sections from each sample were stained by a standard orcein procedure. The individual fibres were clearly marked by the HB8 and this was confirmed by comparison with the standard elastic tissue stain. HB8 provides a new direct, practical and accurate method for the study of elastic tissue.
Central Arterial Compliance Is Associated With Age- and Habitual Exercise–Related Differences in Cardiovagal Baroreflex Sensitivity
Authors: Kevin D. Monahan, Hirofumi Tanaka, Frank A. Dinenno, Douglas R. Seals
Journal: Circulation (2001)

Background Cardiovagal baroreflex sensitivity (BRS) declines with age but is favorably modulated by habitual aerobic exercise. We tested the hypothesis that compliance (transducing capacity) of an elastic artery in which baroreceptors are located is associated with these age-exercise interactions. Methods and Results Nine young (28±1 years old) and 9 older (65±1) sedentary and 10 young (27±1) and 9 older (63±2) endurance-trained healthy men were studied. Cardiovagal BRS was assessed conventionally (R-R interval–systolic blood pressure [SBP] relation) by the Oxford technique. Because of age-associated increases in central arterial stiffness, cardiovagal BRS was expressed with both peripheral (Finapres) and central (applanation tonometry) SBP values. The change in carotid artery end-systolic lumen diameter (ultrasonography) per unit increase in SBP and the slope of the R-R interval–carotid artery diameter relation also were determined. Cardiovagal BRS declined with age in both sedentary (≈65%) and endurance-trained (≈40%) men but was higher in endurance-trained than sedentary older men regardless of the SBP values used (all P &lt;0.05). Changes in carotid artery lumen diameter per unit increase in SBP mirrored these differences in cardiovagal BRS (all P &lt;0.05). Thus, R-R interval prolongation per unit increase in carotid artery diameter was not different among the groups ( P &gt;0.70). Conclusions These results demonstrate that age- and habitual exercise–related differences in cardiovagal BRS are associated with corresponding differences in carotid artery compliance among healthy men.
Ryanodine as a tool to determine the contributions of calcium entry and calcium release to the calcium transient and contraction of cardiac Purkinje fibers.
Authors: E Marban, W G Wier
Journal: Circulation Research (1985)

Our object was to assess the relative roles of transsarcolemmal calcium entry and intracellular calcium release in the contraction of cardiac Purkinje fibers. We observed intracellular calcium transients, membrane potential, and contraction in aequorin-injected canine cardiac Purkinje fibers exposed to highly selective pharmacological modifiers of excitation-contraction coupling. To influence selectively the release of calcium from the sarcoplasmic reticulum, we used the plant alkaloid, ryanodine. To influence calcium entry, selectively, we used either the calcium channel antagonist, nitrendipine, or the calcium channel agonist, Bay k 8644. Ryanodine alone (1 microM) reduced both components of the intracellular aequorin luminescence signal (L1 and L2). In three muscles, the luminescence signals were 3% of control in amplitude (standard error of the mean, 2%) without two distinct components and the twitch tension was 2% of control (standard error of the mean, 3%), whereas the action potential was prolonged. The aequorin signal and twitch remaining in ryanodine were abolished by the calcium antagonist nitrendipine (10 microM), which also lowered the action potential plateau, consistent with the block of functional calcium channels. In two experiments, the calcium-channel agonist, Bay k 8644, in the presence of ryanodine, increased the aequorin luminescence and the contraction, but only to a very small fraction of their control values. Sodium withdrawal in potassium-free, ryanodine-containing solution produced large slow increases in calcium and tension, showing that tension could still be produced, that aequorin remained functional, and that sodium/calcium exchange was not inhibited by ryanodine. Caffeine increased intracellular calcium, showing that calcium stores were not depleted.(ABSTRACT TRUNCATED AT 250 WORDS)
Sequence Variants in Toll-Like Receptor Gene Cluster (TLR6-TLR1-TLR10) and Prostate Cancer Risk
Authors: J. Sun, F. Wiklund, S. L. Zheng, B. Chang, K. Balter, L. Li, J.-E. Johansson, G. Li, H.-O. Adami, W. Liu, A. Tolin, A. R. Turner, D. A. Meyers, W. B. Isaacs, J. Xu, H. Gronberg
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: Chronic inflammation plays an important role in several human cancers and may be involved in the etiology of prostate cancer. Toll-like receptors (TLRs) are important in the innate immune response to pathogens and in cross-talk between innate immunity and adaptive immunity. Our previous finding of an association of TLR4 gene sequence variants and prostate cancer risk provides evidence for a role of TLRs in prostate cancer. In this study, we investigated whether sequence variants in the TLR6-TLR1-TLR10 gene cluster, residing within a 54-kb region on 4p14, were associated with prostate cancer risk. Methods: We selected 32 single-nucleotide polymorphisms (SNPs) covering these three genes and genotyped these SNPs in 96 control subjects from the Cancer Prostate in Sweden (CAPS) population-based prostate cancer case–control study. Five distinct haplotype blocks were inferred at this region, and we identified 17 haplotype-tagging SNPs (htSNPs) that could uniquely describe >95% of the haplotypes. These 17 htSNPs were then genotyped in the entire CAPS study population (1383 case subjects and 780 control subjects). Odds ratios of prostate cancer for the carriers of a variant allele versus those with the wild-type allele were estimated using unconditional logistic regression. Results: The allele frequencies of 11 of the 17 SNPs were statistically significantly different between case and control subjects ( P = .04–.001), with odds ratios for variant allele carriers (homozygous or heterozygous) compared with wild-type allele carriers ranging from 1.20 (95% confidence interval [CI] = 1.00 to 1.43) to 1.38 (95% CI = 1.12 to 1.70). Phylogenetic tree analyses of common haplotypes identified a clade of two evolutionarily related haplotypes that are statistically significantly associated with prostate cancer risk. These two haplotypes contain all the risk alleles of these 11 associated SNPs. Conclusion: The observed multiple associated SNPs at the TLR6-TLR1-TLR10 gene cluster were dependent and suggest the presence of a founder prostate cancer risk variant on this haplotype background. The TLR6-TLR1-TLR10 gene cluster may play a role in prostate cancer risk, although further functional studies are needed to pinpoint the disease-associated variants in this gene cluster.
Hodgkin's Lymphoma in Elderly Patients: A Comprehensive Retrospective Analysis From the German Hodgkin's Study Group
Authors: Andreas Engert, Veronika Ballova, Heinz Haverkamp, Beate Pfistner, Andreas Josting, Eckhart Dühmke, Konrad Müller-Hermelink, Volker Diehl
Journal: Journal of Clinical Oncology (2005)

With improved prognosis for patients with Hodgkin's lymphoma (HL), interest increasingly focuses on high-risk groups such as elderly patients. We thus performed a retrospective analysis using the German Hodgkin's Study Group (GHSG) database to determine clinical risk factors, course of treatment, and outcome in elderly HL patients in comparison with younger adults.A total of 4,251 patients included in the GHSG studies HD5 to HD9 were analyzed, of whom 372 (8.8%) were 60 years or older and 3,879 (91.2%) were younger than 60 years. Patient characteristics, treatment results, toxicity, freedom from treatment failure (FFTF), and overall survival (OS) were compared.Elderly patients more often had mixed cellularity subtype, "B" symptoms, elevated erythrocyte sedimentation rate, and poorer performance status. Less frequently observed were nodular sclerosis subtype, large mediastinal mass, and bulky disease. Acute toxicity during chemotherapy was generally higher in elderly patients. This was most obvious for severe infections (grade 3 or 4; 15% v 6%) correlating with more severe leukopenia in elderly patients (grade 4; 38% v 23%). As a result, significantly fewer elderly patients received the intended full chemotherapy dose (75% v 91%). The survival analysis showed a significantly poorer treatment outcome for elderly patients in terms of 5-year OS (65% v 90%), FFTF (60% v 80%), and HL-specific FFTF (73% v 82%).Elderly patients have a poorer risk profile compared with younger HL patients and experience more severe treatment-associated toxicity. Higher mortality during treatment as well as lower dose-intensity are the major factors explaining the poorer overall outcome of elderly HL patients.
Why the impact factor of journals should not be used for evaluating research
Authors: P. O Seglen
Journal: BMJ (1997)

Evaluating scientific quality is a notoriously difficult problem which has no standard solution.Ideally, published scientific results should be scrutinised by true experts in the field and given scores for quality and quantity according to established rules.In practice, however, what is called peer review is usually performed by committees with general competence rather than with the specialist's insight that is needed to assess primary research data.Committees tend, therefore, to resort to secondary criteria like crude publication counts, journal prestige, the reputation of authors and institutions, and estimated importance and relevance of the research field, 1 making peer review as much of a lottery as of a rational process. 2 3 On this background, it is hardly surprising that alternative methods for evaluating research are being sought, such as citation rates and journal impact factors, which seem to be quantitative and objective indicators directly related to published science.The citation data are obtained from a database produced by the Institute for Scientific Information (ISI) in Philadelphia, which continuously records scientific citations as represented by the reference lists of articles from a large number of the world's scientific journals.The references are rearranged in the database to show how many times each publication has been cited within a certain period, and by whom, and the results are published as the Science Citation Index (SCI).On the Is the journal impact factor really representative of the individual journal articles? Relation of journal impact factor and citation rate of articleFor the journal's impact factor to be reasonably representative of its articles, the citation rate of individual articles in the journal should show a narrow distribution, preferably a Gaussian distribution, around Summary points• Use of journal impact factors conceals the difference in article citation rates (articles in the most cited half of articles in a journal are cited 10 times as often as the least cited half) • Journals' impact factors are determined by technicalities unrelated to the scientific quality of their articles • Journal impact factors depend on the research field: high impact factors are likely in journals covering large areas of basic research with a rapidly expanding but short lived literature that use many references per article
Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells
Authors: Norimitsu Kadowaki, Svetlana Antonenko, Stephen Ho, Marie-Clotilde Rissoan, Vassili Soumelis, Steven A. Porcelli, Lewis L. Lanier, Yong-Jun Liu
Journal: The Journal of Experimental Medicine (2001)

Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1–mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4–dependent manner. Thus, it is important to understand how the development of IL-4– versus interferon (IFN)-γ–producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500–70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-γ, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4+IFN-γ− NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4−IFN-γ+ NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4+IFN-γ− NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-γ.