tbuckley/cabot-search huggingface dataset:
Local Adaptation in the Flowering-Time Gene Network of Balsam Poplar, Populus balsamifera L.
Authors: S. R. Keller, N. Levsen, M. S. Olson, P. Tiffin
Journal: Molecular Biology and Evolution (2012)

Identifying the signature and targets of local adaptation is an increasingly important goal in empirical population genetics. Using data from 443 balsam poplar Populus balsamifera trees sampled from 31 populations, we tested for evidence of geographically variable selection shaping diversity at 27 homologues of the Arabidopsis flowering-time network. These genes are implicated in the control of seasonal phenology, an important determinant of fitness. Using 335 candidate and 412 reference single nucleotide polymorphisms (SNPs), we tested for evidence of local adaptation by searching for elevated population differentiation using F(ST)-based outlier analyses implemented in BayeScan or a Hierarchical Model in Arelquin and by testing for significant associations between allele frequency and environmental variables using BAYENV. A total of 46 SNPs from 14 candidate genes had signatures of local adaptation-either significantly greater population differentiation or significant covariance with one or more environmental variable relative to reference SNP distributions. Only 11 SNPs from two genes exhibited both elevated population differentiation and covariance with one or more environmental variables. Several genes including the abscisic acid gene ABI1B and the circadian clock genes ELF3 and GI5 harbored a large number of SNPs with signatures of local adaptation-with SNPs in GI5 strongly covarying with both latitude and precipitation and SNPs in ABI1B strongly covarying with temperature. In contrast to several other systems, we find little evidence that photoreceptors, including phytochromes, play an important role in local adaptation. Our results additionally show that detecting local adaptation is sensitive to the analytical approaches used and that model-based significance thresholds should be viewed with caution.
New Law May Be Having Some Effect on Publication Bias
Authors: R. S. Tuma
Journal: JNCI Journal of the National Cancer Institute (2010)

P ositive trials get reported more often than negative trials, according to many studies. And despite efforts in the past decade to combat publication bias, it remains a substantial problem, according to two articles published last fall. One found that results had been published from fewer than half of the trials registered in the federal database, clinicaltrials.gov. The second article found that approximately one-third of the trials eventually published in journals changed the trial endpoint prior to publication. Despite the disconcerting results, experts are cautiously optimistic that a federal law may be having an effect. The law requires not only registration of trials but also that researchers enter results into the database. Journal policies had previously encouraged trial registration, but the new law adds clout. “The only way trial registration was going to have an effect was if someone was going to enforce it, and this is the enforcement that is needed. I think it could well address publication bias,” said Virginia Barbour, M.D., chief editor of the open-access journal PLoS Medicine, in the Public Library of Science in London. Although experts look forward to evaluating the infl uence of the law, no one — including Barbour — expects that it can entirely cure the problem. Other efforts are needed, experts say, including increased scrutiny of trial protocols and registration information during the peer-review process.
Randomized, Controlled Trial of a Sustained Delivery Formulation of 5-Fluorouracil for the Treatment of Failing Blebs
Authors: Arun Kumar Narayanaswamy, Kelvin Lee, Ma Zhen, Jocelyn Chua, Shu Ming Chai, Pui Yi Boey, Ce Zheng, Tin Aung, Subramanian Venkatraman, Tina Tzee Ling Wong
Journal: Ophthalmology (2011)
A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β
Authors: Jeffrey J. Iliff, Minghuan Wang, Yonghong Liao, Benjamin A. Plogg, Weiguo Peng, Georg A. Gundersen, Helene Benveniste, G. Edward Vates, Rashid Deane, Steven A. Goldman, Erlend A. Nagelhus, Maiken Nedergaard
Journal: Science Translational Medicine (2012)

Cerebrospinal fluid flows through channels around brain blood vessels that are bounded by astrocytic endfeet, mediated by water transport through aquaporin-4.
HBsAg Carrier Status and the Association Between Gestational Diabetes With Increased Serum Ferritin Concentration in Chinese Women
Authors: Terence T. Lao, Ka-Yu Tse, Louis Y. Chan, Kar-Fai Tam, Lai-Fong Ho
Journal: Diabetes Care (2003)

To determine whether the high prevalence of hepatitis B surface antigen (HBsAg) carriage in our population can explain the previous observation of an association between increased maternal serum ferritin concentration and gestational diabetes in Hong Kong Chinese women.A retrospective study was performed on 767 nonanemic women with singleton pregnancy who had iron status assessed at 28-30 weeks. The result of the routine antenatal HBsAg screening was retrieved from patient records. The HBsAg-positive and -negative groups were compared for maternal characteristics, prevalence of gestational diabetes in the third trimester, prevalence of high serum ferritin and iron concentrations, and transferrin saturation, which is defined as a value in the highest quartile established by the measurements obtained from the HBsAg-negative group.The incidences of oral glucose tolerance test and gestational diabetes were significantly increased in the HBsAg-positive group. The HBsAg-positive women with gestational diabetes had significantly increased prevalence of high serum ferritin compared with the HBsAg-negative women, irrespective of the latter's gestational diabetes status. Multiple logistic regression analysis confirmed the independent association between HBsAg carrier status with gestational diabetes (relative risk 3.51, 95% CI 1.83-6.73) but excluded high ferritin as an independent factor.Our results indicate that maternal HBsAg carriage could explain in part the association between increased serum ferritin concentration with gestational diabetes in Hong Kong Chinese women, and that HBsAg carrier status is an independent risk factor for gestational diabetes.
Tolerance to endotoxin-induced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome.
Authors: C E McCall, L M Grosso-Wilmoth, K LaRue, R N Guzman, S L Cousart
Journal: Journal of Clinical Investigation (1993)

The induction of genes of host cells stimulated by microbial products such as endotoxin and the tolerance of cells to endotoxin excitation play critical roles in the pathogenesis of microbial-induced acute disseminated inflammation with multiorgan failure (the sepsis syndrome). One gene that is induced in phagocytic cells by endotoxin and that appears to play an essential role in the pathogenesis of the sepsis syndrome is IL-1 beta. We report here that blood neutrophils (PMN) of patients with the sepsis syndrome (sepsis PMN) are consistently tolerant to endotoxin-induced expression of the IL-1 beta gene, as determined by decreased synthesis of the IL-1 beta protein and reductions in IL-1 beta mRNA. This down-regulation of the IL-1 beta gene in sepsis PMN occurs concomitant with an upregulation in the constitutive expression of the type 2 IL-1 receptor (IL-1R2). These phenotypic changes do not persist in PMN of patients recovering from the sepsis syndrome. Tolerance has stimulus and response specificity since sepsis PMN tolerant to endotoxin can respond normally to Staphylococcus aureus stimulation of IL-1 beta production and they normally secrete elastase. Uninfected patients with severe trauma or shock from causes are not tolerant to endotoxin and tolerance is not limited to patients infected with Gram-negative bacteria. The mechanism responsible for tolerance involves pretranslational events and is not due to loss of the CD14 surface protein, a receptor required for endotoxin induction of IL-1 beta in PMN. The physiological significance of the tolerance to endotoxin and increased expression of IL-1R2 on sepsis PMN is unknown, but may represent an attempt by the host to protect itself from the deleterious effects of disseminated inflammation.
Protection against graft vs. host-associated immunosuppression in F1 mice. I. Activation of F1 regulatory cells by host-specific anti-major histocompatibility complex antibodies.
Authors: U Hurtenbach, D H Sachs, G M Shearer
Journal: The Journal of Experimental Medicine (1981)

Injection of parental spleen cells into unirradiated F1 hybrid mice results in suppression of the potential to generate cytotoxic T lymphocyte (CTL) responses in vitro. In an attempt to protect the F1 mice from immunosuppression, the recipients were injected with antibodies specific for major histocompatibility complex (MHC)-encoded antigens of the F1 mice 24 h before inoculation of the parental spleen cells. 8-14 d later, the generation of CTL responses in vitro against H-2 alloantigens was tested. Alloantiserum directed against either parental haplotype of the F1 strain markedly diminished the suppression of CTL activity. Furthermore, monoclonal antibodies recognizing H-2 or Ia antigens protected the F2 mice from parental spleen cell-induced suppression. Although this study has been limited to reagents that recognize host H-2 determinants, these findings do not necessarily imply that protection against graft vs. host (GvH) can be achieved only with anti-MHC antibodies. However, protection was observed only by antibodies reactive with F1 antigens, and small amounts of the alloantibodies were sufficient to diminish CTL suppression. Adoptive transfer of spleen cells from syngeneic F1 mice treated with anti-h-2a alloantiserum 24 h previously provided protection equal to that of injection of the recipients with alloantibodies. The cells necessary for this effect were shown to be T cells and to be radiosensitive to 2000 rad. This cell population is induced by antisera against F1 cell surface antigens and effectively counteracts GvH-associated immuno-suppression.
Association of Endogenous Sex Hormones With Diabetes andImpaired Fasting Glucose in Men
Authors: Laura A. Colangelo, Pamela Ouyang, Kiang Liu, Peter Kopp, Sherita Hill Golden, Adrian S. Dobs, Moyses Szklo, Dhananjay Vaidya, Mary Cushman, Susan M. Gapstur
Journal: Diabetes Care (2009)

OBJECTIVE To assess associations of sex hormones with impaired fasting glucose (IFG) and type 2 diabetes in men. RESEARCH DESIGN AND METHODS A total of 3,156 African American, Non-Hispanic white, Hispanic, and Chinese-American men aged 45–84 years who participated in the baseline visit of the Multi-Ethnic Study of Atherosclerosis (MESA) were included. Oddsratios and95% CIs for type 2 diabetes and IFG compared with normal fasting glucose for quartiles of hormones were estimated. RESULTS After adjusting for age, ethnicity, BMI, and waist circumference, IFG and diabetes were associated inversely with total testosterone and sex hormone–binding globulin (SHBG) and positively with estradiol (E2). Dehydroepiandrosterone was positively associated with IFG but not with diabetes. Associations did not differ across ethnic groups. CONCLUSIONS Regardless of obesity, total testosterone and SHBG were associated inversely and E2 was associated positively with IFG and diabetes in men. Further research is warranted to better understand the underlying biological mechanisms.
Effect of Gastric Volume or Emptying on Meal-Related Symptoms After Liquid Nutrients in Obesity: A Pharmacologic Study
Authors: Silvia Delgado-Aros, Michael Camilleri, E Janet Castillo, Filippo Cremonini, Debra Stephens, Irene Ferber, Kari Baxter, Duane Burton, Alan R Zinsmeister
Journal: Clinical Gastroenterology and Hepatology (2005)
Phosphoinositide 3-Kinase Mutations in Breast Cancer: A “Good” Activating Mutation?
Authors: Serena Di Cosimo, José Baselga
Journal: Clinical Cancer Research (2009)

Abstract Gain-of-function mutations in the catalytic subunit of phosphoinositide-3-kinase (PI3KCA) occur frequently in breast cancer. Kalinsky and colleagues show that PI3KCA mutations are associated with favorable clinicopathologic features and better clinical outcome, including survival. These findings will have to be considered in the design and interpretation of clinical trials with inhibitors of the PI3K pathway. (Clin Cancer Res 2009;15(16):5017–9)
Targeted Therapy for Chronic Lymphocytic Leukemia: A Glimpse Into the Future
Authors: Peter Hillmen
Journal: Journal of Clinical Oncology (2011)

ning of a revolution in the treatment of CLL, with a series of small molecules in various stages of clinical development that target novel aspects of CLL biology. This progress results from a better understanding of the biology of CLL, including a realization that it is often a quite proliferative disease, depends on the tissue microenvironment, and upregulates antiapoptotic pathways to avoid programmed cell death. In addition, the mechanisms by which CLL develops resistance to conventional chemotherapy are becomingbetterdefined.Theseinsightsarenowleadingtothedevelopmentofagentsthatspecificallytargetthepathophysiologyofthe disease. The logical combination of these agents promises to dramatically alter the treatment of CLL and may eventually lead to therapy that is both more effective and less toxic. The strategy of targeting Bcl-2 through navitoclax is an important first step in changing our therapeutic approach in CLL.
Characterization of the amplicon on chromosomal segment 4q12 in glioblastoma multiforme
Authors: Nikola Holtkamp, Nicolas Ziegenhagen, Elke Malzer, Christian Hartmann, Alf Giese, Andreas von Deimling
Journal: Neuro-Oncology (2007)

A subset of glioblastomas (GBMs) carry gene amplifications on chromosomal segment 4q12. To characterize this amplicon in detail, we analyzed a set of 100 samples consisting of 65 GBMs, 10 WHO grade III astrocytomas, 12 oligodendrogliomas, and 13 glioma cell cultures. We applied multiplex ligation-dependent probe amplification to determine the gene dosage of PDGFRA, KIT, and KDR and the flanking genes USP46, RASL11B, LNX1, CHIC2, SEC3L1, and IGFBP7. The amplicon was highly variable in size and copy number and extended over a region of up to 5 Mb. Amplifications on 4q12 were observed in 15% of GBMs and 23% of GBM cell cultures but not in 22 other gliomas. We analyzed transcription and translation of some genes within this amplicon. Gene amplification generally correlated with high transcript levels but did not necessarily result in increased protein levels. However, we detected frequent expression of proteins encoded by PDGFRA, KIT, and KDR in GBMs and GBM cell cultures independent of the amplification status. Future treatment of GBM patients may include drugs targeting multiple kinases that are encoded by genes on chromosomal segment 4q12.
Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro
Authors: Robert Y. M. Chen, Ros Edwards, Tim Shaw, Danni Colledge, William E. Delaney, Harriet Isom, Scott Bowden, Paul Desmond, Stephen A. Locarnini
Journal: Hepatology (2003)

Hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame that creates a stop codon, causing premature termination of the PC protein. During lamivudine treatment, drug resistance develops at a similar rate in HBeAg positive and HBeAg negative CHB. Lamivudine-resistant HBV mutants have been shown to replicate inefficiently in vitro in the absence of PC mutations, but it is unknown whether the presence of PC mutations affects replication efficiency or antiviral sensitivity. This study utilized the recombinant HBV baculovirus system to address these issues. HBV baculoviruses encoding the G1896A PC stop codon mutation were generated in wild-type (WT) and lamivudine-resistant (rtM204I and rtL180M + rtM204V) backgrounds, resulting in a panel of 6 related recombinant baculoviruses. In vitro assays were performed to compare the sensitivities of the PC mutant viruses with lamivudine and adefovir and to compare relative replication yields. The PC mutation did not significantly affect sensitivities to either adefovir or lamivudine. WT HBV and PC mutant HBV showed similar replication yields, whereas the replication yields of the lamivudine-resistant mutants were greatly reduced in HBeAg positive HBVs, confirming previous observations. However, the presence of the PC mutation was found to compensate for the replication deficiency in each of the lamivudine-resistant mutants, increasing the replication yields of each virus. In conclusion, the PC stop codon mutation appears to increase the replication efficacy of lamivudine-resistant virus but does not affect in vitro drug sensitivity.
Treatment of Children and Adolescents With Hodgkin Lymphoma Without Radiotherapy for Patients in Complete Remission After Chemotherapy: Final Results of the Multinational Trial GPOH-HD95
Authors: Wolfgang Dörffel, Ursula Rühl, Heike Lüders, Alexander Claviez, Marion Albrecht, Jos Bökkerink, Harald Holte, Jonas Karlen, Georg Mann, Heinz Marciniak, Felix Niggli, Kjeld Schmiegelow, Ernst-Wilhelm Schwarze, Richard Pötter, Lutz Wickmann, Günther Schellong
Journal: Journal of Clinical Oncology (2013)

PURPOSE To minimize the risk of late effects in pediatric Hodgkin lymphoma (HL) by omitting radiotherapy (RT) in patients in complete remission (CR) after chemotherapy and reducing the standard radiation dose to 20 Gy in patients in incomplete remission.Between 1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography or magnetic resonance imaging) did not undergo RT. Those with tumor volume reduction more than 75% received reduced involved-field RT with 20 Gy and an additional 10- or 15-Gy boost only for larger residuals.Rates of overall survival, progression-free survival (PFS), and event-free survival at 10 years were (± SE) 96.3% ± 0.6%, 88.2% ± 1.1%, and 85.4% ± 1.3%, respectively. PFS for TG1 patients without or with RT was 97.0% ± 2.1% versus 92.2% ± 1.7% (P = .214) but was unsatisfactory for nonirradiated patients in TG2 (68.5% ± 7.4% v 91.4% ± 1.9%; P < .0001), with similar but not significant results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate.RT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients with incomplete remission following chemotherapy.
Binding properties of immunoglobulin combining sites specific for terminal or nonterminal antigenic determinants in dextran.
Authors: J Cisar, E A Kabat, M M Dorner, J Liao
Journal: The Journal of Experimental Medicine (1975)

Binding constants of the dextran-reactive BALB/c mouse IgA myeloma proteins W3129 and QUPC 52 have been determined for each member of the isomaltose series of oligosaccharides and for methyl alphaDglucoside. Protein W3129 has maximum complementarity for isomaltopentaose (IM5) deltaf degrees = 7,180 cal/mol) with 55-60% of the total binding energy directed against methylalphaDglucoside. Protein QUPC 52 gives maximum binding with isomaltohexaose (IM6) (deltaF degrees = -5,340 cal/mol) and has about 70% of its total binding energy for isomaltotriose (IM3), but at most only 5% for isomaltose (IM2) or methyl alphaDglucoside. Protein W3129 precipitates with branched dextrans high in alpha (1 yields 6) linkages and reacts with but does not precipitate a synthetic alpha (1 yields 6)-linked linear dextran. Protein QUPC 52 precipitates both branched and linear dextrans. Thus, the immunodominant group for protein W3129 is mimicked by methyl alphaDglucoside and this protein reacts exclusively at the terminal nonreducing ends of alpha (1 yields 6)-linked dextran chains. Protein QUPC 52 has an immunodominant group which is expressed by IM3 but not smaller oligosaccharides and this protein can react at nonterminal locations along alpha (1 yields 6)-linked dextran chains. Precipitation of linear dextran seems to be a valid although not quantitative assay for antidextrans with nonterminal specificity. Quantitative precipitin reactions with branched and linear dextrans suggest that alpha (1 yields 6)-specific human antidextrans are mixtures of molecules having terminal and nonterminal specificities and that the fraction of each type can vary among individuals. Rabbit antisera against IM3 or IM6 coupled to bovine serum albumin also appear to contain antibodies with nonterminal specificity for dextran chains although a large fraction has terminal specificity. Low molecular weight clinical dextran N-150N (congruent to 60,000) reacted more like linear dextran than like its parent native-branched dextran B512. This is thought to result from an abundance of nonterminal determinants in clinical dextran N-150N but a very small number of functional terminal determinants per molecule. An appreciation of terminal and nonterminal specificities and of the different immunodominant structures in isomaltosyl chains has proven to be of a great value in understanding the immunochemical reactions of dextrans. Moreover, certain previous findings with fructosan-reactive mouse myeloma proteins and human antilevans (55, 84) also suggest terminal and nonterminal specificities for levan chains.
Antiangiogenic Effect of Interleukin-10 in Ischemia-Induced Angiogenesis in Mice Hindlimb
Authors: Jean-Sébastien Silvestre, Ziad Mallat, Micheline Duriez, Radia Tamarat, Michel F. Bureau, Daniel Scherman, Nicolas Duverger, Didier Branellec, Alain Tedgui, Bernard I. Levy
Journal: Circulation Research (2000)

Abstract —Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reaction is modulated by production of anti-inflammatory cytokines. This study examined the potential role of a major anti-inflammatory cytokine, interleukin (IL)–10, on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by artery femoral occlusion in both C57BL/6J IL-10 +/+ and IL-10 –/– mice. After 28 days, angiogenesis was quantified by microangiography, capillary, and arteriole density measurement and laser Doppler perfusion imaging. The protein levels of IL-10 and vascular endothelial growth factor (VEGF) were determined by Western blot analysis in hindlimbs. IL-10 was markedly expressed in the ischemic hindlimb of IL-10 +/+ mice. Angiogenesis in the ischemic hindlimb was significantly increased in IL-10 –/– compared with IL-10 +/+ mice. Indeed, angiographic data showed that vessel density in the ischemic leg was 10.2±0.1% and 5.7±0.4% in IL-10 –/– and IL-10 +/+ mice, respectively ( P &lt;0.01). This corresponded to improved ischemic/nonischemic leg perfusion ratio by 1.4-fold in IL-10 –/– mice compared with IL-10 +/+ mice (0.87±0.05 versus 0.63±0.01, respectively; P &lt;0.01). Revascularization was associated with a 1.8-fold increase in tissue VEGF protein level in IL-10 –/– mice compared with IL-10 +/+ mice ( P &lt;0.01). In vivo electrotransfer of murine IL-10 cDNA in IL-10 –/– mice significantly inhibited both the angiogenic process and the rise in VEGF protein level observed in IL-10 –/– mice. No changes in vessel density or VEGF content were observed in the nonischemic hindlimb. These findings underscore the antiangiogenic effect of IL-10 associated with the downregulation of VEGF expression and suggest a role for the inflammatory balance in the modulation of ischemia-induced angiogenesis.