tbuckley/cabot-search huggingface dataset:
A Statistical Evaluation of Models for the Initial Settlement of the American Continent Emphasizes the Importance of Gene Flow with Asia
Authors: N. Ray, D. Wegmann, N.J.R. Fagundes, S. Wang, A. Ruiz-Linares, L. Excoffier
Journal: Molecular Biology and Evolution (2009)

Although there is agreement in that the Bering Strait was the entry point for the initial colonization of the American continent, there is considerable uncertainty regarding the timing and pattern of human migration from Asia to America. In order to perform a statistical assessment of the relative probability of alternative migration scenarios and to estimate key demographic parameters associated with them, we used an approximate Bayesian computation framework to analyze a data set of 401 autosomal microsatellite loci typed in 29 native American populations. A major finding is that a single, discrete, wave of colonization is highly inconsistent with observed levels of genetic diversity. A scenario with two discrete migration waves is also not supported by the data. The current genetic diversity of Amerindian populations is best explained by a third model involving recurrent gene flow between Asia and America, after initial colonization. We estimate that this colonization involved about 100 individuals and occurred some 13,000 years ago, in agreement with well-established archeological data.
Urinary Melatonin Levels, Sleep Disruption, and Risk of Prostate Cancer in Elderly Men
Authors: Lara G. Sigurdardottir, Sarah C. Markt, Jennifer R. Rider, Sebastien Haneuse, Katja Fall, Eva S. Schernhammer, Rulla M. Tamimi, Erin Flynn-Evans, Julie L. Batista, Lenore Launer, Tamara Harris, Thor Aspelund, Meir J. Stampfer, Vilmundur Gudnason, Charles A. Czeisler, Steven W. Lockley, Unnur A. Valdimarsdottir, Lorelei A. Mucci
Journal: European Urology (2014)
Development of TLR9 agonists for cancer therapy
Authors: Arthur M. Krieg
Journal: Journal of Clinical Investigation (2007)

In vertebrates, the TLRs are a family of specialized immune receptors that induce protective immune responses when they detect highly conserved pathogen-expressed molecules. Synthetic agonists for several TLRs, including TLR3, TLR4, TLR7, TLR8, and TLR9, have been or are being developed for the treatment of cancer. TLR9 detects the unmethylated CpG dinucleotides prevalent in bacterial and viral DNA but not in vertebrate genomes. As discussed in this Review, short synthetic oligodeoxynucleotides containing these immune stimulatory CpG motifs activate TLR9 in vitro and in vivo, inducing innate and adaptive immunity, and are currently being tested in multiple phase II and phase III human clinical trials as adjuvants to cancer vaccines and in combination with conventional chemotherapy and other therapies.
Contraction and Intracellular Ca <sup>2+</sup> Handling in Isolated Skeletal Muscle of Rats With Congestive Heart Failure
Authors: Per Kristian Lunde, Anders J. Dahlstedt, Joseph D. Bruton, Jan Lännergren, Peter Thorén, Ole M. Sejersted, Håkan Westerblad
Journal: Circulation Research (2001)

A decreased exercise tolerance is a common symptom in patients with congestive heart failure (CHF). This decrease has been suggested to be partly due to altered skeletal muscle function. Therefore, we have studied contractile function and cytoplasmic free Ca(2+) concentration ([Ca(2+)](i), measured with the fluorescent dye indo 1) in isolated muscles from rats in which CHF was induced by ligation of the left coronary artery. The results show no major changes of the contractile function and [Ca(2+)](i) handling in unfatigued intact fast-twitch fibers isolated from flexor digitorum brevis muscles of CHF rats, but these fibers were markedly more susceptible to damage during microdissection. Furthermore, CHF fibers displayed a marked increase of baseline [Ca(2+)](i) during fatigue. Isolated slow-twitch soleus muscles of CHF rats displayed slower twitch contraction and tetanic relaxation than did muscles from sham-operated rats; the slowing of relaxation became more pronounced during fatigue in CHF muscles. Immunoblot analyses of sarcoplasmic reticulum proteins and sarcolemma Na(+),K(+)-ATPase showed no difference in flexor digitorum brevis muscles of sham-operated versus CHF rats. In conclusion, functional impairments can be observed in limb muscle isolated from rats with CHF. These impairments seem to mainly involve structures surrounding the muscle cells and sarcoplasmic reticulum Ca(2+) pumps, the dysfunction of which becomes obvious during fatigue.
Work-related changes in peak expiratory flow among laboratory animal workers
Authors: A Hollander, D Heederik, B Brunekreef
Journal: European Respiratory Journal (1998)

Laboratory animal workers are at risk of developing allergic symptoms, of which asthmatic symptoms are the most severe. The aim was to study the relationship between allergic symptoms due to working with rats and variability and changes in peak expiratory flow (PEF). Several indices were used on the basis of the amplitude of the PEF or the differences in PEF between days with and without exposure to rat aeroallergens. Of the 398 rat workers, 73% completed PEF readings on at least 9 days, of whom 208 had PEF readings on working days with and without contact with animals. The overall prevalence rate of allergic symptoms (asthmatic, eye, nose and/or skin) among rat workers during the handling of rats was 17.3%. Asthmatic symptoms were reported by 6.7%. The PEF of the workers who reported asthmatic symptoms due to working with rats decreased significantly on days working with the animals (difference between the minimum PEF averaged over working days with animals and over days without animals (deltaPEFmin-min) = -73 L x min(-1)), compared to the workers without symptoms (2.2 L x min(-1)). This effect was more pronounced among workers with a late asthmatic response, i.e. the presence of asthmatic symptoms several hours after working with rats (deltaPEFmin-min = -11.6 L x min(-1)). Multiple regression analyses showed that only those with asthmatic symptoms several hours after working with rats and those with allergic symptoms had an increased deltaPEFmin-min. In addition, workers with asthmatic symptoms were also more likely to have a higher PEF variability than workers without asthmatic symptoms. However, no difference in PEF variability between days with and without animals contact was observed. This study shows that the peak expiratory flow of workers who reported asthmatic symptoms due to working with rats decreased significantly on days working with laboratory animals.
International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology
Authors: Anthony L. Gotter, Andrea L. Webber, Paul J. Coleman, John J. Renger, Christopher J. Winrow
Journal: Pharmacological Reviews (2012)

Orexin signaling is essential for normal regulation of arousal and behavioral state control and represents an attractive target for therapeutics combating insomnia. Alternatively termed hypocretins, these neuropeptides were named to reflect sequence similarity to incretins and their potential to promote feeding. Current nomenclature reflects these molecular and biochemical discovery approaches in which <i>HCRT</i>, <i>HCRTR1</i>, and <i>HCRTR2</i> genes encode prepro-orexin, the orexin 1 receptor (OX<sub>1</sub>) and the orexin 2 receptor (OX<sub>2</sub>)—gene names designated by the Human Genome Organization and receptor names designated by the International Union of Basic and Clinical Pharmacology. Orexinergic neurons are most active during wakefulness and fall silent during inactive periods, a prolonged disruption in signaling most profoundly resulting in hypersomnia and narcolepsy. <i>Hcrtr2</i> mutations underlie the etiology of canine narcolepsy, deficiencies in orexin-producing neurons are observed in the human disorder, and ablation of mouse orexin neurons or the <i>Hcrt</i> gene results in a narcolepsy-cataplexy phenotype. The development of orexin receptor antagonists and genetic models targeting components of the orexin pathway have elucidated the OX<sub>2</sub> receptor-specific role in histamine-mediated arousal and the contribution of both receptors in brainstem pathways involved in vigilance state gating. Orexin receptor antagonists of varying specificity uncovered additional roles beyond sleep and feeding that include addiction, depression, anxiety, and potential influences on peripheral physiology. Combined genetic and pharmacological approaches indicate that orexin signaling may represent a confluence of sleep, feeding, and reward pathways. Selective orexin receptor antagonism takes advantage of these properties toward the development of novel insomnia therapeutics.
Cyclin D1–Specific Cytotoxic T Lymphocytes Are Present in the Repertoire of Cancer Patients: Implications for Cancer Immunotherapy
Authors: Eisei Kondo, Britta Maecker, Martin R. Weihrauch, Claudia Wickenhauser, WanYong Zeng, Lee M. Nadler, Joachim L. Schultze, Michael S. von Bergwelt-Baildon
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Cyclin D1, a key cell cycle regulator, is overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for cancer immunotherapy. Nevertheless, it had previously been suggested that efficient T cells recognizing cyclin D1-derived epitopes are absent from the repertoire because of thymic deletion. We attempted to induce autologous CTL from healthy donors and patients with cyclin D1-overexpressing tumors using a highly efficient T-cell expansion system based on CD40-activated B cells as antigen-presenting cells. Experimental Design: Cyclin D1-derived, HLA-A*0201–restricted epitopes were predicted by multiple computer algorithms, screened in HLA-A2-binding assays, and used for T-cell stimulation. The generated CTL lines and clones were analyzed by IFN-γ enzyme-linked immunosorbent spot assay or cytolysis assay. Results: After screening, at least two naturally processed and presented HLA-A*0201–binding cyclin D1 epitopes were identified. CTL specific for these epitopes could be successfully generated from HLA-A2+ donors. T cells efficiently recognized target cells pulsed with the cognate peptide and cyclin D1-expressing tumor cell lines in an HLA-A*0201–restricted manner. More importantly, HLA-A*0201–matched, primary cyclin D1+ tumor cells were efficiently recognized by cyclin D1-specific CTL. These CTL could be generated from patients with mantle cell lymphoma and cyclin D1+ colon cancer. Conclusions: These results underscore that cyclin D1 needs to be considered as a target for broad-based antitumor immunotherapy.
Ecological Transition Predictably Associated with Gene Degeneration
Authors: Carolyn A. Wessinger, Mark D. Rausher
Journal: Molecular Biology and Evolution (2014)

Gene degeneration or loss can significantly contribute to phenotypic diversification, but may generate genetic constraints on future evolutionary trajectories, potentially restricting phenotypic reversal. Such constraints may manifest as directional evolutionary trends when parallel phenotypic shifts consistently involve gene degeneration or loss. Here, we demonstrate that widespread parallel evolution in Penstemon from blue to red flowers predictably involves the functional inactivation and degeneration of the enzyme flavonoid 3′,5′-hydroxylase (F3′5′H), an anthocyanin pathway enzyme required for the production of blue floral pigments. Other types of genetic mutations do not consistently accompany this phenotypic shift. This pattern may be driven by the relatively large mutational target size of degenerative mutations to this locus and the apparent lack of associated pleiotropic effects. The consistent degeneration of F3′5′H may provide a mechanistic explanation for the observed asymmetry in the direction of flower color evolution in Penstemon: Blue to red transitions are common, but reverse transitions have not been observed. Although phenotypic shifts in this system are likely driven by natural selection, internal constraints may generate predictable genetic outcomes and may restrict future evolutionary trajectories.
Phase II trial of branched peginterferon-α 2a (40 kDa) for patients with advanced renal cell carcinoma
Authors: R.J. Motzer, A. Rakhit, J. Thompson, H. Gurney, P. Selby, R. Figlin, S. Negrier, S. Ernst, M. Siebels, M. Ginsberg, K. Rittweger, L. Hooftman
Journal: Annals of Oncology (2002)
Risk factors for elevated liver function tests (eLFTs) in patients with pulmonary arterial hypertension (PAH) treated with sitaxentan and followed in a European safety registry
Authors: Lie-Ju Hwang, John Teeter, Michael Louie, Henrik Toft Sørensen, Cynthia de Luise
Journal: European Respiratory Journal (2011)

Background:  Endothelin receptor antagonists, including sitaxentan (Thelin®), treat PAH but may cause hepatoxocity. The Thelin Outcomes for Patient Surveillance (TOPS) safety registry monitored prespecified events in European patients (pts).   Aim:  Describe risk factors for eLFTs in TOPS pts.   Methods:  Sites entered data for eligible pts monthly from baseline to discontinuation; eLFTs were defined as ALT or AST levels >3xULN. Logistic regression assessed effects on subsequent eLFTs of: treatment exposure (mo), age (by 10-y periods), functional class (III/IV vs I/II), etiology (idiopathic vs associated, and presence or absence of each variable: female sex; Caucasian race; prior PAH therapy failure; previous bosentan or ambrisentan; concomitant sildenafil or tadalafil; or baseline LFT elevation. Cox regression assessed time to eLFTs using the same factors.   Results:  Of 932 pts, AST or ALT was  P  P  P    Conclusions:  4.9% of pts receiving sitaxentan had e LFTs during followup; age, treatment exposure, and baseline eLFTs were significantly associated with eLFTs during followup.
Concordance between airway inflammation and health status in COPD patients with bacterial colonisation
Authors: Richa Singh, Alex Mackay, Anant Patel, Beverly Kowlessar, Davinder Garcha, Simon Brill, Ray Sapsford, Louise Donnelly, Peter Barnes, Gavin Donaldson, Jadwiga Wedzicha
Journal: European Respiratory Journal (2013)

Lower airway bacterial colonisation (LABC) is often seen in stable COPD patients, contributing to airway inflammation & health status impairment. We examined whether the degree of airway inflammation was related to health status measurements.  Sputa collected from stable patients were analysed using qPCR to detect typical bacteria & ELISAs for airway cytokines. 99 patients completed 112 COPD Assessment Tests (CAT) and 74 St George’s Respiratory Questionnaires (SGRQ).  Clinical characteristics are shown in Table 1.  Airway inflammation was significantly higher LABC patients. Increasing CAT score was significantly related to higher total SGRQ (p  There was no significant relationship between increasing CAT score, SGRQ & airway cytokines.  In this COPD cohort, despite increased airway inflammation in LABC patients, no difference was seen in CAT or total SGRQ scores compared to patients without LABC. There was discordance between these symptoms & health status scores & levels of airway inflammation. Improvement of health status may require improving symptoms rather than solely targeting airway inflammation.
It is not evolutionary models, but models in general that social science needs
Authors: Bruce Bridgeman
Journal: Behavioral and Brain Sciences (2006)

Mathematical models are potentially as useful for culture as for evolution, but cultural models must have different designs from genetic models. Social sciences must borrow from biology the idea of modeling, rather than the structure of models, because copying the product is fundamentally different from copying the design. Transfer of most cultural information from brains to artificial media increases the differences between cultural and biological information.
Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability
Authors: Liran I. Shlush, Noa Chapal-Ilani, Rivka Adar, Neta Pery, Yosef Maruvka, Adam Spiro, Roni Shouval, Jacob M. Rowe, Maty Tzukerman, Dani Bercovich, Shai Izraeli, Guido Marcucci, Clara D. Bloomfield, Tsila Zuckerman, Karl Skorecki, Ehud Shapiro
Journal: Blood (2012)
Profiling of Genetic Variations in Inflammation Pathway Genes in Relation to Bladder Cancer Predisposition
Authors: Hushan Yang, Jian Gu, Xin Lin, H. Barton Grossman, Yuanqing Ye, Colin P. Dinney, Xifeng Wu
Journal: Clinical Cancer Research (2008)

Compelling evidence has indicated that inflammation plays an important role in cancer development. We sought to test the hypothesis that common sequence variants in the inflammation pathway modulate bladder cancer risk.We genotyped 59 potentially functional single nucleotide polymorphisms from 35 candidate inflammation genes in a case-control study including 635 Caucasian bladder cancer patients and 635 matched controls.The most significant finding was in the 3'-untranslated region of PTGS2 (exon10+837T>C, rs5275), which was associated with a significantly reduced risk (odds ratio, 0.68; 95% confidence interval, 0.54-0.87; P=0.002) and remained significant after multiple comparison adjustment. Consistently, the most common PTGS2 haplotype containing the common allele of exon10+837T>C was associated with a significantly increased risk (odds ratio, 1.27; 95% confidence interval, 1.06-1.52; P=0.008). In contrast, the haplotypes containing at least one variant allele of exon10+837T>C were all associated with a decreased risk. In a combined analysis to assess the cumulative effects of inflammation single nucleotide polymorphisms on bladder cancer risk, we found that in the anti-inflammation pathway, but not in the proinflammation pathway, when compared with individuals with a few adverse alleles, individuals with more adverse alleles had a significantly increased risk in a dose-dependent manner (P(trend)=0.012). To further elucidate the functional mechanism of these associations, we redefined the adverse alleles based on literature-reported functional results and found that individuals with a higher number of inflammation-enhancing alleles in the anti-inflammation pathway exhibited a greater bladder cancer risk.Our results strongly suggest that common variants in inflammation genes affect bladder cancer susceptibility individually and jointly.
Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia‐reperfusion injury
Authors: Peter van der Meer, Erik Lipsic, Robert H. Henning, Rudolf A. de Boer, Albert J.H. Suurmeijer, Dirk J. van Veldhuisen, Wiek H. van Gilst
Journal: European Journal of Heart Failure (2004)
Implementing Guidelines for Cancer Pain Management: Results of a Randomized Controlled Clinical Trial
Authors: Stuart L. Du Pen, Anna R. Du Pen, Nayak Polissar, Jennifer Hansberry, Beth Miller Kraybill, Mark Stillman, Joan Panke, Rebecca Everly, Karen Syrjala
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Pain and symptom management is an integral part of the clinical practice of oncology. A number of guidelines have been developed to assist the clinician in optimizing comfort care. We implemented clinical guidelines for cancer pain management in the community setting and evaluated whether these guidelines improved care. PATIENTS AND METHODS: Eighty-one cancer patients, aged 37 to 76 years, were enrolled onto a prospective, longitudinal, randomized controlled study from the outpatient clinic settings of 26 western Washington–area medical oncologists. A multilevel treatment algorithm based on the Agency for Health Care Policy and Research Guidelines for Cancer Pain Management was compared with standard-practice (control) pain and symptom management therapies used by community oncologists. The primary outcome of interest was pain (Brief Pain Inventory); secondary outcomes of interest were all other symptoms (Memorial Symptom Assessment Scale) and quality of life (Functional Assessment of Cancer Therapy Scale). RESULTS: Patients randomized to the pain algorithm group achieved a statistically significant reduction in usual pain intensity, measured as slope scores, when compared with standard community practice (P &lt; .02). Concurrent chemotherapy and patient adherence to treatment were significant mediators of worst pain. There were no significant differences in other symptoms or quality of life between the two treatment groups. CONCLUSION: This guideline implementation study supports the use of algorithmic decision making in the management of cancer pain. These findings suggest that comprehensive pain assessment and evidence-based analgesic decision-making processes do enhance usual pain outcomes.
Phylogeny of Eukaryotes Based on Ribosomal RNA: Long-Branch Attraction and Models of Sequence Evolution
Authors: Hervé Philippe* and, Agnès Germot
Journal: Molecular Biology and Evolution (2000)

The molecular phylogeny of eukaryotes was first based on the comparison of the small-subunit ribosomal RNA (SSU rRNA) and quickly became a paradigm (Sogin 1991). However, serious criticisms have recently been raised against it. In particular, it has been suggested that the various protist lineages that emerged first (e.g., microsporidia, trichomonads, mycetozoans) were misplaced because of the long-branch attraction (LBA) artifact (Philippe and Adoutte 1998; Philippe and Laurent 1998; Germot and Philippe 1999; Moreira, Le Guyader, and Philippe 1999; Roger et al. 1999; Stiller and Hall 1999). Indeed, simulation studies (unpublished data) showed that when a distant outgroup was used, all the standard methods of phylogenetic reconstruction artifactually inferred a phylogeny with an asymmetrical base containing the fast-evolving lineages, leading to a tree shape very similar to the rRNA one. When the substitution rates are considerably variable for different lineages, the use of a model that reflects the actual substitution probability is of utmost importance for obtaining a correct tree topology (Lockhart et al. 1994; Swofford et al. 1996; Yang 1996; Takezaki and Gojobori 1999). In the case of rRNA-based eukaryotic phylogeny, the first model violation noticed was the variation of G 1 C content among species (Hasegawa and Hashimoto 1993). Yet, the overall picture of the rRNA tree remained unchanged when only species with similar G 1 C contents were included (Leipe et al. 1993) or when methods less sensitive to this bias, such as transversion parsimony (Woese et al. 1991) or logDet distance (Lockhart et al. 1994), were applied. Variation in evolutionary rates across sites (RAS) is a further complexity of sequence evolution which also has a significant effect on evolutionary tree building (Olsen 1987; Yang 1996). For instance, the late emergence of fast-evolving lineages such as the nucleomorph of chloroarachniophytes (Van de Peer et al. 1996) or microsporidia (Peyretaillade et al. 1998) can be retrieved only when RAS models are assumed. Finally, the existence of covarion structure constitutes a further model violation that has just begun to be considered (Lockhart et al. 1998; Lopez, Forterre, and Philippe 1999). In this study, we sequenced the complete large-subunit (LSU) rRNA of Trichomonas vaginalis. We con-