tbuckley/cabot-search huggingface dataset:
A Phase I Study of 17-Allylamino-17-Demethoxygeldanamycin Combined with Paclitaxel in Patients with Advanced Solid Malignancies
Authors: Suresh S. Ramalingam, Merrill J. Egorin, Ramesh K. Ramanathan, Scot C. Remick, Rachel P. Sikorski, Theodore F. Lagattuta, Gurkamal S. Chatta, David M. Friedland, Ronald G. Stoller, Douglas M. Potter, S. Percy Ivy, Chandra P. Belani
Journal: Clinical Cancer Research (2008)

Abstract Background: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel. Methods: Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1. Results: Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 ± 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 ± 0.51. Conclusions: The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.
Normative health-related fitness values for children: analysis of 85347 test results on 9–17-year-old Australians since 1985
Authors: Mark J Catley, Grant R Tomkinson
Journal: British Journal of Sports Medicine (2011)

Objectives To provide sex- and age-specific normative values for health-related fitness of 9–17-year-old Australians. Methods A systematic literature search was undertaken to identify peer-reviewed studies reporting health-related fitness data on Australian children since 1985—the year of the last national fitness survey. Only data on reasonably representative s amples of apparently healthy (free from known disease or injury) 9–17-year-old Australians, who were tested using field tests of health-related fitness, were included. Both raw and pseudo data (generated using Monte Carlo simulation) were combined with sex- and age-specific normative centile values generated using the Lambda Mu and Sigma (LMS) method. Sex- and age-related differences were expressed as standardised effect sizes. Results Normative values were displayed as tabulated percentiles and as smoothed centile curves for nine health-related fitness tests based on a dataset comprising 85347 test performances. Boys typically scored higher than girls on cardiovascular endurance, muscular strength, muscular endurance, speed and power tests, but lower on the flexibility test. The magnitude of the age-related changes was generally larger for boys than for girls, especially during the teenage years. Conclusion This study provides the most up-to-date sex- and age-specific normative centile values for the health-related fitness of Australian children that can be used as benchmark values for health and fitness screening and surveillance systems.
NICE calls for end to "postcode lottery" of fertility treatment
Authors: J. Wise
Journal: BMJ (2014)

<h3>Abstract</h3> The bilaterally symmetric animals (Bilateria) are considered to comprise two monophyletic groups, Protostomia and Deuterostomia. Protostomia contains the Ecdysozoa and the Lophotrochozoa; Deuterostomia contains the Chordata and the Xenambulacraria (Hemichordata, Echinodermata and Xenacoelomorpha). Their names refer to a supposed distinct origin of the mouth (stoma) in the two clades, but these groups have been differentiated by other embryological characters including embryonic cleavage patterns and different ways of forming their mesoderm and coeloms. Deuterostome monophyly is not consistently supported by recent studies. Here we compare support for Protostomia and Deuterostomia using five recently published, phylogenomic datasets. Protostomia is always strongly supported, especially by longer and higher quality genes. Support for Deuterostomia is always equivocal and barely higher than support for paraphyletic alternatives. Conditions that can cause tree reconstruction errors - inadequate models, short internal branch, faster evolving genes, and unequal branch lengths - correlate with statistical support for monophyletic deuterostomes. Simulation experiments show that support for Deuterostomia could be explained by systematic error. A survey of molecular characters supposedly diagnostic of deuterostomes shows many are not valid synapomorphies. The branch between bilaterian and deuterostome common ancestors, if real, is very short. This finding fits with growing evidence suggesting the common ancestor of all Bilateria had many deuterostome characteristics. This finding has important implications for our understanding of early animal evolution and for the interpretation of some enigmatic Cambrian fossils such as vetulicolians and banffiids.
Cooperative interaction of factor B and other complement components with mononuclear cells in the antibody-independent lysis of xenogeneic erythrocytes.
Authors: R E Hall, R M Blaese, A E Davis, J M Decker, B F Tack, H R Colten, A V Muchmore
Journal: The Journal of Experimental Medicine (1982)

Synergistic cytotoxicity is a term used to describe a cytotoxic system in which xenogeneic erythrocyte target cells are lysed in the presence of nonimmune human mononuclear effector cells and antibody-depleted normal human serum. Neither the mononuclear cells nor the serum alone are cytolytic to the target erythrocytes. Previous studies have shown that the serum activity is not immunoglobulin and is heat-labile, suggesting a similarity to serum complement. In this report, sera deficient in various complement components as well as highly purified single complement components were tested with whole mononuclear cell populations and purified monocytes and lymphocytes to further characterize this cytotoxicity system. Whole mononuclear cell populations failed to mediate target cell lysis in sera deficient in C5 or factor B. However, C3-deficient serum, even in the presence of anti-C3 antibody, supported synergistic cytotoxicity normally. Purified lymphocytes were also normally cytotoxic in C3-deficient serum but failed to lyse targets in sera deficient in C5, C7, C8, or depleted of factor B. Purified monocytes failed to lyse the target cells only in factor B-depleted serum and could lyse the target cells in serum-free medium when purified factor B alone was added. Monocyte-mediated cytotoxicity induced by factor B was inhibited 73-100% by adding lymphocytes back to the purified monocytes. Thus, both lymphocytes and monocytes can serve as effector cells in this form of cytotoxicity but require cooperative interaction with different sets of complement components. In addition, lymphocytes can modulate the monocyte-mediated form of target cell lysis associated with factor B.
The Neural Basis of Empathy
Authors: Boris C. Bernhardt, Tania Singer
Journal: Annual Review of Neuroscience (2012)

Empathy--the ability to share the feelings of others--is fundamental to our emotional and social lives. Previous human imaging studies focusing on empathy for others' pain have consistently shown activations in regions also involved in the direct pain experience, particularly anterior insula and anterior and midcingulate cortex. These findings suggest that empathy is, in part, based on shared representations for firsthand and vicarious experiences of affective states. Empathic responses are not static but can be modulated by person characteristics, such as degree of alexithymia. It has also been shown that contextual appraisal, including perceived fairness or group membership of others, may modulate empathic neuronal activations. Empathy often involves coactivations in further networks associated with social cognition, depending on the specific situation and information available in the environment. Empathy-related insular and cingulate activity may reflect domain-general computations representing and predicting feeling states in self and others, likely guiding adaptive homeostatic responses and goal-directed behavior in dynamic social contexts.
Accidental carotid artery injury caused by a horse rope
Authors: L Nunnink, F Abu-Zidan
Journal: British Journal of Sports Medicine (2003)

A 37 year old woman who had bred horses for more than 20 years was leading two horses in a horse corral. One horse bolted and the lead rope wrapped around her neck. Four hours after the accident, she developed sudden aphasia, right facial palsy, and right arm weakness. Conventional and magnetic resonance angiography showed complete traumatic occlusion of the left common carotid artery due to thrombosis at the C6/7 level. There was good collateral flow from the other side. The patient was maintained on heparin followed by warfarin and recovered completely by the third day. This case shows the importance of suspecting vascular injury and thrombosis after trauma to sites of major vessels.
New Potential Ligand-Receptor Signaling Loops in Ovarian Cancer Identified in Multiple Gene Expression Studies
Authors: Giancarlo Castellano, James F. Reid, Paola Alberti, Maria Luisa Carcangiu, Antonella Tomassetti, Silvana Canevari
Journal: Cancer Research (2006)

Abstract Based on the hypothesis that gene products involved in the same biological process would be coupled at transcriptional level, a previous study analyzed the correlation of the gene expression patterns of ligand-receptor (L-R) pairs to discover potential autocrine/paracrine signaling loops in different cancers (Graeber and Eisenberg. Nat Genet 2001; 29:295). By refining the starting database, a list of 511 L-R pairs was compiled, combined to eight data sets from a single pathology, epithelial ovarian cancer, and examined as a proof-of-principle of the statistical and biological validity of the correlation of the L-R gene expression patterns in cancer. Analysis revealed a Bonferroni-corrected significant correlation of 105 L-R pairs in at least one data set and, by systematic analysis, identified 39 more frequently correlated L-R pairs, 7 of which were already biologically confirmed. In four data sets examined for an L-R correlation associated with patient survival time, 15 L-R pairs were significantly correlated in short surviving patients in two of the data sets. Immunohistochemical analysis of one of the newly identified correlated L-R pairs (i.e., EFNB3-EPHB4) revealed the correlated expression of ephrin-B3 and EphB4 proteins in 45 of 55 epithelial ovarian tumor samples (P &amp;lt; 0.0001). Together, these data not only support the validity of cross-comparison analysis of gene expression data because known and expected correlations were confirmed but also point to the promise of such analysis in identifying new L-R signaling loops in cancer. (Cancer Res 2006; 66(22): 10709-19)
M<scp>EGALIN</scp>- <scp>AND</scp> C<scp>UBILIN</scp>-M<scp>EDIATED</scp> E<scp>NDOCYTOSIS OF</scp> P<scp>ROTEIN</scp>-B<scp>OUND</scp> V<scp>ITAMINS</scp>, L<scp>IPIDS</scp>, <scp>AND</scp> H<scp>ORMONES IN</scp> P<scp>OLARIZED</scp> E<scp>PITHELIA</scp>
Authors: Søren K Moestrup, Pierre J Verroust
Journal: Annual Review of Nutrition (2001)

▪ Abstract Polarized epithelia have several functional and morphological similarities, including a high capacity for uptake of various substances present in the fluids facing the apical epithelial surfaces. Studies during the past decade have shown that receptor-mediated endocytosis, rather than nonspecific pinocytosis, accounts for the apical epithelial uptake of many carrier-bound nutrients and hormones. The two interacting receptors of distinct evolutionary origin, megalin and cubilin, are main receptors in this process. Both receptors are apically expressed in polarized epithelia, in which they function as biological affinity matrices for overlapping repertoires of ligands. The ability to bind multiple ligands is accounted for by a high number of replicated low-density lipoprotein receptor type-A repeats in megalin and CUB (complement C1r/C1s, Uegf, and bone morphogenic protein-1) domains in cubilin. Here we summarize and discuss the structural, genetic, and functional aspects of megalin and cubilin, with emphasis on their function as receptors for uptake of protein-associated vitamins, lipids, and hormones.
Does a loss of TDP-43 function cause neurodegeneration?
Authors: Zuo-Shang Xu
Journal: Molecular Neurodegeneration (2012)

In 2006, TAR-DNA binding protein 43 kDa (TDP-43) was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.
Prenatal Diagnosis of Sickle-Cell Anemia
Authors: Yuet Wai Kan, Mitchell S. Golbus, Richard Trecartin
Journal: New England Journal of Medicine (1976)

Prenatal diagnosis of β thalassemia and sickle-cell anemia by the study of hemoglobin synthesis in fetal blood is currently under evaluation. In β thalassemia, the diagnoses of the normal, heterozygous and homozygous states in the fetus have been accomplished.1 2 3 Experience with prenatal diagnosis in sickle-cell anemia is more limited. Although a number of fetuses with sickle-cell trait have been identified by the study of fetal blood obtained after abortion,4 5 6 7 the homozygous state in the fetus has not yet been described. We report here the successful diagnosis of sickle-cell anemia in utero.Materials and MethodsThis was the first pregnancy of . . .
Insulin pump therapy, multiple daily injections, and cardiovascular mortality in 18 168 people with type 1 diabetes: observational study
Authors: I. Steineck, J. Cederholm, B. Eliasson, A. Rawshani, K. Eeg-Olofsson, A.-M. Svensson, B. Zethelius, T. Avdic, M. Landin-Olsson, J. Jendle, S. Gudbjornsdottir
Journal: BMJ (2015)

<b>Objective</b> To investigate the long term effects of continuous subcutaneous insulin infusion (insulin pump therapy) on cardiovascular diseases and mortality in people with type 1 diabetes. <b>Design </b>Observational study. <b>Setting </b>Swedish National Diabetes Register, Sweden 2005-12. <b>Participants</b> 18 168 people with type 1 diabetes, 2441 using insulin pump therapy and 15 727 using multiple daily insulin injections. <b>Main outcome measures</b> Cox regression analysis was used to estimate hazard ratios for the outcomes, with stratification of propensity scores including clinical characteristics, risk factors for cardiovascular disease, treatments, and previous diseases. <b>Results</b> Follow-up was for a mean of 6.8 years until December 2012, with 114 135 person years. With multiple daily injections as reference, the adjusted hazard ratios for insulin pump treatment were significantly lower: 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. Hazard ratios were lower, but not significantly so, for fatal or non-fatal coronary heart disease and fatal or non-fatal cardiovascular disease. Unadjusted absolute differences were 3.0 events of fatal coronary heart disease per 1000 person years; corresponding figures were 3.3 for fatal cardiovascular disease and 5.7 for all cause mortality. When lower body mass index and previous cardiovascular diseases were excluded, results of subgroup analyses were similar to the results from complete data. A sensitivity analysis of unmeasured confounders in all individuals showed that an unmeasured confounders with hazard ratio of 1.3 would have to be present in &gt;80% of the individuals treated with multiple daily injections versus not presence in those treated with pump therapy to invalidate the significantly lower hazard ratios for fatal cardiovascular disease. Data on patient education and frequency of blood glucose monitoring were missing, which might have influenced the observed association. <b>Conclusion</b> Among people with type 1 diabetes use of insulin pump therapy is associated with lower cardiovascular mortality than treatment with multiple daily insulin injections.
Neuroblastoma: Molecular Pathogenesis and Therapy
Authors: Chrystal U. Louis, Jason M. Shohet
Journal: Annual Review of Medicine (2014)

Neuroblastoma is a developmental tumor of young children arising from the embryonic sympathoadrenal lineage of the neural crest. Neuroblastoma is the primary cause of death from pediatric cancer for children between the ages of one and five years and accounts for ∼13% of all pediatric cancer mortality. Its clinical impact and unique biology have made this aggressive malignancy the focus of a large concerted translational research effort. New insights into tumor biology are driving the development of new classification schemas. Novel targeted therapeutic approaches include small-molecule inhibitors as well as epigenetic, noncoding-RNA, and cell-based immunologic therapies. In this review, recent insights regarding the pathogenesis and biology of neuroblastoma are placed in context with the current understanding of tumor biology and tumor/host interactions. Systematic classification of patients coupled with therapeutic advances point to a future of improved clinical outcomes for this biologically distinct and highly aggressive pediatric malignancy.
An Integrative Model of the Maturation of Cognitive Control
Authors: Beatriz Luna, Scott Marek, Bart Larsen, Brenden Tervo-Clemmens, Rajpreet Chahal
Journal: Annual Review of Neuroscience (2015)

Brains systems undergo unique and specific dynamic changes at the cellular, circuit, and systems level that underlie the transition to adult-level cognitive control. We integrate literature from these different levels of analyses to propose a novel model of the brain basis of the development of cognitive control. The ability to consistently exert cognitive control improves into adulthood as the flexible integration of component processes, including inhibitory control, performance monitoring, and working memory, increases. Unique maturational changes in brain structure, supported by interactions between dopaminergic and GABAergic systems, contribute to enhanced network synchronization and an improved signal-to-noise ratio. In turn, these factors facilitate the specialization and strengthening of connectivity in networks supporting the transition to adult levels of cognitive control. This model provides a novel understanding of the adolescent period as an adaptive period of heightened experience-seeking necessary for the specialization of brain systems supporting cognitive control.
Childhood Obesity: Adrift in the “Limbic Triangle”
Authors: Michele L. Mietus-Snyder, Robert H. Lustig
Journal: Annual Review of Medicine (2007)

The prevalence and severity of childhood obesity have increased steadily over the past three decades. The human species evolved to rigorously defend its lower limit for weight and adiposity but is tolerant of the upper limit, which, until recent times, was rarely approached. Neuroendocrine mechanisms within the limbic core of the brain prevent starvation (ventromedial hypothalamus), heighten reward (ventral tegmental area and nucleus accumbens), and attenuate stress (amygdala), in order to promote food-seeking and ingestive behavior and to conserve energy output. In a stressful modern environment with ready access to calorie-dense, highly palatable foods and limited venues for activity, normal, reflexive responsiveness to these three drives makes weight gain all but inevitable. The obesity that ensues often engenders insulin resistance, which undermines the ability of normal hunger and satiety signals to accurately modulate energy intake versus expenditure. Obesity interventions that rely on cognitive information alone cannot free children from this “limbic triangle.” Integrated multidisciplinary family- and community-based education, effective stress reduction, and a societal commitment to alter the food and built environments are all necessary components to battle the global obesity epidemic.
Genetic adaptation to high altitude in the Ethiopian highlands
Authors: Laura B Scheinfeldt, Sameer Soi, Simon Thompson, Alessia Ranciaro, Dawit Woldemeskel, William Beggs, Charla Lambert, Joseph P Jarvis, Dawit Abate, Gurja Belay, Sarah A Tishkoff
Journal: Genome biology (2012)

Genomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. Here, we have extended this work to high- and low-altitude populations living in Ethiopia, for which we have measured hemoglobin levels. We genotyped the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.We have identified a set of candidate genes for positive selection in our high-altitude population sample, demonstrated significantly different hemoglobin levels between high- and low-altitude Ethiopians and have identified a subset of candidate genes for selection, several of which also show suggestive associations with hemoglobin levels.We highlight several candidate genes for involvement in high-altitude adaptation in Ethiopia, including CBARA1, VAV3, ARNT2 and THRB. Although most of these genes have not been identified in previous studies of high-altitude Tibetan or Andean population samples, two of these genes (THRB and ARNT2) play a role in the HIF-1 pathway, a pathway implicated in previous work reported in Tibetan and Andean studies. These combined results suggest that adaptation to high altitude arose independently due to convergent evolution in high-altitude Amhara populations in Ethiopia.