tbuckley/cabot-search huggingface dataset:
High DNA Methyltransferase 3B Expression Mediates 5-Aza-Deoxycytidine Hypersensitivity in Testicular Germ Cell Tumors
Authors: Maroun J. Beyrouthy, Kristen M. Garner, Mary P. Hever, Sarah J. Freemantle, Alan Eastman, Ethan Dmitrovsky, Michael J. Spinella
Journal: Cancer Research (2009)

Abstract Testicular germ cell tumors (TGCT) are the most common solid tumors of 15- to 35-year-old men. TGCT patients are frequently cured with cytotoxic cisplatin-based therapy. However, TGCT patients refractory to cisplatin-based chemotherapy have a poor prognosis, as do those having a late relapse. Pluripotent embryonal carcinomas (EC) are the malignant counterparts to embryonic stem cells and are considered the stem cells of TGCTs. Here, we show that human EC cells are highly sensitive to 5-aza-deoxycytidine (5-aza-CdR) compared with somatic solid tumor cells. Decreased proliferation and survival with low nanomolar concentrations of 5-aza-CdR is associated with ATM activation, H2AX phosphorylation, increased expression of p21, and the induction of genes known to be methylated in TGCTs (MGMT, RASSF1A, and HOXA9). Notably, 5-aza-CdR hypersensitivity is associated with markedly abundant expression of the pluripotency-associated DNA methyltransferase 3B (DNMT3B) compared with somatic tumor cells. Knockdown of DNMT3B in EC cells results in substantial resistance to 5-aza-CdR, strongly indicating that 5-aza-CdR sensitivity is mechanistically linked to high levels of DNMT3B. Intriguingly, cisplatin-resistant EC cells retain an exquisite sensitivity to low-dose 5-aza-CdR treatment, and pretreatment of 5-aza-CdR resensitizes these cells to cisplatin-mediated toxicity. This resensitization is also partially dependent on high DNMT3B levels. These novel findings indicate that high expression of DNMT3B, a likely byproduct of their pluripotency and germ cell origin, sensitizes TGCT-derived EC cells to low-dose 5-aza-CdR treatment. [Cancer Res 2009;69(24):9360–6]
Phase IB study of the EpCAM antibody adecatumumab combined with docetaxel in patients with EpCAM-positive relapsed or refractory advanced-stage breast cancer
Authors: M. Schmidt, D. Rüttinger, M. Sebastian, C.A. Hanusch, N. Marschner, P.A. Baeuerle, A. Wolf, G. Göppel, D. Oruzio, G. Schlimok, G.G. Steger, C. Wolf, W. Eiermann, A. Lang, M. Schuler
Journal: Annals of Oncology (2012)
The δ <sub>C</sub> Isoform of CaMKII Is Activated in Cardiac Hypertrophy and Induces Dilated Cardiomyopathy and Heart Failure
Authors: Tong Zhang, Lars S. Maier, Nancy D. Dalton, Shigeki Miyamoto, John Ross, Donald M. Bers, Joan Heller Brown
Journal: Circulation Research (2003)

Recent studies have demonstrated that transgenic (TG) expression of either Ca 2+ /calmodulin-dependent protein kinase IV (CaMKIV) or CaMKIIδ B , both of which localize to the nucleus, induces cardiac hypertrophy. However, CaMKIV is not present in heart, and cardiomyocytes express not only the nuclear CaMKIIδ B but also a cytoplasmic isoform, CaMKIIδ C . In the present study, we demonstrate that expression of the δ C isoform of CaMKII is selectively increased and its phosphorylation elevated as early as 2 days and continuously for up to 7 days after pressure overload. To determine whether enhanced activity of this cytoplasmic δ C isoform of CaMKII can lead to phosphorylation of Ca 2+ regulatory proteins and induce hypertrophy, we generated TG mice that expressed the δ C isoform of CaMKII. Immunocytochemical staining demonstrated that the expressed transgene is confined to the cytoplasm of cardiomyocytes isolated from these mice. These mice develop a dilated cardiomyopathy with up to a 65% decrease in fractional shortening and die prematurely. Isolated myocytes are enlarged and exhibit reduced contractility and altered Ca 2+ handling. Phosphorylation of the ryanodine receptor (RyR) at a CaMKII site is increased even before development of heart failure, and CaMKII is found associated with the RyR in immunoprecipitates from the CaMKII TG mice. Phosphorylation of phospholamban is also increased specifically at the CaMKII but not at the PKA phosphorylation site. These findings are the first to demonstrate that CaMKIIδ C can mediate phosphorylation of Ca 2+ regulatory proteins in vivo and provide evidence for the involvement of CaMKIIδ C activation in the pathogenesis of dilated cardiomyopathy and heart failure.
Estrogen Receptor β1 Expression Is Regulated by miR-92 in Breast Cancer
Authors: Hakeemah Al-Nakhle, Philip A. Burns, Michele Cummings, Andrew M. Hanby, Thomas A. Hughes, Sampoorna Satheesha, Abeer M. Shaaban, Laura Smith, Valerie Speirs
Journal: Cancer Research (2010)

Abstract Estrogen receptor β1 (ERβ1) downregulation occurs in many breast cancers, but the responsible molecular mechanisms remain unclear. Here, we report that levels of ERβ1 expression are negatively regulated by the microRNA miR-92. Expression analysis in a cohort of primary breast tumors confirmed a significant negative correlation between miR-92 and both ERβ1 mRNA and protein. Inhibition of miR-92 in MCF-7 cells increased ERβ1 expression in a dose-dependent manner, whereas miR-92 overexpression led to ERβ1 downregulation. Reporter constructs containing candidate miR-92 binding sites in the 3′-untranslated region (UTR) of ERβ1 suggested by bioinformatics analysis confirmed that miR-92 downregulated ERβ1 via direct targeting of its 3′-UTR. Our results define a potentially important mechanism for downregulation of ERβ1 expression in breast cancer. Cancer Res; 70(11); 4778–84. ©2010 AACR.
Structural Calibration of the Rates of Amino Acid Evolution in a Search for Darwin in Drifting Biological Systems
Authors: Christina Toft, Mario A. Fares
Journal: Molecular Biology and Evolution (2010)

In the last two decades, many reports of proteins under positive selection have brought the neutral theory into question. However, the methods used to detect selection have ignored the evolvability of amino acids within proteins, which is fundamental to distinguishing positive selection from the relaxed constraints caused by genetic drift. Disentangling these two counterbalancing forces is essential to test the neutral theory. Here, we calibrate rates of amino acid divergence by using structural information from the full set of crystallized proteins in bacteria. In agreement with previous reports, we show that rates of amino acid evolution correlate negatively with the number of per-amino acid atomic interactions. Calibration of the rates of evolution allows identifying signatures of selection in biological systems that evolve under strong genetic drift, such as endosymbiotic bacteria. Application of this method identifies different rates and dynamics of evolution for highly connected amino acids in the structure compared with sparsely connected ones. We also unearth patterns of Darwinian selection in fundamental cellular proteins in endosymbiotic bacteria including the cochaperonin GroES, ribosomal proteins, proteins involved in cell cycle control, DNA-binding proteins, and proteins involved in DNA replication and repair. This is, to our knowledge, the first attempt to distinguish adaptive evolution from relaxed constraints in biological systems under genetic drift.
PTU-011 A Survey on Provision of Teaching for Nasogastric Tube Placement as part of the Curricula of UK Medical Schools: Abstract PTU-011 Table 1
Authors: P N Brennan, L L Wong, G Robins
Journal: Gut (2013)

<h3>Introduction</h3> Nasogastric tube (NGT) insertion for enteral feeding is common practise, but is associated with the risk of tube misplacement or malposition in both the immediate and subsequent time points.<sup>1</sup> Between 2005 to 2010, 21 deaths and 79 other cases of harm have been reported on the updated National Patient Safety Agency (NPSA) Alert (2011), “Reducing harm caused by nasogastric feeding tubes”. In 45% of cases, misinterpretation of the chest X-ray was directly responsible for the harm inflicted. The General Medical Council’s (GMC) guidance for undergraduate education, “Tomorrow’s Doctors (2009)” does not specify NGT placement as a core competency for a graduate or Foundation Trainee.<sup>2</sup> The purpose of this survey was to ascertain the number of medical schools in the United Kingdom (UK) which provide specific teaching on NGT placement and correct identification of tube position (using either pH method or clinical interpretation of a plain chest X-ray film). Furthermore, the authors sought to identify whether these medical schools included formative or summative assessment of the respective methods. <h3>Methods</h3> All 30 GMC recognised Medical Schools within the UK were invited to participate by means of a standardised survey proforma. This proforma was emailed to relevant staff members who were either responsible for course development or were personnel within the clinical skills faculty. <h3>Results</h3> To date, there has been a 57% (17/30) response rate (<i>Table 1</i>). Of the 10 medical schools that provide formal teaching on NGT insertion, 8 of them required formative assessment for both the practical technique and the interpretation of correct tube position. Of the 7 medical schools that do not to provide formal teaching of NGT insertion, 6 of them stated that this was due to the GMC’s “Tomorrow’s Doctors” guidance not including NGT placement as a mandatory proficiency for a graduate. <h3>Conclusion</h3> This survey found that 59% (10/17) of the participating UK medical schools provide formal teaching on NGT placement and correct identification of tube position. There is variable emphasis on NGT procedure proficiency in undergraduate medical education. Given the risks highlighted by the 2011 NPSA report, we would suggest that NGT placement instruction and training should be facilitated at the undergraduate level. <h3>Disclosure of Interest</h3> None Declared <h3>References</h3> National Patient Safety Alert (PSA 002): Reducing the harm caused by misplaced nasogastric feeding tubes in adults, children and infants; Mar 2011. URL: http://www.nrls.npsa.nhs.uk/alerts/?entryid45 = 129640 General Medical Council (GMC) Tomorrow’s Doctors 2009; URL: http://www .gmc-uk.org/TomorrowsDoctors_2009.pdf_39260971.pdf
Effect of Heparin and Heparin Fractions on Platelet Aggregation
Authors: Edwin W. Salzman, Robert D. Rosenberg, Marianne H. Smith, Jack N. Lindon, Leonard Favreau
Journal: Journal of Clinical Investigation (1980)

Porcine intestinal mucosal heparin induced aggregation of platelets in citrated platelet-rich plasma and enhanced platelet aggregation and serotonin secretion induced by other agents. This action of heparin was blocked by substances that elevate platelet cyclic AMP and by EDTA but not by inhibitors of platelet cyclooxygenase. The effect was not inhibited by apyrase or by N-amylthio-5'-AMP and therefore did not require the action of ADP, nor was there activation of platelet phospholipase. Platelet aggregation by heparin required a plasma cofactor different from the cofactor required for ristocetin. Fractionation of heparin yielded preparations that varied in molecular weight and, within a given molecular weight fraction, in affinity for antithrombin III. Fractions of high molecular weight (average 20,000) were more reactive with platelets than were fractions of low molecular weight (7,000). Anticoagulant activity did not parallel the platelet reactivity of heparin fractions. Among high molecular weight fractions, preparations of high or low antithrombin affinity were equally active in induction of platelet aggregation. In low molecular weight fractions, there was an inverse relationship between platelet reactivity and anticoagulant activity in normal platelet-rich plasma, but, in platelet-rich plasma depleted of antithrombin, low molecular weight fractions of high and low antithrombin affinity reacted equally with platelets. These results suggest that formation of an antithrombin-heparin complex protected platelets from aggregation by heparin. Selection of heparin fractions of low molecular weight and high antithrombin affinity may improve anticoagulant therapy and development of thromboresistant heparin-coated artificial materials.
Gut bacteria side-step lymph nodes
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Invasive bacteria can take more than one route from the gut to distant organs, say Barnes and colleagues on page 1591.






Figure 1

Dissemination of gut bacteria to the liver and spleen of mice is comparable in the presence (closed triangles) and absence (open triangles) of Peyer's patches.




According to conventional wisdom, pathogenic gut bacteria spread to distant tissues via an orderly march from gut to local lymph nodes (LNs) and then on to distant organs. But some mutant bugs that cannot invade the lymphoid tissues of the gut can still spread, hinting at the existence of an alternative route.

Barnes and colleagues infected mice orally with Yersinia pseudotuberculosis. They noted two waves of bacteria that spread to both the spleen and liver in the infected mice. The first wave occurred within 30 minutes of infection and was rapidly cleared from these distant organs. The second began later and stuck around.

Only the second wave of bacteria side-stepped the LNs, as mice lacking Peyer's patches—the gut lymphoid tissue that bacteria traverse to reach the LNs—developed only late-stage infections in the liver and spleen.

Marking individual bacteria with unique oligonucleotide tags revealed that the bugs entrenched in distant organs were descendants only of those that migrated later, after first replicating in the gut—possibly because replication triggers the expression of virulence factors that protect the bug against the host immune response.

How the disseminating bugs bypass the LNs remains to be determined. Perhaps they piggy-back on dendritic cells, which can reach directly across the gut epithelium to grab antigens and then head straight for the circulation.
Randomized phase II three-arm trial with three platinum-based doublets in metastatic non-small-cell lung cancer. An Italian Trials in Medical Oncology study
Authors: P. Bidoli, N. Zilembo, D. Cortinovis, L. Mariani, L. Isa, E. Aitini, D. Cullurà, F. Pari, P. Nova, M. Mancin, B. Formisano, E. Bajetta
Journal: Annals of Oncology (2006)
Multilineage Differentiation of Dental Pulp Stem Cells from Green Fluorescent Protein Transgenic Mice
Authors: Brian E Grottkau, P Prasad Purudappa, Yun‐feng Lin
Journal: International Journal of Oral Science (2010)

The aim of this study was to confirm the multilineage differentiation ability of dental pulp stem cells (DPSCs) from green fluorescent protein (GFP) transgenic mice. The expression of GFP in DPSCs was also observed during differentiation. DPSCs were harvested from the dental pulp tissue of transgenic nude mice, and then transferred to osteogenic, adipogenic, and chondrogenic media. The morphological characterization of induced cells was observed by microscopy and histological staining. The expression of marker genes was measured by RT‐PCR. The endogenous GFP and multilineage potential of transgenic DPSCs had no influence on each other. Moreover, the results of fluorescence microscopic imaging suggest that there was no significant decline of GFP expression during DPSCs differentiation. As the population of GFP labeled DPSCs can be easily identified, this will be a promising method for tracking DPSCs in vivo.
Memorial to the Late Dr. Moxon
Authors: R. C. Lucas
Journal: BMJ (1886)

<h3>Abstract</h3> In fast moving cells such as amoeba and immune cells, spatio-temporal regulation of dendritic actin filaments shapes large-scale plasma membrane protrusions. Despite the importance in migration as well as in particle and liquid ingestion, how these processes are affected by the micrometer-scale surface features is poorly understood. Here, through quantitative imaging analysis of <i>Dictyostelium</i> on micro-fabricated surfaces, we show that there is a distinct mode of topographically guided cell migration ‘phagotaxis’ directed by the macropinocytic Ras/PI3K signaling patches. The topography guidance was PI3K-dependent and involved nucleation of a patch at the convex curved surface and confinement at the concave surface. Due to the topography-dependence, constitutive cup formation for liquid uptake in the axenic strain is also destined to trace large surface features. Given the fact that PI3K-dependency of phagocytosis are restricted to large particles in both <i>Dictyostelium</i> and immune cells, topography-dependency and the dual-use of membrane cups may be wide-spread.
Sport concussion assessment tool: baseline values for varsity collision sport athletes
Authors: N Shehata, J P Wiley, S Richea, B W Benson, L Duits, W H Meeuwisse
Journal: British Journal of Sports Medicine (2009)

To determine baseline symptom and neurocognitive norms for non-concussed and previously concussed varsity athletes using the sport concussion assessment tool (SCAT).Descriptive cohort study.University of Calgary.260 male and female university football, ice hockey and wrestling athletes over three seasons (2005-7).A baseline SCAT was completed during preseason medical evaluation. Subjects were grouped as follows: all participants, men, women, never concussed (NC) and previously concussed (PC).The mean age of participants was 20.5 years (range 17-32). In total, 41.2% of all athletes had a total post-concussion symptom scale (PCSS) score of 0. The mean baseline PCSS scores were as follows: all participants 4.29; men 3.52; women 6.39; NC 3.75 and PC 5.25. The five most frequently reported symptoms for all athletes were fatigue/low energy (37% of subjects), drowsiness (23%), neck pain (20%), difficulty concentrating (18%) and difficulty remembering (18%). The median immediate recall score was 5/5 for all groups. Women scored a median of 5/5 on delayed recall, whereas all remaining groups scored a median of 4/5. Months in reverse order were successfully completed by 91.6% of subjects. All participants, women and PC scored a median of 6 on reverse digits, whereas men and NC scored a median of 5.The mean SCAT baseline PCSS score was approximately 5, although just under half of the athletes scored 0. Female athletes scored better on tests of neurocognitive function. PC athletes scored better than NC athletes on all neurocognitive tests except delayed five-word recall.
Complement C3a Regulates Muc5ac Expression by Airway Clara Cells Independently of Th2 Responses
Authors: Patricia Dillard, Rick A. Wetsel, Scott M. Drouin
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

The factors that control the secretion of epithelial mucins are essential to understanding obstructive airway diseases such as asthma. Although the complement anaphylatoxin C3a and its receptor have been shown to promote many features of allergic lung inflammation, the contribution to mucin expression has not been elucidated.To determine if the C3a receptor with its ligand regulates airway epithelial mucin production.Mice deficient in the C3a receptor were examined in a model of allergic airway disease for the presence of goblet cells and the gel-forming secreted mucin Muc5ac.Lungs from antigen-challenged C3a receptor-deficient mice revealed a dramatic decrease in goblet cells and Muc5ac compared with challenged wild-type control animals. These differences were dependent on C3a binding to its receptor since intranasal challenge with C3a induced the formation of goblet cells only in wild-type but not C3a receptor-deficient mice. Increased numbers of goblet cells were also found in C3a-stimulated RAG-1-deficient mice demonstrating a mechanism independent of T lymphocytes and Th2 cytokines, mediators which have been shown to regulate mucin expression. A direct physiological role for C3a in these models was further demonstrated in cultures of airway epithelial Clara cells, which not only express the C3a receptor but also produce Muc5ac in response to C3a.These studies identify a novel C3a receptor-dependent mechanism in the development of airway epithelial goblet cells and regulation of Muc5ac production and implicate C3a as a mediator of airway obstruction in asthma.
Nonredundant and locus-specific gene repression functions of PRC1 paralog family members in human hematopoietic stem/progenitor cells
Authors: Vincent van den Boom, Marjan Rozenveld-Geugien, Francesco Bonardi, Donatella Malanga, Djoke van Gosliga, Anne Margriet Heijink, Giuseppe Viglietto, Giovanni Morrone, Fabrizia Fusetti, Edo Vellenga, Jan Jacob Schuringa
Journal: Blood (2013)
Splanchnic and systemic but not renal hemodynamic responses to atrial natriuretic factor depend on sympathetic outflow changes in cirrhotic patients
Authors: R. Brenard, R. Moreau, E. Pussard, C. Gaudin, B. Champigneulle, B. Debaene, J.L. Poo, T. Sekiyama, A. Berdeaux, A. Braillon, D. Lebrec
Journal: Journal of Hepatology (1990)
Developmental Mechanisms of Topographic Map Formation and Alignment
Authors: Jianhua Cang, David A. Feldheim
Journal: Annual Review of Neuroscience (2013)

Brain connections are organized into topographic maps that are precisely aligned both within and across modalities. This alignment facilitates coherent integration of different categories of sensory inputs and allows for proper sensorimotor transformations. Topographic maps are established and aligned by multistep processes during development, including interactions of molecular guidance cues expressed in gradients; spontaneous activity-dependent axonal and dendritic remodeling; and sensory-evoked plasticity driven by experience. By focusing on the superior colliculus, a major site of topographic map alignment for different sensory modalities, this review summarizes current understanding of topographic map development in the mammalian visual system and highlights recent advances in map alignment studies. A major goal looking forward is to reveal the molecular and synaptic mechanisms underlying map alignment and to understand the physiological and behavioral consequences when these mechanisms are disrupted at various scales.
Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies
Authors: Andrew J Murray
Journal: Genome Medicine (2009)

In most tissues of the body, cellular ATP production predominantly occurs via mitochondrial oxidative phosphorylation of reduced intermediates, which are in turn derived from substrates such as glucose and fatty acids. In order to maintain ATP homeostasis, and therefore cellular function, the mitochondria require a constant supply of fuels and oxygen. In many disease states, or in healthy individuals at altitude, tissue oxygen levels fall and the cell must meet this hypoxic challenge to maintain energetics and limit oxidative stress. In humans at altitude and patients with respiratory disease, loss of skeletal muscle mitochondrial density is a consistent finding. Recent studies that have used cultured cells and genetic mouse models have elucidated a number of elegant adaptations that allow cells with a diminished mitochondrial population to function effectively in hypoxia. This article reviews these findings alongside studies of hypoxic human skeletal muscle, putting them into the context of whole-body physiology and acclimatization to high-altitude hypoxia. A number of current controversies are highlighted, which may eventually be resolved by a systems physiology approach that considers the time-or tissue-dependent nature of some adaptive responses. Future studies using high-throughput metabolomic, transcriptomic, and proteomic technologies to investigate hypoxic skeletal muscle in humans and animal models could resolve many of these controversies, and a case is therefore made for the integration of resulting data into computational models that account for factors such as duration and extent of hypoxic exposure, subjects' backgrounds, and whether data have been acquired from active or sedentary individuals. An integrated and more quantitative understanding of the body's metabolic response to hypoxia and the conditions under which adaptive processes occur could reveal much about the ways that tissues function in the very many disease states where hypoxia is a critical factor.