tbuckley/cabot-search huggingface dataset:
Fusion Protein Vaccine by Domains of Bacterial Exotoxin Linked with a Tumor Antigen Generates Potent Immunologic Responses and Antitumor Effects
Authors: Chao-Wei Liao, Chi-An Chen, Chien-Nan Lee, Yi-Ning Su, Ming-Cheng Chang, Ming-Houg Syu, Chang-Yao Hsieh, Wen-Fang Cheng
Journal: Cancer Research (2005)

Abstract Antigen-specific immunotherapy represents an attractive approach for cancer treatment because of the capacity to eradicate systemic tumors at multiple sites in the body while retaining the requisite specificity to discriminate between neoplastic and nonneoplastic cells. It has been shown that certain domains of bacterial exotoxins facilitate translocation from extracellular and vesicular compartments into the cytoplasm. This feature provides an opportunity to enhance class I and/or II presentation of exogenous antigen to T lymphocytes. We investigated previously whether the translocation domain (domain II) of Pseudomonas aeruginosa exotoxin A with a model tumor antigen, human papillomavirus type 16 E7, in the context of a DNA vaccine could enhance vaccine potency. We then attempted to determine whether this chimeric molecule could also generate strong antigen-specific immunologic responses and enhance the potency of cancer vaccine in the protein format. Our results show that vaccination with the PE(ΔIII)-E7-KDEL3 fusion protein enhances MHC class I and II presentation of E7, leading to dramatic increases in the number of E7-specific CD8+ and CD4+ T-cell precursors and markedly raised titers of E7-specific antibodies. Furthermore, the PE(ΔIII)-E7-KDEL3 protein generates potent antitumor effects against s.c. E7-expressing tumors and preestablished E7-expressing metastatic lung tumors. Further, mice immunized with PE(ΔIII)-E7-KDEL3 protein vaccine also retained long-term immunologic responses and antitumor effects. Our results indicate that retrograde-fusion protein via the delivery domains of exotoxins with an antigen greatly enhances in vivo antigen-specific immunologic responses and represents a novel strategy to improve cancer vaccine potency.
Canonical Wnt Signaling Regulates Atrioventricular Junction Programming and Electrophysiological Properties
Authors: Benjamin S. Gillers, Aditi Chiplunkar, Haytham Aly, Tomas Valenta, Konrad Basler, Vincent M. Christoffels, Igor R. Efimov, Bastiaan J. Boukens, Stacey Rentschler
Journal: Circulation Research (2014)

Proper patterning of the atrioventricular canal (AVC) is essential for delay of electrical impulses between atria and ventricles, and defects in AVC maturation can result in congenital heart disease.To determine the role of canonical Wnt signaling in the myocardium during AVC development.We used a novel allele of β-catenin that preserves β-catenin's cell adhesive functions but disrupts canonical Wnt signaling, allowing us to probe the effects of Wnt loss of function independently. We show that the loss of canonical Wnt signaling in the myocardium results in tricuspid atresia with hypoplastic right ventricle associated with the loss of AVC myocardium. In contrast, ectopic activation of Wnt signaling was sufficient to induce formation of ectopic AV junction-like tissue as assessed by morphology, gene expression, and electrophysiological criteria. Aberrant AVC development can lead to ventricular pre-excitation, a characteristic feature of Wolff-Parkinson-White syndrome. We demonstrate that postnatal activation of Notch signaling downregulates canonical Wnt targets within the AV junction. Stabilization of β-catenin protein levels can rescue Notch-mediated ventricular pre-excitation and dysregulated ion channel gene expression.Our data demonstrate that myocardial canonical Wnt signaling is an important regulator of AVC maturation and electric programming upstream of Tbx3. Our data further suggest that ventricular pre-excitation may require both morphological patterning defects, as well as myocardial lineage reprogramming, to allow robust conduction across accessory pathway tissue.
Ulipristal Acetate versus Placebo for Fibroid Treatment before Surgery
Authors: Jacques Donnez, Tetyana F. Tatarchuk, Philippe Bouchard, Lucian Puscasiu, Nataliya F. Zakharenko, Tatiana Ivanova, Gyula Ugocsai, Michal Mara, Manju P. Jilla, Elke Bestel, Paul Terrill, Ian Osterloh, Ernest Loumaye
Journal: New England Journal of Medicine (2012)

The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain.We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13, after which patients could undergo surgery.At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, 92% of those receiving 10 mg of ulipristal acetate, and 19% of those receiving placebo (P<0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were -21%, -12%, and +3% (P=0.002 for the comparison of 5 mg of ulipristal acetate with placebo, and P=0.006 for the comparison of 10 mg of ulipristal acetate with placebo). Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy. Serious adverse events occurred in one patient during treatment with 10 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo.Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. (Funded by PregLem; ClinicalTrials.gov number, NCT00755755.).
Regulation of ribosomal DNA transcription during neonatal cardiomyocyte hypertrophy
Authors: R. D. Hannan, L. I. Rothblum
Journal: Cardiovascular Research (1995)

In summary, the increased capacity for protein synthesis that is a constant feature in all forms of cardiac hypertrophy is largely mediated by accelerated ribosome biogenesis. Experiments with neonatal cardiomyocytes in culture indicate that the activity of the rDNA transcription factor, UBF, may contribute to the regulation of rDNA transcription during the hypertrophic growth process. The observations of parallel responses in three different models of neonatal cardiomyocyte hypertrophy suggest that further studies on the regulation of UBF should lead to a clearer understanding of the pathways that lead to hypertrophy. Possible alterations in the activities and/or amounts of other factors associated with rDNA transcription including SL-1, TFIC and the polymerase I enzyme itself, may also contribute to the regulation of cardiomyocyte growth; however, this remains to be demonstrated.
Case not proven
Authors: Wendy Moore
Journal: Journal of the Royal Society of Medicine (2010)

Don Shelton's article1 raises some interesting questions about the sources of William Hunter's and William Smellie's subjects for their obstetric atlases but it does not add up to a convincing case that they received murdered bodies. I cannot comment on Smellie's atlas, but it is not true that most of the subjects in Hunter's book were women in the final month of pregnancy. Hunter's atlas contains 34 plates of which the first 10 relate to just one woman, who died at full-term. Hunter refers in the text to two more women who died in or near their last month, amounting to a total of three women at full-term. But the point of the atlas was to depict pregnancy at all stages, so the book shows fetuses at various stages of development, working backwards from full-term. So there were three full-term, or almost full-term women, all obtained in the years 1750–1751. Certainly it is unusual for full-term women to die. And Hunter was evasive about the source of his pregnant subjects, although he describes the second as having died ‘of a flooding in the last month of pregnancy’. If the body-snatchers dug up graves randomly, it would be highly unlikely they would find three full-term women in this space of time. But the bodysnatchers did not work randomly. Even in the mid-18th century, they had connections with gravediggers and sextons – in fact some of them were gravediggers and sextons – who knew who had died and where they were buried so they could arrange resurrections to order. When pregnant women died in hospital, those deaths were obviously known to doctors there who could simply order an exhumation (as Astley Cooper later described). Furthermore, when John Hunter mentioned the ‘leading steps’ to procuring a body being secret, he was probably referring to bodysnatching rather than murder. Surgeons were certainly discreet about this practice – with good reason. John's own house was mobbed when human remains were discovered being taken away and at least one 18th-century surgeon was prosecuted for receiving dead bodies. So while it is not impossible that the women in Hunter's and Smellie's atlases were murdered (it is not correct to describe them as being ‘burked’ since that term did not come into use until after the Burke and Hare murders in 1827) it is not possible to make out a case based on laws of probability.
A Randomized Clinical Trial of Three Options for N95 Respirators and Medical Masks in Health Workers
Authors: C. Raina MacIntyre, Quanyi Wang, Holly Seale, Peng Yang, Weixian Shi, Zhanhai Gao, Bayzid Rahman, Yi Zhang, Xiaoli Wang, Anthony T. Newall, Anita Heywood, Dominic E. Dwyer
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

We compared three policy options for the use of medical masks and N95 respirators in healthcare workers (HCWs).A cluster randomized clinical trial of 1,669 hospital-based HCWs in Beijing, China in the winter of 2009-2010.Participants were randomized to medical masks, N95 respirators, or targeted use of N95 respirators while doing high-risk procedures or barrier nursing. Outcomes included clinical respiratory illness (CRI) and laboratory-confirmed respiratory pathogens in symptomatic subjects.The rate of CRI was highest in the medical mask arm (98 of 572; 17%), followed by the targeted N95 arm (61 of 516; 11.8%), and the N95 arm (42 of 581; 7.2%) (P < 0.05). Bacterial respiratory tract colonization in subjects with CRI was highest in the medical mask arm (14.7%; 84 of 572), followed by the targeted N95 arm (10.1%; 52 of 516), and lowest in the N95 arm (6.2%; 36 of 581) (P = 0.02). After adjusting for confounders, only continuous use of N95 remained significant against CRI and bacterial colonization, and for just CRI compared with targeted N95 use. Targeted N95 use was not superior to medical masks.Continuous use of N95 respirators was more efficacious against CRI than intermittent use of N95 or medical masks. Most policies for HCWs recommend use of medical masks alone or targeted N95 respirator use. Continuous use of N95s resulted in significantly lower rates of bacterial colonization, a novel finding that points to more research on the clinical significance of bacterial infection in symptomatic HCWs. This study provides further data to inform occupational policy options for HCWs. Clinical trial registered with Australian New Zealand Clinical Trials Registry http://www.anzctr.org.au (ACTRN 12609000778280).
iPS Genomes Investigated
Authors: Ruth Williams
Journal: Circulation Research (2011)

A series of recent articles have examined the genomes and epigenomes of induced pluripotent stem (iPS) cell lines.The results appear discouraging for the clinical future of iPS cells, but researchers don't seem worried.In August 2006, Kazutoshi Takahashi and Shinya Yamanaka reported that just four specific factors were sufficient to convert a fully differentiated adult cell into a pluripotent stem cell. 1 Not only was the concept scientifically gripping, but also the implications for the technique's clinical application were tremendous.A patient's own cells might be used to generate replacement cells for therapy, avoiding the worry of transplant rejection, as well as the ethical concerns and tricky techniques of embryonic stem (ES) cell generation.So began a proliferative burst of related research studies.Publications on iPS cell research have become so plentiful, in fact, that it is hard to believe the field is not yet five years old.New approaches to improve safety and efficiency have been suggested, different adult cell types have been converted, and numerous disease model cell lines have been made, and yet, as the fifth birthday draws near, a series of recent research articles threaten to spoil the party.The reports reveal that the genomes of iPS cell lines exhibit chromosome abnormalities, residual epigenetic marks from the parent somatic cell type, and a higher than normal number of coding sequence mutations.In one recent article, for example, Pasi et al 2 report that genomic deletions and amplifications (copy number variations) are abundant at fragile sites in the genomes of mouse iPS cells.In another, Hussein et al 3 show that such copy number variation exists in human iPS cell lines too, and that, on average, copy number variation is two-fold higher in iPS cells compared with ES cells and cultured fibroblasts.Interestingly, this copy number variation dropped to levels similar to ES cells and fibroblasts when the cells were grown for longer periods, suggesting the iPS reprogramming process itself prompted the genomic variability and that this variation was selected against during prolonged culture.An article by Laurent et al 4 indicates that loss of tumor suppressor genes from the iPS genomes is associated with the reprogramming process, while amplification of such genes can occur during iPS (and ES) cell passaging , again suggesting that reprogramming and culturing exposes iPS cells to different genomic pressures.
How to decide whether a neural representation is a cognitive concept?
Authors: Maartje E. J. Raijmakers, Peter C. M. Molenaar
Journal: Behavioral and Brain Sciences (1995)

Abstract A distinction should be made between the formation of stimulus-driven associations and cognitive concepts. To test the learning mode of a neural network, we propose a simple and classic input-output test: the discrimination shift task. Feed-forward PDP models appear to form stimulus-driven associations. A Hopfield network should be extended to apply the test.
Medical relevance of UK-funded non-human primate research published from January 1997 to July 2012
Authors: Edward Moore
Journal: Journal of the Royal Society of Medicine (2014)

In 2012, the Bateson Review of research using non-human primates (NHPs) recommended the commissioning of a working group to identify and follow-up the results of UK-funded NHP research of potential benefit for human health (Recommendation 4), but the Medical Research Council (MRC) has postponed implementation of the recommendation. Information on results and potential benefits of NHP research therefore remains unavailable. To fill this gap in knowledge, this study identified all published NHP research studies funded by the MRC, Wellcome Trust and Biotechnology and Biological Sciences Research Council (BBSRC) from January 1997 to July 2012 and assessed full texts for medical relevance. In total, 284 papers were identified, of which 51 (18%) involved invasive NHP research, compared to 176 (61%) which used NHP tissue and cell lines, indicating a shift in research emphasis from invasive whole animal to cell-based research. Of these studies, 98 (35%) were medically relevant, of which 22 had potential therapeutic or public health applications. The relatively low proportion of medical studies together with the small number of applied studies raises questions over the level of investment in medical research and the effectiveness of knowledge transfer from basic to applied research. Implementation of the Bateson Review’s Recommendation 4 would address these questions.
Evolution of Developmental Genes: Molecular Microevolution of Enhancer Sequences at the Ubx Locus in Drosophila and Its Impact on Developmental Phenotypes
Authors: J. Phinchongsakuldit
Journal: Molecular Biology and Evolution (2003)

Homeotic genes, which function to specify segment identity along the anterior-posterior axis of embryos, are controlled by extensive batteries of enhancer sequences. We have investigated patterns of interspecific and intraspecific molecular variation in three enhancers of the Ultrabithorax (Ubx) locus, which are bx-32.8, pbx32.7, and bxd4.1, from the Drosophila melanogaster species group. These enhancer sequences control Ubx expression by binding to multiple transcription factors encoded by gap, pair-rule, and dorsoventrally expressed genes. Sequence comparisons reveal purifying selection acting on all three enhancers, both in bases binding transcription factors and in bases whose functions are as yet unknown. Neutrality tests largely fail to reject a neutral evolution model. However, using a matrix similarity value to reflect the binding affinity of the protein-binding sites, interspecific and intraspecific variation that may have potential to affect the binding affinity of the sequences homologous to those binding transcription factors in D. melanogaster are discovered, suggesting evolutionary flexibility in the way in which these sequences function in the control of development. As a means of measuring the impact of intraspecific variation on observable phenotypes, we have induced Ubx mutant phenocopies with embryonic ether treatment, and find strong and highly significant variation between D. melanogaster strains in their phenocopy frequencies. This variation shows no significant correlation with the strengths of the mutant phenotypes when the strains are heterozygous with a Ubx null mutation. Estimated phylogenetic trees have been constructed for the three enhancer regions investigated. Neither of the two phenotypic traits investigated shows any significant associations with the phylogeny of any of the three enhancers.
Heparin Inhibits Hyperventilation-Induced Late-Phase Hyperreactivity in Dogs
Authors: RYOICHI SUZUKI, ARTHUR N. FREED
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Inhalation of heparin attenuates hyperventilation-induced bronchoconstriction in humans and dogs. The purpose of this study was to determine whether heparin inhibits the late-phase response to hyperventilation, which is characterized by increased peripheral airway resistance (RP), eicosanoid mediator production, neutrophilic/ eosinophilic inflammation, and airway hyperreactivity (AHR) at 5 h after dry air challenge (DAC). Fiberoptic bronchoscopy was used to record RP and airway reactivity (DeltaRP) to aerosol and intravenous histamine before and 5 h after DAC. Bronchoalveolar lavage fluid (BALF) cells and eicosanoid mediators were also measured approximately 5 h after DAC. DAC of vehicle-treated bronchi resulted in late-phase airway obstruction (approximately 120% increase over baseline RP), inflammation, increased BALF concentrations of leukotriene (LT) C(4), LTD(4), and LTE(4) and prostaglandin (PG)D(2), and AHR. Pretreatment with aerosolized heparin attenuated late-phase airway obstruction by approximately 50%, inhibited eosinophil infiltration, reduced BALF concentrations of LTC(4), LTD(4), and LTE(4) and PGD(2), and abolished AHR. We conclude that heparin inhibits hyperventilation-induced late-phase changes in peripheral airway function, and does so in part via the inhibition of eosinophil migration and eicosanoid mediator production and release.
Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease
Authors: Carlos Jose Pirola, Tomas Fernández Gianotti, Adriana Laura Burgueño, Manuel Rey-Funes, Cesar Fabian Loidl, Pablo Mallardi, Julio San Martino, Gustavo Osvaldo Castaño, S Sookoian
Journal: Gut (2012)

Nonalcoholic fatty liver disease (NAFLD) is a clinical condition that refers to progressive histological changes ranging from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). We evaluated the status of cytosine methylation (5mC) of liver mitochondrial DNA (mtDNA) in selected regions of the mtDNA genome, such as D-loop control region, and mitochondrially encoded NADH dehydrogenase 6 (MT-ND6) and cytochrome C oxidase I (MT-CO1), to contrast the hypothesis that epigenetic modifications play a role in the phenotypic switching from SS to NASH.We studied liver biopsies obtained from patients with NAFLD in a case-control design; 45 patients and 18 near-normal liver-histology subjects.MT-ND6 methylation was higher in the liver of NASH than SS patients (p < 0.04) and MT-ND6 methylated DNA/unmethylated DNA ratio was significantly associated with NAFLD activity score (p < 0.02). Liver MT-ND6 mRNA expression was significantly decreased in NASH patients (0.26 ± 0.30) versus SS (0.74 ± 0.48), p < 0.003, and the protein level was also diminished. The status of liver MT-ND6 methylation in NASH group was inversely correlated with the level of regular physical activity (R = -0.54, p < 0.02). Hepatic methylation levels of D-Loop and MT-CO1 were not associated with the disease severity. DNA (cytosine-5) methyltransferase 1 was significantly upregulated in NASH patients (p < 0.002). Ultrastructural evaluation showed that NASH is associated with mitochondrial defects and peroxisome proliferation.Hepatic methylation and transcriptional activity of the MT-ND6 are associated with the histological severity of NAFLD. Epigenetic changes of mtDNA are potentially reversible by interventional programs, as physical activity could modulate the methylation status of MT-ND6.