tbuckley/cabot-search huggingface dataset:
Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice
Authors: Tillmann Cyrus, Joseph L. Witztum, Daniel J. Rader, Rajendra Tangirala, Sergio Fazio, MacRae F. Linton, Colin D. Funk
Journal: Journal of Clinical Investigation (1999)

Atherosclerosis may be viewed as an inflammatory disease process that includes early oxidative modification of LDLs, leading to foam cell formation. This "oxidation hypothesis" has gained general acceptance in recent years, and evidence for the role of lipoxygenases in initiation of, or participation in, the oxidative process is accumulating. However, the relative contribution of macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown. Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E-deficient mice (apo E-/-/L-12LO-/-). In chow-fed 15-week-old apo E-/-/L-12LO-/- mice, the extent of lesions in whole-aorta en face preparations (198 +/- 60 microm2) was strongly reduced (P < 0.001, n = 12) when compared with 12/15-lipoxygenase-expressing controls (apo E-/-/L-12LO+/+), which showed areas of lipid deposition (15,700 +/- 2,688 microm2) in the lesser curvature of the aortic arch, branch points, and in the abdominal aorta. These results were observed despite cholesterol, triglyceride, and lipoprotein levels that were similar to those in apo E-deficient mice. Evidence for reduced lesion development was observed even at 1 year of age in apo E-/-/L-12LO-/- mice. The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest that inhibition of this enzyme may decrease disease progression.
Laser Doppler flowmetry is useful in the clinical management of small bowel transplantation
Authors: E J Corbett
Journal: Gut (2000)

<h3>OBJECTIVE</h3> Laser Doppler flowmetry (LDF) has been used as a research tool to measure splanchnic perfusion. In this report, we aim to demonstrate the clinical value of this technique in perioperative monitoring of transplanted small bowel. <h3>METHODS</h3> A 24 year old man underwent small bowel transplantation using a previously described technique. Microvascular blood flow in the transplanted bowel was measured using an LDF splanchnic probe. Postoperatively this was applied to the stoma facilitating direct measurements of graft mucosal flow. Measurements (perfusion units (PU)) were documented prior to implantation, post-reperfusion, postoperatively, during graft ischaemia, and in response to therapeutic interventions (dopexamine and phenylephrine infusions). <h3>RESULTS</h3> Prior to transplantation, biological zero was established. Flow at five, 15, and 60 minutes after reperfusion was 74 (1.9) PU, 87.5 (3.3) PU, and 141.5 (2.5) PU, respectively. Postoperative mucosal flow was 141.6 (2.9) PU. Subsequent LDF measurement detected absence of flow even though clinical signs suggested only moderate reduction. This was confirmed on surgical re-exploration and facilitated prompt resection of a non-viable segment. Fluid and dopexamine administration resulted in a dose dependent improvement in flow, independent of blood pressure. Addition of phenylephrine increased total mucosal flow and unmasked a cyclical component. <h3>CONCLUSION</h3> This case demonstrates the clinical value of LDF as an “alarm” to indicate graft perfusion failure and as a monitor for therapeutic interventions. Phenylephrine and dopexamine may both be of value in improving mucosal flow in the transplanted small bowel.
B Cell Antigen Receptor Engagement Inhibits Stromal Cell–derived Factor (SDF)-1α Chemotaxis and Promotes Protein Kinase C (PKC)-induced Internalization of CXCR4
Authors: Rodolphe Guinamard, Nathalie Signoret, Masamichi Ishiai, Mark Marsh, Tomohiro Kurosaki, Jeffrey V. Ravetch
Journal: The Journal of Experimental Medicine (1999)

The entry of B lymphocytes into secondary lymphoid organs is a critical step in the development of an immune response, providing a site for repertoire shaping, antigen-induced activation and selection. These events are controlled by signals generated through the B cell antigen receptor (BCR) and are associated with changes in the migration properties of B cells in response to chemokine gradients. The chemokine stromal cell–derived factor (SDF)-1α is thought to be one of the driving forces during those processes, as it is produced inside secondary lymphoid organs and induces B lymphocyte migration that arrests upon BCR engagement. The signaling pathway that mediates this arrest was genetically dissected using B cells deficient in specific BCR-coupled signaling components. BCR-induced inhibition of SDF-1α chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)γ2 but independent of Ca2+ mobilization, suggesting that the target of BCR stimulation was a protein kinase C (PKC)-dependent substrate. This target was identified as the SDF-1α receptor, CXCR4, which undergoes PKC- dependent internalization upon BCR stimulation. Mutation of the internalization motif SSXXIL in the COOH terminus of CXCR4 resulted in B cells that constitutively expressed this receptor upon BCR engagement. These studies suggest that one pathway by which BCR stimulation results in inhibition of SDF-1α migration is through PKC-dependent downregulation of CXCR4.
Does This Patient With Chest Pain Have Acute Coronary Syndrome?
Authors: Alexander C. Fanaroff, Jennifer A. Rymer, Sarah A. Goldstein, David L. Simel, L. Kristin Newby
Journal: JAMA (2015)

About 10% of patients with acute chest pain are ultimately diagnosed with acute coronary syndrome (ACS). Early, accurate estimation of the probability of ACS in these patients using the clinical examination could prevent many hospital admissions among low-risk patients and ensure that high-risk patients are promptly treated.To review systematically the accuracy of the initial history, physical examination, electrocardiogram, and risk scores incorporating these elements with the first cardiac-specific troponin.MEDLINE and EMBASE were searched (January 1, 1995-July 31, 2015), along with reference lists from retrieved articles, to identify prospective studies of diagnostic test accuracy among patients admitted to the emergency department with symptoms suggesting ACS.We identified 2992 unique articles; 58 met inclusion criteria.Sensitivity, specificity, and likelihood ratio (LR) of findings for the diagnosis of ACS. The reference standard for ACS was either a final hospital diagnosis of ACS or occurrence of a cardiovascular event within 6 weeks.The clinical findings and risk factors most suggestive of ACS were prior abnormal stress test (specificity, 96%; LR, 3.1 [95% CI, 2.0-4.7]), peripheral arterial disease (specificity, 97%; LR, 2.7 [95% CI, 1.5-4.8]), and pain radiation to both arms (specificity, 96%; LR, 2.6 [95% CI, 1.8-3.7]). The most useful electrocardiogram findings were ST-segment depression (specificity, 95%; LR, 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia (specificity, 91%; LR, 3.6 [95% CI,1.6-5.7]). Both the History, Electrocardiogram, Age, Risk Factors, Troponin (HEART) and Thrombolysis in Myocardial Infarction (TIMI) risk scores performed well in diagnosing ACS: LR, 13 (95% CI, 7.0-24) for the high-risk range of the HEART score (7-10) and LR, 6.8 (95% CI, 5.2-8.9) for the high-risk range of the TIMI score (5-7). The most useful for identifying patients less likely to have ACS were the low-risk range HEART score (0-3) (LR, 0.20 [95% CI, 0.13-0.30]), low-risk range TIMI score (0-1) (LR, 0.31 [95% CI, 0.23-0.43]), or low to intermediate risk designation by the Heart Foundation of Australia and Cardiac Society of Australia and New Zealand risk algorithm (LR, 0.24 [95% CI, 0.19-0.31]).Among patients with suspected ACS presenting to emergency departments, the initial history, physical examination, and electrocardiogram alone did not confirm or exclude the diagnosis of ACS. Instead, the HEART or TIMI risk scores, which incorporate the first cardiac troponin, provided more diagnostic information.
Oestrogen induces mucoid conversion of<i>Pseudomonas Aeruginosa</i>in women with cystic fibrosis, and increases exacerbations
Authors: Gemma Hayes
Journal: Thorax (2012)

CLUB Oestrogen induces mucoid conversion of Pseudomonas Aeruginosa in women with cystic fibrosis, and increases exacerbationsThis study assesses whether oestradiol contributes to early mucoid pseudomonas colonisation and increased exacerbation frequency in female patients with cystic fibrosis (CF).In vitro oestradiol induced more alginate production, defining mucoid conversion, at 3 days and 4 weeks compared with ethanol and testosterone, and more mucoid colonies were seen at 4 weeks following oestradiol culture.In 80% of oestradiol-exposed colonies, a frameshift mutation in the mucA gene was identified causing loss of gene function and development of pseudomonas mucoidy.Exacerbations closely followed oestradiol levels with increased numbers seen during the high oestradiol follicular phase.However, the sample size was small, 44 patients and 139 exacerbations, with only 23 patients and 72 exacerbations analysed.The percentage of mucoid sputum isolates was also higher during the follicular phase, compared with the luteal phase when no mucoid strains were isolated, although again the sample size was small.Oestradiol was higher during exacerbations in women than in the stable disease state, validating the relationship between oestradiol and exacerbation frequency.This trend was not seen in men and women taking the oral contraceptive pill.Estradiol induces mucoid conversion of Pseudomonas aeruginosa in women with CF, through mutation of mucA, and is associated with increased exacerbations.The oral contraceptive pill appears to attenuate this effect, and may prove to be an effective therapeutic intervention in postpubertal females colonised with pseudomonas, although further trials are needed.
Computed tomographic colonography versus colonoscopy for investigation of patients with symptoms suggestive of colorectal cancer (SIGGAR): a multicentre randomised trial
Authors: Wendy Atkin, Edward Dadswell, Kate Wooldrage, Ines Kralj-Hans, Christian von Wagner, Rob Edwards, Guiqing Yao, Clive Kay, David Burling, Omar Faiz, Julian Teare, Richard J Lilford, Dion Morton, Jane Wardle, Steve Halligan
Journal: The Lancet (2013)
Using Genetic Diagnosis to Determine Individual Therapeutic Utility
Authors: C. Thomas Caskey
Journal: Annual Review of Medicine (2010)

Humans have considerable genetic variation, as shown by their DNA sequence differences. Drug responsiveness and toxicity are affected by this variability. Genetic variation affects prodrug activation, drug targets, downstream activation pathways, drug elimination, and toxicity activation. Molecular diagnostic methods have discovered the genetic basis of several of these "outlier" drug responses. By predicting a patient's response, such diagnostics can improve both the safety and efficacy of drugs. The article illustrates the matching of molecular diagnosis to drug therapy for improved patient outcomes.
Vascular Endothelial Growth Factor-D and Its Receptor VEGFR-3: Two Novel Independent Prognostic Markers in Gastric Adenocarcinoma
Authors: Stefan Jüttner, Christoph Wiβmann, Thomas Jöns, Michael Vieth, Johannes Hertel, Stephan Gretschel, Peter M. Schlag, Wolfgang Kemmner, Michael Höcker
Journal: Journal of Clinical Oncology (2005)

Vascular endothelial growth factor (VEGF)-D and its homolog VEGF-C influence lymphangiogenesis through activation of VEGF receptor 3 (VEGFR-3), and have been implicated in lymphatic tumor spread. Nodal dissemination of gastric adenocarcinomas critically determines clinical outcome and therapeutic options of affected patients. Therefore, we analyzed expression and prognostic significance of VEGF-D along with VEGF-C, and VEGFR-3 in gastric adenocarcinomas.VEGF-C, VEGF-D, and VEGFR-3 were analyzed in 91 R(0)-resected primary gastric adenocarcinomas, corresponding noncancerous gastric mucosa, and lymph node metastases employing immunohistochemistry and/or in situ hybridization. Blood and lymph vessel densities were assessed after staining with CD31 and LYVE-1-specific antibodies.VEGF-D and VEGF-C were detected in 67.0% and 50.5% of gastric cancers, respectively. Healthy gastric mucosa was negative for VEGF-C and in 12.5% positive for VEGF-D. Presence of VEGF-D (P = .005) or VEGF-C (P = .006) was correlated with lymphatic metastases and decreased survival (VEGF-D, P < .05; VEGF-C, P < .05). VEGFR-3 was correlated with reduced carcinoma-specific survival (P < .05), and Cox multivariate regression analysis qualified VEGF-D and VEGFR-3, but not VEGF-C, as independent prognostic parameters. In lymph node-positive gastric cancers, presence of VEGF-D/VEGFR-3 was associated with poor survival, whereas absence of VEGF-D/VEGFR-3 defined a subgroup of patients with clearly favorable prognosis.VEGF-D and VEGFR-3 are novel independent prognostic marker molecules aiding to identify patients with poor prognosis after curative resection of gastric adenocarcinomas. Combined analysis of the VEGF-C/VEGF-D/VEGFR-3 system can be useful to identify patients with unfavorable clinical outcome and thereby may help to refine therapeutic decisions in gastric cancer.
Protein Turnover Via Autophagy: Implications for Metabolism
Authors: Noboru Mizushima, Daniel J. Klionsky
Journal: Annual Review of Nutrition (2007)

Autophagy is a process of cellular “self-eating” in which portions of cytoplasm are sequestered within double-membrane cytosolic vesicles termed autophagosomes. The autophagosome cargo is delivered to the lysosome, broken down, and the resulting amino acids recycled after release back into the cytosol. Autophagy occurs in all eukaryotes and can be up-regulated in response to various nutrient limitations. Under these conditions, autophagy may become essential for viability. In addition, autophagy plays a role in certain diseases, acting to prevent some types of neurodegeneration and cancer, and in the elimination of invading pathogens. We review the current information on the mechanism of autophagy, with a focus on its role in protein metabolism and intracellular homeostasis.
Primary therapy for adults with T-cell lymphoblastic lymphoma with hematopoietic stem-cell transplantation results in favorable outcomes
Authors: K.W. Song, M.J. Barnett, R.D. Gascoyne, M. Chhanabhai, D.L. Forrest, D.E. Hogge, J.C. Lavoie, S.H. Nantel, T.J. Nevill, J.D. Shepherd, C.A. Smith, H.J. Sutherland, C.L. Toze, N.J. Voss, J.M. Connors
Journal: Annals of Oncology (2006)
Perturbed IFN-γ-Jak-Signal Transducers and Activators of Transcription Signaling in Tuberous Sclerosis Mouse Models
Authors: Nisreen El-Hashemite, Hongbing Zhang, Victoria Walker, Karin M. Hoffmeister, David J. Kwiatkowski
Journal: Cancer Research (2004)

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by widespread development of hamartomas, which is caused by mutations in either TSC1 or TSC2. We demonstrate a dramatic decrease of IFN-γ expression in tumors and mouse embryo fibroblast cell lines that lack either Tsc1 or Tsc2, which is reversed by rapamycin (mammalian target of rapamycin inhibitor) therapy. Increased signal transducers and activators of transcription (STAT) 1 expression and phosphorylation at Ser 727 and increased pSTAT3 Tyr705 levels also are seen in Tsc1 null and Tsc2 null cells and in tumors. Treatment of Tsc1 or Tsc2 null cells with IFN-γ induces apoptosis, in contrast to control cell lines, with reduction in pSTAT3 Tyr705 levels and major increases in pSTAT1 Tyr701, bax, and caspase-1 and −9 levels. A combination of IFN-γ and rapamycin is markedly synergistic in induction of apoptosis in Tsc1 or Tsc2 null cells because pSTAT3 Tyr705 phosphorylation is abolished completely and the other effects of IFN-γ are maintained or enhanced. Rapamycin-IFN-γ has unique potential therapeutic benefit for management of TSC tumors.
Phenotypic Profiling of <i>DPYD</i> Variations Relevant to 5-Fluorouracil Sensitivity Using Real-time Cellular Analysis and <i>In Vitro</i> Measurement of Enzyme Activity
Authors: Steven M. Offer, Natalie J. Wegner, Croix Fossum, Kangsheng Wang, Robert B. Diasio
Journal: Cancer Research (2013)

In the 45 years since its development, the pyrimidine analog 5-fluorouracil (5-FU) has become an integral component of many cancer treatments, most notably for the management of colorectal cancer. An appreciable fraction of patients who receive 5-FU suffer severe adverse toxicities, which in extreme cases may result in death. Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) rapidly degrades 85% of administered 5-FU, and as such, limits the amount of drug available for conversion into active metabolites. Clinical studies have suggested that genetic variations in DPYD increase the risk for 5-FU toxicity, however, there is not a clear consensus about which variations are relevant predictors. In the present study, DPYD variants were expressed in mammalian cells, and the enzymatic activity of expressed protein was determined relative to wild-type (WT). Relative sensitivity to 5-FU for cells expressing DPYD variations was also measured. The DPYD*2A variant (exon 14 deletion caused by IVS14+1G>A) was confirmed to be catalytically inactive. Compared with WT, two variants, S534N and C29R, showed significantly higher enzymatic activity. Cells expressing S534N were more resistant to 5-FU-mediated toxicity compared with cells expressing WT DPYD. These findings support the hypothesis that selected DPYD alleles are protective against severe 5-FU toxicity, and, as a consequence, may decrease the effectiveness of 5-FU an antitumor drug in carriers. In addition, this study shows a method that may be useful for phenotyping other genetic variations in pharmacologically relevant pathways.
The Role of Surface Functionality in Nanoparticle Exocytosis
Authors: Chang Soo Kim, Ngoc D. B. Le, Yuqing Xing, Bo Yan, Gulen Yesilbag Tonga, Chaekyu Kim, Richard W. Vachet, Vincent M. Rotello
Journal: Advanced Healthcare Materials (2014)

Getting out is just as important for nano­therapeutics as getting in. Exocytosis rates determine residency time in the cell, an important determinant for therapeutic efficacy and also for eventual clearance from the cell. In this study, it is shown that exocytosis efficiency is determined by surface functionality, providing a strategy for optimizing nanocarriers. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The Complex History of a Gene Proposed to Participate in a Sexual Isolation Mechanism in House Mice
Authors: Robert C. Karn, Annie Orth, François Bonhomme, Pierre Boursot
Journal: Molecular Biology and Evolution (2002)

Previous behavioral experiments showed that mouse salivary androgen–binding protein (ABP) was involved in interindividual recognition and might play a role in sexual isolation between house mouse (Mus musculus) subspecies. The pattern of evolution of Abpa, the gene for the alpha subunit of ABP, was found to be consistent with this hypothesis. Abpa apparently diverged rapidly between species and subspecies with a large excess of nonsynonymous substitutions, a lack of exon polymorphism within each of the three subspecies, and a lack of intron polymorphism in the one subspecies studied (M. musculus domesticus). Here we characterized the intron and exon sequence variations of this gene in house mouse populations from central Eurasia, a region yet unsampled and thought to be close to the cradle of the radiation of the subspecies. We also determined the intron and exon sequences in seven other species of the genus Mus. We confirmed the general pattern of rapid evolution by essentially nonsynonymous substitutions, both inter- and intraspecifically, supporting the idea that Darwinian selection has driven the evolution of this gene. We also observed a uniform intron sequence in five samples of M. musculus musculus, suggesting that a selective sweep might have occurred for that allele. In contrast to previous results, however, we found extensive intron and exon polymorphism in some house mouse populations from central Eurasia. We also found evidence for secondary admixture of the subspecies-specific alleles in regions of transition between the subspecies in central Eurasia. Furthermore, an abnormal intron phylogeny suggested that interspecific exchanges had occurred between the house mouse subspecies and three other Palearctic species. These observations appear to be at variance with the simple hypothesis that Abpa is involved in reproductive isolation. Although we do not rule out a role in recognition, the situation appears to be more complex than previously thought. Thus the selective mechanism behind the evolution of Abpa remains to be resolved, and we suggest that it may have changed during the recent colonization history of the house mouse.
Chorus of <i>k</i> prototypes or discord of contradictory representations?
Authors: David R. Andresen, Chad J. Marsolek
Journal: Behavioral and Brain Sciences (1998)

The human visual system is capable of learning both abstract and specific mappings to underlie shape recognition. How could dissimilar shapes be mapped to the same location in visual representation space, yet similar shapes be mapped to different locations? Without fundamental changes, Chorus, like other single-system models, could not accomplish both mappings in a manner that accounts for recent evidence.
Genetic Screen Identifies Insulin-like Growth Factor Binding Protein 5 as a Modulator of Tamoxifen Resistance in Breast Cancer
Authors: Bo Young Ahn, Adam N. Elwi, Byoungchun Lee, Diane L.N. Trinh, Alexander C. Klimowicz, Annie Yau, Jennifer A. Chan, Anthony Magliocco, Sung-Woo Kim
Journal: Cancer Research (2010)

Abstract Tamoxifen resistance is one of the overarching challenges in the treatment of patients with estrogen receptor (ER)–positive breast cancer. Through a genome-wide RNA interference screen to discover genes responsible for tamoxifen resistance in vitro, we identified insulin-like growth factor binding protein 5 (IGFBP5) as a determinant of drug sensitivity. Specific knockdown of IGFBP5 by retroviral infection with short hairpin RNA–expressing cassette in MCF7 human breast cancer cells (pRS-shIGFBP5) conferred tamoxifen resistance in vitro due to concomitant loss of ERα expression and signaling. IGFBP5 expression was also reduced in MCF7 cells selected for tamoxifen resistance in culture (TAMR). Both tamoxifen-resistant MCF7-TAMR and MCF7-pRS-shIGFBP5 cells could be resensitized to drug by treatment with exogenous recombinant IGFBP5 (rIGFBP5) protein. Treatment with rIGFBP5 protein in mouse tumor xenografts reversed the in vivo tamoxifen resistance of MCF7-pRS-shIGFBP5 cell–derived tumors by reducing tumor cell proliferation. IGFBP5 immunohistochemical staining in a cohort of 153 breast cancer patients showed that low IGFBP5 expression was associated with shorter overall survival after tamoxifen therapy. Thus, IGFBP5 warrants investigation as an agent to reverse tamoxifen resistance. Cancer Res; 70(8); 3013–9. ©2010 AACR.
Surface functionalisation of PLGA nanoparticles for gene silencing
Authors: Morten Ø. Andersen, Agata Lichawska, Ayyoob Arpanaei, Stig Møller Rask Jensen, Harpreet Kaur, David Oupicky, Flemming Besenbacher, Peter Kingshott, Jørgen Kjems, Kenneth A. Howard
Journal: Biomaterials (2010)