tbuckley/cabot-search huggingface dataset:
<i>In Vivo</i> Imaging of Drug-Induced Mitochondrial Outer Membrane Permeabilization at Single-Cell Resolution
Authors: Sarah Earley, Claudio Vinegoni, Joshua Dunham, Rostic Gorbatov, Paolo Fumene Feruglio, Ralph Weissleder
Journal: Cancer Research (2012)

Abstract Observing drug responses in the tumor microenvironment in vivo can be technically challenging. As a result, cellular responses to molecularly targeted cancer drugs are often studied in cell culture, which does not accurately represent the behavior of cancer cells growing in vivo. Using high-resolution microscopy and fluorescently labeled genetic reporters for apoptosis, we developed an approach to visualize drug-induced cell death at single-cell resolution in vivo. Stable expression of the mitochondrial intermembrane protein IMS-RP was established in human breast and pancreatic cancer cells. Image analysis was then used to quantify release of IMS-RP into the cytoplasm upon apoptosis and irreversible mitochondrial permeabilization. Both breast and pancreatic cancer cells showed higher basal apoptotic rates in vivo than in culture. To study drug-induced apoptosis, we exposed tumor cells to navitoclax (ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w, both in vitro and in vivo. Although the tumors responded to Bcl-2 inhibition in vivo, inducing apoptosis in around 20% of cancer cells, the observed response was much higher in cell culture. Together, our findings show an imaging technique that can be used to directly visualize cell death within the tumor microenvironment in response to drug treatment. Cancer Res; 72(12); 2949–56. ©2012 AACR.
The Role of<i>P53</i>and<i>MDM2</i>Polymorphisms in the Risk of Esophageal Squamous Cell Carcinoma
Authors: Yuan Hong, Xiaoping Miao, Xuemei Zhang, Fang Ding, Aiping Luo, Yongli Guo, Wen Tan, Zhihua Liu, Dongxin Lin
Journal: Cancer Research (2005)

Abstract The tumor suppressor P53 pathway plays a crucial role in preventing carcinogenesis and genetic variations of this pathway may be associated with cancer susceptibility. We tested this hypothesis by examining the contribution of functional polymorphisms in P53 and MDM2 to risk of esophageal squamous cell carcinoma (ESCC). DNA from 758 ESCC patients and 1,420 controls were genotyped for P53 codon 72Arg&amp;gt;Pro and MDM2 309T&amp;gt;G polymorphisms. Odds ratios (OR) and 95% confidence intervals (CI) of ESCC were estimated by logistic regression. We observed an increased risk of ESCC associated with the P53 Pro/Pro (OR, 1.83; 95% CI, 1.43-2.35; P &amp;lt; 0.001) or MDM2 GG (OR, 1.49; 95% CI, 1.16-1.91; P = 0.002) genotype, compared with the P53 Arg/Arg or MDM2 TT genotype, respectively. Interaction between these P53 and MDM2 polymorphisms increased risk of ESCC in a multiplicative manner, with the OR being 3.10 (95% CI, 2.07-4.69) for subjects carrying both P53 Pro/Pro and MDM2 GG genotypes. Significant interactions were observed between these polymorphisms and smoking, with risk being the highest (OR, 5.29; 95% CI, 2.91-9.61) in smokers having both P53 Pro/Pro and MDM2 GG genotypes. The MDM2 GG genotype was also associated with risk of developing poorly differentiated and advanced ESCC compared with the GT or TT genotype (OR for high-grade and stages III-IV versus low-grade and stages I-II = 1.60; 95% CI, 1.00-2.64; P = 0.049). The P53 and MDM2 polymorphisms may be genetic determinants for the development of ESCC.
Requirement of Cyclin D1 in Mesangial Cell Mitogenesis
Authors: STEFAN LANG, ANDREA HARTNER, R. BERND STERZEL, HARALD O. SCHO[Combining Diaeresis]CKLMANN
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Hyperplasia of mesangial cells (MC) is a frequent finding in glomerulonephritis. The control and function of cyclin D1, a regulator of cell cycle progression, in MC proliferation in vivo and in vitro were investigated. In a rat model of mesangioproliferative glomerulonephritis, increases in the number of cyclin D1-positive MC nuclei were prominent on day 5 of the disease, preceding the peak of MC hyperplasia. In growth-arrested rat MC in culture, mitogenic stimulation with serum or platelet-derived growth factor (PDGF) led to rapid increases in cyclin D1 protein expression. Transforming growth factor-β1 inhibited PDGF induction of cyclin D1 protein at 12 h. In an examination of the subcellular distribution of cyclin D1, it was observed that stimulation of MC with PDGF for 6 h caused translocation of cyclin D1 from the cytoplasm into the nucleus. Coincubation with PDGF and transforming growth factor-β1 completely inhibited this effect, without altering the cellular cyclin D1 protein abundance at that time point. To test whether reduction of cyclin D1 protein levels was sufficient to inhibit mitogenesis, MC were transfected with antisense oligonucleotides (ODN) complementary to rat cyclin D1 mRNA. Antisense ODN against cyclin D1 reduced the serum- or PDGF-induced protein expression of cyclin D1 to 27 or 10% of control levels, respectively. These inhibitory effects were correlated with diminished cyclin-dependent kinase 4 activity. Antisense ODN against cyclin D1 also decreased the PDGF-induced increase in p21 Waf-1 protein levels. The MC proliferation caused by serum or PDGF was markedly inhibited by antisense ODN against cyclin D1, as measured by [ 3 H]thymidine uptake and cell counts. It is concluded that increased cyclin D1 protein expression of MC is required for MC proliferation. Targeting cyclin D1 expression may represent an effective means to inhibit MC proliferation in vitro and in vivo.
Factor VIII alters tubular organization and functional properties of von Willebrand factor stored in Weibel-Palade bodies
Authors: Eveline A. M. Bouwens, Marjon J. Mourik, Maartje van den Biggelaar, Jeroen C. J. Eikenboom, Jan Voorberg, Karine M. Valentijn, Koen Mertens
Journal: Blood (2011)
Cardiovascular Effects of Tricyclic and Tetracyclic Antidepressants
Authors: Dieter Burckhardt
Journal: JAMA (1978)

Cardiovascular effects of therapeutic doses of tricyclic or tetracyclic antidepressants (TCA) were examined in 66 patients. After three weeks of therapy, heart rate and PR interval were increased (P less than .02, P less than .05), while prolongation of the QTc time and the QRS interval did not reach significant levels. We observed significant flattening of T waves (P less than .05), which was not associated with changes in the serum potassium level. These changes were reversible after treatment was discontinued. When therapy was maintained for 13 months, only the heart rate continued to be increased, whereas all other ECG values had returned to normal. The TCA therapy led to a significant prolongation of the preejection period (P less than .01) and slight shortening of the left ventricular ejection time, indicating a decrease in myocardial contractility. There was no difference of effects on the values studied between tricyclic and tetracyclic antidepressants.
Novel Role of Lactosylceramide in Vascular Endothelial Growth Factor–Mediated Angiogenesis in Human Endothelial Cells
Authors: Mohanraj Rajesh, Antonina Kolmakova, Subroto Chatterjee
Journal: Circulation Research (2005)

Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with coronary heart disease, vascular complications in diabetes, inflammatory vascular diseases, and tumor metastasis. The mechanism of VEGF-driven angiogenesis involving glycosphingolipids such as lactosylceramide (LacCer), however, is not known. To demonstrate the involvement of LacCer in VEGF-induced angiogenesis, we used small interfering RNA (siRNA)-mediated silencing of LacCer synthase expression (GalT-V) in human umbilical vein endothelial cells. This gene silencing markedly inhibited VEGF-induced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and angiogenesis. Second, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of LacCer synthase and glucosylceramide synthase, that significantly mitigated VEGF-induced PECAM-1 expression and angiogenesis. Interestingly, these phenotypic changes were reversed by LacCer but not by structurally related compounds such as glucosylceramide, digalactosylceramide, and ceramide. In a human mesothelioma cell line (REN) that lacks the endogenous expression of PECAM-1, VEGF/LacCer failed to stimulate PECAM-1 expression and tube formation/angiogenesis. In REN cells expressing human PECAM-1 gene/protein, however, both VEGF and LacCer-induced PECAM-1 protein expression and tube formation/angiogenesis. In fact, VEGF-induced but not LacCer-induced angiogenesis was mitigated by SU-1498, a VEGF receptor tyrosine kinase inhibitor. Also, VEGF/LacCer-induced PECAM-1 expression and angiogenesis was mitigated by protein kinase C and phospholipase A2 inhibitors. These results indicate that LacCer generated in VEGF-treated endothelial cells may serve as an important signaling molecule for PECAM-1 expression and in angiogenesis. This finding and the reagents developed in our report may be useful as anti-angiogenic drugs for further studies in vitro and in vivo.
Autoreactive B Cells in the Marginal Zone that Express Dual Receptors
Authors: Yijin Li, Hui Li, Martin Weigert
Journal: The Journal of Experimental Medicine (2002)

Allotype and isotype exclusion is a property of most lymphocytes. The reason for this property is not known but it guarantees a high concentration of a single receptor, and threshold numbers of receptors may be required for efficient positive and negative selection. Receptor editing compromises exclusion by sustaining recombination even after a functional receptor is formed. Consequently, B cells expressing multiple receptors arise. We have studied such B cells in which one of the two receptors is anti-self, and find that these partially autoreactive B cells accumulate in the marginal zone. The restriction of these cells in this location may help to prevent them from undergoing diversification and developing into fully autoreactive B cells.
Sub maximal oxygen uptake related to fat free mass and lean leg volume in trained runners.
Authors: E. M. Winter, E. J. Hamley
Journal: British Journal of Sports Medicine (1976)

The sub maximal oxygen uptake (VO2) of 32 trained male middle and long distance runners aged 19.5-36.0 years was determined at five treadmill speeds. There was a significant linear relationship (p less than 0.01) between VO2 at each of the treadmill speeds and Fat-Free Mass (FFM) and Lean Leg Volume (LLV). To explain the relationship other factors are considered, the most important of which may be the mechanical configuration of muscle and mitochondrial function.
Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection
Authors: Christopher A. Haskell, Wayne W. Hancock, David J. Salant, Wei Gao, Vilmos Csizmadia, Wendy Peters, Kerrie Faia, Omar Fituri, James B. Rottman, Israel F. Charo
Journal: Journal of Clinical Investigation (2001)

Fractalkine (Fk) is a structurally unusual member of the chemokine family. To determine its role in vivo, we generated mice with a targeted disruption of CX3CR1, the receptor for Fk. CX3CR1–/– mice were phenotypically indistinguishable from wild-type mice in a pathogen-free environment. In response to antibody-induced glomerulonephritis, CX3CR1–/– and CX3CR1+/+ mice had similar levels of proteinuria and injury. CX3CR1–/– and CX3CR1+/+ mice also developed similar levels of disease in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. We performed heterotopic MHC class I/II cardiac transplants from BALB/c mice into C57BL/6 mice. In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX3CR1–/– and CX3CR1+/+ recipient mice. However, in the presence of subtherapeutic levels of CsA, graft survival time was significantly increased in the CX3CR1–/– mice. Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX3CR1–/– recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA. We conclude that Fk plays an important role in graft rejection. The development of CX3CR1 antagonists may allow reductions in the doses of immunosuppressive drugs used in transplantation.
Use of culture and molecular analysis to determine the effect of antibiotic treatment on microbial community diversity and abundance during exacerbation in patients with cystic fibrosis
Authors: M. M. Tunney, E. R. Klem, A. A. Fodor, D. F. Gilpin, T. F. Moriarty, S. J. McGrath, M. S. Muhlebach, R. C. Boucher, C. Cardwell, G. Doering, J. S. Elborn, M. C. Wolfgang
Journal: Thorax (2011)

<h3>Background</h3> Anaerobic bacteria are increasingly regarded as important in cystic fibrosis (CF) pulmonary infection. The aim of this study was to determine the effect of antibiotic treatment on aerobic and anaerobic microbial community diversity and abundance during exacerbations in patients with CF. <h3>Methods</h3> Sputum was collected at the start and completion of antibiotic treatment of exacerbations and when clinically stable. Bacteria were quantified and identified following culture, and community composition was also examined using culture-independent methods. <h3>Results</h3> <i>Pseudomonas aeruginosa</i> or <i>Burkholderia cepacia</i> complex were detected by culture in 24/26 samples at the start of treatment, 22/26 samples at completion of treatment and 11/13 stable samples. Anaerobic bacteria were detected in all start of treatment and stable samples and in 23/26 completion of treatment samples. Molecular analysis showed greater bacterial diversity within sputum samples than was detected by culture; there was reasonably good agreement between the methods for the presence or absence of aerobic bacteria such as <i>P aeruginosa</i> (κ=0.74) and <i>B cepacia</i> complex (κ=0.92), but agreement was poorer for anaerobes. Both methods showed that the composition of the bacterial community varied between patients but remained relatively stable in most individuals despite treatment. Bacterial abundance decreased transiently following treatment, with this effect more evident for aerobes (median decrease in total viable count 2.3×10<sup>7</sup> cfu/g, p=0.005) than for anaerobes (median decrease in total viable count 3×10<sup>6</sup> cfu/g, p=0.046). <h3>Conclusion</h3> Antibiotic treatment targeted against aerobes had a minimal effect on abundance of anaerobes and community composition, with both culture and molecular detection methods required for comprehensive characterisation of the microbial community in the CF lung. Further studies are required to determine the clinical significance of and optimal treatment for these newly identified bacteria.
Cholecystokinin in the control of gastric acid secretion in man.
Authors: J W Konturek, R Stoll, S J Konturek, W Domschke
Journal: Gut (1993)

This study was designed to determine the role of cholecystokinin in the control gastric acid secretion in men using loxiglumide, a specific cholecystokinin receptor blocker. Three groups of healthy subjects (A, B, and C) were used; group A--for studies with postprandial gastric secretion, group B--for studies with exogenous gastric secretagogues and group C--for 12 hour intragastric pH-metry. Cephalic phase stimulated by modified sham feeding in group A subjects increased gastric acid secretion to about 50% of pentagastrin maximum and the treatment with loxiglumide in a standard dose (20 mumol/kg iv loading dose plus infusion of 20 mumol/kg/h afterwards) failed to affect this secretion. Gastric acid response to a 5% peptone meal instilled intragastrically greatly enhanced gastric acid secretion and plasma gastrin concentration but the addition of loxiglumide in the standard dose resulted in further increase in both gastric acid and plasma gastrin responses to peptone meal. Infusion of caerulein in gradually increasing doses (15-120 pmol/kg/h) and gastrin releasing peptide (25-200 pmol/kg/h) resulted in a dose dependent stimulation of gastric acid secretion reaching about 35% and 25% of maximum attained with pentagastrin. When loxiglumide was added in a standard dose, the acid responses to caerulein and gastrin releasing peptide were further increased two to three fold attaining the peak reaching, respectively, about 100% and 50% of pentagastrin maximum. In group C subjects, 12 hour pH-metry revealed the usual increase in gastric pH after each meal in tests with placebo. Loxiglumide (1200 mg tablets tid, po) resulted in significantly lower pH after each meal and this was accompanied by significantly higher gastrin responses than in placebo tests. We conclude that cholecystokinin released by peptone meal, ordinary meals or gastrin releasing peptide exerts a potent inhibitory influence on gastric acid secretion and gastrin release in men and this inhibition involves subtype A cholecystokinin receptors.
The PGE2-Stat3 connection in cardiac hypertrophy
Authors: M SCHAUB, M HEFTI
Journal: Cardiovascular Research (2006)

Journal Article The PGE2-Stat3 connection in cardiac hypertrophy Get access Marcus C. Schaub, Marcus C. Schaub * Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland *Corresponding author. Tel.: +41 44 635 59 19; fax: +41 44 635 68 71. Email address: [email protected] Search for other works by this author on: Oxford Academic PubMed Google Scholar Martin A. Hefti Martin A. Hefti Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 73, Issue 1, January 2007, Pages 3–5, https://doi.org/10.1016/j.cardiores.2006.11.012 Published: 01 January 2007 Article history Received: 30 October 2006 Revision received: 06 November 2006 Accepted: 09 November 2006 Published: 01 January 2007
Ouabain-Sensitive α1 Na,K-ATPase Enhances Natriuretic Response to Saline Load
Authors: Elizabeth L. Loreaux, Baksho Kaul, John N. Lorenz, Jerry B. Lingrel
Journal: Journal of the American Society of Nephrology (2008)

Na,K-ATPase is ubiquitously expressed and is essential for maintaining electrochemical and osmotic gradients. The alpha subunit of Na,K-ATPase is the receptor for cardiotonic steroids, which act through the ouabain-binding site and are important in cardiovascular regulation. Interestingly, the presence of endogenous Na,K-ATPase ligands has been implicated in the natriuretic response to perturbations such as hypertension and salt loading; therefore, it is important to characterize the role of the ouabain-binding sites in this context. Because the alpha1 isoform of mice and rats is relatively ouabain resistant, gene-targeting strategies were used to produce mice with reversed responses of the alpha1 and/or alpha2 isoforms to ouabain to assess for altered natriuretic responses to acute salt loading. Regardless of the sensitivity of the alpha2 isoform to ouabain, conferring ouabain sensitivity to alpha1 augmented the natriuretic response to an acute salt load. In addition, when endogenous Na,K-ATPase inhibitors were sequestered with an anti-digoxin antibody fragment, the sodium excretion rates in the ouabain-sensitive alpha1 isoform mice were equivalent to the ouabain-resistant alpha1 isoform mice. These data suggest that the ouabain-binding site of the alpha1 Na,K-ATPase can participate in the natriuretic response to a salt load by responding to endogenous Na,K-ATPase ligands.
THE STERILIZATION OF THE SKIN WITH TINCTURE OF IODINE
Authors: J. L. Stretton
Journal: BMJ (1915)

<h3>Abstract</h3> We recently developed <b>Di</b>rected <b>Me</b>thylation with <b>Lo</b>ng-read <b>seq</b>uencing (DiMeLo-seq) to map protein-DNA interactions genome wide. DiMeLo-seq maps multiple interaction sites on single DNA molecules, profiles protein binding in the context of endogenous DNA methylation, and maps protein-DNA interactions in repetitive regions of the genome that are difficult to study with short-read methods. Adenines in the vicinity of a protein of interest are methylated in situ by tethering the Hia5 methyltransferase to an antibody using protein A. Protein-DNA interactions are then detected by direct readout of adenine methylation with long-read, single-molecule, DNA sequencing platforms such as Nanopore sequencing. Here, we present a detailed protocol and guidance for performing DiMeLo-seq. This protocol can be run on nuclei from fresh, lightly fixed, or frozen cells. The protocol requires 1 day for performing in situ targeted methylation, 1-5 days for library preparation depending on desired fragment length, and 1-3 days for Nanopore sequencing depending on desired sequencing depth. The protocol requires basic molecular biology skills and equipment, as well as access to a Nanopore sequencer. We also provide a Python package, <i>dimelo</i>, for analysis of DiMeLo-seq data.
Metabolic Reprogramming of Stromal Fibroblasts through p62-mTORC1 Signaling Promotes Inflammation and Tumorigenesis
Authors: Tania Valencia, Ji Young Kim, Shadi Abu-Baker, Jorge Moscat-Pardos, Christopher S. Ahn, Miguel Reina-Campos, Angeles Duran, Elias A. Castilla, Christian M. Metallo, Maria T. Diaz-Meco, Jorge Moscat
Journal: Cancer Cell (2014)
Optimization of skin testing
Authors: N. R. Niemeijer, B. Goedewaagen, H. F. Kauffman, J. G. R. de Monchy
Journal: Allergy (1993)

Standardized extracts of Phleum pratensis (grass) and Dermatophagoides pteronyssinus (house‐dust mite) were used as test allergens for multiple regression in order to determine optimum concentrations and cutoff values with regard to diagnostic capacity and safety. If a RAST value of class 1 or more was taken as an indication of sensitization, it was found that the optimum concentrations for the detection of sensitization are in the range 10–100 BU/ml and 1500–10000 BU/ml for intracutaneous tests (ICT) and skin prick tests (SPT), respectively. The skin test results were expressed as histamine ratios. Using allergen concentrations of 30 and 3000 BU/ml, we found cutoff values of 0.87 and 0.53 and predictive values of 87.1% and 19.1% for ICT and SPT, respectively. The maximum wheal size (mean wheal size + 2 SD) to be expected in 95% of the population was 26.6 mm (ICT) and 10.9 mm (SPT), sizes regarded as safe by most clinicians. In conclusion, by using this method with a limited number of patients, one can probably improve the diagnostic precision and safety of the skin test. In the second part of this study, these hypotheses were prospectively tested in a multicenter study.
Attributes of clinical guidelines that influence use of guidelines in general practice: observational study
Authors: R. Grol, J. Dalhuijsen, S. Thomas, C. i.'t Veld, G. Rutten, H. Mokkink
Journal: BMJ (1998)

To determine which attributes of clinical practice guidelines influence the use of guidelines in decision making in clinical practice.Observational study relating the use of 47 different recommendations from 10 national clinical guidelines to 12 different attributes of clinical guidelines-for example, evidence based, controversial, concrete.General practice in the Netherlands.61 general practitioners who made 12 880 decisions in their contacts with patients.Compliance of decisions with clinical guidelines according to the attribute of the guideline.Recommendations were followed in, on average, 61% (7915/12 880) of the decisions. Controversial recommendations were followed in 35% (886/2497) of decisions and non-controversial recommendations in 68% (7029/10 383) of decisions. Vague and non-specific recommendations were followed in 36% (826/2280) of decisions and clear recommendations in 67% (7089/10 600) of decisions. Recommendations that demanded a change in existing practice routines were followed in 44% (1278/2912) of decisions and those that did not in 67% (6637/9968) of decisions. Evidence based recommendations were used more than recommendations for practice that were not based on research evidence (71% (2745/3841) v 57% (5170/9039)).People and organisations setting evidence based clinical practice guidelines should take into account some of the other important attributes of effective recommendations for clinical practice.