tbuckley/cabot-search huggingface dataset:
Expression of a Functionally Active gp91phox-Containing Neutrophil-Type NAD(P)H Oxidase in Smooth Muscle Cells From Human Resistance Arteries
Authors: Rhian M. Touyz, Xin Chen, Fatiha Tabet, Guoying Yao, Gang He, Mark T. Quinn, Patrick J. Pagano, Ernesto L. Schiffrin
Journal: Circulation Research (2002)

A major source of vascular smooth muscle cell (VSMC) superoxide is NAD(P)H oxidase. However, the molecular characteristics and regulation of this enzyme are unclear. We investigated whether VSMCs from human resistance arteries (HVSMCs) possess a functionally active, angiotensin II (Ang II)-regulated NAD(P)H oxidase that contains neutrophil oxidase subunits, including p22phox, gp91phox, p40phox, p47phox, and p67phox. mRNA expression of gp91phox homologues, nox1 and nox4, was also assessed in HVSMCs, human aortic smooth muscle cells, and rat VSMCs. HVSMCs were obtained from resistance arteries from gluteal biopsies of healthy subjects. gp91phox and nox4, but not nox1, were detected in HVSMCs. Nox1 and nox4, but not gp91phox, were expressed in human aortic smooth muscle cells and rat VSMCs. All NAD(P)H oxidase subunits were present in HVSMCs as detected by reverse transcriptase-polymerase chain reaction and immunoblotting. Ang II increased NAD(P)H oxidase subunit abundance. These effects were inhibited by cycloheximide. Acute Ang II stimulation (10 to 15 minutes) increased p47phox serine phosphorylation and induced p47phox and p67phox translocation. This was associated with NAD(P)H oxidase activation. In cells transfected with gp91phox antisense oligonucleotides, Ang II-mediated actions were abrogated. NADPH-induced superoxide generation was reduced by gp91ds-tat and apocynin, inhibitors of p47phox-gp91phox interactions. Our results suggest that HVSMCs possess a functionally active gp91phox-containing neutrophil-like NAD(P)H oxidase. Ang II regulates the enzyme by inducing phosphorylation of p47phox, translocation of cytosolic subunits, and de novo protein synthesis. These novel findings provide insight into the molecular regulation of NAD(P)H oxidase by Ang II in HVSMCs. Furthermore, we identify differences in gp91phox homologue expression in VSMCs from rats and human small and large arteries.
A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
Authors: N Petrelli, L Herrera, Y Rustum, P Burke, P Creaven, J Stulc, L J Emrich, A Mittelman
Journal: Journal of Clinical Oncology (1987)

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.
Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation
Authors: Safak Caglayan, Shizuka Takagi-Niidome, Fan Liao, Anne-Sophie Carlo, Vanessa Schmidt, Tilman Burgert, Yu Kitago, Ernst-Martin Füchtbauer, Annette Füchtbauer, David M. Holtzman, Junichi Takagi, Thomas E. Willnow
Journal: Science Translational Medicine (2014)

A familial AD mutation in SORL1 disrupts the ability of the sorting receptor SORLA to mediate intracellular degradation of Aβ peptides.
Brief, Large Tidal Volume Ventilation Initiates Lung Injury and a Systemic Response in Fetal Sheep
Authors: Noah H. Hillman, Timothy J. M. Moss, Suhas G. Kallapur, Cindy Bachurski, J. Jane Pillow, Graeme R. Polglase, Ilias Nitsos, Boris W. Kramer, Alan H. Jobe
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Premature infants are exposed to potentially injurious ventilation in the delivery room. Assessments of lung injury are confounded by effects of subsequent ventilatory support.Objectives: To evaluate the injury response to a brief period of large tidal volume (Vt) ventilation, simulating neonatal resuscitation in preterm neonates.Methods: Preterm lambs (129 d gestation; term is150 d) were ventilated (Vt = 15 ml/kg, no positive end-expiratory pressure) for 15 minutes to simulate delivery room resuscitation, either with the placental circulation intact (fetal resuscitation [ FR]) or after delivery (neonatal resuscitation [NR]). After the initial 15 minutes, lambs received surfactant and were maintained with either ventilatory support (FR-VS and NR-VS) or placental support (FR-PS) for 2 hours, 45 minutes. A control group received no resuscitation and was maintained with placental support. Samples of bronchoalveolar lavage fluid, lung, and liver were analyzed.Measurements and Main Results: Inflammatory cells and protein in bronchoalveolar lavage fluid, heat shock protein-70 immunostaining, IL-1β, IL-6, IL-8, monocyte chemotactic protein-1, serum amyloid A (SAA)-3, Toll-like receptor (TLR)-2, and TLR4 mRNA in the lungs were increased in the FR-PS group compared with control animals. There were further elevations in neutrophils, IL-6, and IL-8 mRNA in the FR-VS and NR-VS groups compared with FR-PS. SAA3, TLR2, and TLR4 mRNA increased in the liver in all resuscitation groups relative to control animals.Conclusions: Ventilation for 15 minutes with a Vt of 15 ml/kg initiates an injurious process in the preterm lung and a hepatic acute-phase response. Subsequent ventilatory support causes further increases in some injury indicators.
Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin.
Authors: J P Wiener-Kronish, K H Albertine, M A Matthay
Journal: Journal of Clinical Investigation (1991)

Although intravenous Escherichia coli endotoxin has been used extensively in experimental studies to increase lung endothelial permeability, the effect of E. coli endotoxin on lung epithelial permeability has not been well studied. To examine this issue in sheep, bidirectional movement of protein across the lung epithelial barrier was studied by labeling the vascular space with 131I-albumin and by instilling 3 ml/kg of an isosmolar protein solution with 125I-albumin into the alveoli. E. coli endotoxin was administered according to one of three protocols: intravenous alone (5-500 micrograms/kg), intravenous (5 micrograms/kg) plus low-dose alveolar endotoxin (10 micrograms/kg), and high-dose alveolar endotoxin alone (50-100 micrograms/kg). Alveolar liquid clearance was estimated based on the concentration of the instilled native protein. Sheep were studied for either 4 or 24 h. Although intravenous E. coli endotoxin produced a marked increase in transvascular protein flux and interstitial pulmonary edema, there was no effect on the clearance of either the vascular (131I-albumin) or the alveolar (125I-albumin) protein tracer across the epithelial barrier. High-dose alveolar E. coli endotoxin caused a 10-fold increase in the number of leukocytes, particularly neutrophils, that accumulated in the air spaces. In spite of the marked chemotactic effect of alveolar endotoxin, there was no change in the permeability of the epithelial barrier to the vascular or alveolar protein tracers. Also, alveolar epithelial liquid clearance was normal. Morphologic studies confirmed that the alveolar epithelial barrier was not injured by either intravenous or alveolar E. coli endotoxin. Thus, the alveolar epithelium in sheep is significantly more resistant than the lung endothelium to the injurious effects of E. coli endotoxin.
OC-071 Screening For Anal Pre-cancer In Hiv Positive And Negative Men Who Have Sex With Men (msm) And Renal Transplant Recipients: Early Experience From A Manchester Based Prospective Study
Authors: AM Schofield, R McMahon, A Sukthankar, M Desai, J Hill, J Patnick, EJ Crosbie, HC Kitchener
Journal: Gut (2014)

<h3>Introduction</h3> The UK National Screening Committee has suggested that screening for anal intraepithelial neoplasia (AIN) in populations at high-risk of anal squamous cell carcinoma may be of benefit, but that further information is needed. In these groups the risk of developing anal cancer is increased up-to 100-fold. <h3>Methods</h3> ANALOGY is an ongoing prospective cohort study addressing the feasibility and acceptability of anal screening in high-risk groups, based on liquid based cytology (LBC), HPV testing and high-resolution anoscopy (HRA). High-risk patients aged over 25 with no previous history of anal pre-cancer or cancer who are HIV+ men who have sex with men (MSM), HIV- MSM, HIV+ women with a gynaecological neoplasia history or transplant recipients who are 2-years post-procedure were all recruited. All participants had baseline LBC, HPV typing and HRA at recruitment and at 6-months, with a diagnostic biopsy being taken for participants with an abnormal HRA, referral for colorectal opinion was sought in high-grade AIN (HGAIN 3) on biopsy or HSIL on LBC. Data are presented for participants recruited from March 2013. <h3>Results</h3> To date, 173 participants have baseline data;78 HIV+ and 25 HIV- MSM, 4 HIV+ women, 42 male and 24 female transplant recipients. Overall 65.8% (114/173) were HPV positive of whom 34.2% (39/114) were HPV 16 positive (30 HIV+ MSM, 7 HIV- MSM, 1 male and 1 female transplant recipients). Abnormal cytology was found in 28.3% (49/173). Abnormal HRA requiring a biopsy was found in 43.3% (75/173) of patients, in HIV+ MSM this proportion was 61.5% (48/78), including 20 high-grade AIN (HGAIN 2 or 3) and one invasive cancer. This constitutes a prevalence of high-grade disease of 26.9% (21/78), 4% (1/25) and 12.5% (3/24) for HIV+, HIV- MSM and renal transplant women respectively. Colorectal referral for HGAIN diagnosed at first visit was required in 7.5% (13/173) of patients, 69.2% (9/13) were HIV+ MSM, 23.1% (3/13) and 7.7% (1/13) were HIV- MSM and a renal transplant woman respectively. <h3>Conclusion</h3> Early experience of anal screening in high-risk groups suggests that it is both acceptable and feasible. Colorectal referral for assessment of HGAIN was more frequent in HIV+ MSM than other high-risk groups. These prevalence data are similar to a recently published meta-analysis. <h3>Disclosure of Interest</h3> None Declared.
Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain
Authors: S Matsumoto, Y Okabe, H Setoyama, K Takayama, J Ohtsuka, H Funahashi, A Imaoka, Y Okada, Y Umesaki
Journal: Gut (1998)

Background —A new subline of the senescence accelerated mouse (SAM) P1/Yit strain has been established which shows spontaneous enteric inflammation under specific pathogen free (SPF) conditions. Aims —To elucidate the pathogenesis of enteric inflammation in this new subline. Methods —The SPF and germ free (GF) SAMP1/Yit strains were used. Histological, immunological, and microbiological characterisation of the mice with enteric inflammation was performed. Results —Histologically, enteritic inflammation developed as a discontinuous lesion in the terminal ileum and caecum with the infiltration of many inflammatory cells after 10 weeks of age. The activity of myeloperoxidase, and both immunolocalisation and mRNA expression of inducible nitric oxide synthase increased in the lesion. CD3-ε positive T cells, neutrophils, and macrophages were more numerous in the inflamed mucosa of the SAMP1/Yit strain. The GF SAMP1/Yit strain did not show any inflammation in the intestinal wall, by the age of 30 weeks, and the enteritis and caecitis developed 10 weeks after the conventionalisation of the GF SAMP1/Yit strain. Conclusion —Enteric inflammation in the ileum and caecum developed in the SAMP1/Yit strain. The pathophysiological characteristics of the disease in this mouse have some similarities to those of human inflammatory bowel disease (IBD). This mouse strain should be a useful model system for elucidating the interaction between the pathogenesis of IBD and the gut microflora.
High mutation rate of a long microsatellite allele in Drosophila melanogaster provides evidence for allele-specific mutation rates
Authors: C. Schlotterer, R. Ritter, B. Harr, G. Brem
Journal: Molecular Biology and Evolution (1998)

Within recent years, microsatellite have become one of the most powerful genetic markers in biology. For several mammalian species, microsatellite mutation rates have been estimated on the order of 10(-3)-10(-5). A recent study, however, demonstrated mutation rates in Drosophila melanogaster of at least one order of magnitude lower than those in mammals. To further test this result, we examined mutation rates of different microsatellite loci using a larger sample size. We screened 24 microsatellite loci in 119 D. melanogaster lines maintained for approximately 250 generations and detected 9 microsatellite mutations. The average mutation rate of 6.3 x 10(-6) is identical to the mutation rate from a previous study. Most interestingly, all nine mutations occurred at the same allele of one locus (DROYANETSB). This hypermutable allele has 28 dinucleotide repeats and is among the longest microsatellite reported in D. melanogaster. The allele-specific mutation rate of 3.0 x 10(-4) per generation is within the range of mammalian mutation rates. Future microsatellite analyses will have to account for the dramatic differences in allele-specific mutation rates.
Artificial nutrition and hydration in the last week of life in cancer patients. A systematic literature review of practices and effects
Authors: N.J.H. Raijmakers, L. van Zuylen, M. Costantini, A. Caraceni, J. Clark, G. Lundquist, R. Voltz, J.E. Ellershaw, A. van der Heide
Journal: Annals of Oncology (2011)
Release of vasoactive intestinal peptide by distention of the proximal stomach in dogs.
Authors: J A Chayvialle, M Miyata, P L Rayford, J C Thompson
Journal: Gut (1980)

The effect of transient proximal gastric distention was studied in six conscious dogs previously submitted to antrectomy and Billroth I anastomosis (and in which the intragastric pH was not altered), and in five anaesthetised dogs prepared with an innervated acute fundic pouch in which the pouch lumen was acidified with 0.15 M hydrochloric acid. Levels of vasoactive intestinal peptide (VIP) in portal and peripheral plasma were measured by radioimmunoassay. In conscious antrectomised dogs, distention of the proximal stomach to volumes of 250 and 500 ml evoked a significant rise of portal VIP concentration, with a maximal variation of 32.7 +/- 4.4 to 67.7 +/- 14.8 pg ml-1, which was hardly reflected in systemic blood. In the anaesthetised dogs, transient distention of the acute fundic pouch with 0.15 M hydrochloric acid under a pressure of 40 cm of water elicited a significant rise of portal VIP from 36.2 +/- 8.9 to 59.8 +/- 12.4 pg ml-1 (P &lt; 0.05) without any significant variation of the peptide concentration in peripheral plasma. These results indicate that vasoactive intestinal peptide is released under transient proximal gastric distention in dogs, and that this response is not solely dependent upon the acid secretory effect of distention in this species.
Mechanism of Ventricular Defibrillation for Near-Defibrillation Threshold Shocks
Authors: Nipon Chattipakorn, Isabelle Banville, Richard A. Gray, Raymond E. Ideker
Journal: Circulation (2001)

Background To study the mechanism by which shocks succeed (SDF) or fail (FDF) to defibrillate, global cardiac activation and recovery and their relationship to defibrillation outcome were investigated for shock strengths with approximately equal SDF and FDF outcomes (DFT 50 ). Methods and Results In 6 isolated pig hearts, dual-camera video imaging was used to record optically from ≈8000 sites on the anterior and posterior ventricular surfaces before and after 10 DFT 50 biphasic shocks. The interval between the shock and the last ventricular fibrillation activation preceding the shock (coupling interval, CI) and the time from shock onset to 90% repolarization of the immediate postshock action potential (RT 90 ) were determined at all sites. Of 60 shocks, 31 were SDF. The CI (59±7 versus 52±6 ms) and RT 90 (108±19 versus 88±8 ms) were significantly longer for SDF than FDF episodes. Spatial dispersions of CI (36±5 versus 34±3 ms) and RT 90 (40±16 versus 40±8 ms) were not significantly different for SDF versus FDF episodes. The first global activation cycle appeared focally on the left ventricular apical epicardium 78±32 ms after the shock. Conclusions For near-threshold shocks, defibrillation outcome correlates with the electrical state of the heart at the time of the shock and on RT. Global dispersion of RT was similar in both SDF and FDF episodes, suggesting that it is not crucial in determining defibrillation outcome after DFT 50 shocks.
Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN)
Authors: Philip Van Kerrebroeck, François Haab, Javier C. Angulo, Viktor Vik, Ferenc Katona, Alberto Garcia-Hernandez, Monique Klaver, Klaudia Traudtner, Matthias Oelke
Journal: European Urology (2013)
What Sets the Long-Term Level of Renal Sympathetic Nerve Activity
Authors: Carolyn J. Barrett, Rohit Ramchandra, Sarah-Jane Guild, Aneela Lala, David M. Budgett, Simon C. Malpas
Journal: Circulation Research (2003)

Increasing evidence suggests elevated sympathetic outflow may be important in the genesis of hypertension. It is thought that peripheral angiotensin II, in addition to its pressor actions, may act centrally to increase sympathetic nerve activity (SNA). Without direct long-term recordings of SNA, testing the involvement of neural mechanisms in angiotensin II-induced increases in arterial pressure is difficult. Using a novel telemetry-based implantable amplifier, we made continuous recordings of renal SNA (RSNA) before, during, and after 1 week of angiotensin II-based hypertension in rabbits living in their home cages. Angiotensin II infusion (50 ng x kg(-1) x min(-1)) caused a sustained increase in arterial pressure (18+/-3 mm Hg). There was a sustained decrease in RSNA from 18+/-2 normalized units (n.u.) before angiotensin II to 8+/-2 n.u. on day 2 and 9+/-2 n.u. on day 7 of the angiotensin II infusion (P<0.01) before recovering to 17+/-2 n.u. after ceasing angiotensin II. Analysis of the baroreflex response showed that although angiotensin II-induced hypertension led to resetting of the relationship between mean arterial pressure (MAP) and heart rate, there was no evidence of resetting of the MAP-RSNA relationship. We propose that the lack of resetting of the MAP-RSNA curve, with the resting point lying near the lower plateau, suggests the sustained decrease in RSNA during angiotensin II is baroreflex mediated. These results suggest that baroreflex control of RSNA and thus renal function is likely to play a significant role in the control of arterial pressure not only in the short term but also in the long term.
The Timing of Selection at the Human FOXP2 Gene
Authors: Graham Coop, Kevin Bullaughey, Francesca Luca, Molly Przeworski
Journal: Molecular Biology and Evolution (2008)

Krause J, Lalueza-Fox C, Orlando L, et al. recently examined patterns of genetic variation at FOXP2 in 2 Neanderthals. This gene is of particular interest because it is involved in speech and language and was previously shown to harbor the signature of recent positive selection. The authors found the same 2 amino acid substitutions in Neanderthals as in modern humans. Assuming that these sites were the targets of selection and no interbreeding between the 2 groups, they concluded that selection at FOXP2 occurred before the populations split, over 300 thousand years ago. Here, we show that the data are unlikely under this scenario but may instead be consistent with low rates of gene flow between modern humans and Neanderthals. We also collect additional data and introduce a modeling framework to estimate levels of modern human contamination of the Neanderthal samples. We find that, depending on the assumptions, additional control experiments may be needed to rule out contamination at FOXP2.
BT-08 * AUTOPSY DERIVED ORTHOTOPIC XENOGRAFT (ADOX) MOUSE MODELS FOR TERMINAL PEDIATRIC BRAIN TUMORS
Authors: Q. Li, P. Baster, M. Kogiso, Y. Du, H. Lindsay, Z. Liu, X. Zhao, J. Su, A. Adesina, A. Walter, J. Murray, R. McNall-Knapp, J. Nazarian, W. Parsons, M. Chintagumpala, S. Blaney, X.-N. Li
Journal: Neuro-Oncology (2015)

Accumulating evidences suggest that recurrent tumors may acquire genetic abnormalities different from their treatment naive counterparts. Since surgery is rarely an option for terminal brain tumors, autopsy is frequently the only chance to obtain therapy resistant tumor tissues. To determine and if (some) tumor cells can survival postmortem anoxia/starvation and to identify the seed cells that repopulate orthotopic xenograft tumors, we collected 29 autopsied brain tumors, including 15 DIPGs, 7 GBMs, 4 medulloblastomas (MB), 2 ependymomas and 1 ATRT, and made the following discoveries. i) A small fraction of tumor cells exhibited strong survival capacity and remained viable, ranging from 0.5%-40% (13.5% ± 10.9%), in tumors harvested 5-72 hrs (31.2 ± 25 hrs) after patients' death. ii) Many autopsied tumor cells stayed alive for short terms in culture and one pair of permanent lines (monolayer and neurosphere) were established from a GBM tumor. iii) Direct implantation of tumor cells into the brains of SCID mice led to the formation of orthotopic xenograft tumors in 17 of 22 tumors. 8 of the 17 autopsy derived orthotopic (ADOX) models have been subtransplanted in mouse brains for >3 times (5 DIPGs and 1 each of GBM, MB and ATRT). These ADOX tumors replicated histopathological features and genetic/genomic abnormalities of the patient tumors. iv) Time course analysis of putative cancer stem cells (CD133, CD15, CD24/CD44, CD57, CD117) identified CD57+ tumor cells as the most abundant viable subpopulation in the autopsied tumors, and their fractions increased in the ADOX tumors during serial subtransplantations. v) Purified CD57+ cells were able to form orthotopic xenografts, establishing their role as cancer stem cells. In conclusion, we have established a novel panel of ADOX mouse models for terminal brain tumors, and identified CD57 as a new marker for therapy-resistant cells that exhibited extraordinary survival and tumorigenic capabilities.