tbuckley/cabot-search huggingface dataset:
Venous Myogenic Tone and Its Regulation Through K <sup>+</sup> Channels Depends on Chronic Intravascular Pressure
Authors: Mátyás Szentiványi, Viktor Bérczi, Tivadar Hüttl, Robert S. Reneman, Emil Monos
Journal: Circulation Research (1997)

Abstract In this study, we compared the level of myogenic tone and its negative-feedback control through specific K + channels in two types of human veins (saphenous [SV] and cephalic [CV] veins), which experience different ranges of pressure in vivo. We also investigated whether an experimental model of increased venous pressure in rats exposed to head-up tilt for 2 weeks produced changes similar to those observed in the human veins. Cylindrical vein segments were cannulated, their diameters were measured, and the intraluminal pressure was set at different levels (2 to 30 mm Hg) in vitro. Acetylcholine test showed that during the regular harvesting process 76% of the human SVs exposed for coronary bypass grafts had no functional endothelium. We found significant myogenic tone in the human SV, where the in vivo pressure is high, but it was not present in the human CV, where the in vivo pressure is low. The nonspecific K + channel antagonist, tetraethylammonium (TEA), decreased the diameter of the human SV but not the CV. Iberiotoxin and 4-aminopyridine, blockers of the Ca 2+ -sensitive (K Ca ) and voltage-gated K + (K V ) channels, also decreased the diameter of the human SV by 10.2±4.8% and 19.5±4.7%, respectively. In the rat SV, significant myogenic tone was found, but TEA had no effect, even after 2 weeks of in vivo pressure increase in the hindlimb by head-up tilt. We conclude that (1) an increased venous myogenic tone correlates with higher chronic intraluminal pressure loads, (2) K Ca and K V channels counterregulate the myogenic tone in human, but not in rat, saphenous vein, (3) the counterregulatory effect is more effective at high than at low intraluminal in vitro pressure levels, and (4) its development is probably a long-term process.
Selective Sweeps at the Organophosphorus Insecticide Resistance Locus, Rop-1, Have Affected Variation across and beyond the -Esterase Gene Cluster in the Australian Sheep Blowfly, Lucilia cuprina
Authors: C. J. Rose, J. R. Chapman, S. D. G. Marshall, S. F. Lee, P. Batterham, H. A. Ross, R. D. Newcomb
Journal: Molecular Biology and Evolution (2011)

A major theoretical consequence of selection at a locus is the genetic hitchhiking of linked sites (selective sweep). The extent of hitchhiking around a gene is related to the strength of selection and the rate of recombination, with its impact diminishing with distance from the selected site. At the Rop-1 locus of the sheep blowfly, Lucilia cuprina, polymorphisms at two different sites within the LcαE7 gene encode forms of the protein that confer organophosphorus insecticide resistance. To assess the impact of selection at these two sites on variation around LcαE7, we sequenced regions within six other genes along chromosome IV across isogenic (IV) strains of L. cuprina. High levels of linkage disequilibrium, characterized by low haplotype number (K) and diversity (H), and significant R2 values were observed for two genes, LcαE1 and LcαE10, both members of the same α-esterase gene cluster as LcαE7. A significant R2 value was also observed for a gene predicted to be the next closest to LcαE7, AL03, but not for any of the other genes, LcRpL13a, Lcdsx, or LcAce. Skews in the site frequency spectra toward high-frequency variants were significant for LcαE1 (Fay and Wu's H = −2.91), LcαE10 (H = −1.85), and Lcdsx (H = −2.00). Since the selective sweeps, two forms of likely returning variation were observed, including variation in microsatellites in an intron of LcαE10 and a recombination event between LcαE7 and LcαE10. These data suggest that two incomplete soft sweeps have occurred at LcαE7 that have significantly affected variation across, and beyond, the α-esterase gene cluster of L. cuprina. The speed and impact of these selective sweeps on surrounding genomic variation and the ability of L. cuprina to respond to future environmental challenges are discussed.
Ilk conditional deletion in adult animals increases cyclic GMP-dependent vasorelaxation
Authors: Isabel Serrano, Sergio De Frutos, Mercedes Griera, Diana Medrano, Manuel Rodríguez-Puyol, Shoukat Dedhar, Maria Piedad Ruiz-Torres, Diego Rodríguez-Puyol
Journal: Cardiovascular Research (2013)

Integrin-linked kinase (ILK) regulates proliferation, differentiation, cell adhesion, and motility in many cell types and has been related to cancer progression, fibrosis, and vascular diseases. We designed the present study to directly explore the effect of ILK deletion on the regulation of vascular tone through the soluble guanylate cyclase (sGC) /protein kinase G (PKG) pathway in healthy adult mice. Experiments were carried out using a tamoxifen-inducible CRE-LOX system to conditionally delete the ILK gene in adult mice. Mice lacking ILK expression (cKO) presented increased vascular content and increased activity of sGC and PKG, resulting in a more intense vasodilatory response to a single dose of a nitric oxide (NO) donor [sodium nitroprusside (SNP)] or PKG agonist [8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt (8-Br)]. Five minutes after SNP or 8-Br administration the reduction in the systolic arterial pressure was enhanced in cKO mice (SNP WT: −7.4 ± 1.2 mmHG; SNP cKO: −14.0 ± 2.5; 8-Br WT: −2.9 ± 1.5 mmHG; 8-Br cKO: −10.0 ± 3.4 mmHG). ILK deletion restored the vascular response to SNP after chronic oral nitrite administration. In addition, ILK deletion also increased hypotensive SNP effect in angiotensin II-treated animals, suggesting a role for ILK in basal and pathological states. Deletion of ILK in adult animals increased the vascular response to NO. These findings show, for the first time, a requirement for ILK in regulating sGC–PKG expression in vivo.
Sternal fracture with fatal outcome in cystic fibrosis
Authors: P Latzin
Journal: Thorax (2005)

<h3>Abstract</h3> Effective suppression of transposable elements (TEs) is paramount to maintain genomic integrity and organismal fitness. In <i>D. melanogaster, flamenco</i> is a master suppressor of TEs, preventing their movement from somatic ovarian support cells to the germline. It is transcribed by Pol II as a long (100s of kb), single-stranded, primary transcript, that is metabolized into Piwi-interacting RNAs (piRNAs) that target active TEs via antisense complementarity. <i>flamenco</i> is thought to operate as a trap, owing to its high content of recent horizontally transferred TEs that are enriched in antisense orientation. Using newly-generated long read genome data, which is critical for accurate assembly of repetitive sequences, we find that <i>flamenco</i> has undergone radical transformations in sequence content and even copy number across <i>simulans</i> clade Drosophilid species. <i>D. simulans flamenco</i> has duplicated and diverged, and neither copy exhibits synteny with <i>D. melanogaster</i> beyond the core promoter. Moreover, <i>flamenco</i> organization is highly variable across <i>D. simulans</i> individuals. Next, we find that <i>D. simulans</i> and <i>D. mauritiana flamenco</i> display signatures of a dual-stranded cluster, with ping-pong signals in the testis and embryo. This is accompanied by increased multicopy elements, consistent with these regions operating as functional dual stranded clusters. Overall, the physical and functional diversity of <i>flamenco</i> orthologs is testament to the extremely dynamic consequences of TE arms races on genome organization, not only amongst highly related species, but even amongst individuals.
Weaning from mechanical ventilation
Authors: J-M. Boles, J. Bion, A. Connors, M. Herridge, B. Marsh, C. Melot, R. Pearl, H. Silverman, M. Stanchina, A. Vieillard-Baron, T. Welte
Journal: European Respiratory Journal (2007)

Weaning covers the entire process of liberating the patient from mechanical support and from the endotracheal tube. Many controversial questions remain concerning the best methods for conducting this process. An International Consensus Conference was held in April 2005 to provide recommendations regarding the management of this process. An 11-member international jury answered five pre-defined questions. 1) What is known about the epidemiology of weaning problems? 2) What is the pathophysiology of weaning failure? 3) What is the usual process of initial weaning from the ventilator? 4) Is there a role for different ventilator modes in more difficult weaning? 5) How should patients with prolonged weaning failure be managed? The main recommendations were as follows. 1) Patients should be categorised into three groups based on the difficulty and duration of the weaning process. 2) Weaning should be considered as early as possible. 3) A spontaneous breathing trial is the major diagnostic test to determine whether patients can be successfully extubated. 4) The initial trial should last 30 min and consist of either T-tube breathing or low levels of pressure support. 5) Pressure support or assist–control ventilation modes should be favoured in patients failing an initial trial/trials. 6) Noninvasive ventilation techniques should be considered in selected patients to shorten the duration of intubation but should not be routinely used as a tool for extubation failure.
Efficacy and safety of percutaneous treatment of iatrogenic femoral artery pseudoaneurysm by biodegradable collagen injection
Authors: Karim Hamraoui, Sjef M.P.G Ernst, Pascal F.H.M van Dessel, Johannes C Kelder, Jurriën M ten Berg, Maarten Jan Suttorp, Wybren Jaarsma, Thijs H.W Plokker
Journal: Journal of the American College of Cardiology (2002)
β-Catenin-Gli1 interaction regulates proliferation and tumor growth in medulloblastoma
Authors: Jenny Zinke, Fabian T Schneider, Patrick N Harter, Sonja Thom, Nicole Ziegler, Rune Toftgård, Karl H Plate, Stefan Liebner
Journal: Molecular Cancer (2015)

The Wnt/beta-catenin and the Hedgehog (Hh) pathway interact in various cell types while eliciting opposing or synergistic cellular effects. Both pathways are known as exclusive drivers of two distinct molecular subtypes of medulloblastoma (MB). In sonic hedgehog (Shh)-driven MB, activation of Wnt signaling has been shown to suppress tumor growth by either beta-catenin-dependent or -independent inhibition of Shh signaling. However, mechanistic insight in how beta-catenin inhibits the Hh pathway is not known. Here we show that beta-catenin stabilization by the glycogen synthase kinase 3 inhibitor lithium chloride (LiCl) reduced growth of primary hedgehog-driven MB tumor spheres from patched heterozygous mice (Ptch+/-) in vitro. LiCl treatment of MB spheres down-regulated the Hh target Gli1, whereas the repressive Gli3 protein (Gli3R) was increased. Mechanistically, we show by co-immunoprecipitation and proximity ligation assay that stabilized beta-catenin physically interacts with Gli1, leading to Gli1 sequestration and inhibition of its transcriptional activity. Reduction of Hh signaling upon LiCl stimulation resulted in reduced proliferation, sphere self renewal, a G2/M arrest and induction of a senescent-like state, indicated by p21 upregulation and by increased staining of senescence-associated beta-galactosidase (SA-betaGal). Moreover, LiCl treatment of subcutaneously transplanted MB cells significantly reduced tumor initiation defined as "tumor take". Although tumor progression was similar, LiCl-treated tumors showed decreased mitotic figures and phospho-histone H3 staining. We propose that beta-catenin stabilization increases its physical interaction with Gli1, leading to Gli1 degradation and inhibition of Hh signaling, thereby promoting tumor cell senescence and suppression of "tumor take" in mice.
A “Vascular Normalization Index” as Potential Mechanistic Biomarker to Predict Survival after a Single Dose of Cediranib in Recurrent Glioblastoma Patients
Authors: A. Gregory Sorensen, Tracy T. Batchelor, Wei-Ting Zhang, Poe-Jou Chen, Priscilla Yeo, Meiyun Wang, Dominique Jennings, Patrick Y. Wen, Johanna Lahdenranta, Marek Ancukiewicz, Emmanuelle di Tomaso, Dan G. Duda, Rakesh K. Jain
Journal: Cancer Research (2009)

Abstract Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti–vascular endothelial growth factor (VEGF) therapy can “normalize” brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging–measured changes in vascular permeability/flow (i.e., Ktrans) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in Ktrans, microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P &amp;lt; 0.05). When we combined these three parameters into a “vascular normalization index,” we found that it closely associated with overall survival (ρ = 0.54; P = 0.004) and progression-free survival (ρ = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials. [Cancer Res 2009;69(13):5296–300]
Induced sputum examination: diagnosis of pulmonary involvement in Fabry's disease
Authors: M. M Kelly
Journal: Thorax (2000)

Fabry9s disease is a rare inherited metabolic disorder caused by a deficiency in the enzyme α-galactosidase A. It can affect almost every organ, including the lungs. Confirmation of lung involvement has depended on invasive bronchial biopsy specimens or brushings to confirm the presence of typical lamellar inclusion bodies within bronchial epithelial cells. We report a patient with known Fabry9s disease in whom these inclusion bodies were identified by examination of induced sputum.
Targeting self-antigens through allogeneic TCR gene transfer
Authors: Moniek A. de Witte, Miriam Coccoris, Monika C. Wolkers, Marly D. van den Boom, Elly M. Mesman, Ji-Ying Song, Martin van der Valk, John B. A. G. Haanen, Ton N. M. Schumacher
Journal: Blood (2006)
Regulation of ERBB2 Receptor by t-DARPP Mediates Trastuzumab Resistance in Human Esophageal Adenocarcinoma
Authors: Jun Hong, Ahmed Katsha, Pengcheng Lu, Yu Shyr, Abbes Belkhiri, Wael El-Rifai
Journal: Cancer Research (2012)

Esophageal adenocarcinoma (EAC) is an aggressive malignancy with a poor outcome. Although targeting ERBB2 with trastuzumab has been evaluated in clinical trials, the molecular mechanisms of trastuzumab resistance remain uncharacterized in EAC. The dopamine and cyclic AMP-regulated phosphoprotein of MR 32000 (DARPP-32), also known as PPP1R1B, is located together with ERBB2 at the 17q12-q21 amplicon. We evaluated the expression of a transcript variant of DARPP-32 (t-DARPP) and ERBB2 in 141 primary tumors and investigated the role of t-DARPP in trastuzumab resistance using OE19 and OE33 EAC cell models. Overexpression of t-DARPP mRNA was detected in two-thirds of tumors with a correlation between ERBB2 and t-DARPP overexpression levels (r = 0.58, P = 0.003). Cell viability and clonogenic survival assays showed that t-DARPP increased survival by 40% in response to trastuzumab (P < 0.01). The Annexin-V staining and Western blot analysis indicated that t-DARPP effectively abrogated trastuzumab-induced apoptosis, inhibited cleavage of caspase-3, and blocked trastuzumab-induced dephosphorylation of ERBB2 and AKT proteins. The knockdown of endogenous t-DARPP reversed these effects and sensitized cells to trastuzumab (P < 0.01). The cycloheximide-based protein degradation analysis indicated that t-DARPP extended the half-life of ERBB2, explaining the increase in the basal levels of ERBB2, p-ERBB2(Y1248), and p-AKT(S473). Coimmunoprecipitation and Western blot analysis showed that t-DARPP associated with ERBB2 in a protein complex, and interfered with trastuzumab binding to the ERBB2 receptor. Using EAC-xenografted mouse model, t-DARPP enhanced tumor growth and rendered tumors unresponsive to trastuzumab. This study establishes t-DARPP as a mediator of trastuzumab resistance and underscores its potential importance in clinical trials of EAC.
Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard WHO protocol in Gambian mothers and infants: a randomised controlled trial
Authors: Momodou K Darboe, David I Thurnham, Gareth Morgan, Richard A Adegbola, Ousman Secka, Juan A Solon, Sarah J Jackson, Christine Northrop-Clewes, Tony J Fulford, Conor P Doherty, Andrew M Prentice
Journal: The Lancet (2007)
Development of Antibody Against Epitope of Lipoprotein(a) Modified by Oxidation
Authors: Shingo Yamada, Ryuichi Morishita, Shigefumi Nakamura, Toshio Ogihara, Yoshiaki Kusumi, Isamu Sakurai, Nobuhiko Kubo, Ikunosuke Sakurabayashi
Journal: Circulation (2000)

Background —Recently, the biological effects of oxidized lipoprotein(a) [Lp(a)] have been reported to be more potent than Lp(a), the arteriosclerosis-relevant lipoprotein. Thus, investigations with oxidized Lp(a) are expected to provide viewpoints different from the conventional ones based on Lp(a). Methods and Results —An anti-Lp(a) monoclonal antibody (161E2) was produced against synthetic peptide antigen (Arg-Asn-Pro-Asp-Val-Ala-Pro). This epitope was characterized as having various properties because its external exposure was induced as a result of oxidative modification. Using 161E2 antibody, we developed a new enzyme-linked immunosorbent assay to measure Lp(a) modified by oxidative stress. The present data demonstrated that oxidized Lp(a) that contains the epitope of 161E2 antibody was present in the serum of humans. Therefore, we used this new enzyme-linked immunosorbent assay to evaluate the role of oxidized Lp(a) in patients with hypertension, which induces oxidative stress . Interestingly, hypertensive patients with complications showed a significantly higher level of oxidized Lp(a) in serum than did normotensive subjects ( P &lt;0.01), whereas there was no significant difference in native Lp(a) between normotensive and hypertensive subjects. Importantly, positive immunostaining with 161E2 monoclonal antibody was found in the human arteriosclerotic tissue. Conclusions —We developed a new antibody against an epitope in Lp(a) as a result of oxidation treatment but not in native Lp(a). The present data demonstrated in vivo the presence of oxidized Lp(a) in the atherosclerotic tissue and its elevation in hypertensive patients. The presence of oxidized Lp(a) may be important in understanding the role of Lp(a) in cardiovascular disease.
Functional genetic polymorphisms and female reproductive disorders: Part I: polycystic ovary syndrome and ovarian response
Authors: M. Simoni, C.B. Tempfer, B. Destenaves, B.C.J.M. Fauser
Journal: Human Reproduction Update (2008)

BACKGROUNDThe identification of polymorphisms associated with a disease can help to elucidate its pathogenesis, and this knowledge can be used to improve prognosis for women with a particular disorder, such as polycystic ovary syndrome (PCOS). Since an altered response to ovarian stimulation is also a characteristic of the disease, further knowledge about its aetiology could help in defining the parameters that determine the response of an individual to ovarian stimulation.
Prospective Trial of Chemotherapy and Donor Leukocyte Infusions for Relapse of Advanced Myeloid Malignancies After Allogeneic Stem-Cell Transplantation
Authors: John E. Levine, Thomas Braun, Samuel L. Penza, Patrick Beatty, Kenneth Cornetta, Rodrigo Martino, William R. Drobyski, A. John Barrett, David L. Porter, Sergio Giralt, Jose Leis, Houston E. Holmes, Matthew Johnson, Mary Horowitz, Robert H. Collins
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)–primed DLIs. PATIENTS AND METHODS: Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF–primed DLIs. No prophylactic immunosuppression was provided. RESULTS: Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortality was 23%. Overall survival at 2 years for the entire cohort was 19%. Patients with a complete response were more likely to survive, with 1- and 2-year survival rates of 51% and 41%, respectively, with a median follow-up of more than 2 years. The 1-year survival for nonresponders was 5%. A posttransplant remission lasting more than 6 months before relapse was associated with a higher likelihood of response. GVHD was not required for durable remission. CONCLUSION: Salvage treatment with chemotherapy before DLI can help some patients with advanced myeloid relapse and is not dependent on GVHD. Patients with short remissions after BMT are unlikely to benefit from this approach, and the approach is associated with significant treatment-related mortality. Modifications of this approach or entirely different approaches will be required for most patients with this difficult clinical problem.
Early Detection Tools for Pancreatic Cancer
Authors: C. Schmidt
Journal: JNCI Journal of the National Cancer Institute (2012)

Finding pancreatic cancer while it’s still curable with surgery remains one of oncology’s most frustrating challenges. A growing pancreatic tumor can take more than 15 years to metastasize, during which patients generally aren’t symptomatic. When they finally experience abdominal pain, weight loss, and other hallmarks of the disease, it’s usually too late: Pancreatic cancer almost always kills within 2 years of diagnosis. But research funding for pancreatic cancer is up from $17.3 million in 1999 to $96.5 million today, according to the Pancreatic Cancer Action Network in Manhattan Beach, Calif. Meanwhile, researchers are making steady progress in early detection, focusing on blood biomarkers that might reveal the illness noninvasively and imaging tools that reveal potentially curable precursor lesions. Between them, imaging has made much bigger gains, according to Teri Brentnall, M.D., a gastroenterologist and professor at the University