tbuckley/cabot-search huggingface dataset:
An evolutionary and functional assessment of regulatory network motifs
Authors: Aurélien Mazurie, Samuel Bottani, Massimo Vergassola
Journal: Genome biology (2005)

Abstract Background Cellular functions are regulated by complex webs of interactions that might be schematically represented as networks. Two major examples are transcriptional regulatory networks, describing the interactions among transcription factors and their targets, and protein-protein interaction networks. Some patterns, dubbed motifs, have been found to be statistically over-represented when biological networks are compared to randomized versions thereof. Their function in vitro has been analyzed both experimentally and theoretically, but their functional role in vivo , that is, within the full network, and the resulting evolutionary pressures remain largely to be examined. Results We investigated an integrated network of the yeast Saccharomyces cerevisiae comprising transcriptional and protein-protein interaction data. A comparative analysis was performed with respect to Candida glabrata , Kluyveromyces lactis , Debaryomyces hansenii and Yarrowia lipolytica , which belong to the same class of hemiascomycetes as S. cerevisiae but span a broad evolutionary range. Phylogenetic profiles of genes within different forms of the motifs show that they are not subject to any particular evolutionary pressure to preserve the corresponding interaction patterns. The functional role in vivo of the motifs was examined for those instances where enough biological information is available. In each case, the regulatory processes for the biological function under consideration were found to hinge on post-transcriptional regulatory mechanisms, rather than on the transcriptional regulation by network motifs. Conclusion The overabundance of the network motifs does not have any immediate functional or evolutionary counterpart. A likely reason is that motifs within the networks are not isolated, that is, they strongly aggregate and have important edge and/or node sharing with the rest of the network.
Moving Forward in Advanced Bladder Cancer
Authors: David J. Vaughn
Journal: Journal of Clinical Oncology (2007)

strated an increased number of metastases compared with HER-2/ neu–negative patients (two v one; P .014), a greater probability of having two or more metastatic sites (51%v 31%;P .051), and a trend toward more liver and bone metastases. Perhaps, then, the group treated in the TPCG trial represents a cohort of patients with an especially poor prognosis. Previously, Bajorin et al 8 reported that Karnofsky performance status less than 80% and the presence of visceral sites of metastases (liver, lung, or bone) had independent poor prognostic significance for patients with advanced urothelial cancer treated with cisplatin-based chemotherapy. Patients with zero, one, and two risk factors had median survivals of 33, 13.4, and 9.3 months, respectively (P .0001). An important message of the Bajorin study is that advanced bladder cancer trials should report the proportion of patients with zero, one, and two risk factors to allow more meaningful interpretation of the results. Does the choice of the platinum analog matter in bladder cancer? From the toxicity point of view, carboplatin certainly offers some advantages, especially in a group of patients in which a significant proportion may present with impaired renal function. Small randomized phase II trials comparing regimens that differ mainly in the choice of the platinum compound favor the cisplatin arms. 9,10 Phase II trials of carboplatin plus either gemcitabine or paclitaxel doublets generally result in median survivals consistently less than those seen with the M-VAC and GC regimens. Although the evidence is indirect, cisplatin is probably the better agent. The effectiveness of the carboplatin-containing PCG triplet may be accounted for by the addition of a third cytotoxic agent. Certainly,
Is Fluorouracil-Induced Severe Toxicity in <i>DPYD*2A</i> Individuals Related to Sex or to Treatment Regimen?
Authors: Maarten J. Deenen, Jos H. Beijnen, Jan H.M. Schellens
Journal: Journal of Clinical Oncology (2008)

TO THEEDITOR:We very much appreciate the prospective manner of the study conducted by Schwab et al, 1 in which fluorouracil (FU) treatment-related toxicity was correlated with genetic and nongenetic factors in patients treated with FU monotherapy-based regimens. The study elegantly illustrated the complex and diverse clinical pictureallelicvariantsmayinduce,andservesasamodelforprospective pharmacogenetic validation studies. However, we propose that theauthorstakeanotherpotentiallycrucialparameterintheiranalysis into account that might lead to a different interpretation of the study results. Toxicity to FU depends on the type of treatment regimen, also illustrated by Schwab et al, with the bolus Mayo regimen resulting in the highest overall grade 3/4 toxicity rate. Based on the study results presented,webelievethatdevelopmentofseveretoxicityinDPYD*2A heterozygotes is determined by the treatment regimen and not by mode of administration nor by sex. Schwabetalobservedthatonlysixoutof13DPYD*2Aheterozy
The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB
Authors: Juan A. Moreno, Maria C. Izquierdo, Maria D. Sanchez-Niño, Beatriz Suárez-Alvarez, Carlos Lopez-Larrea, Aniela Jakubowski, Julia Blanco, Rafael Ramirez, Rafael Selgas, Marta Ruiz-Ortega, Jesus Egido, Alberto Ortiz, Ana B. Sanz
Journal: Journal of the American Society of Nephrology (2011)

Proinflammatory cytokines contribute to renal injury, but the downstream effectors within kidney cells are not well understood. One candidate effector is Klotho, a protein expressed by renal cells that has antiaging properties; Klotho-deficient mice have an accelerated aging-like phenotype, including vascular injury and renal injury. Whether proinflammatory cytokines, such as TNF and TNF-like weak inducer of apoptosis (TWEAK), modulate Klotho is unknown. In mice, exogenous administration of TWEAK decreased expression of Klotho in the kidney. In the setting of acute kidney injury induced by folic acid, the blockade or absence of TWEAK abrogated the injury-related decrease in renal and plasma Klotho levels. TWEAK, TNFα, and siRNA-mediated knockdown of IκBα all activated NFκB and reduced Klotho expression in the MCT tubular cell line. Furthermore, inhibition of NFκB with parthenolide prevented TWEAK- or TNFα-induced downregulation of Klotho. Inhibition of histone deacetylase reversed TWEAK-induced downregulation of Klotho, and chromatin immunoprecipitation showed that TWEAK promotes RelA binding to the Klotho promoter, inducing its deacetylation. In conclusion, inflammatory cytokines, such as TWEAK and TNFα, downregulate Klotho expression through an NFκB-dependent mechanism. These results may partially explain the relationship between inflammation and diseases characterized by accelerated aging of organs, including CKD.
Ascorbic acid in Charcot–Marie–Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial
Authors: Davide Pareyson, Mary M Reilly, Angelo Schenone, Gian Maria Fabrizi, Tiziana Cavallaro, Lucio Santoro, Giuseppe Vita, Aldo Quattrone, Luca Padua, Franco Gemignani, Francesco Visioli, Matilde Laurà, Davide Radice, Daniela Calabrese, Richard AC Hughes, Alessandra Solari
Journal: The Lancet Neurology (2011)
Effect of lung function and mode of inhalation on penetration of aerosol into the human lung.
Authors: D Pavia, M L Thomson, S W Clarke, H S Shannon
Journal: Thorax (1977)

The method using radioactive tracer particles has been applied to study the effect of the mode of inhalation of aerosols on the depth of deposition in the lungs of 50 patients with airways obstruction. The findings show that the penetration of particles is directly related to: (1) volume inspired per breath (VI); (2) forced expiratory volume in one second (FEV1); and inversely related to (3) flow rate during inhalation (V). In mathematical terms, alveolar deposition (%) = 40-3 (VI)+10-98 (FEV1)--0-75 (V)+40-4; for this regression F = 4-41 and P less than 0-01.
Proof-of-Principle Evaluation of the Efficacy of Fewer Than Three Doses of a Bivalent HPV16/18 Vaccine
Authors: Aimée R. Kreimer, Ana Cecilia Rodriguez, Allan Hildesheim, Rolando Herrero, Carolina Porras, Mark Schiffman, Paula González, Diane Solomon, Silvia Jiménez, John T. Schiller, Douglas R. Lowy, Wim Quint, Mark E. Sherman, John Schussler, Sholom Wacholder
Journal: JNCI Journal of the National Cancer Institute (2011)

Three-dose regimens for human papillomavirus (HPV) vaccines are expensive and difficult to complete, especially in settings where the need for cervical cancer prevention is greatest. We evaluated the vaccine efficacy of fewer than three doses of the HPV16/18 vaccine Cervarix in our Costa Rica Vaccine Trial. Women were randomly assigned to receive three doses of the HPV16/18 vaccine or to a control vaccine and were followed for incident HPV16 or HPV18 infection that persisted in visits that were 10 or more months apart (median follow-up 4.2 years). After excluding women who had no follow-up or who were HPV16 and HPV18 DNA positive at enrollment, 5967 women received three vaccine doses (2957 HPV vaccine vs 3010 control vaccine), 802 received two doses (422 HPV vs 380 control), and 384 received one dose (196 HPV vs 188 control). Reasons for receiving fewer doses and other pre- and post-randomization characteristics were balanced within each dosage group between women receiving the HPV and control vaccines. Incident HPV16 or HPV18 infections that persisted for 1 year were unrelated to dosage of the control vaccine. Vaccine efficacy was 80.9% for three doses of the HPV vaccine (95% confidence interval [CI] = 71.1% to 87.7%; 25 and 133 events in the HPV and control arms, respectively), 84.1% for two doses (95% CI = 50.2% to 96.3%; 3 and 17 events), and 100% for one dose (95% CI = 66.5% to 100%; 0 and 10 events). Four years after vaccination of women who appeared to be uninfected, this nonrandomized analysis suggests that two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses.
Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial
Authors: Freddy Cornillie, Stephen B Hanauer, Robert H Diamond, Jianping Wang, Kezhen L Tang, Zhenhua Xu, Paul Rutgeerts, Séverine Vermeire
Journal: Gut (2014)

Serum infliximab trough levels correlate with efficacy; dose escalation is often beneficial in patients with Crohn's disease who stop responding to infliximab treatment.To carry out a post hoc analysis of A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen I (ACCENT I) to evaluate the association between serum infliximab trough levels and C-reactive protein (CRP) after 14 weeks of induction treatment with durable sustained long-term response (Crohn's Disease Activity Index decrease ≥70 points and reduction ≥25% from baseline).ACCENT I was a multicentre, randomised, placebo-controlled study. Week 14 trough levels and CRP percentage decrease from baseline to week 14 were compared between patients with and without durable sustained response through week 54. Sensitivity and specificity were determined to predict durable sustained response. Receiver operating characteristic (ROC) curves identified optimal cut-off points; logistic regression determined ORs.After induction with 5 mg/kg infliximab, 25% (37/147) and 33% (47/144) of patients sustained week 14 response to infliximab 5 or 10 mg/kg, respectively, administered every 8 weeks without dose escalation, through week 54. Median week 14 trough levels of patients with and without durable sustained response to infliximab 5 mg/kg were 4.0 and 1.9 μg/mL, respectively (p=0.0331). Optimal predictors of durable sustained response to maintenance infliximab 5 mg/kg were week 14 trough level ≥3.5 µg/mL and ≥60% CRP decrease (ORs (95% CI), 3.5 (1.1 to 11.4) and 7.3 (1.4 to 36.7)), respectively, in patients with raised baseline CRP (>8.0 mg/L); area under the ROC curve was 0.75 for both predictors. A ≥3.5 µg/mL week 14 infliximab serum level did not predict durable sustained response to 10 mg/kg maintenance infliximab.Patients with durable sustained response to maintenance infliximab 5 mg/kg had higher postinduction trough levels than patients without durable sustained response. Serum infliximab trough levels ≥3.5 µg/mL and ≥60% CRP decrease were significantly associated with durable sustained response.
Long-term follow-up of interferon alfa treatment in chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications
Authors: Man-Fung Yuen, Chee-Kin Hui, Chi-Chung Cheng, Chi-Hang Wu, Yim-Ping Lai, Ching-Lung Lai
Journal: Hepatology (2001)

The long-term effect of interferon alfa (IFN-alpha) in Chinese patients with chronic hepatitis B infection is unknown. A total of 411 chronic hepatitis B patients (208 treated with IFN-alpha and 203 as control) were followed up for hepatitis B serology and the development of hepatoma and other cirrhosis-related complications. The hepatitis B e antigen (HBeAg) seroconversion rate in the IFN-alpha-treated group, though significantly greater at 6 and 24 months, was comparable with the control group on subsequent follow-up, irrespective of pretreatment alanine transaminase (ALT) levels. HBeAg seroreversion rate was higher in the IFN-alpha group compared with the control group (21.1% vs. 2.2%; P =.001). Loss of hepatitis B surface antigen (HBsAg) occurred in 2.4% of the IFN-alpha-treated patients and 0.49% of the control patients (P = NS). Around 90% of the anti-HBe-positive patients in both groups were still hepatitis B virus (HBV)-DNA-positive by polymerase chain reaction (PCR) assay. Two patients suffered from hepatic reactivation during the course of treatment. Nine (4.3%) patients in the IFN-alpha group and 2 (1.0%) in the control group developed complications of cirrhosis and hepatoma (P =.062). In Chinese HBsAg carriers, IFN-alpha was of no long-term benefit in inducing HBeAg seroconversion or in the prevention of hepatoma and other cirrhosis-related complications.
Cardioplegic Strategies for Calcium Control : Low Ca2+, High Mg2+, Citrate, or Na+/H+ Exchange Inhibitor HOE-642
Authors: Y. Fukuhiro, M. Wowk, R. Ou, F. Rosenfeldt, S. Pepe
Journal: Circulation (2000)

Ca(2+) overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca(2+) overload has been to reduce Ca(2+) in the cardioplegic solution (CP). Recent reports suggest that Na(+)/H(+) exchange inhibitors can also prevent Ca(2+) overload. We compared 4 crystalloid CPs that might minimize Ca(2+) overload in comparison with standard Mg(2+)-containing CP: (1) low Ca(2+) CP (0.25 mmol/L), (2) citrate CP/normal Mg(2+) (1 mmol/L Mg(2+)), (3) citrate CP/high Mg(2+) (9 mmol/L Mg(2+)), and (4) the addition of the Na(+)/H(+) exchange inhibitor HOE-642 (Cariporide). We also tested the effect of citrate titration in vitro on the level of free Ca(2+) and Mg(2+) in CPs.Isolated working rat heart preparations were perfused with oxygenated Krebs-Henseleit buffer and subjected to 60 minutes of 37 degrees C arrest and reperfusion with CPs with different Ca(2+) concentrations. Cardiac performance, including aortic flow (AF), was measured before and after ischemia. Myocardial high-energy phosphates were measured after reperfusion. The in vitro addition of citrate to CP (2%, 21 mmol/L) produced parallel reductions in Mg(2+) and Ca(2+). Because only Ca(2+) was required to be low, the further addition of Mg(2+) increased free Mg(2+), but the highest level achieved was 9 mmol/L. Citrate CP significantly impaired postischemic function (AF 58.3+/-2. 5% without citrate versus 41.6+/-3% for citrate with normal Mg(2+), P:<0.05, versus 22.4+/-6.2% for citrate with high Mg(2+), P:<0.05). Low-Ca(2+) CP (0.25 mmol/L Ca(2+)) significantly improved the recovery of postischemic function in comparison with standard CP (1.0 mmol/L Ca(2+)) (AF 47.6+/-1.7% versus 58.3+/-2.5%, P:<0.05). The addition of HOE-642 (1 micromol/L) to CP significantly improved postischemia function (47.6+/-1.7% without HOE-642 versus 62.4+/-1. 7% with HOE-642, P:<0.05). Postischemia cardiac high-energy phosphate levels were unaffected by Ca(2+) manipulation.(1) A lowered Ca(2+) concentration in CP is beneficial in Mg(2+)-containing cardioplegia. (2) The use of citrate to chelate Ca(2+) is detrimental in the crystalloid-perfused isolated working rat heart, especially with high Mg(2+). (3) The mechanism of citrate action is complex, and its use limits precise simultaneous control of Ca(2+) and Mg(2+). (4) HOE-642 in CP is as efficacious in preservation of the ischemic myocardium as is the direct reduction in Ca(2+).
The safety of inhaled β-agonist bronchodilators during pregnancy
Authors: Michael Schatz, Robert S. Zeiger, Kathleen M. Harden, Clement P. Hoffman, Alan B. Forsythe, Linda M. Chilingar, Richard P. Porreco, Abram S. Benenson, William L. Sperling, Brian S. Saunders, Marcia C. Kagnoff
Journal: Journal of Allergy and Clinical Immunology (1988)
The Expanding Roles of G<i>βγ</i>Subunits in G Protein–Coupled Receptor Signaling and Drug Action
Authors: Shahriar M. Khan, Rory Sleno, Sarah Gora, Peter Zylbergold, Jean-Philippe Laverdure, Jean-Claude Labbé, Gregory J. Miller, Terence E. Hébert
Journal: Pharmacological Reviews (2013)

G<i>βγ</i> subunits from heterotrimeric G proteins perform a vast array of functions in cells with respect to signaling, often independently as well as in concert with G<i>α</i> subunits. However, the eponymous term "G<i>βγ</i>" does not do justice to the fact that 5 G<i>β</i> and 12 G<i>γ</i> isoforms have evolved in mammals to serve much broader roles beyond their canonical roles in cellular signaling. We explore the phylogenetic diversity of G<i>βγ</i> subunits with a view toward understanding these expanded roles in different cellular organelles. We suggest that the particular content of distinct G<i>βγ</i> subunits regulates cellular activity, and that the granularity of individual G<i>β</i> and G<i>γ</i> action is only beginning to be understood. Given the therapeutic potential of targeting G<i>βγ</i> action, this larger view serves as a prelude to more specific development of drugs aimed at individual isoforms.
A new ultrasonographic device for within-breath measurements of diaphragm thickness during breathing
Authors: Dario Bovio, Alberto Biancardi, Giorgio Gobitti, Marianna Laviola, Barbara Uva, Rita Priori, Andrea Aliverti
Journal: European Respiratory Journal (2012)

Preliminary studies have shown the possibility to use ultrasounds (US) to measure diaphragmatic thickness (DT). In order to allow accurate and operator-free US measurements of within-breath DT during tidal breathing, we have designed and prototyped an innovative US device composed by a single piezo-element probe (SPEP, 7.5 MHz) able to generate and detect radio frequency (RF) echo signals of the pleural and peritoneal membranes of the diaphragm. The prototype was tested on a phantom and successively on 6 healthy subjects (3M, 3F), who were studied in supine position during spontaneous quiet breathing at rest. The SPEP was fixed by adhesive tape on the lateral ribcage (9th or 10th intercostal space) and data were acquired continuously and synchronously with a pneumotachograph. The in-vitro validation showed an accuracy of ±0.05 mm. In average, DT thickness was 1.55±0.17 and 1.9±0.21 mm, respectively at end-expiration and end-inspiration. DT variations during tidal breathing were in average 0.35±0.05 mm with different patterns of within-breath DT changes (see figure for a representative example). In conclusion, the SPEP device: a) is characterized by measurement accuracy able to detect the small changes of DT during quiet breathing; b) allows an operator-free method to monitor DT during breathing and to study different patterns of DT variations, corresponding to different timing of diaphragm activation.
Molecular internalization of a region of myelin basic protein
Authors: JN Whitaker, CHJ Chou, FCH Chou, RF Kibler
Journal: The Journal of Experimental Medicine (1977)

The conformation of myelin encephalitogenic or basic protein (BP) was investigated with a double-antibody radioimmunoassay by studying the reaction of BP or its fragments with antibodies produced in two rabbits against peptide 43-88 linked to rabbit serum albumin. Both antisera reacted well with peptide 43-88 but showed little or no reaction with BP. Absorption of these antisera with a BP-immunoadsorbent did not remove the antibody activity against peptide 43-88. Within the region of peptide 43- 88 it was shown that peptides 68-88 and 79-88 gave an equivalent or better reaction than peptide 43-88, whereas peptides 43-67 and 64-73 had very little reactivity. In the BP fragments containing region 43-88, peptide 1-88 showed the best reactivity, peptide 20-166 showed minimal reactivity, while peptide 1-115 showed none. These data document the internal position of at least a portion of peptide 43-88 and all of residues 79-88 in the BP molecule. The much greater reactivity of peptide 1-88 as compared to peptide 1-115 suggests that the region or a portion of the region of BP containing residues 89- 115 participates in the conformational alignment of BP restricting access to peptide 79-88. After absorption with BP, neither of the antisera prepared to peptide 43-88 reacted with PNS myelin in fixed tissue sections but continued to react with CNS myelin in similarly treated sections. The present findings demonstrate the need to consider the role of shielded antigenic determinants in the investigation of antigens or of immune responses.
Circulation of Iodinated Albumin Through Aortic and Other Connective Tissues of the Rabbit
Authors: LEROY E. DUNCAN, JEROME CORNFIELD, KATHERIN BUCK
Journal: Circulation Research (1958)

A method is presented for the determination of the rates of movement of macromolecules into and out of specific tissues by analysis of the serum and tissue concentrations of the intravenously injected labeled macromolecule. Transfer rates of albumin into and out of rabbit aorta, skin, tendon, sclera, and cornea are given. These rates, and the steady-state ratios of tissue albumin to serum albumin, are interpreted in terms of current theory regarding the diffusion and filtration of albumin at capillary and lymphatic exchange sites in the tissues. Transfer rates for average body tissue, obtained by analysis of the serum concentration of intravenously injected labeled albumin, are compared with the transfer rates for the specific tissues studied.
Correlation between gas-exchange dynamics in recovery of exercise tests and cardiovascular parameters in pulmonary hypertension
Authors: Patrick Jak, Harm-Jan Boogaard, Anton Vonk-Noordegraaf
Journal: European Respiratory Journal (2012)

Introduction: In pulmonary hypertension (PH), cardiac dysfunction and gas exchange abnormalities within the lung may both delay the rate of recovery in O2-uptake (V'O2) and CO2-release (V'CO2) after a cardiopulmonary exercise test (CPET).

Aim: Determine the correlation between recovery rates of V'O2,V'CO2 after CPET with pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF).

Method: In this retrospective study measurements on 12 PH-patients were used. 1-4 CPETs and heart catheterisations (for PVR measurement) per patient were done. Sometimes also a cardiac MRI was performed, rendering RVEF.

View this table:

test group characteristics





Results: Changes in V'O2,V'CO2 strongly correlated with PVR and RVEF.

![Figure][1] 



![Figure][1] 



Conclusion: In PH-patients, slow recovery-rates of VO2 and VCO2 are associated with a high PVR and low RVEF.

 [1]: pending:yes