tbuckley/cabot-search huggingface dataset:
Abstract 1727: Development of novel TAK1 inhibitors for pancreatic cancer
Authors: Paul J. Chiao, Zhuonan Zhuang, Qianghua Xia, Paul T. Schuber, Duoli Sun, Zhenghong Peng, David S. Maxwell, William G. Bornmann
Journal: Cancer Research (2014)

Abstract Transforming growth factor- (TGF-) activation kinase (TAK1, MAP3K7) is a member of MAPKKK family [1]. It was well established that TAK1 plays a key role in both TNFα and IL-1 pathway. Knock down of TAK1 impaired the activation of IKK and JNK by TNFα and IL-1 [2, 3]. NF-B activation induced by TNFα and IL-1 are severely impaired in TAK1 knock out MEF cells [4]. TAK1 acts as the kinase of IKK and therefore regulates NF-κB activation. Our previous work has demonstrated that TAK1 is upregulated and plays an important role in chemotherapeutic drug resistance in pancreatic cancer cells. Block TAK1 activity can reverse pancreatic cancer cell resistance to chemotherapeutic drug and reduce tumor size in Orthotopic Xenograft models [5]. These findings underscore the significance of TAK1 in mediating drug resistance. Strategies to target TAK1 may play a critical role in the treatment of this deadly malignancy. Utilizing computational-based structural modeling and a recently published crystal structure of TAK1, compounds were designed to inhibit the ATP-binding pocket of the TAK1. Synthetic templates were proposed for building a urea based library of potential inhibitors. A multiple stage docking involving both pre- and post-filtering and progressively more stringent docking criteria led to approximately 1,000 structures. The resulting scores from two docking programs were fed into workflow software that combined the results and calculated ADME properties. To provide better consistency in scoring and less bias in setting the filtering cutoffs, we also included docking decoys and utilized a more statistically relevant Z-score. After application of a final binding mode filter, there were 22 structures that were selected and ranked. A seven-step synthesis was developed and a focused library of compounds was synthesized from those top-ranked compounds. Note: This abstract was not presented at the meeting. Citation Format: Paul J. Chiao, Zhuonan Zhuang, Qianghua Xia, Paul T. Schuber, Duoli Sun, Zhenghong Peng, David S. Maxwell, William G. Bornmann. Development of novel TAK1 inhibitors for pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1727. doi:10.1158/1538-7445.AM2014-1727
Blood Glucose and Risk of Cardiovascular Disease in the Asia Pacific Region
Journal: Diabetes Care (2004)

OBJECTIVE—To assess the shape and strength of the association between usual blood glucose and cardiovascular disease (CVD) in Asian and Australasian cohorts and to determine the impact of adjusting for other determinants of CVD risk and excluding people with diabetes. RESEARCH DESIGN AND METHODS—Relative risk estimates and 95% CIs were calculated from Cox models, stratified by sex and cohort, and adjusted for age at risk on individual participant data from 17 cohort studies. Repeat measurements of blood glucose were used to adjust for regression dilution bias. RESULTS—Fasting blood glucose data were available for 237,468 participants, and during ∼1.2 million person-years of follow-up, there were 1,661 stroke and 816 ischemic heart disease (IHD) events. Data were also available on 27,996 participants with nonfasting glucose measurements. Continuous positive associations were demonstrated between usual fasting glucose and the risks of CVD down to at least 4.9 mmol/l. Overall, each 1 mmol/l lower usual fasting glucose was associated with a 21% (95% CI 18–24%) lower risk of total stroke and a 23% (19–27%) lower risk of total IHD. The associations were similar in men and women, across age-groups, and in Asian compared with Australasian (Australia and New Zealand) populations. Adjusting for potential confounders or removing those with diabetes as baseline did not substantially affect the associations. Associations for nonfasting glucose were weaker than those with fasting glucose. CONCLUSIONS—Fasting blood glucose is an important determinant of CVD burden, with considerable potential benefit of usual blood glucose lowering down to levels of at least 4.9 mmol/l.
Salivary oral cancer transcriptome biomarkers (SOCTB) for clinical detection
Authors: Jianghua Wang, Sharon Henry, Tianwei Yu, Li Yang, David Elashoff, Myungshin Oh, Ker-Chau Li, xuelian Wei, David Wong
Journal: Cancer Research (2006)

4468   Objectives: Seven salivary oral cancer transcriptome biomarkers (SOCTB: SAT1, S100P, OAZ1, IL1B, IL8, H3F3A and DUSP1) have been identified to distinguish oral cancer from normal controls by relative quantification. However, technological variables inherent in DNA-based standard quantitative RT-PCR, as well as differential RNA degradation and RNA input created baseline shifts that prevented use of a cut-off threshold between experiments to segregate oral cancer from controls. The purpose of this study is to further validate the 7 biomarkers and to establish a genuine absolute quantitative PCR using RNA-based standard quantification, and using saliva internal control gene to normalize input RNA quantity, to make salivary RNA biomarker measurement more accurate and reproducible and solve the base-line shifting problem. Methods: For detecting each of the SOCTB, technology variance was explored by utilizing genuine absolute quantification. Primers for specific amplification of each of 7 SOCTB mRNAs with T 7  promoter sequence fused to 5’ end were designed and used to generate recombinant RNA(recRNA). Quantitation of recRNA was accurately measured with Nanodrop bioanalyser, and serial dilution was used to generate standard. Each set of standard was quantified by real time quantitativePCR (qPCR) parallel with saliva RNA samples. RNA input and degradation was explored by normalization to saliva internal reference (SIR) genes. WilCOXon test and ROC analysis were used to judge the quality of makers. Results: qPCR data has shown that in 4 independent detection trials, the 7 SOCTB gene expression levels are significantly elevated (> 1.5 fold, p
Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition
Authors: Mingyu Lee, Dae Woo Kim, Haejin Yoon, Daeho So, Roza Khalmuratova, Chae-Seo Rhee, Jong-Wan Park, Hyun-Woo Shin
Journal: Journal of Allergy and Clinical Immunology (2015)
Abstract 1071: Expression and Pharmacological Correction of a LQT2 Mutant (hERG) Channel in Native Cardiomyocytes
Authors: Katherine M Holzem, Ravi C Balijepalli, Eric C Lin, Jing Wang, Timothy J Kamp, Brian P Delisle, Craig T January
Journal: Circulation (2007)

Mutations within the human Ether-a-go-go Related Gene (hERG) encoding for the hERG K + channel can lead to long QT syndrome type 2 (LQT2). Previous investigations have been performed using non-cardiac heterologous expression systems, and in mammalian systems most LQT2-linked missense mutations are trafficking deficient, with the channel protein failing to express at the cell surface membrane. Furthermore, the majority of these mutations can be induced to traffic to the cell surface by incubation in drugs (pharmacological correction), which has suggested that pharmacological correction might be developed as a clinical therapy. To further establish the feasibility of pharmacological correction in the heart, we demonstrated it in cardiomyocytes. We studied expression of WT-hERG and the trafficking-deficient LQT2-linked N470D-hERG mutation in HEK293 cells (using Superfect) or cardiomyocytes (using electroporation) isolated from 2-day-old mice. Using the patch clamp method to measure I hERG , peak tail current amplitude for N470D-hERG was reduced by 74% compared to WT-hERG in HEK293 cells (n=7–13 cells, p&lt;0.05) and 94% in cardiomyocytes (n=6 –9 cells, p&lt;0.05). HEK293 cells or cardiomyocytes expressing N470D-hERG were incubated with or without E-4031 (10 μM for 24 hrs) and E-4031 was washed out prior to recording I hERG . Incubation in E-4031 increased I hERG by 447% in HEK293 cells (n=9 –13 cells, p&lt;0.05) and 1300% in cardomyocytes (n=6 –9 cells, p&lt;0.05). We also measured the activation properties for I hERG . The potentials for half-maximal activation (V 1/2 ) of WT-hERG expressed in HEK293 cells or cardiomyocytes were −7.5±1.8 and −12.9±1.1mV with slope factors of 6.7±0.2 and 6.2±0.3mV/ e -foldΔ, respectively (n=5 cells each). The V 1/2 for N470D-hERG after pharmacological correction in E-4031 was -38.1±2.4mV for HEK293 cells and -50.6±5.3mV for cardiomyocytes with slope factors of 7.1±0.3 and 9.9±1.1 mV/ e -foldΔ, respectively (n=5 cells each). Our results demonstrate functional expression of WT- and N470D-hERG in a native cardiomyocyte system and that hERG channel properties are similar between expression systems. These are the first data to show pharmacological correction in cardiomyocytes.
Long-term cognitive function in very low-birth-weight infants.
Authors: Lane Strathearn
Journal: JAMA (2003)

not clear how much of that reflects regional differences in epidemiology and how much is lack of case ascertainment in other parts of the country where HSV-2 infection is equally prevalent. Dr Cohan questions our finding of the protection from HSV transmission by cesarean delivery. Although we agree that the number of infected infants was small, a similar degree of protectionbycesareandeliverywasnotedinboththeunivariateand multivariate analyses, with a 7-fold higher risk of neonatal infection among women with vaginal deliveries; the multivariate estimate did not reach statistical significance. We disagree with Cohanthatwomenwhohadnegativecultureresultswouldhave had less benefit from cesarean delivery. Viral cultures are not a sensitivemethodfordetectionofHSVonmucosalsurfaces.High levels of HSV DNA can be detected and transmission can occur evenwithnegativeviralcultureresults. 4,5 WeshareCohan’sconcern regarding morbidity of cesarean delivery, but recent data are reassuring and suggest that there may not be excess mortality. 6,7 The risk of an infant exposed to infected secretions developing neonatal herpes is 5%—much higher than the maternal risk of serious complications from cesarean delivery. We hope thatevensaferandlessinvasiveapproachestoneonatalHSVprevention can be developed.
Abstract 18692: Association of Sleep Medication with Cardiorespiratory Fitness in Normotensives, Prehypertensives and Hypertensives
Authors: Faye S Routledge, Rebecca Gary, Ann E Rogers, Sudeshna Paul, Sandra B Dunbar
Journal: Circulation (2014)

Background: Recent studies link insomnia with increased risk of hypertension. The reasons for this association are unknown but may be related, in part, to decreased levels of physical activity and cardiorespiratory fitness. Additionally, sleep medication often has multiple deleterious side effects that may impact a person’s engagement in physical activity. We hypothesized that insomnia symptoms and sleep medication use were associated with reduced cardiorespiratory fitness. Methods: Adults (n=606) enrolled in the Emory-Georgia Tech Predictive Health Institute study completed baseline demographic, clinical, depression (Beck Depression Inventory II; BDI-II), sleep (Pittsburg Sleep Quality Index , PSQI) and cardiorespiratory fitness (maximal oxygen consumption; VO2max) measures. Insomnia symptoms (sleep latency of ≥30 minutes, nighttime or early morning awakenings) and sleep medication use ≥1 times/week were derived from the PSQI. Multiple linear regression was performed to test for associations between cardiorespiratory fitness and insomnia symptoms or sleep medication use. Results: The sample was 68% female, 25% African American, 41% normotensive, 33% prehypertensive, 26% hypertensive with a mean age of 48±11 years and mean body mass index (BMI) 27.6±6.3 kg/m2. Sleep medication use was reported in 11.9% of normotensives and was inversely associated with VO2max adjusting for age, gender, ethnicity, BMI, and heart rate (β=-0.12, p=.03, adjusted R2=.36) and remained significant after further adjustment for blood pressure, HDL cholesterol, depression and smoking (β=-0.11, p=.03, adjusted R2=.41). Sleep medication use was reported in 18.4% of prehypertensives and 22.8% of hypertensives but was not significantly associated with VO2max in either group. No evidence of association between insomnia symptoms and VO2max was found. Conclusion: Sleep medication was related to reduced cardiorespiratory fitness in normotensives. People who use sleep medication may be less physically active placing them at greater cardiovascular risk which has important clinical implications for risk reduction. This relationship is attenuated in prehypertension or hypertension and may reflect the influence of pathophysiology and other variables.
3D molecular MR imaging of liver fibrosis and response to rapamycin therapy in a bile duct ligation rat model
Authors: Christian T. Farrar, Danielle K. DePeralta, Helen Day, Tyson A. Rietz, Lan Wei, Gregory Y. Lauwers, Boris Keil, Arun Subramaniam, Anthony J. Sinskey, Kenneth K. Tanabe, Bryan C. Fuchs, Peter Caravan
Journal: Journal of Hepatology (2015)
Association of <i>FCGR3A</i> and <i>FCGR3B</i> Copy Number Variations With Systemic Lupus Erythematosus and Rheumatoid Arthritis in Taiwanese Patients
Authors: Ji‐Yih Chen, Chin‐Man Wang, Su‐Wei Chang, Ching‐Hui Cheng, Yeong‐Jian Jan Wu, Jing‐Chi Lin, Bing Yang, Huei‐Huang Ho, Jianming Wu
Journal: Arthritis & Rheumatology (2014)

To determine whether copy number variations (CNVs) in FCGR3A and FCGR3B are associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese individuals.FCGR3A and FCGR3B CNV genotypes were determined in 846 patients with SLE, 948 patients with RA, and 1,420 healthy control subjects, using custom TaqMan CNV assays. The FCGR3A and FCGR3B CNV genotypes were compared between healthy control subjects and patients and among patients stratified according to clinical characteristics.A low (<2) FCGR3A copy number was significantly associated with SLE (for <2 copies versus 2 copies, P = 5.06 × 10(-4) , false discovery rate-corrected P [PFDR ] = 0.001, odds ratio [OR] 3.26, 95% confidence interval [95% CI] 1.68-6.35) and RA (for <2 copies versus 2 copies, P = 5.83 × 10(-4) , PFDR = 0.0012, OR 2.82, 95% CI 1.56-5.1). A low FCGR3B copy number was also significantly associated with SLE (for <2 copies versus 2 copies, P = 0.0032, PFDR = 0.0032, OR 1.59, 95% CI 1.17-2.18). Notably, a high (>2) FCGR3A copy number was also associated with SLE (for >2 copies versus 2 copies, P = 0.003, PFDR = 0.0061, OR 1.6, 95% CI 1.17-2.18). Additionally, the FCGR3A low copy number genotype was significantly enriched in subsets of patients with SLE (those with ulcer, arthritis, rash, discoid rash, photosensitivity, nephritis, leukopenia, thrombocytopenia, depressed complement levels, and autoantibody positivity) and patients with RA (those positive for rheumatoid factor) compared with healthy control subjects. The FCGR3B low copy number genotype was also significantly enriched in SLE patients with ulcer, rash, discoid rash, photosensitivity, ascites, nephritis, complement level depression, and anti-double-stranded DNA antibody positivity compared with control subjects. However, FCGR3B CNVs were not associated with RA susceptibility (for <2 copy numbers versus 2 copy numbers, P = 0.3584, OR 1.15, 95% CI 0.85-1.55) and clinical characteristics.In Taiwanese individuals, a low FCGR3A copy number is a common risk factor for SLE and RA, while a low FCGR3B copy number confers a risk of SLE but not RA.
THE CLINICAL DIAGNOSIS OF PERIARTERITIS NODOSA: REPORT OF FOUR CASES
Authors: Boyd G. King
Journal: Annals of Internal Medicine (1950)

ExcerptInterest in periarteritis nodosa has accompanied the increasing literature on this disease. Over 400 cases have been reported and various theories of its etiology have been propounded. The diagnosis, however, is still most frequently made post mortem.The diagnoses in the four cases described in this report were made clinically: three were confirmed at autopsy and the fourth by biopsy. They were observed in a period of 11 months in 1942 and 1943 on the Medical Service of the Fourth General Hospital while stationed overseas. The clinical diagnosis was not made in any other cases among the first 35, 000...
Abstract 18529: Smooth Muscle Specific Rac1 Deficiency Induces Hypertension by Over Activation of RhoA/Rho-kinase Signaling Pathway
Authors: Gwennan Andre, Gervaise Loirand, Vincent Sauzeau
Journal: Circulation (2014)

Introduction: The small GTPase RhoA and its target, Rho kinase, play essential role in both blood pressure regulation and vascular smooth muscle contraction. Increasing evidence implicates over activation of this signaling pathway as a critical event in the pathogenesis of hypertension. Interestingly, it has been recently described that Rac1 could antagonize RhoA-dependent functions. However, the role of Rac1 in the regulation of vascular tone and blood pressure is not fully elucidated.

Hypothesis: Here we assessed the hypothesis that smooth muscle Rac1 participates in the control of blood pressure.

Methods: To define the role of vascular smooth muscle cells (vSMC) Rac1 in vivo in the control of blood pressure, we generated inducible, smooth muscle (SM)-specific Rac1 knockout mice (SM-Rac1-KO) and analyzed cardiovascular parameters.

Results: Following induction of Rac1 deletion, SM-Rac1-KO mice rapidly develop high systolic blood pressure (+15±2 mmHg, n=19, p=0.02). Treatment with the Rho kinase inhibitor fasudil (5mg/kg and 30 mg/kg) decreases systolic arterial pressure to a level similar in control and SM-Rac1-KO mice suggesting that RhoA/Rho kinase signaling is involved in the rise in systolic blood pressure induced by SM-Rac1 deletion. This is confirmed by immunoblot analysis in aorta that reveals an increase of activated RhoA (348± 19% of control, n=4, p<0.05) and Rho-kinase activity (390±25% of control, n=4, p<0.05) in SM-Rac1-KO compared to control mice. This overactivation of RhoA signaling in SM-Rac1-KO mice is associated with a 75%-reduction of the inhibitory phosphorylation of RhoA on Ser188 compared to control mice. At functional level, while NO production is not modified, NO-dependent vasodilation is decreased in SM-Rac1-KO arteries (≈ 56% of control). By in vitro experiments in vSMC, we demonstrate that the loss of Rac1 leads to a defective production of cGMP and a down-regulation of the cGMP-dependent kinase-mediated inhibition of RhoA/Rho kinase signaling.

Conclusions: These results thus identified a blood pressure-lowering effect of vSMC Rac1, that tonically antagonizes RhoA/Rho kinase activity to modulate arterial tone and blood pressure through cGMP/ cGMP-dependent kinase pathway.
Effect of oral talactoferrin (TLF) on levels of cytokines involved in the Th1-mediated immune response in clinical studies
Authors: T. G. Hayes, R. Digumarti, J. Engelmeyer, M. Fodor, K. Petrak, Y. Wang, R. Malik, A. Varadhachary
Journal: Journal of Clinical Oncology (2008)

3080 Background: TLF is a novel dendritic cell (DC) activating drug with clinical activity in NSCLC and other cancers. Orally administered TLF binds gut epithelium, is transported into the Gut Associated Lymphoid Tissue, recruits circulating immature DCs (iDCs) bearing tumor antigens and induces their maturation. DC activation in the presence of tumor antigens and lymphoid effector cells induces a strong systemic innate and adaptive immune response mediated by anti-cancer Natural Killer (NK), CD8+ T and NK-T cells. In vitro, TLF induces a Th1-polarized maturation of iDCs. Tumor-bearing mice and healthy rats demonstrate a significant increase of key Th1 cytokines and chemotactic chemokines in the gut and portal vein after oral TLF. These include IFN-γ, IL-2, IL-8, IL-12, IL-18, GM-CSF, IFN-α, and macrophage inflammatory protein (MIP)-3α. Production of Th2 cytokines is either inhibited or unchanged. Following first-pass metabolism and dilution, smaller increases in a subset of cytokines are observed in the systemic circulation. Methods: Cytokine levels were evaluated in peripheral blood following oral administration of TLF in 3 studies: a 110 patient combination Phase 2 of carboplatin/paclitaxel (C/P) + either oral TLF or placebo in advanced/metastatic NSCLC; and 2 single agent studies in various solid tumors - a 34 patient pilot phase II and 10 patients in the Phase 1 portion of a Phase 1/2. Serum cytokines were measured by ELISA at baseline and at subsequent timepoints. Results: In the combination study, the baseline cytokine levels were similar in both groups. The TLF + C/P group demonstrated increased levels of IL-8, IL-12, IL-18 and GM-CSF relative to the placebo + C/P group, with the increase in GM-CSF reaching statistical significance. Similar increases in cytokine levels were also detected in the single agent studies. Th2 cytokines (IL-4, IL-6, IL-10) were measured in the pilot phase II, and no increases were detected. Conclusions: Oral TLF increased the serum levels of cytokines involved in enhancing Th1 cellular immune responses, consistent with results observed in preclinical experiments. These data support the postulated TLF mechanism of action, consisting of DC recruitment and activation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Agennix Incorporated Agennix Incorporated
Assessment of neutrophil serine proteinases activity in bronchoalveolar lavage fluids from patients with interstitial lung diseases using innovative intramolecular quenched substrates
Authors: Beata Poplawska-Wisniewska, Jadwiga Popow-Stellmaszyk, Radoslaw Struniawski, Magdalena Wysocka, Adam Lesner, Adam Szpechcinski, Joanna Chorostowska-Wynimko
Journal: European Respiratory Journal (2014)

Background: Neutrophil serine proteinases (NSPs): human neutrophil elastase (HNE), proteinase 3 (PR3) and cathepsin G (CG) are released by activated inflammatory cells and are involved in the degradation of elastin fibers during inflammation. Data concerning the potential role of three NSPs in the pathophysiology of interstitial lung diseases (IDL) are lacking.  Material and methods: Bronchoalveolar lavage (BAL) collected from 25 patients with IDL: hypersensitivity pneumonitis, HP (n=8), pulmonary fibrosis, PF (n=7) and sarcoidosis (n=10) was analyzed for HNE, PR3 and CG activity by innovative fluorescence resonance energy transfer (FRET) method utilizing highly sensitive, specific substrates for respective NSPs. Total protein content was determined by the Bradford procedure. The NSPs activity were shown as pM/1 ml of recovered BAL.  Results: PR3 activity was demonstrated in all analyzed BAL samples (median 0.09 pM, IQR 0.05-0.29; 0.08, 0.03-0.27 and 0.13, 0.06-0.21 for HP, PF and sarcoidosis respectively). Detectable HNE activity was found in 75% HP (0.11 pM, 0.01-0.25), 71% PF (0.10 pM, 0.00-0.20) and 70% sarcoidosis (0.05 pM, 0.00-0.12) BAL samples. CG activity was observed in 38% HP (0.00 pM, 0.00-0.19), 29% PF (0.00 pM, 0.00-0.52) and 20% sarcoidosis (0.00 pM, 0.00-0.00) BAL samples.  Conclusions: The innovative intramolecular quenched substrate based method allowed successful detection of individual NSPs activity in BAL samples. Considerable differences observed in theNSPs activity levels might suggest a diverse role of respective NSPs in the pathogenesis of particular ILD. The study is on-going.