tbuckley/cabot-search huggingface dataset:
Abstract 41: The Effect Of Maternal Weight On Offspring Blood Pressure At 18 Years Of Age: A Causal Natural-effects Mediation Analysis
Authors: Nicole M Brunton, Allison Dart, Meghan Azad, Jonathan M McGavock
Journal: Circulation (2020)

Objectives: Examine the relationship between maternal pre-pregnancy body mass index (BMI) and offspring systolic blood pressure (SBP) at 18 yrs old. Methods: We performed multivariate regression and causal mediation analysis within 3700 mother - offspring pairs from a prospective birth cohort. The main exposure was maternal pre-pregnancy BMI categorized as healthy weight, overweight, or obese according to international criteria. The main outcomes were high-normal BP and hypertension defined as SBP between the 90-95 th centile and &gt;95 th centile for height and sex at 18 years, respectively, as per 2017 AAP guidelines. Analyses were adjusted for social class, pre-eclampsia, sex, and maternal tobacco use during pregnancy. The Canadian Pediatric Endocrine Group R Shiny app was used to obtain age-standardized BMI Z-scores and latent class analysis (LCA) was used to quantify the mediating factor of offspring BMIZ trajectories from 7 to 18 yrs. Results: Before pregnancy 14% of women were overweight and 5% were obese. At 18 yrs, SBP (122 ± 12 vs 118 ±11mmHg, p &lt; 0.001), DBP (67 ± 7 vs 63 ± 6mmHg, p &lt; 0.001) and the odds of elevated BP (aOR: 1.6; 95% CI: 1.1-2.3) and hypertension (aOR: 2.1; 95% CI: 1.4-3.1) were higher in offspring from women that were obese prior to pregnancy compared to those that were normal weight. LCA identified five distinct offspring BMIZ trajectories shown in the figure. SBP (125 ± 12 vs 117 ± 10 mmHg, p &lt; 0.001) and the odds of hypertension (aOR: 3.8; 95% CI: 2.8-5.1) at 18 years were significantly higher in offspring with sustained high BMIZ (teal) compared to sustained low normal BMIZ (green). Casual mediation analysis revealed that maternal BMI directly (OR: 1.14; 95% CI: 1.03-1.25) and indirectly through offspring BMIZ trajectories (OR: 1.12; 95% CI: 1.08-1.15) increased offspring SBP at 18 years of age. Conclusion: Maternal obesity prior to pregnancy is associated with an increased risk of hypertension in offspring at 18 yrs of age, partly mediated by an elevated BMIZ score trajectory throughout childhood and adolescence.
Preoperative lactate dehydrogenase (LDH) serum level has impact on survival of melanoma patients after therapeutic lymph node dissection (TLND) but not on patients after completion lymph node dissection (CLND)
Authors: W. Ruka, Z. I. Nowecki, P. Rutkowski, W. Dziewirski, A. Pienkowski, M. Salamacha, Z. Zurawski, M. Zdzienicki
Journal: Journal of Clinical Oncology (2007)

8568 Background: The aim of the study was to evaluate the additional prognostic value of preoperative LDH serum level on overall survival (OS) of AJCC stage III cutaneous melanoma patients. Methods: The preoperative LDH serum level was available in 402 consecutive melanoma patients, who underwent radical LND (196 CLND after positive sentinel node biopsy and 206 TLND for clinically/cytologically detected regional lymph node metastases) between 1994 and 2004. Median follow-up time was 36 months (range: 6–110 months). Results: LDH serum level was increased before LND in 92 patients (22.9%) in the entire group of stage III melanoma patients [56 patients (27%) in TLND group and in 36 patients (18.4%) in CLND group (p=0.03)]. There were significant differences for OS (calculated from the date of LND) between patients with normal and high preoperative LDH level in the entire group of patients: median OS time was 51.2 months (95% CI: 34.8–91.9) and 27.9 months (95% CI: 18.2-); 5-year OS rate was 45.2% and 37.5%, respectively (p=0.0079 in univariate analysis and p=0.02 in multivariate analysis). However, to these differences mainly contributed the patients from TLND group: for patients with normal and high preoperative LDH level median OS time was 36.6 months (95% CI: 24.9–57.6) and 15.1 months (95% CI: 12.4- 27.9); 5-year OS rate was 40.0% and 20.3%, respectively (p=0.0013 in univariate analysis and p=0.01 in multivariate analysis). We did not observe any differences between patients with normal and high preoperative LDH level in CLND group: median OS time was 60.0 months (95% CI: 39.8-) and 65 months (95% CI: 45.6-); 5-year OS rate was 51% and 58%, respectively (p=0.703 in univariate analysis). Conclusions: Pre-LND increased LDH serum level has additional negative impact on OS of melanoma patients with palpable nodal metastases after TLND. [Table: see text]
A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in patients (pts) with advanced/metastatic solid tumors: Safety, pharmacokinetic (PK), and pharmacodynamic (PD) findings
Authors: D. J. Jonker, L. S. Rosen, M. Sawyer, G. Wilding, C. Noberasco, G. Jayson, G. Rustin, G. McArthur, L. Velasquez, S. Galbraith
Journal: Journal of Clinical Oncology (2007)

3559 Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Part A of this study defined an MTD of 800 mg qd (Abstract # 3051, ASCO 2006). Part B investigated expanded doses / schedules for safety, PK and PD. Methods: In Part B, sequential cohorts were treated with 320 mg qd, 800 mg 5 days on/2 off (800I), 800 mg qd (800C), or 400 mg bid. Available data are reported for pts treated at these doses in Part A + B. PK samples were obtained Days 1, 8 and 26. Tumor DCE- MRI parameters, transfer constant (K trans ), area under the concentration-time curve - first 60 s post contrast injection (AUC 60 ) were measured baseline X 2, Days 2, 8 and 26. Reproducibility was assessed by within pt %CV (wCV). Exposure-response analysis was performed using logistic regression. Serum ELISAs for soluble VEGFR2 and Collagen IV were measured at baseline, Days 8 and 26. Results: Fourteen, 9 and 18 pts were treated at 320, 800I and 800C, respectively. G3/4 AEs at 320, 800I, and 800C respectively were fatigue (21%, 0%, 22%), ↑ transaminase (8%, 11%, 17%), diarrhea (0%, 11%, 11%), hypertension (0%, 0%, 11%), platelets (8%, 0%, 11%). 800C had the greatest change in K trans , AUC 60 and serum markers at Day 8 and 26 ( Table ). 800I had some recovery Day 2 to Day 8 and a smaller change at Day 26 than 800C. wCV for K trans and AUC 60 was 26% and 22% respectively. The probability of DCE-MRI change increased with exposure (AUC tau ) to BMS-540215. Conclusions: Brivanib has dose-proportional PK and a tolerable safety profile = 800C. PD changes were greatest at 800C. Some recovery in DCE-MRI effect after 2 day dosing break suggests continuous dosing is preferable for biological activity. [Table: see text] No significant financial relationships to disclose.
Abstract P442: Periodontal Disease is Associated With Risk of Incident Diabetes Among Non-obese Individuals
Authors: Hamdi S Adam, Shaoping Zhang, Kamaira Philips, Kevin Moss, Di Wu, Elizabeth Selvin, Faye L Norby, James S Pankow, Ryan Demmer, Indra Mustapha, James D Beck
Journal: Circulation (2020)

Background: Strong evidence suggests that diabetes is a risk factor for periodontal disease and that periodontal disease, once established in the diabetic state, then contributes to worsened glycemic control. Recent studies suggest that periodontal disease is also associated with diabetes development. Hypothesis: Incident Type 2 Diabetes (T2D) rates will be higher among participants with baseline periodontal disease vs. those with periodontal health. The relationship is modified by Body Mass Index (BMI). Methods: We included 5586 diabetes-free eligible participants (aged 52-75 years) from Visit 4 (1996-1999) of The Atherosclerosis Risk in Communities (ARIC) Study. Participants received full-mouth periodontal exams and periodontal disease status was classified using Periodontal Profile Classes (PPC-Stages). T2D was defined based on participant-self report of physician diagnosis during annual telephone follow-ups. Time-to-event was computed from baseline through 2018. Competing risk, multivariable Cox proportional hazard models examined T2D and All-Cause Mortality risk according to baseline periodontal disease status. We tested the interaction with BMI. Multivariable adjustment was performed for race/center, age, gender, smoking and education. Results: Participants were mean age (SD) 62.4 (5.6), 55.0% female, 16.7% African American. During the average 21.1 years of follow-up there were 1,359 incident T2D cases and 1,531 deaths. Cumulative incidence rates were 24.3% and 27.4% for T2D and deaths, respectively. Among underweight participants, the hazard ratios[95%Cis] for incident diabetes among severe periodontitis or severe tooth loss (vs. periodontally healthy) were 1.84[1.14-2.96] and 2.29[1.57-3.33], respectively. Hazard ratios[95%Cis] among normal weight participants were 1.54[1.06-2.23] and 1.88[1.41-2.51], respectively. There were no significant associations with T2D in obese participants (p for interaction = 0.06. Conclusion: Severe periodontal disease was associated with a modestly increased risk for T2D among a multi-racial community-based sample. Two periodontal disease stages in the PPC-Stages index system are significantly associated with increased risk for incident diabetes. This periodontal disease-associated risk is modified by BMI levels and only associated with incident diabetes in study participants with lower BMI.
CircMUC16 promotes autophagy of epithelial ovarian cancer via interaction with ATG13 and miR-199a
Authors: Xiaoling Gan, Hongtao Zhu, Xingwei Jiang, Samuel C. Obiegbusi, Min Yong, Xingtao Long, Jianguo Hu
Journal: Molecular Cancer (2020)

Abstract Background Circular RNA (circRNA) has been proven to play a significant role in multiple types of cancer. However, the expression and role of circRNAs in epithelial ovarian cancer (EOC) remains elusive. Methods CircRNA and mRNA expression profiles of EOC were screened with sequencing analysis. Gene silencing and over-expression were used to study circRNA function. Cell proliferation and Matrigel invasion assays were used to detect cell proliferation and invasion, respectively. The expression of circRNAs, mRNAs and miRNAs was detected using qPCR. The location of circRNAs was detected using FISH. The expression of proteins was detected using western blot and immunohistochemistry. Results CircMUC16 had increased expression in EOC tissues as compared to healthy ovarian tissues. The expression of circMUC16 was linked to the progression in stage and grade of EOC. Hence, silencing circMUC16 suppressed autophagy flux of SKOV3 cells. In contrast, ectopic expression of circMUC16 promoted autophagy flux of A2780 cells. CircMUC16-mediated autophagy exacerbated EOC invasion and metastasis. Mechanistically, circMUC16 could directly bind to miR-199a-5p and relieve suppression of target Beclin1 and RUNX1. In turn, RUNX1 elevated the expression of circMUC16 via promotion of its transcription. CircMUC16 could directly bind to ATG13 and promote its expression. Conclusion This study demonstrated that circMUC16 regulated Beclin1 and RUNX1 by sponging miR-199a-5p. The data suggested that circMUC16 could be a potential target for EOC diagnosis and therapy.
COX-2 inhibitor assay in InvTCC.
Authors: Deepika Dhawan, Antonella Jeffreys, Jane C. Stewart, Rong Zheng, Deborah W. Knapp
Journal: Cancer Research (2006)

5272  Urinary bladder cancer (transitional cell carcinoma, TCC) affects more than 2 million people worldwide. Even with aggressive treatment, invasive TCC (InvTCC) is lethal in up to 50% of cases. A promising new target for InvTCC treatment is cyclooxygenase-2 (COX-2). COX-2 is up-regulated in InvTCC. COX inhibitors have antitumor activity against naturally occurring invasive TCC in pet dogs and in experimentally induced bladder tumors in rodents. Mechanisms of the antitumor activity of COX inhibitors, however, remain to be fully defined, and this prevents optimal use of these drugs. One reason why mechanisms have not been defined is that COX inhibiting drugs do not have antiproliferative effects in standard in vitro assays. The purpose of this work was to define different in vitro systems for studies of COX-2 inhibitor antitumor effects, and to study the mechanism of action of a COX-2 inhibitor, celecoxib. Human InvTCC cell lines used included: HT1376 (high COX-2 expression), TCC-SUP (modest COX-2 expression), and UMUC-3 (no detectable COX-2 expression). Assay variables tested included different microenvironment (monolayer, soft agar, collagen, and poly HEMA coated culture dishes); length of treatment (72-120 hrs); presence or absence of serum and fatty acids; and concentration of the COX-2 inhibitor, celecoxib. In addition, cell proliferation was “rescued” from COX-2 inhibitor effects by the addition of prostaglandin E2 (PGE2). Soft agar assays were found to be useful for the study of COX-2 inhibitors (38% reduction in colony number) with relevant celecoxib concentrations (i.e. those safely achieved in vivo in humans;
Abstract P191: Metabolites Associated With Coffee Consumption and Incident Chronic Kidney Disease
Authors: William He, Jingsha Chen, Emily Hu, Bing Yu, Morgan Grams, Chirag Parikh, Eric Boerwinkle, Josef Coresh, Casey M Rebholz
Journal: Circulation (2020)

Introduction: Several studies have found moderate coffee consumption to be inversely associated with chronic kidney disease (CKD), however the biological mechanisms underlying this benefit are unclear. Metabolomic studies allow for the characterization of metabolites in biological specimens and are useful for detecting biomarkers of coffee consumption and metabolic pathways underlying the association between coffee and CKD. Hypothesis: We hypothesized that metabolites altered by coffee consumption would be associated with CKD incidence. Methods: A total of 3,809 African-American and Caucasian ARIC study participants had measurements of serum metabolites: 373 metabolites in sample 1 and 758 metabolites in sample 2. Linear regression models were used to estimate cross-sectional associations between metabolites and average cups of coffee consumed per day. Cox regression models were used to estimate associations between coffee metabolites and incident CKD. Results: In sample 1, 13 metabolites were significantly and positively associated with coffee consumption (p&lt;0.05/373=1.3х10 -4 ), one of which (hippurate) was inversely associated with incident CKD ( Table ). In sample 2, 29 metabolites were positively associated and 20 were negatively associated with coffee consumption (p&lt;0.05/758=6.6х10 -5 ). All 13 metabolites detected in sample 1 were also significantly associated with coffee in sample 2. Higher levels of three metabolites (O-sulfo-L-tyrosine, erythritol, and N-acetylserine) were associated with lower intake of coffee and higher risk of incident CKD. Conclusions: We detected 13 candidate biomarkers of coffee consumption that replicated across two samples. Four metabolites, consisting of a food component (erythritol), chemical (O-sulfo-L-tyrosine), and compounds that are involved in the metabolism of benzoate (hippurate), glycine, serine, and threonine (N-acetylserine), may play contribute to the favorable health outcomes observed with coffee consumption.
Abstract P488: Discrimination and Hypertension Risk Among African Americans in The Jackson Heart Study
Authors: Allana T Forde, Mario Sims, Paul Muntner, Tené Lewis, Amanda Onwuka, Kari Moore, Ana V Diez Roux
Journal: Circulation (2020)

Background: African Americans have a higher risk for hypertension compared to other racial or ethnic groups in the United States. One possible explanation for this health disparity is perceived discrimination. Few studies have prospectively examined the association between discrimination and the incidence of hypertension. Methods: We examined the associations of everyday, lifetime, and stress from lifetime discrimination with incident hypertension and whether these associations differed by sex, discrimination attribution (i.e. the main reason for the discrimination event), and coping responses to discrimination among African Americans enrolled in the Jackson Heart Study. Discrimination was self-reported by 1845 African Americans aged 21 to 85 years without hypertension at baseline (2000-2004). Participants completed two follow-up study visits from 2005-2008 and 2009-2013. We used interval-censored Cox regression to estimate associations of discrimination with incident hypertension (antihypertensive medication use; and/or systolic blood pressure ≥ 140 mm Hg and diastolic blood pressure ≥ 90 mm Hg at follow-up visits 2 or 3) after adjustment for confounding variables. Results: Overall, 52% (954 of 1845) of participants developed hypertension over the follow-up period. After adjustment for age, sex, education and hypertension risk factors (body mass index, alcohol use, smoking, diet and physical activity), medium versus low levels of lifetime discrimination (hazard ratio-HR: 1.45, 95% confidence interval-CI: 1.15-1.82) and high versus low levels of lifetime discrimination (HR: 1.35, CI: 1.08-1.68) were associated with a higher incidence of hypertension. High versus low stress from lifetime discrimination was associated with hypertension risk after adjustment for demographics (HR: 1.20, CI: 1.02-1.41), but the association was attenuated after adjustment for hypertension risk factors (HR: 1.14, CI: 0.97-1.35). Lifetime discrimination and stress from discrimination were associated with an increased hypertension risk among females, but not males. No interactions with age, attribution or coping were present for any type of discrimination. Conclusions: Findings from this study support an association between lifetime discrimination and incident hypertension in African Americans.
Glomerular filtration rate (GFR) in patients with stage I testicular seminoma treated with adjuvant carboplatin: A comparison of six formulae compared to a radioisotope gold standard
Authors: R. Cathomas, A. Harle, G. M. Mead, R. von Moos, P. Simmonds, T. R. Geldart
Journal: Journal of Clinical Oncology (2007)

15504 Background: Carboplatin (Carbo) is an effective adjuvant treatment for patients (pts) with stage I testicular seminoma. Accurate estimation of GFR is necessary to establish carbo dose. Calculation of GFR following injection of a radiolabelled isotope (e.g. Tc 99 mDTPA) is considered the gold standard, but may not be readily available in all centres. Calculation of creatinine clearence via 24-h urine collection is often unreliable. The aim of this study was to assess different formulae for GFR calculation in this patient population. Methods: We performed a retrospective analysis of all patients with stage I seminoma treated with adjuvant carbo in Southampton between 1999 and 2005. All patients underwent GFR measurement with Tc 99 mDTPA and this was compared with six standard formulae for the calculation of GFR based on serum creatinine. Bias was quantified by Mean Percentage Error (MPE %) and precision by Mean Absolute Percentage Error (MAPE%). Tc 99 mDTPA GFR was not corrected for body surface area (BSA). Results: 202 Caucasian male pts were included (mean age 40 yrs; mean Tc 99 mDTPA GFR 123ml/min). Results are illustrated in Table 1 . Conclusions: In general, formulae underestimate GFR leading to significant decreases in carbo dose. The Cockcroft-Gault and Martin formulae were most accurate in this cohort of pts. Formulae developed for use in pts with chronic kidney disease (MDRD), elderly cancer patients (Wright) or which correct for BSA (Jelliffe, MDRD, Mayo), greatly underestimate GFR and should not be used in this setting. [Table: see text] No significant financial relationships to disclose.
Rapid effects of VEGF Trap on angiogenesis and tumor cell proliferation
Authors: Alexander Adler, Baosheng Li, Amy Xia, Darya Burakov, Nicholas Papadopoulos, Gavin Thurston
Journal: Cancer Research (2007)

2127  Blockade of VEGF has been shown to be effective at inhibiting tumor growth in various preclinical models and in diverse human cancers. Preclinical and clinical data suggest that ongoing VEGF signaling is necessary to maintain the angiogenic tumor vasculature, as treatment with VEGF blockers results in a rapid loss of tumor vessels and a decrease in tumor perfusion. In this study, we sought to characterize in more detail the rapid changes in angiogenic vessels, and to relate the vessel loss to corresponding effects on tumor cell proliferation. SCID mice bearing established tumors of different origins (two human renal cell carcinomas (786-0, A498), a human fibrosarcoma (HT1080), a human and a rat glioblastoma (U87-MG, C6), and a human basal cell carcinoma (A431) or polyvinyl acetate sponge implants (a simplified model of angiogenesis) were treated with a single subcutaneous dose of VEGF Trap (25 mg/kg), a potent inhibitor of all isoforms of VEGF-A and placental growth factor (PlGF) that is currently in Phase II clinical trials. At 24 or 72 hr after treatment, tumors and sponges were excised and stained for blood vessels (PECAM/CD31), and tumors were stained for hypoxia (HypoxyProbe) or cell proliferation (Ki67). We found that VEGF Trap induced a reduction in vessel density in all tumor types and in the sponges at both 24 and 72 hr, although the magnitude of the vessel loss varied (ranging from 24% reduction in HT1080 tumors to 69% reduction in A498 tumors at 72 hr). The vessel loss was characterized by decreased angiogenic sprouting, pruning of small vessels, and a more uniform size and appearance of the remaining vessels. Similarly, all tumors showed an increase in tumor hypoxia and a decrease in tumor cell proliferation, although again the magnitude of these effects varied in the different tumors. The relative magnitude of the vessel loss was not directly proportional to the levels of VEGF expression by the tumor cells, as assessed by quantitative RT-PCR. These results show that while VEGF blockade results in rapid vessel loss in all tumors and other models of angiogenesis, the extent of the vessel loss varies significantly and may affect the subsequent pattern and extent of tumor cell proliferation.
Half of smokers think nicotine vaping products are at least as harmful as smoking
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Deaths from vaping in the US have led over half (56%) of smokers in England to believe that nicotine vaping products are as harmful as smoking (42%) or more so (14%), despite those deaths being caused by substances that are banned in the UK.1

The report from researchers at King’s College, London, commissioned by Public Health England, looked at the use of nicotine vaping products among young people and adults, as well as public perceptions of the harmfulness of vaping.

It found that, …
Swine Disease Models for Optimal Vascular Engineering
Authors: Michael Sturek, Mouhamad Alloosh, Frank W. Sellke
Journal: Annual Review of Biomedical Engineering (2020)

Swine disease models are essential for mimicry of human metabolic and vascular pathophysiology, thereby enabling high-fidelity translation to human medicine. The worldwide epidemic of obesity, metabolic disease, and diabetes has prompted the focus on these diseases in this review. We highlight the remarkable similarity between Ossabaw miniature swine and humans with metabolic syndrome and atherosclerosis. Although the evidence is strongest for swine models of coronary artery disease, findings are generally applicable to any vascular bed. We discuss the major strengths and weaknesses of swine models. The development of vascular imaging is an example of optimal vascular engineering in swine. Although challenges regarding infrastructure and training of engineers in the use of swine models exist, opportunities are ripe for gene editing, studies of molecular mechanisms, and use of swine in coronary artery imaging and testing of devices that can move quickly to human clinical studies.