tbuckley/cabot-search huggingface dataset:
Abstract PD8-10: Regulation of breast tumor metastasis by the dynamic interaction between the TMEM doorway macrophage, tumor and endothelial cells
Authors: Chinmay Surve, Allison S. Harney, Mary Chen, Yarong Wang, Xianjun Ye, Yu Lin, Ved Sharma, Richard Stanley, Maja H. Oktay, John S. Condeelis
Journal: Cancer Research (2020)

Abstract Tumor cell intravasation is an essential step in the metastatic cascade, but its exact mechanism is not completely understood. We have previously shown that the direct physical association of a tumor cell over-expressing Mena, a Tie2hi/Vegfhi macrophage and an endothelial cell, creates a micro-anatomic doorway called “tumor microenvironment of metastasis” (TMEM). TMEM are responsible for cancer cell intravasation and dissemination to distant sites. The density of TMEM doorways is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that TMEM doorways create increased localized vascular permeability which cancer cells utilize to intravasate, the precise molecular mechanisms relating TMEM-doorway function and intravasation has not been elucidated. Active TMEM doorways are found in pre-invasive and invasive ductal breast carcinoma as well as in metastatic foci in lymph nodes and lungs, indicating that TMEM-mediated cancer cell dissemination occurs not only at the primary tumor site but also at metastatic sites, which may perpetuate metastatic dissemination even after removal of the primary tumor. Thus it is essential to understand the exact molecular mechanism of TMEM-doorway function so that specific targeted therapies can be developed to intercept systemic cancer cell dissemination. We outline here the exact molecular mechanism of TMEM-doorway functions. TMEM doorway endothelial cell-secreted Ang2 (a Tie2 ligand) stimulates VEGF expression and production by the Tie2hi TMEM macrophage. Subsequently, the TMEM doorway tumor cell- secreted CSF1 stimulates local secretion of VEGF from the Tie2hi TMEM macrophages, leading to dissociation of endothelial adherens and tight junctions near TMEM and cancer cell intravasation. In addition, we show that acute blockage of CSF1R and Tie2-Ang2 signaling by inhibitors and blocking antibodies both in vitro and in mammary tumors leads to decreased macrophage VEGF production and secretion, decreased tumor cell trans-endothelial migration, and decreased TMEM-dependent vascular permeability, tumor cell dissemination and circulating tumor cells. This is the first description of the molecular mechanisms regulating TMEM doorway function and thus represents a major step in defining new biomarkers and targets for the treatment of metastatic tumors. Citation Format: Chinmay Surve, Allison S. Harney, Mary Chen, Yarong Wang, Xianjun Ye, Yu Lin, Ved Sharma, Richard Stanley, Maja H. Oktay, John S. Condeelis. Regulation of breast tumor metastasis by the dynamic interaction between the TMEM doorway macrophage, tumor and endothelial cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD8-10.
Stimulation of the beta-2-adrenergic receptor causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway
Authors: Adam E. Carie, Said M. Sebti
Journal: Cancer Research (2006)

3024  A chemical biology approach identifies a beta 2 adrenergic receptor (β2AR) agonist ARA-211, which causes apoptosis and human tumor regression in animal models. β2AR stimulation of cAMP formation and PKA activation leads to Raf-1 kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-Erk1/2 levels. ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. β2AR stimulation results in inhibition of anchorage-dependent and -independent growth and induction of apoptosis in vitro and tumor regression in vivo. β2AR antagonists and constitutively active Mek-1 rescue from ARA-211 demonstrating that β2AR stimulation and Mek kinase inhibition are required for ARA-211 anti-tumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, β2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway. These findings have major implications for cancer therapy.
Abstract P190: Untargeted Metabolomics Study of Glycemic Outcomes Among Bogalusa Heart Study Participants
Authors: Kirsten S Dorans, Jiang He, Jovia L Nierenberg, Changwei Li, Xiaoying Gu, Lydia A Bazzano, Tanika N Kelly
Journal: Circulation (2020)

Background: The increasing prevalence of diabetes mellitus, a major cause of morbidity and mortality worldwide, is a critical public health concern. Though a number of studies have evaluated the associations of metabolites with prediabetes and diabetes, further exploration in this relatively new field may identify novel biomarkers for predicting, detecting, and managing hyperglycemia and diabetes. Objective: We conducted a metabolome-wide association study among 805 white and 426 African-American participants of the Bogalusa Heart Study (BHS) to identify metabolites associated with markers of glycemia and diabetes. Methods: After rigorous quality control, 1,202 metabolites quantified by untargeted, ultra-high performance liquid chromatography tandem-mass spectroscopy were tested for association with fasting glucose, hemoglobin A1c and diabetes. Multiple regression analyses were run in race-stratified and combined samples, adjusting for age, sex, education, blood pressure, body mass index, HDL-cholesterol, smoking, eGFR, fasting glucose (for HbA1c and diabetes), and race (in combined analyses). For fasting glucose and HbA1c, those taking diabetes medications were excluded. Metabolites were considered significant if they were significant (P&lt;4.15х10 -5 ; Bonferroni corrected for 1,202 metabolites) in one race group and the entire cohort, with a similar trend observed in the other race group. Results: After Bonferroni corrections, among 72 metabolites significantly associated with at least one glycemic outcome, 27 were novel and in known pathways: 5 from amino acid, 1 from carbohydrate, 18 from lipid, 1 from xenobiotics, and 2 from nucleotide pathways. Metabolites consistently associated with diabetes are shown in the Table . Conclusions: These results identified novel metabolites associated with glycemic outcomes, providing additional evidence on the importance of serum metabolites in hyperglycemia and diabetes.
Abstract MP34: Acceleration of Kidney Function Decline After Incident Hospitalization With Cardiovascular Disease: The Stockholm Creatinine Measurements (scream) Project
Authors: Junichi Ishigami, Marco Trevisan, Lars Lund, Tomas Jernberg, Josef Coresh, Kunihiro Matsushita, juan jesus carrero
Journal: Circulation (2020)

Background: The cardiorenal syndrome suggests a bidirectional relationship between worsening kidney function and cardiac dysfunction. However, to our knowledge, no studies have quantified changes in slopes of kidney function decline before and after the incidence of major cardiovascular disease (CVD) subtypes. Methods: We compared the individual slopes of estimated glomerular filtration rate (eGFR) decline in the 2 years before vs. after the incident hospitalization with heart failure (HF) (n=20,420), coronary heart disease (CHD) (n=18,152), and stroke (n=1,808) using data from the complete laboratory data collection of Stockholm healthcare (Sweden) between 2006 and 2011. Using mixed effect models with unstructured residual correlation matrix, we examined changes in individual slopes of eGFR decline before and after incident CVD in the overall population, and by index eGFR strata (≥60, 30-59, &lt;30 ml/min/1.73m 2 ). Results: Incident hospitalization with HF and CHD, but not stroke, was significantly associated with a subsequent acceleration of eGFR decline, with a faster eGFR decline and greater slope change after HF than CHD. The pre-event vs. post-event eGFR slope (ml/min/1.73m 2 per year) were -1.67 (-1.77 to -1.57) vs. -2.76 (-2.82 to -2.71), with Δslope of -1.09 (-1.16 to -1.02) for HF; -1.09 (-1.20 to -0.98) vs. -1.87 (-1.92 to -1.81), with Δslope of -0.78 (-0.85 to -0.70) for CHD; and -1.00 (-1.37 to -0.63) vs. -0.99 (-1.19 to -0.78), with , Δslope of 0.02 (-0.24 to 0.27) for stroke ( Figure ). The accelerated eGFR declines after HF and CHD were consistently observed across eGFR strata, with pre-event eGFR slopes steeper in lower eGFR (e.g., pre-event eGFR slope for HF -0.64 (-0.76 to -0.53) for eGFR ≥60, -1.43 (-1.57 to -1.30) for eGFR 30-59, and -2.42 (-2.71 to -2.12) for eGFR &lt;30 ml/min/1.73m 2 ). Conclusions: Incident hospitalization with cardiac diseases (ie, HF and CHD) was significantly associated with a subsequent acceleration of eGFR decline.
STK15 F31I polymorphisms and uterine cancer risk: A case-control analysis
Authors: M. R. Milam, J. Gu, H. Yang, J. Celestino, W. Wu, I. Horwitz, R. A. Lacour, S. N. Westin, D. M. Gershenson, X. Wu, K. H. Lu
Journal: Journal of Clinical Oncology (2007)

5511 Background: STK15 is a serine threonine kinase which assists chromosomal separation and mitotic spindle stability through interaction with the centrosome during mitosis. STK15 polymorphisms have been associated with an increased risk for breast cancer in several case-control studies. We hypothesized that STK15 polymorphisms might modulate risk of uterine cancer. Methods: Uterine cancer patients treated at M. D. Anderson Cancer Center were identified from the tumor bank database from January 1, 2000 to June 30, 2006. Two common STK15 single nucleotide polymorphisms (SNPs), F31I (T/A) and V57I (G/A), were genotyped in patients with uterine cancer and in a control population matched for age, race, and smoking status. Odds ratios (OR) and 95% confidence intervals (CI) were obtained using unconditional logistic regression analysis. Results: A total of 193 women with uterine cancer and 218 controls were genotyped for both SNPs. After adjustment for age, race, and smoking status for the F31I SNP, the homozygous variant genotype (AA) was associated with a significantly increased uterine cancer risk (OR 10.2; 95% CI 2.23–46.5). Individuals with the heterozygous genotype (TA) and a history of tobacco use also exhibited an increased risk for uterine cancer (OR 2.63; 95% CI 1.20–5.76). For the V57I SNP, neither the homozygous (AA) nor the heterozygous (GA) variant genotypes were associated with significantly altered risk for uterine cancer (OR 0.76; 95% CI 0.18–3.25 and OR 0.88; 95% CI 0.52–1.49). Conclusions: Our study demonstrates that STK15 F31I SNP is associated with an increased risk for uterine cancer. Confirmation of this pilot study is needed in a larger case-control population to evaluate this genetic variant with other known risk factors for uterine cancer. No significant financial relationships to disclose.
Abstract P110: High Serum Urate Levels are Associated With an Increased Risk for Sudden Cardiac Death in the Reasons for Geographic and Racial Differences in Stroke (regards) Study
Authors: Lisandro D Colantonio, Richard Reynolds, Tony Merriman, Angelo Gaffo, Jasvinder A Singh, Timothy B Plante, Ninad S Chaudhary, Elsayed Soliman, S. Louis Bridges, George Howard, Monika M Safford, Kenneth Saag, Paul Muntner, Marguerite M Irvin
Journal: Circulation (2020)

Background: Higher serum urate (SU) levels were shown to causally increase the risk for sudden cardiac death (SCD) in a Mendelian randomization analysis of white adults, most of whom had coronary heart disease (CHD). It is unclear if these results are generalizable to more racially diverse adults without CHD. Objective: To assess the risk for SCD and incident CHD associated with SU levels in adults without a history of CHD using data from a large, population-based cohort of US black and white men and women ≥45 years of age, the REason for Geographic And Racial Differences in Stroke (REGARDS) study. Methods: We conducted a case-cohort analysis of REGARDS study participants without a history of CHD at baseline between 2003 and 2007. Participants were followed for SCD or incident CHD (i.e., myocardial infarction or CHD death excluding SCD) from baseline through December 31, 2013. Baseline SU levels were measured in a random sample of participants (n=840) and among 235 participants with SCD and 851 participants with incident CHD. Results: Participants with higher SU levels were older and more likely to be black and male. The crude hazard ratio (95%CI) per 1 mg/dL higher SU level was 1.26 (1.14, 1.40) for SCD and 1.17 (1.09, 1.26) for incident CHD. Analyses modeling SU levels using splines supported that these associations were linear. After multivariable adjustment, higher SU levels remained associated with an increased risk for SCD, but not for incident CHD ( Table ). There was no effect modification in the association of SU levels with SCD or incident CHD by either age, gender, race or chronic kidney disease. However, the increased risk for SCD associated with higher SU levels was present in whites but not among blacks. Limitations: The study has limited statistical power for subgroup comparisons. Race differences in the association between SU levels and SCD require further investigation. Conclusions: In adults without a history of CHD, higher SU levels appear to be an independent risk factor for SCD, but no association was detected with incident CHD.
Abstract P362: Metabolomic Markers of Southern Dietary Patterns in the Jackson Heart Study
Authors: Casey M Rebholz, Yan Gao, Sameera Talegawkar, Katherine L Tucker, Lisandro Colantonio, Paul Muntner, Robert E Gerszten, James Wilson
Journal: Circulation (2020)

Background: Diet is an important modifiable risk factor for hypertension and other chronic diseases. New biomarkers are needed for the objective assessment of dietary intake. The aim was to investigate metabolites associated with Southern dietary patterns. Methods: We used available dietary and metabolomics data from 1,042 Jackson Heart Study participants, a population of African-American men and women in Jackson, Mississippi, to determine metabolites associated with Southern dietary patterns. Three dietary patterns were empirically derived using factor analysis: meat and fast food, fish and vegetables, and starchy foods. Multivariate regression models were adjusted for age, sex, education, smoking status, physical activity, alcohol consumption, multi-vitamin use, kidney function, body mass index, and batch. We randomly selected two subsets of the study population: 2/3 sample for discovery (n=683) and 1/3 sample for validation (n=359). False discovery rate (FDR) was used to account for multiple comparisons in the analysis of the discovery sample and α=0.05 was used to assess statistical significance in the validation sample. Results: Among the 357 metabolites analyzed, one was associated with the meat and fast food dietary pattern (proline betaine), ten were associated with the fish and vegetables dietary patterns [1,7-dimethyluric acid, caffeine, C22:6 lysophosphatidylethanolamine (LPE), C38:6 phosphatidylethanolamine (PE), C38:7 phosphatidylcholine plasmologen, C38:7 PE plasmalogen, N-acetylornithine, NH4 C38:5 diacylglycerol or triacylglycerol fragment, pantothenate, and pantothenic acid], and none were associated with the starchy foods dietary pattern (all FDR&lt;0.05). Two metabolites remained statistically significantly associated with dietary patterns in the validation sample: proline betaine and meat and fast food (β: -0.16, 95% CI: -0.30, -0.01, p=0.03) and C22:6 LPE and fish and vegetables (β: 0.12, 95% CI: 0.01, 0.23, p=0.03). Conclusion: Two potential biomarkers (proline betaine and C22:6 LPE) were discovered and replicated in association with dietary patterns detected in a Southern U.S. African-American population.
Left Atrial Phasic Function in Type 2 Diabetes Mellitus Patients with Preserved Left Ventricular Ejection Fraction Assessed by Feature Tracking CMR Imaging
Authors: Meng-ting Shen, Zhi-gang Yang, Kai-yue Diao, Li Jiang, Xi Liu, Yue Gao, Pei-lun Han, Ying-kun Guo
Journal: Metabolism (2020)
Abstract P541: High Allostatic Load is Associated With Increased Risk of All-cause Mortality - A Systematic Review and Meta-analysis
Authors: Haley W Parker, Alyssa M Abreu, Mary Sullivan, Maya K Vadiveloo
Journal: Circulation (2020)

Introduction: Allostatic load (AL) is a measure of physiological damage from chronic stress, quantified using a variety of neuroendocrine, metabolic, cardiovascular, and immune biomarkers. While AL has been associated with several mortality risk factors (e.g., metabolic disorders, inflammation, cardiovascular disease (CVD), frailty), to date, no meta-analyses have examined the relationship between AL and mortality. This systematic review and meta-analysis examines the relationship between AL and mortality (CVD and all-cause). Hypothesis: Higher AL (i.e., increased dysregulation) will be associated with an increased risk of all-cause and CVD mortality. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guided this review. Two databases (PubMed and EMBASE) were searched in Feb 2019 with the terms: ((mortality) OR survival) AND ((allostatic load) OR allostasis); references of included studies were also screened. Included studies met the a priori inclusion criteria (i.e. compared mortality (all-cause and/or CVD) in high vs. low AL (defined by study) in adults). Study quality was assessed with the Newcastle Ottawa Criteria. Findings were qualitatively synthesized then the meta-analysis was completed in Review Manager 5.3. Subgroups were examined by design and sample age. Results: Database searches and references identified 400 studies; after removing duplicates, 266 abstracts were screened and 32 full texts were reviewed. The systematic review included 12 observational studies (2001-18) examining all-cause mortality; half were also included in meta-analyses. Of the 12 included studies, most examined CVD mortality (n=7), were longitudinal (n=7), from the US (n=7), and had a balanced sex distribution. In the qualitative review, high AL was consistently associated with increased risk of all-cause mortality (n=11 of 12 studies, hazard ratio (HR) range=1.13-2.98), however, the association was less consistent for CVD mortality (n=4 of 7 studies, HR=1.12-3.06). In meta-analyses, high AL was associated with increased risk of all-cause (HR= 1.46 [1.24, 1.72], n=6) and CVD mortality (HR= 1.18 [1.02, 1.38], n=4). High AL was associated with all-cause mortality in subgroup analyses stratified by design (cross-sectional HR=1.44 [1.14, 1.81], n=3; longitudinal HR=1.61 [1.11, 2.33], n=3) and sample age (older adults HR=1.17 [1.10, 1.24], n=3; all adults HR=1.94 [1.45, 2.60], n=3). Heterogeneity was high (I 2 =85-96%) in analyses except for the older adults subgroup (I 2 =18%). Study quality was good in 7 studies (including all studies in the meta-analysis), fair in 3 studies, and poor in 2 studies. Conclusions: In this review of relatively high-quality studies, high AL was associated with a 46% increased risk of all-cause mortality and may also be associated with CVD mortality. Thus, AL shows promise as a prognostic indicator for mortality.
A patterns-of-care study of post-progression treatment (Rx) among patients (pts) with advanced pancreas cancer (APC) after gemcitabine therapy on Cancer and Leukemia Group B (CALGB) study #80303
Authors: D. Schrag, L. Archer, X. Wang, D. Romanus, M. Mulcahy, R. Goldberg, H. Kindler
Journal: Journal of Clinical Oncology (2007)

4524 Background: Gemcitabine is the mainstay of Rx for pts with APC. Practice guidelines encourage participation in trials after disease progression. We evaluated Rx after APC progression for pts in CALGB 80303 a randomized trial of gemcitabine + bevacizumab (GB) or placebo (GP). Methods: Of the 552 pts who began GP or GB Rx, 457 had comprehensive medical record review. Of these 355 progressed on protocol Rx. We evaluated post-progression Rx for these 355 pts - the record review (RecR) group. We also phoned a subgroup of 126 pts to inquire about Rx delivered at sites other than the accruing center - the record review &amp; interview group (RecR + I) to determine whether any Rx had been administered and the specific agents used. Results: ChemoRx after progression on gemcitabine was distinctly uncommon. Based on RecR 239/355=67.3% and on RecR + I, 70/126=55.6% of pts received no chemoRx after progression on the study Rx. These proportions did not vary based on Rx assignment. Worse ECOG performance status at baseline and older age were associated with lower likelihood of post progression Rx. Notably, 99/355=27.9% of pts died within 4 weeks of progression. Conclusions: After progression on a clinical trial of gemcitabine Rx, &lt;half of pts receive 2nd line Rx and remarkably few (&lt;2%) receive further experimental Rx. Given the lack of well established Rx options, there appear to be lost opportunities for participation in early phase clinical trials. Coordinated strategies for second line Rx options might increase the evidence base for this challenging malignancy. Patterns of Post-Progression ChemoRx after Progression on Gemcitabine ± Bevacizumab in APC. [Table: see text] [Table: see text]
Abstract P132: Anti-Müllerian Hormone Levels and Risk of Type 2 Diabetes in Women
Authors: Renée M Verdiesen, N. Charlotte Onland-Moret, Carla H van Gils, Annemieke M Spijkerman, H Susan J Picavet, Frank J Broekmans, W M Monique Verschuren, Yvonne T van der Schouw
Journal: Circulation (2020)

Introduction: Given its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is correlated with timing of menopause. Accordingly, women with higher AMH levels become menopausal at a higher age. Previous research suggests that a higher age at menopause is associated with a decreased risk of type 2 diabetes (T2D). In contrast, AMH levels are increased in women with polycystic ovary syndrome (PCOS), who have a higher risk of insulin resistance and T2D than women without PCOS. However, it is not clear yet whether AMH actually plays a role in the development of T2D. We aimed to investigate whether plasma AMH levels and age-related AMH trajectories are associated with risk of T2D in women. Hypothesis: Higher age-specific plasma AMH levels are associated with a decreased risk of T2D. Methods: We analyzed longitudinal data from 3104 female participants, aged 20-60 years at recruitment, in the population-based Doetinchem Cohort Study. In total, we analyzed 12460 plasma AMH measurements. We calculated age-specific AMH tertiles, to account for the strong AMH-age correlation. Cox Proportional hazards models adjusted for known risk factors for diabetes were used to assess the relation between age-specific AMH tertiles and T2D. We applied linear mixed models to compare age-related AMH trajectories between T2D cases and non-cases. Results: After a median follow-up of 20 years, 163 incident T2D cases were identified. Higher age-specific AMH levels were associated with a lower risk of T2D (hazard ratio (HR) T2vsT1 = 0.77, 95%CI: 0.53-1.11; HR T3vsT1 =0.62, 95%CI: 0.40-0.94; p for trend = 0.02). These findings were supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages and declined at a slower rate in women who were diagnosed with T2D compared to women who were not. However, differences in trajectories between T2D cases and non-cases were not statistically significant. Conclusions: We observed that women with higher age-specific AMH levels were at a lower risk of T2D. In addition, our longitudinal analyses may suggest that AMH is lower in women who develop T2D compared to women who do not. These findings are in line with previous studies that observed that a higher age at menopause was associated with a decreased risk of T2D.