tbuckley/cabot-search huggingface dataset:
Abstract 4002: EGR1 downregulation by miR-377-3p mediated lung tumorgenesis following benzo[a]pyrene exposure
Authors: Xinxin Ke, Jing Shen, Jimin Shao, Hongyan Qi
Journal: Cancer Research (2018)

Abstract Polycyclic aromatic hydrocarbons (PAHs), especially Benzo[a]pyrene (B[a]P), contained in cigarette smoke and air pollution, belong to a category of important carcinogens for lung cancer. B[a]p exerts its carcinogenic function by causing mutations, cytotoxicity and inhibiting DNA synthesis. However, the early molecular events and related mechanisms of B[a]P-induced cell transformation and tumor initiation remains unclear. In this study, we showed that EGR1 was significantly downregulated during human bronchial epithelial BEAS-2B cell transformation and mice lung carcinogenesis after B[a]P and its active form B[a]PDE exposures, respectively. Using RNA-seq to screening and using qRT-PCR, western-blot and immunohistochemistry for validation. In contrast, overexpression of EGR1 inhibited the cell malignant transformation upon B[a]PDE exposure. Furthermore, miR377-3p was strongly increased by B[a]PDE/B[a]P in vitro and in vivo. And luciferase reporter assays showed that the exposure-induced miR377-3p was crucial for inhibition of EGR1 by targeting its 3'-UTR. Importantly, miR-377-3p antagomir reversed the effect of EGR1 downregulation in the cell malignant transformation and tumor initiation models. The target genes of EGR1, ANKRD1 and ATF3, which could be involved in B[a]P-induced lung tumorgenesis, were also analyzed in cell and mice model, respectively. Finally, the B[a]P exposure-induced molecular changes were examined by immunohistochemistry in clinical lung cancer tissues and evaluated with TCGA data. Taken together, the results demonstrated that Benzo[a]pyrene exposure may induce lung tumorgenesis through miR-377-3p mediated reduction of EGR1 expression, suggesting an important role of the tumor suppressor EGR1 in PAH-induced lung carcinogenesis. Keywords: EGR1, miR-377-3p, malignant transformation, lung tumorgenesis, gene regulation Citation Format: Xinxin Ke, Jing Shen, Jimin Shao, Hongyan Qi. EGR1 downregulation by miR-377-3p mediated lung tumorgenesis following benzo[a]pyrene exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4002.
Abstract 17491: Prognostic Value of Serial Change of Serum Chloride Level During Hospitalization in Patients With Acute Decompensated Heart Failure
Authors: Takumi Kondo, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Tatsuhisa Ozaki, Yoshihiro Sato, Masahiro Seo, Iyo Ikeda, Eiji Fukuhara, Jun Nakamura, Makoto Abe, Masatake Fukunami
Journal: Circulation (2016)

Background: Although hyponatremia had been reported to be a strong predictor of morbidity and mortality in patients (pts) with acute decompensated heart failure (ADHF), recent studies have shown that hypochloremia is independently associated with poor prognosis in ADHF pts. However, little is known about the prognostic value of serial change in serum chloride level during hospitalization in ADHF pts. Method and Results: We prospectively enrolled 124 ADHF patients discharged with survival (LVEF: 48±15%). We performed venous blood sampling at admission and discharge. All study pts were divided into 4 groups according to serum chloride level at admission and discharge;(i)persistent hypochloremia (n=8) with hypochloremia (<98.0mEq/L) both at admission and before discharge, (ii)progressive hypochloremia (n=32) with the development of hypochloremia after admission, (iii)improved hypochloremia (n=6) with hypochloremia only at admission but not at discharge, and (iv) no hypochloremia during hospitalization (n=78)...
A Mirror-Symmetric Excitatory Link Coordinates Odor Maps across Olfactory Bulbs and Enables Odor Perceptual Unity
Authors: Mark Grobman, Tal Dalal, Hagar Lavian, Ronit Shmuel, Katya Belelovsky, Fuqiang Xu, Alon Korngreen, Rafi Haddad
Journal: Neuron (2018)
Abstract 3953: The role of USF1 in the regulation of lipogenesis and breast cancer tumor progression
Authors: Jessica Lewis, Iqbal Mahmud, Daiqing Liao
Journal: Cancer Research (2018)

Abstract Breast cancer accounts for nearly one-quarter of all cancer diagnoses and is the principal cause of cancer-related mortality in women worldwide. Triple negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer commonly resistant to therapeutics that have been successful in increasing survival in patients with ER+, PR+ and HER2+ breast cancer subtypes. As such, identifying factors that contribute to poor patient outcomes and mediate the growth and survival of TNBC cells remain important areas of investigation. USF1 (upstream stimulatory factor 1), a gene linked to drive lipogenesis and cellular proliferation, is over-expressed in human malignancies, yet its contribution to cancer remains unclear. In analyzing large number of genomic datasets including The Cancer Genome Atlas (TCGA), we found that USF1 expression is significantly higher in TNBC tumor samples and cell lines. Also, USF1 gene expression positively correlates with key lipogenic enzymes. Significantly, we found that high expression of USF1 in breast cancer correlates with decreased patient survival. We found that USF1 shRNA expression resulted in cell death in breast cancer cell lines. We therefore hypothesize that USF1 drives de novo lipogenesis to promote breast tumorigenesis. Further studies are underway to determine the mechanisms by which USF1 promotes de novo lipogenesis, tumorigenesis and metastatic progression. Our studies will shed lights on the roles of USF1 in breast cancer tumor biology and undercover potential novel anticancer drug targets. (Supported by McKnight Foundation, Bankhead-Coley Cancer Research Program and James and Esther King Biomedical Research Program, Florida Department of Health.) Citation Format: Jessica Lewis, Iqbal Mahmud, Daiqing Liao. The role of USF1 in the regulation of lipogenesis and breast cancer tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3953.
Renin Release in Patients with Benign Essential Hypertension
Authors: Yoshihirokaneko, Takaoikeda, Tadanaotakeda, Gosukeinoue, Hrroshitagawa, Hideoueda
Journal: Circulation (1968)

In 16 of 28 patients with benign essential hypertension, reduction of mean arterial pressure to 75 to 120 mm Hg by infusion of sodium nitroprusside caused significant increase in renin release estimated by the renal-systemic difference of renin activity and renal plasma flow (RPF). The threshold at which renin release increased was shifted to a range that was intermediate between that previously reported for normotensive subjects and that for patients with renovascular hypertension, but the average magnitude of renin release was almost comparable to that in normotensive subjects. In the other 12 patients, no significant renin release occurred during reduction in pressure of comparable degree. The difference in renin release was difficult to explain by the difference in severity of hypertensive disease or in sodium excretion, but increased renin release was usually associated with a decrease in RBF and a rise in renal vascular resistance, while insignificant release was usually associated with an insignifi...
Abstract 23232: NHLBI-sponsored Trial of Postconditioning During PCI for ST-elevation Myocardial Infarction
Authors: Jay Traverse, Cory Swingen, Timothy D Henry, Yale Wang, Ivan Chavez, Daniel Lips, John R Lesser, Jane Fox, Wesley R Pedersen, Nicholas M Burke, Akila Pai, Ross F Garberich, Jana L Lindberg
Journal: Circulation (2016)

Introduction: Postconditioning (PC) is a powerful mechanism to reduce infarct size in animals following ischemia / reperfusion (I/R) injury. However, clinical trials outside the United States have ...
Resistance to Endotoxin Shock in Transgenic Mice Overexpressing Endothelial Nitric Oxide Synthase
Authors: TomoyaYamashita, SeinosukeKawashima, YoshitakaOhashi, MasaoriOzaki, TomomiUeyama, TatsuroIshida, NobutakaInoue, Ken-ichiHirata, HozukaAkita, MitsuhiroYokoyama
Journal: Circulation (2000)

Background—Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice. Methods and Results—LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97±3 to 59±3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84±4 to 71±4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in...
Abstract 4962: Metabolic rewiring of macrophages by CpG stimulates anti-tumor activity that overrides CD47-resistance in pancreatic cancer
Authors: Mingen Liu, Roddy S. O'Connor, Sophie Trefely, Nathaniel W. Snyder, Gregory L. Beatty
Journal: Cancer Research (2018)

Abstract Although macrophages commonly support cancer growth, they can be induced with anti-tumor functions - such as the ability to phagocytose and kill tumor cells. This activity is governed by stimulatory as well as inhibitory signals (e.g. CD47). The role of central carbon metabolism in determining macrophage function, however, remains poorly understood. Here, we identify CpG-activated changes in the metabolism of macrophages to be a major determinant of their phagocytic and anti-tumor capabilities, including the ability to overcome inhibitory CD47 expressed by tumor cells. In a fully syngeneic model of murine pancreatic ductal adenocarcinoma (PDAC), systemic delivery of CpG re-directed macrophages to mediate anti-tumor activity against PDAC tumor cells independent of CD47 expressed by tumor cells. The anti-tumor potential stimulated by CpG was not associated with polarization of macrophages toward classical M1 or M2 phenotypes, but rather was dependent on a hybrid state of metabolic features found in M1 and M2 macrophages. These metabolic changes required shunting of tricarboxylic acid (TCA) cycle intermediates for de novo biosynthesis of lipids and elevated fatty acid oxidation (FAO) that was supported by glutamine anaplerosis. Coordination of these processes by carnitine palmitoyltransferase 1A (CPT1A) and ATP citrate lyase (ACLY) supported the ability of macrophages to bypass the CD47 inhibitory pathway and mediate anti-tumor functions. Our findings underscore a novel role for the metabolic state of macrophages in overriding barriers to anti-tumor activity, and reveal potential targets that may enhance CD47-based therapies. Citation Format: Mingen Liu, Roddy S. O'Connor, Sophie Trefely, Nathaniel W. Snyder, Gregory L. Beatty. Metabolic rewiring of macrophages by CpG stimulates anti-tumor activity that overrides CD47-resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4962.
Randomized Clinical Trial Needed to Confirm Whether Dalcetrapib Improves Outcomes for Specific <i>ADCY9</i> Genotype
Authors: Marc A. Pfeffer, Marie-Pierre Dubé, Jean-Claude Tardif
Journal: JAMA Cardiology (2018)

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The Ausculatory Gap in Arteriosclerotic Heart Disease
Authors: Simonrodbard, Jackmargolis
Journal: Circulation (1957)

Auscultatory gaps, found in some patients with arteriosclerotic heart disease, can be elicited in others by reducing blood flow in the extremity. Reactive hyperemia eliminates the gap in every instance. The gap therefore appears to represent a vasospastic disturbance that limits the blood flow to the extremities, despite the presence of an enhanced pressure head.
Abstract 3327: Correlating blood-based DNA methylation markers and prostate cancer risk factors in African-American men
Authors: Bernard Kwabi-Addo, Emmauel Moses-Fynn, Wei Tang, Desta Beyene, Victor Apprey, Yasmine Kanaan
Journal: Cancer Research (2018)

Abstract Background: Detection of prostate cancer at an early stage is key for successful treatment and improvement of outcome. However, the limitations of PSA screening are well recognized and therefore novel approaches to prostate cancer screening are necessary. We have investigated the clinical significance of DNA methylation in the blood serum of African-American men with prostate cancer. Method: We used pyrosequencing to examine the promoter methylation for a panel of 8 genes in blood samples extracted from 91 prostate cancer cases and 91 noncancerous control cases. Results: Seven of the 8-gene panel–RARβ2, TIMP3, SPARC, CDH13, LINE1, CYB5R2 and DRD2–tested achieved significant difference between the cancer cases when compared to control cases. The RARβ2 and TIMP3 demonstrated significant association of DNA methylation with age for all cases analyzed. Associations of methylation status and various clinicopathologic features and patient survival were evaluated: we observed significant inverse association of serum vitamin D levels in the cancer cases and DNA methylation of CDH13 and also an inverse correlation between TIMP3 and DRD2 methylation with supplementary vitamin D in the cancer cases. On the other hand, we observed a direct correlation between HIN1 methylation and serum vitamin D level. In addition, we observed a direct correlation between RARβ2 and Sparc methylation with PSA level in the control but not the cancer cases. Conclusion: Promoter methylation occurred more frequently in the serum of patients with prostate cancer than noncancerous cases, suggesting that epigenetic markers in serum have potential for diagnosis of prostate cancer in AA men. Citation Format: Bernard Kwabi-Addo, Emmauel Moses-Fynn, Wei Tang, Desta Beyene, Victor Apprey, Yasmine Kanaan. Correlating blood-based DNA methylation markers and prostate cancer risk factors in African-American men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3327.
Stem Cells and Transplant Arteriosclerosis
Authors: QingboXu
Journal: Circulation Research (2008)

Stem cells can differentiate into a variety of cells to replace dead cells or to repair damaged tissues. Recent evidence indicates that stem cells are involved in the pathogenesis of transplant arteriosclerosis, an alloimmune initiated vascular stenosis that often results in transplant organ failure. Although the pathogenesis of transplant arteriosclerosis is not yet fully understood, recent developments in stem cell research have suggested novel mechanisms of vascular remodeling in allografts. For example, stem cells derived from the recipient may repair damaged endothelial cells of arteries in transplant organs. Further evidence suggests that stem cells or endothelial progenitor cells may be released from both bone marrow and non–bone marrow tissues. Vascular stem cells appear to replenish cells that died in donor vessels. Concomitantly, stem/progenitor cells may also accumulate in the intima, where they differentiate into smooth muscle cells. However, several issues concerning the contribution of stem ...
Metastatic pancreatic cancer (MPC): Contrast of short- (STS) and long-term (LTS) survivor characteristics.
Authors: Mark Kowalczyk, Margaret T. Mandelson, Bruce Shih-Li Lin, Vincent J. Picozzi
Journal: Journal of Clinical Oncology (2018)

415 Background: MPC is associated with 6-12 month (mo) median overall survival (OS) in published clinical series. However, there is wide variability in OS using standard chemotherapy (CTX) regimens (e.g. gemcitabine/nab-paclitaxel, FOLFIRINOX). 10-20% of patients (pts) live ≤ 3 mo (STS); conversely 5-10% pts live ≥ 24 mo (LTS). We examined pretreatment characteristics of our institutional MPC population for their association with STS/LTS. Methods: From our institutional database, we identified over 400 pts with MPC who received CTX between the years 2003 and 2015. Pts who 1) received all of their CTX at our institution 2) had complete longitudinal follow- up available and 3) lived either ≤ 3 or ≥ 24 mo were further analyzed. A number of pretreatment characteristics were considered, including A) patient and B) disease-related factors. Results: To date,37 pts (median OS 2.0 mo)/ 41 pts (median 28.2 mo) have been identified as STS/LTS respectively. In univariate analysis factors significantly associated with STS/LTS ( p &lt; 0.0001) were ECOG ≥2 and neutrophil /lymphocyte ratio (NLR) &gt; 5. Age at dx, pain at dx, BMI &gt; 30, albumin &lt; 4.0 g/dL, Ca19.9 &gt; 500U/mL, ascites at dx and liver involvement also were statistically significant (all p≤ 0.05 or greater). Among factors not statistically different between STS/LTS were sex, race, yr of dx, presence of diabetes or biliary obstruction at dx. A multivariate model that included ECOG ≥2 and NLR ≥5 along with other of the above factors correctly discriminated between STS and LTS with 90% accuracy (95% CI 83-97%) . Conclusions: 1) Examination of pretreatment characteristics in MPC can aid in identification of pts more likely to be STS / LTS. 2) For STS and LTS these data may aid in identifying candidates for new initial and new consolidation treatment strategies, respectively. 3) Prognostics models for STS/LTS require additional validation in independent data sets. 4) Integrating additional pretreatment information (e.g. molecular, clinical, therapeutic) may further improve OS prognostication in MPC.
Abstract 440: Single-cell whole-genome sequencing reveals somatic mutation signatures in normal somatic cells predictive of cancer later in life
Authors: Xiao Dong, Lei Zhang, Moonsook Lee, Alexander Y. Maslov, Jan Vijg
Journal: Cancer Research (2018)

Abstract Single-cell sequencing for analyzing DNA mutations across the genome in somatic tissues is critically important for studying development, cancer and aging. However, current procedures are prone to artifacts and to date a reliable protocol for single-cell somatic mutation analysis remains to be developed. We address the two largest sources of artifacts, i.e., DNA denaturation-related cytosine deamination and allelic bias-driven whole genome amplification errors. We first reconfigured multiple displacement amplification (MDA) into an efficient protocol for whole genome amplification of single cells without cytosine deamination artifacts, i.e., Single Cell MDA (SCMDA). We then developed a new single-cell SNV caller (SCcaller) that distinguishes real somatic mutations and amplification errors by utilizing a SNP-based localized estimate of allelic amplification bias. The procedure was validated by comparing SCMDA-amplified single cells with unamplified clones derived from single cells from the same population. Using this highly accurate single-cell whole-genome sequencing method we analyzed human B lymphocytes from donors varying in age from birth to over 100 year, studying both genome distribution and functional impact of base substitution mutations. Mutations per cell were found to increase with age from less than 500 in cord blood to over 3,000 in cells from individuals over 100. While overall mutations were randomly distributed across the genome with all chromosomes equally affected, 24 hotspot regions were identified, five of which were part of immunoglobulin variable regions subject to somatic hypermutation. Age-related mutation accumulation was found to be significantly slower in genomic sequences directly involved in cellular function, such as exons and gene regulatory sequences. Still, on average, B lymphocytes from aged individuals contained 3-15 damaging mutations in the transcribed part of the exome identified by RNA-seq, plus 15-50 mutations in transcription factor binding sites identified by ATAC-seq. Analysis of the spontaneous mutation spectra in these normal cells revealed signatures similar to those previously found associated with B cell leukemia and other cancers. These results indicate that cancer risk is already part of age-related mutation accumulation in normal cells. Taken together, our single-cell sequencing method provides a firm foundation for analyzing cellular genetic heterogeneity in normal human tissues. Citation Format: Xiao Dong, Lei Zhang, Moonsook Lee, Alexander Y. Maslov, Jan Vijg. Single-cell whole-genome sequencing reveals somatic mutation signatures in normal somatic cells predictive of cancer later in life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 440.