tbuckley/cabot-search huggingface dataset:
Abstract 4824: Rac1b overexpression confers resistance to chemotherapy treatment in colorectal cancer
Authors: Pallavi Chaturvedi, Erik Goka, Adriana De La Garza, Dayrelis Mesa Lopez, Marc E. Lippman
Journal: Cancer Research (2018)

Abstract Acquired resistance to chemotherapy represents a major limitation in the treatment of colorectal cancer. New strategies to circumvent this problem are critical to prolonging patient survival. Previous studies have shown that Rac1b, a constitutively activate isoform of the small GTPase Rac1, is upregulated with disease progression and promotes cell proliferation and inhibits apoptosis by activation of NFκB signaling. In the present study, we show that Rac1b overexpression correlates with colorectal cancer stage with the highest levels identified in metastatic cancer. We show that Rac1b expression is associated with increased growth of colon adenocarcinoma cells and that modulation of Rac1b expression in colon adenocarcinoma cells reduces NFκB activity. The use of a Rac inhibitor in colon cancer cells reduces the 2D and 3D colony formation of colon adenocarcinoma cells, reduces the migratory capacity of these cells, and suppresses NFκB signaling. Rac inhibition also reduces tumor growth in a xenograft model of colon adenocarcinoma cells. Surprisingly, Rac1b expression and NFκB activity was upregulated in colon carcinoma cells treated with 5-FU and oxaliplatin (two components of the standard of care FOLFOX chemotherapy regimen), suggesting that Rac1b facilitates chemo-resistance by activation of NFκB signaling. Knock down of Rac1b in colon cancer cells or Rac inhibitor increases the sensitivity of the cells to oxaliplatin. When used in combination, inhibition of Rac in the colon cancer cells prevents the increase in NFκB activity associated with chemotherapy treatment and increases the sensitivity of the cells to oxaliplatin. Moreover, while Rac inhibition or oxaliplatin treatment alone reduces the growth of colorectal cancer in vivo, combination therapy results in significant further reduction of tumor growth than either single agent alone. Thus, we provide the first evidence that Rac1b expression confers resistance to standard of care chemotherapy in colorectal cancer. Additionally, we show that the use of a Rac inhibitor prevents chemoresistance by blocking activation of chemotherapy induced NFκB signaling providing a novel strategy to overcome resistance to chemotherapy in colorectal cancer. Citation Format: Pallavi Chaturvedi, Erik Goka, Adriana De La Garza, Dayrelis Mesa Lopez, Marc E. Lippman. Rac1b overexpression confers resistance to chemotherapy treatment in colorectal 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 4824.
Abstract 4380: Role of FAM3B/PANDER in inhibition of cell death and tumor growth in breast and prostate cancer
Authors: Izabela D. Caldeira
Journal: Cancer Research (2018)

Abstract FAM3B/PANDER is a novel cytokine-like protein that induces apoptosis in beta-cells and regulates the effects of insulin in peripheral tissues. Since previous data revealed that FAM3B can be expressed by prostate and breast tumors, we evaluated the role of this cytokine in prostate and breast tumor progression. FAM3B expression was compared by quantitative PCR in LnCAP, PC-3 and DU145 prostate tumor cell lines and MCF-7 and MDA-MB- 231 breast tumor cell lines. After treatment with either recombinant FAM3B protein or secreted FAM3B obtained from conditioned media (CM) derived from FAM3B-overexpressing 293T cells, the cell death and viability of DU145 and MDA-MB- 231 cell lines were evaluated. DU145 and MDA-MB- 231 cells overexpressing FAM3B protein were produced by lentiviral-mediated transduction of full-length FAM3B cDNA. Cell viability and apoptosis were analyzed in DU145-FAM3B and MDA-231-FAM3B cells after treatment with cell death inducers. Anchorage-independent growth and scratch wound assays were used to evaluate in vitro tumorigenicity and cell migration, respectively. In vivo tumorigenicity and invasiveness were evaluated by tumor xenograft growth in nude mice. We observed that FAM3B was highly expressed by hormone responsive cells (LnCAP and MCF-7) and low expressed in unresponsive hormone cells (PC-3, DU145 and MDA-MB- 231). Cell viability and survival of DU145 and MDA-MB- 231 cells increased after exogenous treatment with recombinant FAM3B protein or CM containing FAM3B-secreted protein. Overexpression of FAM3B in DU145 and MDA-MB- 231 cells promoted an inhibition of apoptosis triggered by TNF-alpha and staurosporine. Cell death inhibition was accompanied by increased gene expression of the anti-apoptotic Bcl-2 and Bcl-xL genes, and by slight decrease in expression of pro-apoptotic gene Bax and with a decrease of caspases proteolytic activities. When compared to control, cells overexpressing FAM3B displayed a decreased anchorage independent growth and increased motility in vitro, as well as an increased tumor growth in xenografted nude mice. In agreement Immunohistochemistry analysis from tumor xenografts revealed similar anti-apoptotic phenotype in FAM3B overexpression, with an increase of Bcl-2. The results showed that FAM3B was capable to activates pro-survival mechanisms with an increasing of tumor growth by, activation of Bcl-2 and Bcl-xl pathways, suggesting the role of this cytokine in breast and in prostate tumors progression. Citation Format: Izabela D. Caldeira. Role of FAM3B/PANDER in inhibition of cell death and tumor growth in breast and prostate 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 4380.
Abstract 17606: Unbiased Whole Blood RNA Profiling in Patients With Acute Coronary Syndrome and at Follow-Up
Authors: Maarten Vanhaverbeke, Denise Veltman, Thibault Petit, Sander Trenson, Arief Wibowo, Hilde Gillijns, Jozef Bartunek, Heinrich J Huber, Stefan Janssens, Peter Sinnaeve
Journal: Circulation (2016)

Introduction: Stabilized whole blood RNA samples are collected in clinical trials in acute coronary syndromes (ACS), using convenient tubes that are easily transported and stored. To date however, gene signatures, potential biomarkers for treatment effect or outcome, have not been comprehensively studied in unselected ACS patients. We aimed at establishing an unbiased whole blood gene expression profile of ACS patients and investigated to what extent it clusters with known clinical variables in the acute phase and at follow-up. Methods: Peripheral blood RNA was profiled on the Affymetrix GeneChip® HTA 2.0 micro-array in patients with ACS on admission and at day 30 (n=65, 34 NSTEMI and 31 STEMI) and compared to stable CAD (n=22). An unbiased RNA signature was determined by differential expression between ACS and CAD (FDR p<0.001, fold change 2). At 1-year follow-up, 10 patients had experienced a new cardiovascular event, and 11 patients had developed ischemic cardiomyopathy. Results: We established a gene ...
New-Onset Diabetes After Acute Kidney Injury Requiring Dialysis
Authors: Yu-Feng Lin, Shuei-Liong Lin, Tao-Min Huang, Shao-Yu Yang, Tai-Shuan Lai, Likwang Chen, Vin-Cent Wu, Tzong-Shinn Chu, Kwan-Dun Wu
Journal: Diabetes Care (2018)

OBJECTIVE Acute kidney injury (AKI) is related to a high prevalence of insulin resistance. However, information is lacking on the sequelae of further metabolic change among AKI requiring dialysis in patients who could be weaned off dialysis (acute kidney disease [AKD]). RESEARCH DESIGN AND METHODS Using the National Health Insurance Research Database from 2000 to 2010, with the exclusion of those with diabetes at the start, we identified 3,307 subjects with AKD and 9,921 matched control subjects from 963,037 hospitalized patients for the comparison of the outcomes, including new-onset diabetes and all-cause mortality. RESULTS Within the median follow-up period of 5.99 years, AKD patients had a higher incidence of new-onset diabetes than the matched control patients (5.16% vs. 4.17% per person-year, P = 0.001). AKD patients were at higher risk of mortality than control patients (adjusted hazard ratio [aHR] 1.27 [95% CI 1.18–1.36], P &amp;lt; 0.001). With mortality as a competing risk, a Cox proportional hazards analysis showed that AKD patients had a higher risk of subsequent diabetes (subhazard ratio [sHR] 1.18 [95% CI 1.07–1.30], P &amp;lt; 0.001) compared with the matched control patients. Subgroup analysis showed that patients with baseline hypertension (aHR 1.15 [95% CI 1.04–1.28]), hyperlipidemia (aHR 1.23 [95% CI 1.02–1.48]), and gout (aHR 1.23 [95% CI 1.03–1.46]) had increased odds of developing new-onset diabetes during follow-up. CONCLUSIONS Patients who experienced AKI had a higher incidence of developing new-onset diabetes and mortality. This observation adds evidence regarding potential metabolic dysregulation after AKI.
Abstract 4484: Synthetic essentiality of chromatin remodeling factor CHD1 in PTEN-deficient cancer
Authors: Di Zhao
Journal: Cancer Research (2018)

Abstract Background: Prostate cancer (PCa) is the second leading cause of cancer death for men in the United States. Up to 70% of primary prostate tumors show loss of heterozygosity (LOH) at the PTEN locus, and loss of PTEN is a key initiation event in PCa development. Synthetic and collateral lethality have provided conceptual frameworks to identify cancer-specific vulnerabilities. Here, we explored an approach to identify potential synthetic lethal interactions through screening mutually exclusive deletion patterns in cancer genomes. Methods: We sought to identify ‘synthetic essential' genes, which might be occasionally deleted in some cancers but almost always retained in the context of a specific tumor suppressor deficiency, and posited that such synthetic essential genes would be therapeutic targets in cancers harboring specific tumor suppressor deficiencies. Results: In addition to known synthetic lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic essential gene in PTEN-deleted cancers. In PTEN-deleted prostate and breast cancers, the functional analysis showed that CHD1 depletion profoundly and specifically suppressed cell proliferation, survival, and tumorigenic potential. Mechanistically, functional PTEN stimulates GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via β-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in CHD1 protein stabilization, which in turn engages the H3K4me3 mark to activate transcription of the pro-tumorigenic TNFα/NF-κB gene network. In addition, we found CHD1 depletion significantly inhibits the progression of Pten-deficient prostate cancer genetic engineered mouse model. Conclusions: Together, this study identifies CHD1 as a novel downstream effector in PTEN pathway, and verifies CHD1 as a novel therapeutic target in PTEN deficient prostate cancer and breast cancer. Additionally, this study provides a framework for the discovery of trackable targets in cancers harboring specific tumor suppressor deficiencies. Citation Format: Di Zhao. Synthetic essentiality of chromatin remodeling factor CHD1 in PTEN-deficient 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 4484.
Abstract 1864: Pharmacologic inhibition of NAMPT sensitizes pancreatic cancer cells to the antineoplastic effects of metformin
Authors: Gerardo Ferbeyre, Maxime Parisotto, Marie-Camille Rowell, Véronique Bourdeau, Andreea R. Schmitzer
Journal: Cancer Research (2018)

Abstract The use of the anti-diabetic drug metformin has been correlated with a reduced cancer incidence, suggesting an unexpected anti-neoplastic activity for this compound. Since metformin treatment is safe and economical, there is considerable interest in exploring its anticancer activity in patients. Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases, for which there is no treatment significantly increasing patient's survival. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. In vitro, metformin decreases cell survival and growth of pancreatic cancer cells and appears to target tumor-initiating cells. In vivo, metformin decreases growth of human pancreatic cancer cell lines xenografts in mice. However, clinical trials using metformin failed to decrease pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We discovered a new mechanism of resistance to the anti-oncogenic properties of metformin in PDAC cells through up-regulation of NAMPT and increase of NAD+ synthesis. Using an inhibitor specific to NAMPT, FK866, we sensitized PDAC cells to the effects of metformin in vitro. In vivo, FK866 increased the efficiency of metformin treatment on KP4 cells xenografts. As both metformin and FK866 clinical trials have failed to efficiently treat cancer, the combination of these two compounds may be a promising strategy to treat pancreatic cancer and maybe other malignancies. Citation Format: Gerardo Ferbeyre, Maxime Parisotto, Marie-Camille Rowell, Véronique Bourdeau, Andreea R. Schmitzer. Pharmacologic inhibition of NAMPT sensitizes pancreatic cancer cells to the antineoplastic effects of metformin [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 1864.
Abstract 4409: Developing brain tumor-specific gold-liposomal nanocarriers for a noninvasive delivery of microRNA inhibitors
Authors: Nilmary Grafals, Blanca I. Quiñoes-Diaz, Janixa Del Valle, Gabriel L. Barletta-Bonano, Pablo E. Vivas-Mejía
Journal: Cancer Research (2018)

Abstract MicroRNAs are non-coding RNA molecules that regulate more than 60% of the protein coding genes and their dysregulation has proven to be involved in the initiation, progression and maintenance of malignant brain tumors such as glioblastoma multiforme (GBM). Targeting microRNAs in GBM has shown therapeutic value, although their translation to the clinic have been halted due to their rapid renal clearance, short circulatory life and inability to reach the brain tumor after systemic administration. Over the last years, nanodelivery systems such as liposomes (Lip) and gold nanoparticles (AuNPs) have gained acceptance for the treatment of cancer. This project is focused on developing anti-miRNA gold carriers further encapsulated inside nanoliposomes that are labeled with blood brain barrier specific peptides (Apolipoprotein E and Rabies Virus Glycoprotein). The synthesis of these dual gold-liposomal particles has three important steps: (a) Peptide Pegylation, (b) anti-microRNA conjugation to gold nanoparticles and, (c) nanoparticle assembly. To achieve each of them the corresponding peptide was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)]-Malemide (DSPE-PEG-Mal) by a thioester bond and incorporated into DOPC and cholesterol lipid mixture. Afterwards, anti-microRNAs were functionalized to 15 nm gold nanoparticles (AuNPs) to obtain RNAi-AuNPs. Finally, the nanoparticles of interest where produce: RNAi-AuNP-Lip, RNAi-AuNP-Lip-APOE and RNAi-AuNP-Lip-RVG. These nanoparticles where characterized by dynamic light scattering, zeta potential and encapsulation efficiency. Additionally, we determine their toxicity in U-87 GBM cell lines. Our results obtained show sizes that range from 30 nm, 60 nm and 95 nm for gold-RNAi, gold-liposomes and gold-liposome-peptides respectively. These particles are slightly negative and have encapsulation efficiencies that are greater than 50%. Cell viability analysis also show that gold nanoparticles carrying microRNA inhibitor negative controls are not toxic to GBM cell lines. Additional studies for cell internalization, reactive oxygen species generation and RNA delivery and release are ongoing now. Developing systemic viable microRNA based therapeutics its a big challenge, but they are crucial to assure the patient a non-invasive therapy that could improve their quality of life and their overall survival. Citation Format: Nilmary Grafals, Blanca I. Quiñoes-Diaz, Janixa Del Valle, Gabriel L. Barletta-Bonano, Pablo E. Vivas-Mejía. Developing brain tumor-specific gold-liposomal nanocarriers for a noninvasive delivery of microRNA inhibitors [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 4409.
Abstract 2670: Natural compound tetrocarcin-A downregulates junctional adhesion molecule-A in conjunction with erα, her2 and inhibitor of apoptosis proteins and inhibits tumor cell growth
Authors: Sri Harikrishna Vellanki, Lance Hudson, Hanne Jahns, Rodrigo G.B. Cruz, Giovanni Sette, Adriana Eramo, Ann M. Hopkins
Journal: Cancer Research (2018)

Abstract Overexpression of the tight junction protein Junctional Adhesion Molecule-A (JAM-A) has been linked to aggressive disease in breast and several other cancers, but JAM-targeting drugs remain elusive. Screening of a natural compound library identified the cytotoxic antibiotic Tetrocarcin-A as a novel downregulator of JAM-A protein expression in breast cancer cells. Specifically, Tetrocarcin-A-induced cytotoxicity was accompanied by downregulation of JAM-A protein expression in conjunction with that of estrogen receptor alpha (ERα) and human epidermal growth factor receptor 2 (HER2) in MCF7-HER2-overexpressing breast cells. Lysosomal inhibition partially rescued the downregulation of JAM-A, HER2 and ERα caused by Tetrocarcin-A, and attenuated its cytotoxicity. Interestingly, Tetrocarcin-A repressed the transcriptional activity of c-FOS by inhibiting ERK1/2-mediated phosphorylation at Threonine-232, and downregulated protein expression of the inhibitor of apoptosis proteins (IAP). Investigation of cell death pathways revealed that Tetrocarcin-A induced caspase-dependent apoptosis. To begin testing the potential clinical relevance of our findings, we extended our studies into various other models. Encouragingly, Tetrocarcin-A downregulated JAM-A expression and caused cytotoxicity in primary breast cancer and lung cancer stem cells, and inhibited the growth of model human breast tumors in an in vivo model involving invasion across the chicken egg chorioallantoic membrane. Taken together, our data suggest that Tetrocarcin-A merits future evaluation as a novel cancer therapeutic by virtue of its ability to downregulate JAM-A expression, induce apoptosis and reduce tumorigenic signalling. This work was financially supported by Science Foundation Ireland (grant 13/IA/1994 to AMH). Tetrocarcin-A was provided by the NCI/DTP Open Chemical Repository https://dtp.cancer.gov. (NSC 333856) Citation Format: Sri Harikrishna Vellanki, Lance Hudson, Hanne Jahns, Rodrigo G.B. Cruz, Giovanni Sette, Adriana Eramo, Ann M. Hopkins. Natural compound tetrocarcin-A downregulates junctional adhesion molecule-A in conjunction with erα, her2 and inhibitor of apoptosis proteins and inhibits tumor cell growth [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 2670.
Abstract 553: p53 target BRMS1A is a metastatic suppressor
Authors: Takashi Tokino, Ryota Koyama, Masashi Idogawa, Yasushi Sasaki
Journal: Cancer Research (2018)

Abstract Tumor suppressor p53 plays an important role in the cell fate determination in response to diverse upstream signals. As a transcription factor, p53 regulates a number of genes that are involved in cell-cycle arrest, apoptosis, senescence, and maintenance of genomic stability. Recent studies revealed that p53 is critical for the regulation of cell invasion and migration. Microarray analysis showed that breast cancer metastasis-suppressor 1-like (BRMS1L) is upregulated by p53. We identified two responsive sequences of p53 in the first intron and upstream of the BRMS1L gene. These two response elements are well conserved among mammals. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration. In contrast, knockdown of BRMS1L by siRNA induced the opposite effect. Notably, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. Altogether, these results strongly indicate that BRMS1L is one of the mediators downstream of the p53 pathway, and inhibits cancer cell invasion and migration, which are essential steps in cancer metastasis. Collectively, our results demonstrate that BRMS1L is involved in cancer cell invasion and migration, and may be a therapeutic target for cancer. Citation Format: Takashi Tokino, Ryota Koyama, Masashi Idogawa, Yasushi Sasaki. p53 target BRMS1A is a metastatic suppressor [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 553.
Measurements and a Simplified Interpretation of Magnetocardiograms from Humans
Authors: Davidcohen, Louischandler
Journal: Circulation (1969)

To understand and assess the magnetocardiograph, the magnetic field produced by electrical heart activity was mapped around the torsos of one abnormal and six normal heart subjects, at different times during QRS. The measurements are here presented in the form of instantaneous distributions of vector segments 6 cm from the skin, anteriorly. An electrical model is presented which explains the first-order features of these distributions. This model is a simple, rotating bipole heart source of changing strength which produces the same ion currents as measured with surface electrocardiograms and vectorcardiograms; these currents produce a time-changing magnetic field extending outside the torso. Further analysis of second-order details of the distributions can reveal information not obtainable with various forms of surface electrocardiography.