tbuckley/cabot-search huggingface dataset:
Abstract 11650: Association of Macrophage Inflammation Biomarkers With Progression of Subclinical Carotid Atherosclerosis in HIV-infected Women and Men
Authors: David B Hanna, Juan Lin, Wendy S Post, Xiaonan Xue, Kathryn Anastos, Mardge H Cohen, Stephen J Gange, Sonya L Heath, Jason M Lazar, Chenglong Liu, Wendy J Mack, Igho Ofotokun, Phyllis C Tien, Howard N Hodis, Alan L Landay, Lawrence A Kingsley, Russell P Tracy, Robert C Kaplan
Journal: Circulation (2016)

Introduction: Monocytes and monocyte-derived macrophages promote atherosclerosis through inflammation and vascular remodeling. We suspect that this is especially true in chronic HIV infection due to increased inflammation. We hypothesized that 4 serum macrophage inflammation markers, soluble (s)CD163, sCD14, galectin-3 binding protein (Gal-3BP), and galectin-3 (Gal-3), are associated with progression of subclinical carotid artery atherosclerosis even after adjustment for the systemic inflammation markers C-reactive protein (CRP) and interleukin-6 (IL-6). Methods: We examined 778 women (74% HIV+) in the Women’s Interagency HIV Study and 503 men (65% HIV+) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004–2013. Baseline marker levels were determined from previously frozen serum specimens. We assessed the association of each marker with new plaque formation (focal IMT &gt;1.5 mm) over a median 7 years, adjusting for demographic, behavioral, and cardiometabolic risk factors, and levels of high sensitivity CRP and IL-6. Results: Levels of each marker were significantly higher in HIV+ compared with HIV- individuals. Presence of focal plaque increased from 8 to 15% in women and 25 to 34% in men over 7 years. After adjustment for risk factors plus hsCRP and IL-6, each standard deviation (SD) of sCD14 was associated with a 21% increased risk of new plaque formation (RR 1.21, 95% CI 1.05-1.41), and this pattern was consistent in women and men. sCD163 was marginally associated with increased risk in men (RR 1.24 per SD, 95% CI 0.97-1.59) but not women (RR 0.96, 95% CI 0.75-1.23). Gal-3BP and Gal-3 were not associated with new plaque formation, nor was IL-6. Among men, the association of sCD163 with plaque formation was most pronounced among HIV+ with CD4+ counts &lt;200 cells/uL. Among women, the association between sCD163 and plaque formation was greatest among HIV/HCV co-infected individuals. Conclusions: Higher sCD14 and sCD163 levels were associated with new carotid artery plaque formation over 7 years in the context of HIV infection. Monocyte activation may play a disproportionately strong role in the development of atherosclerosis among HIV+ compared with HIV- individuals.
Cancer-Associated MORC2-Mutant M276I Regulates an hnRNPM-Mediated CD44 Splicing Switch to Promote Invasion and Metastasis in Triple-Negative Breast Cancer
Authors: Fang-Lin Zhang, Jin-Ling Cao, Hong-Yan Xie, Rui Sun, Li-Feng Yang, Zhi-Ming Shao, Da-Qiang Li
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with a high propensity for distant metastasis and limited treatment options, yet its molecular underpinnings remain largely unknown. Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein whose mutations have been causally implicated in several neurologic disorders. Here, we report that a cancer-associated substitution of methionine to isoleucine at residue 276 (M276I) of MORC2 confers gain-of-function properties in the metastatic progression of TNBC. Expression of mutant MORC2 in TNBC cells increased cell migration, invasion, and lung metastasis without affecting cell proliferation and primary tumor growth compared with its wild-type counterpart. The M276I mutation enhanced binding of MORC2 to heterogeneous nuclear ribonucleoprotein M (hnRNPM), a component of the spliceosome machinery. This interaction promoted an hnRNPM-mediated splicing switch of CD44 from the epithelial isoform (CD44v) to the mesenchymal isoform (CD44s), ultimately driving epithelial–mesenchymal transition (EMT). Knockdown of hnRNPM reduced the binding of mutant MORC2 to CD44 pre-mRNA and reversed the mutant MORC2-induced CD44 splicing switch and EMT, consequently impairing the migratory, invasive, and lung metastatic potential of mutant MORC2-expressing cells. Collectively, these findings provide the first functional evidence for the M276I mutation in promoting TNBC progression. They also establish the first mechanistic connection between MORC2 and RNA splicing and highlight the importance of deciphering unique patient-derived mutations for optimizing clinical outcomes of this highly heterogeneous disease. Significance:A gain-of-function effect of a single mutation on MORC2 promotes metastasis of triple-negative breast cancer by regulating CD44 splicing. Cancer Res; 78(20); 5780–92. ©2018 AACR.
Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells
Authors: François Bélanger, Emile Fortier, Maxime Dubé, Jean-François Lemay, Rémi Buisson, Jean-Yves Masson, Abdelhamid Elsherbiny, Santiago Costantino, Euridice Carmona, Anne-Marie Mes-Masson, Hugo Wurtele, Elliot Drobetsky
Journal: Cancer Research (2018)

Abstract Intrinsic and acquired resistance to cisplatin remains a primary hurdle to treatment of high-grade serous ovarian cancer (HGSOC). Cisplatin selectively kills tumor cells by inducing DNA crosslinks that block replicative DNA polymerases. Single-stranded DNA (ssDNA) generated at resulting stalled replication forks (RF) is bound and protected by heterotrimeric replication protein A (RPA), which then serves as a platform for recruitment and activation of replication stress response factors. Cells deficient in this response are characterized by extensive ssDNA formation and excessive RPA recruitment that exhausts the available pool of RPA, which (i) inhibits RPA-dependent processes such as nucleotide excision repair (NER) and (ii) causes catastrophic failure of blocked RF. Here, we investigated the influence of RPA availability on chemosensitivity using a panel of human HGSOC cell lines. Our data revealed a striking correlation among these cell lines between cisplatin sensitivity and the inability to efficiently repair DNA via NER, specifically during S phase. Such defects in NER were attributable to RPA exhaustion arising from aberrant activation of DNA replication origins during replication stress. Reduced RPA availability promoted Mre11-dependent degradation of nascent DNA at stalled RF in cell lines exhibiting elevated sensitivity to cisplatin. Strikingly, defective S-phase NER, RF instability, and cisplatin sensitivity could all be rescued by ectopic overexpression of RPA. Taken together, our findings indicate that RPA exhaustion represents a major determinant of cisplatin sensitivity in HGSOC cell lines. Significance: The influence of replication protein A exhaustion on cisplatin sensitivity harbors important implications toward improving therapy of various cancers that initially respond to platinum-based agents but later relapse due to intrinsic or acquired drug resistance. Cancer Res; 78(19); 5561–73. ©2018 AACR.
Activation of Mitogen-Activated Protein Kinases in Human Heart During Cardiopulmonary Bypass
Authors: DanielTalmor, AzaiApplebaum, AssafRudich, YoramShapira, AmirTirosh
Journal: Circulation Research (2000)

Abstract—Mitogen-activated protein kinases (MAPKs) have been shown to be activated in both in vitro and in vivo models of cardiac tissue in response to ischemia/reperfusion injury. We investigated whether MAPKs are activated in human heart during coronary artery bypass grafting (CABG) surgery. During elective CABG surgery of 8 patients, 3 right atrial appendage biopsies were obtained at baseline, at the end of cross-clamping, and after coronary reperfusion. The expression of the p38-MAPK, c-Jun N-terminal kinase (JNK), and extracellular signal–regulated kinases (ERK1/2) MAPKs was not altered during CABG. The phosphorylation and activation of both ERK1/2 and p38-MAPK were increased ≈2-fold by ischemia and even more (8- and 4-fold, respectively) by reperfusion. Although the ischemic period did not result in a significant activation of JNK, an ≈6-fold increase in JNK activity could be observed after reperfusion. In conclusion, distinct activation patterns of ERK1/2, p38, and JNK MAPKs can be observed in huma...
Cost-Effectiveness of the Implantable Cardioverter-Defibrillator Versus Antiarrhythmic Drugs in Survivors of Serious Ventricular Tachyarrhythmias
Authors: GregLarsen, AlfredHallstrom, JohnMcAnulty, SergioPinski, AnnaOlarte, SeanSullivan, MichaelBrodsky, JudyPowell, ChristyMarchant, CherylJennings, ToshioAkiyama
Journal: Circulation (2002)

Background— The implantable cardioverter-defibrillator (ICD) is an effective but expensive device. We used prospectively collected data from a large randomized clinical trial of secondary prevention of life-threatening ventricular arrhythmias to determine the cost-effectiveness of the ICD compared with antiarrhythmic drug (AAD) therapy, largely with amiodarone. Methods and Results— Charges for initial and repeat hospitalizations, emergency room, and day surgery stays and the costs of antiarrhythmic drugs were collected on 1008 patients. Detailed records of all other medical encounters and expenses were collected on a subgroup of 237 patients. Regression models were then created to attribute these expenses to the rest of the patients. Charges were converted to 1997 costs using standard methods. Costs and life years were discounted at 3% per year. Three-year survival data from the Antiarrhythmics Versus Implantable Defibrillators trail were used to calculate the base-case cost-effectiveness (C/E) ratio. Six...
Abstract P366: Primary Prevention of Cardiovascular Disease with Low Dose Aspirin Use: Lessons from the Minnesota Heart Health Program
Authors: Niki C Oldenburg, Sue Duval, Russell V Luepker, John R Finnegan, Heather LaMarre, Kevin A Peterson, Nicole D Zantek, Ginny Jacobs, Karen H Miller, Alan T Hirsch
Journal: Circulation (2013)

Introduction: Heart attack and stroke represent the primary causes of cardiovascular disease (CVD) morbidity and mortality. Primary prevention of these events might be achieved via population-based...
Abstract 15241: Proteinase-activated Receptor 1 Antagonist Inhibited the Progression of Monocrotaline Induced Pulmonary Hypertension in Rats
Authors: Yukimitsu Kuwabara, Kohtaro Abe, Mayumi Hirano, Yoshitaka Hirooka, Kenji Sunagawa, Katsuya Hirano
Journal: Circulation (2015)

Introduction: Pulmonary hypertension (PH) is characterized by thrombus formation, vasoconstriction and vascular remodeling. The normal pulmonary artery, in contrast to the systemic artery, has a unique property to contract in response to thrombin via thrombin receptor Proteinase-activated receptor 1 (PAR1). Hypothesis: We hypothesized that PAR1 plays a key role in the pathogenesis and pathophysiology in PH and examined the therapeutic effects of PAR1 antagonist on PH. Methods and Results: Adult male SD rats developed PH after a single subcutaneous injection of 60 mg/kg monocrotaline (MCT) on day 0. The indexes of pulmonary vascular resistance (PVR: RV systolic pressure/cardiac output) and RV hypertrophy (RVH: RV/LV+septum) increased from 0.33±0.03 (normal, n=5) to 1.3±0.1 mmHg•min/mL (MCT, n=10, p&lt;0.01) and from 0.28±0.01 (n=6) to 0.49±0.02 (n=15, p&lt;0.01), respectively, on day 21. We administered PAR1 antagonist (atopaxar: 30mg/kg/day, p.o.) on day 0 (preventive protocol) or day 14 (treatment protocol) of MCT injection. In comparison with MCT rats, the preventive and treatment protocols significantly reduced PVR (0.68±0.09 and 0.89±0.11 mmHg•min/mL, n=8 and 10, p&lt;0.01 and p&lt;0.05) and RVH (0.37±0.02 and 0.40±0.03, n=10 and 12, p&lt;0.01 and p&lt;0.05). Atopaxar had no effect on systemic blood pressure. In the isolated perfused lung preparations, a bolus infusion of 300 nmol PAR1-activating peptide elevated pulmonary arterial pressure by 0.33±0.08 mmHg in the normal (n=6) and 11.8±2.4 mmHg in MCT (n=9; p&lt;0.01 vs. normal), while attenuated in the preventive protocol (1.99±0.96 mmHg, n=6). Atopaxar significantly prolonged the survival periods of MCT rat (median survival time: 26 days, n=17) in both preventive (median survival time: more than 56 days, n=14, p&lt;0.01) and treatment (median survival time: 30 days, n=17, p&lt;0.05) protocols. Conclusion: The PAR1 activity increased in MCT rats. Inhibiting the increased activity of PAR1 was effective in preventing the progression of PH without decreasing systemic blood pressure. PAR1 is thus a potentially novel therapeutic target for the treatment of PH.
Response to the Comments on Cicalese et al.: “An Ecological Study of the Association between Air Pollution and Hepatocellular Carcinoma Incidence in Texas”
Authors: Loren Raun, Ali Shirafkan, Laura Campos, Daria Zorzi, Mauro Montalbano, Colin Rhoads, Valia Gazis, Katherine Ensor, Cristiana Rastellini, Luca Cicalese
Journal: Liver Cancer (2018)
Abstract 3220: Preliminary evaluation of212Pb BB2r targeted radiotherapy in prostate cancer
Authors: Tammy L. Rold, Nkemakonam C. Okoye, Hoffman Timothy
Journal: Cancer Research (2018)

Abstract Introduction: Treating castration resistant prostate cancer (CRPC) continues to be a challenge for clinicians. We have recently shown that gamma emitting 203Pb-RM2 (DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) efficiently targets the BB2r expressed on CRPC cells in vivo. We are now exploring the potential of using the alpha-emitting radioisotope 212Pb to generate the radiotherapeutic 212Pb-RM2. Using 212Pb-RM2, we have performed in vitro cell studies to examine treatment effects in terms of DNA damage, clonogenic potential, and cell viability and preliminary in vivo xenograft targeting proof of principle studies. Methods: 212Pb-RM2 was prepared using an automated radiosynthesizer using 212Pb eluted from a 212Ra/212Pb generator. DNA damage, colony formation, and cell viability were evaluated in PC-3 cells following treatment with 212Pb-RM2 at 0.51, 1, 2, and 4uCi/160uL. DNA damage was assessed using 53BP1 foci following a 4hr incubation with 212Pb-RM2 (T0) and at 24hrs and 48hrs. Colony formation assays were performed on cells treated with TRT for 4hrs, and analyzed at 12-14 days. The MTT assay was conducted up to 144hrs. All cell experiments were performed in triplicate on different occurrences. PC-3 xenografted SCID mice were administered 212Pb-RM2 and organs/tissues were harvested and counted at 15 min, 1hr, 4hr, and 24hrs post injection. Results: DNA damage was found to be sustained over time with 53BP1 foci/cell at 48hrs of 14.8+1.6, 33.8+2. 6, 29.6+1.1, and 40.6+1.6 (avg+SEM) at 0.51, 1, 2, and 4uCi of 212Pb-RM2/160uL, respectively. Colony formation followed a dose dependent response with surviving fraction decreasing as TRT increased with 17.7+3.2, 4.4+2.9, 0.5+0.5, and 0.0+0.0 (avg+SEM) at 0.51, 1, 2, and 4uCi of 212Pb-RM2/160uL, respectively. 212Pb-RM2 tumor uptake in PC-3 xenografts was found to be 5.2+0.7, 5.0+0.9, 3.9+0.7, and 2.6+0.3 %ID/g at 15min, 1hr, 4hr, and 24hrs respectively. In vivo BB2r blocking studies confirmed 212Pb-RM2 targeting of the BB2r with &amp;gt; 72% blocking of normal pancreas uptake measured at 4hr post injection. Conclusions: Treatment with alpha emitting 212Pb-RM2 TRT showed sustained levels of DNA damage which was confirmed by impaired colony formation at all dose levels of 212Pb-RM2 TRT studied. Preliminary in vivo tumor targeting and retention of 212Pb-RM2 was observed out to 24hrs post injection warranting further evaluation of 212Pb-RM2 in multiple CRPC cell line models assessing potential therapeutic efficacy. Acknowledgements: US Veterans Administration (VA) BX001699 and USVA Research Career Scientist (TJH) Citation Format: Tammy L. Rold, Nkemakonam C. Okoye, Hoffman Timothy. Preliminary evaluation of 212Pb BB2r targeted radiotherapy in 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 3220.
Abstract 1920: Targeting structural RET and MET kinase alterations in lung adenocarcinoma patients
Authors: Dennis Plenker, Carina Lorenz, Miriam Bertrand, Richard Riedel, Joop de Langen, Johannes Brägelmann, Reinhard Büttner, Jürgen Wolf, Roman K. Thomas, Johannes Heuckmann, Martin L. Sos
Journal: Cancer Research (2018)

Abstract Structural rearrangements that activate receptor kinases account for an ever-increasing pool of druggable targets in lung adenocarcinoma patients. Among these tumors RET kinase fusions and MET alterations represent two genetically distinct groups that share a common lack of clinically effective strategies. While RET rearranged tumors show a limited susceptibility to currently available RET inhibitors, MET rearranged tumors have not been yet fully appreciated as a relevant group that may benefit from treatment with MET targeted drugs. Using systematic molecular profiling of genetically engineered RET rearranged in vitro and models and patient-derived in vivo models we identified the type II kinase inhibitors ponatinib and AD80 as the most potent drugs. While both inhibitors are effective against gatekeeper mutant RET we identified a novel resistance mutation RETI788N that triggers a selective resistance against AD80 and other RET inhibitors but retains susceptibility to ponatinib. Furthermore, we studied the clinical and preclinical activity of MET targeted drugs. We specifically characterized genomic rearrangements of KIF5B-MET and STARD3NL-MET in cellular models that were found in two distinct LADC. In parallel we identified and characterized a MET kinase domain duplication that developed in an EML4-ALK rearranged positive tumor as a resistance mechanism to ceritinib. All three patients showed a partial response to crizotinib that effectively inhibits MET and ALK in these tumors. Thus, our molecular characterization of drug-target engagement in genetically defined models may further enhance the clinical efficacy of kinase inhibitors in lung tumors driven by rare oncogenic kinase alterations. Citation Format: Dennis Plenker, Carina Lorenz, Miriam Bertrand, Richard Riedel, Joop de Langen, Johannes Brägelmann, Reinhard Büttner, Jürgen Wolf, Roman K. Thomas, Johannes Heuckmann, Martin L. Sos. Targeting structural RET and MET kinase alterations in lung adenocarcinoma patients [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 1920.
Molecular Cloning and Characterization of Human Cardiac Homeobox Gene CSX1
Authors: IchiroShiojima, IsseiKomuro, TakehikoMizuno, RyuichiAikawa, HiroshiAkazawa, ToruOka, TsutomuYamazaki, YoshioYazaki
Journal: Circulation Research (1996)

Accumulating evidence has suggested that homeodomain-containing proteins play critical roles in regulating the tissue-specific gene expression essential for tissue differentiation and in determining the temporal and spatial patterns of development. In order to elucidate the mechanisms of human heart development, we have isolated a human homologue of the murine cardiac homeobox gene Csx (also called Nkx-2.5) and denoted it as CSX1. The amino acid sequence of the CSX1 homeodomain is 100% and 67% identical to that of murine Csx/Nkx-2.5 and Drosophila tinman, respectively. CSX1 has at least three isoforms generated by an alternative splicing mechanism. One of these isoforms (CSX1a) encodes a protein of ≈35 kD that possesses the homeodomain, whereas the other two (CSX1b and CSX1c) encode a truncated protein of ≈12 kD that is identical to the CSX1a protein at the amino-terminal 112 amino acids but lacks the homeodomain. Northern blot analysis showed that CSX1 transcripts are abundantly expressed in both fetal a...
Abstract 1136: Decrease in maturation of stem cells along the neuroendocrine lineage contributes to stem cell overpopulation that drives human CRC development
Authors: Bruce M. Boman, Tao Zhang, Shirin Modarai, Lynn Opdenacker, Fields Jeremy
Journal: Cancer Research (2018)

Abstract Stem cell (SC) overpopulation is thought to drive tumor initiation and progression during colon cancer development, but it is unclear what causes the SC overpopulation. Because most neuroendocrine (NE) cells (NECs) in normal colonic crypts reside within the SC niche at the crypt bottom, we thought that aberrant NECs might be linked to the SC overpopulation. We hypothesized that (i) in normal crypts, SC and NEC populations are anatomically and functionally related, and (ii) during tumorigenesis, changes in these relationships quantitatively correlate with increased SC numbers. We tested this hypothesis - using quantitative immunohistochemical mapping - as a first step towards understanding how interactions between SC and NEC might become altered during colon tumorigenesis. In normal human colonic crypts, most (&amp;gt;80%) cells staining for ALDH1, a colonic SC marker, co-stained for chromogranin-A (CGA) and several other NE markers. Neither ALDH1+ nor CGA+ cells co-stained for MCM2, a marker for proliferating cells. These findings indicate that, in normal colonic crypts, many ALDH1+ cells have NE characteristics. In contrast, the proportion of ALDH1+ cells that co-stained for NE markers progressively decreased (to &amp;lt;20%) during the stepwise progression to cancer (from normal crypts to normal-appearing FAP crypts to adenomatous crypts to colon carcinomas). However, the absolute number of ALDH+ cells progressively increased during this progression, reflecting the extent of the SC overpopulation. These findings suggest that (i) NEC maturation is integral to regulation of SC population size and (ii) a decreased rate of NEC maturation contributes to SC overpopulation during colon tumorigenesis. Citation Format: Bruce M. Boman, Tao Zhang, Shirin Modarai, Lynn Opdenacker, Fields Jeremy. Decrease in maturation of stem cells along the neuroendocrine lineage contributes to stem cell overpopulation that drives human CRC development [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 1136.
Abstract 16606: High-sensitive Cardiac Troponin T Level is Associated With Replacement Fibrosis in Community-dwelling Adults Without Known Cardiovascular Disease: the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Christopher deFilippi, Susie Hong-Zohlman, James deLemos, Lori B Daniels, Joao Lima, Alain Bertoni, Robert Christenson, Stephen Seliger
Journal: Circulation (2016)

Introduction: Although small elevations of high sensitive cardiac troponin T (hs-cTnT) are associated with incident heart failure in the general population, the underlying mechanisms are not well d...