tbuckley/cabot-search huggingface dataset:
Abstract 3444: EGFR-dependent matriptase activation in ErbB2-amplified breast cancer
Authors: Darius Gaymon
Journal: Cancer Research (2018)

Abstract Of the nearly 250,000 new breast cancer cases expected annually, nearly 25% will have ErbB2 (HER2) gene amplification, which is associated with increased growth signaling, more aggressive disease, and poor patient prognosis. Matriptase is a type II transmembrane serine protease that plays a role in normal epithelial cell biology. The expression and activation of matriptase are tightly regulated in normal cells partly through co-expression with endogenous inhibitor, HAI-1, which rapidly inhibits the protease, once activated, by the formation of a high affinity complex. Matriptase has oncogenic potential when its regulation is deranged and it activates downstream substrates known to play a role in tumor progression such as pro-HGF. ErbB2 activity can regulate matriptase activity in prostate cancer and so we set out to elucidate the relationship between ErbB2 and matriptase in ErbB2-amplified breast cancer. SKBR3, AU565, and ErbB2 transfected MCF7 cells (MB7) were used to explore the relationship between ErbB2 levels and matriptase activation as they express higher levels of ErbB2 compared with MCF7 cells. Under standard growth conditions, high level of ErbB2 activation was associated with extensive matriptase activation. Activation of ErbB2 by stimulating EGFR with EGF resulted in increased matriptase activation. Inhibition of ErbB2 activity by serum deprivation or Lapatinib (a dual ErbB2 and EGFR kinase inhibitor) treatment resulted in decreased matriptase activation. Treatment with Lapatinib or the EGFR-specific inhibitor, Gefitinib, blocked matriptase activation whereas the ErbB2 inhibitor, AG825, has no effect. Using inhibitors of downstream signaling pathways, EGFR-induced matriptase activation was shown to be mediated by PI3K signaling. Further elucidation of the pathway is ongoing. In summary, our data suggest that EGFR signaling in this context modulates matriptase activation, which may also contribute to breast cancer progression. Citation Format: Darius Gaymon. EGFR-dependent matriptase activation in ErbB2-amplified breast 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 3444.
Abstract 5232: 1,25-Dihydroxyvitamin D3 mitigates lung cancer cell mediated mitochondrial dysfunction in human skeletal muscle
Authors: Zachary C. Ryan, Theodore A. Craig, Xuewei Wang, Philippe Delmotte, Jeffrey L. Salisbury, Ian R. Lanza, Gary C. Sieck, Rajiv Kumar
Journal: Cancer Research (2018)

Abstract To assess cellular mechanisms that could contribute to muscle weakness in the context of cancer cachexia, we evaluated the effect of conditioned medium (CM) from highly tumorigenic Lewis lung carcinoma (LLC1) cells, CM from less tumorigenic MLE12 cells and non-CM on human skeletal muscle mitochondrial morphology and function. We assessed mitochondrial oxygen consumption, morphology, enzyme activity and gene expression in human skeletal muscle cells in the presence of tumor conditioned medium or control medium. We examined the secretome of LLC1 cells for mediators of skeletal muscle changes. We demonstrate that LLC1 CM inhibits cellular O2 consumption rate (OCR) and increases the proton production rate in human skeletal muscle cells. Mitochondrial fragmentation and the expression of the fission mediator, FIS1, are increased, whereas the expression of fusion mediators, OPA1 and MFN2 are reduced by LLC1 CM. LLC1 CM reduces pyruvate dehydrogenase (PDH) activity thereby limiting the production of acetyl CoA. Reduced PDH activity is associated with reduced PDHA1 sub-unit expression. The amount inactive phospho-PDH is increased in association with reduced PDP2 expression and increased PDK4 and SIRT4 expression in human skeletal muscle cells treated with LLC1 CM. The expression of several signaling pathways is altered by LLC1 CM in human skeletal muscle cells. When compared to MLE12 cells, LLC1 cells show increased expression of mRNAs encoding several potential mediators of altered muscle function such as Gdf15, TGFβ-induced protein, IL11, Il27, Il33, Il34, and PTH-like protein. We show that the active vitamin D metabolite, 1α,25(OH)2D3, that we previously demonstrated increases myoblast mitochondrial oxygen consumption and PDH activity, mitigates LLC1 CM effects on hSkMC OCR, mitochondrial fragmentation and mediators thereof. Mitochondrial oxygen consumption, morphology and enzyme activity in human skeletal muscle cells are inhibited or altered by tumor cell conditioned medium, and are reversed by 1α,25(OH)2D3, the active metabolite of vitamin D. Citation Format: Zachary C. Ryan, Theodore A. Craig, Xuewei Wang, Philippe Delmotte, Jeffrey L. Salisbury, Ian R. Lanza, Gary C. Sieck, Rajiv Kumar. 1,25-Dihydroxyvitamin D3 mitigates lung cancer cell mediated mitochondrial dysfunction in human skeletal muscle [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 5232.
Blood Pressure Studies Among American and Foreign-Born Students
Authors: Nándorszent-Györgyi
Journal: Circulation (1956)

The relation of hypertension to race, sex, environment, and geographic origin in a young adult population is analyzed. Of the 3508 university students, 6.7 per cent were hypertensive. Among American men and women the incidence was 8.1 per cent and 3.1 per cent, respectively. The incidence of hypertension in all racial groups is significantly higher among American-born than among foreign-born males. After 10 years of residence in the United States, foreign-born students have the same high incidence of hypertension as those born in the United States and Canada. Detailed study is presented regarding the incidence of hypertension in different age groups among American and foreign-born white, Negro and Asian students.
Circulating Cardiac Troponin T in Potential Heart Transplant Donors
Authors: BrunoRiou, SophieDreux, SabineRoche, MartineArthaud, Jean-PierreGoarin, PhilippeLéger, MichelSaada, PierreViars
Journal: Circulation (1995)

Background Brain death may induce myocardial dysfunction, the mechanisms of which are not yet fully understood. Circulating cardiac troponin T is considered a highly sensitive and specific marker of myocardial cell injury. Methods and Results We prospectively measured circulating cardiac troponin T in 100 brain-dead patients and measured the left ventricular ejection fraction area (LVEFa), using transesophageal echocardiography. Sixty-one patients had normal LVEFa, 25 had moderate decrease in LVEFa (30% to 50%), and 14 had severe decrease in LVEFa (≤30%). Circulating cardiac troponin T concentrations were significantly higher (1.68±1.03 μg/L−1, P<.01) in patients with a severe decrease in LVEFa than in the two other groups (0.42±0.43 and 0.12±0.16 μg/L−1, respectively), and there was a significant correlation between LVEFa and cardiac troponin T concentration (ρ=−0.59, P<.0001). An elevated circulating cardiac troponin T concentration (≥0.5 μg/L−1) was more accurate (sensitivity, 1.00; specificity, 0.84) ...
Abstract 1709: Enhanced proliferation and effector functions of human immune cells in response to immune checkpoint therapy of MDA-MB-231 tumor bearing huNOG mice engrafted with human CD34+ cells
Authors: Thi Bui, Karyn McArtan Shinn, Emily G. O'Koren, Ashleigh Derrick, Beverly Godfrey, Ian Belle, Jason Davis, Aidan Synnott, Anya Avrutskaya, Paula L. Miliani De Marval
Journal: Cancer Research (2018)

Abstract Given the recent success of cancer immunotherapies, well characterized pre-clinical models are needed to enable drug discovery efforts. The recently developed humanized mouse models composed of various types of immune cells offer a unique tool to evaluate aspects of the human immune system in response to immunotherapy. MDA-MB231 cells express high levels of the T-inhibitory molecule PD-L1 making this breast cancer line an ideal candidate for testing the efficacy of the immune-checkpoint inhibitors pembrolizumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in the CD34+ huNOG humanized mouse strain. We analyzed the distribution of CD4 and CD8 T lymphocytes, Treg cells, NK cells and B cells in blood, spleen and tumor samples from MDA-MB231 tumor bearing huNOG humanized treated-mice via flow cytometry. We found that combination therapy enhanced the effector functions of CD4+ and CD8+ T cells associated with increased expression of IFN-gamma and Granzyme B. Supporting this data, we observed an increase in Ki-67+ cells which correlates with a decrease in PD-1 expression in response to pembrolizumab therapy associated with activation of T lymphocytes. In summary, these results demonstrate the potential of humanized mouse models to evaluate the anti-tumor activity of human immune cells in a preclinical setting in response to human specific immune checkpoint targeted therapies. Citation Format: Thi Bui, Karyn McArtan Shinn, Emily G. O'Koren, Ashleigh Derrick, Beverly Godfrey, Ian Belle, Jason Davis, Aidan Synnott, Anya Avrutskaya, Paula L. Miliani De Marval. Enhanced proliferation and effector functions of human immune cells in response to immune checkpoint therapy of MDA-MB-231 tumor bearing huNOG mice engrafted with human CD34+ cells [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 1709.
Race, Ethnicity, and End-of-Life Care in Dialysis Patients in the United States
Authors: Robert N. Foley, Donal J. Sexton, Paul Drawz, Areef Ishani, Scott Reule
Journal: Journal of the American Society of Nephrology (2018)

End-of-life care is a prominent consideration in patients on maintenance dialysis, especially when death appears imminent and quality of life is poor. To date, examination of race- and ethnicity-associated disparities in end-of-life care for patients with ESRD has largely been restricted to comparisons of white and black patients.We performed a retrospective national study using United States Renal Data System files to determine whether end-of-life care in United States patients on dialysis is subject to racial or ethnic disparity. The primary outcome was a composite of discontinuation of dialysis and death in a nonhospital or hospice setting.Among 1,098,384 patients on dialysis dying between 2000 and 2014, the primary outcome was less likely in patients from any minority group compared with the non-Hispanic white population (10.9% versus 22.6%, P<0.001, respectively). We also observed similar significant disparities between any minority group and non-Hispanic whites for dialysis discontinuation (16.7% versus 31.2%), as well as hospice (10.3% versus 18.1%) and nonhospital death (34.4% versus 46.4%). After extensive covariate adjustment, the primary outcome was less likely in the combined minority group than in the non-Hispanic white population (adjusted odds ratio, 0.55; 95% confidence interval, 0.55 to 0.56; P<0.001). Individual minority groups (non-Hispanic Asian, non-Hispanic black, non-Hispanic Native American, and Hispanic) were significantly less likely than non-Hispanic whites to experience the primary outcome. This disparity was especially pronounced for non-Hispanic Native American and Hispanic subgroups.There appear to be substantial race- and ethnicity-based disparities in end-of-life care practices for United States patients receiving dialysis.
Abstract 2216: A novel prognostic model based on the tumor and its microenvironment in tongue squamous cell carcinoma
Authors: Pei Yu, Weiwang Wang, Zehang Zhuang, Jieyun Xu, Xiqiang Liu
Journal: Cancer Research (2018)

Abstract Objective: Pathological factors of tumor including tumor budding, invasive type and invasive depth has been reported to predict survival in tongue squamous cell carcinoma (TSCC). However, their prognostic value remains inconclusive and the role of tumor microenvironment is unknown. In the current study, both parameters of tumor and its microenvironment were examined and a new grading system associated with high impact on patient outcome has been proposed. Methods: A total of 246 patients with TSCC were included in this retrospective study. Using H&amp;E stained sections, factors including pathological differentiation, T classification, lymph node metastasis (LNM), intensity of tumor budding, invasive pattern, depth, inflammation response (KM grade), tumor stroma percentage (TSP) were evaluated; the prognostic models including BD model (combination of tumor budding and invasive depth) and GMS grade (combination of KM grade and TSP) were also scored. The associations between variables and the survival was examined. Results: High intensity of tumor budding was associated with increasing T classification and positive LNM. Deep invasive depth was correlated with poorly differentiation, high degree of T classification, positive LNM, late clinical stage, and recurrence. BD score had strong correlation with T classification, LNM and clinical stage. Low KM grade showed significant correlation with late clinical stage and high tumor budding. TSP is positively related to tumor budding. GMS grade had significant association with clinical stage. Cox's regression models indicated that both tumor budding and KM grade were independent variables for predicting overall survival (OS) and disease-free survival (DFS). BD score and GMS grade had significant prognostic impact on survival but showed inferior separation between score 0 and 1, score 1 and 2, respectively. The novel designed model based on the combination of the inflammatory infiltration (KM grade) and BD score, iBD model, was proved to be strongly correlated with T classification, LNM, clinical stage, and recurrence. Patients with high iBD score showed reduced OS and DFS with excellent separation of score 0, 1 and 2. Conclusion: iBD scoring model was a promising predictor of survival and strongly associated with lymph node metastasis and recurrence in TSCC. Citation Format: Pei Yu, Weiwang Wang, Zehang Zhuang, Jieyun Xu, Xiqiang Liu. A novel prognostic model based on the tumor and its microenvironment in tongue squamous cell carcinoma [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 2216.
Abstract 4905: Utility of human FcRn transgenic mice for preclinical screening of immunotherapeutics
Authors: Gregory J. Christianson, Emily Lowell, Cat Lutz
Journal: Cancer Research (2018)

Abstract Preclinical assessment is required for the growing number of immunotherapeutics in development. Clinically relevant pharmacokinetic analysis can be achieved by using transgenic mice that uniquely express the human Fc receptor neonatal (hFcRn). To demonstrate the utility of the human FcRn Tg mouse model platform, three immunotherapeutics (pembrolizumab, ipilimumab, and belatacept) were administered IV to Tg32, Tg276, FcRn null, and B6 wild type mice. The mice were blood sampled (25 µL) at 1, 3, 5, 7, 9, 12, 16, 19, 22, 26, and 30 days. Immunotherapeutic plasma concentations, assessed by human IgG ELISA, were pharmacokinetically analyzed. Tg32 mice yielded half-life values for these immunotherapeutics with ranges that mimicked patient data. Though reduced in scale, Tg276 mice also produced half-life data that correlated with the established human half-life data for pembrolizumab, ipilimumab, and belatacept. These results confirm that the human FcRn Tg model platform can be broadly applied to preclinical pharmacokinetic screening of mAb and Fc-fusion based immunotherapeutics. Citation Format: Gregory J. Christianson, Emily Lowell, Cat Lutz. Utility of human FcRn transgenic mice for preclinical screening of immunotherapeutics [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 4905.
Abstract 3717: α3β1-Integrin targeted DM1 micellar prodrug for targeted therapy against ovarian cancer
Authors: Xiaocen Li, Wenwu Xiao, Yayu Wang, Xiaojia Chen, Ruiwu Liu, Kit S. Lam
Journal: Cancer Research (2018)

Abstract Ovarian cancer ranks fifth in cancer deaths among women in America. The standard treatment for advanced stages ovarian cancer consists of primary debulking surgery followed by i.v. and i.p. chemotherapy. DM1, or mertansine, is a thiol-containing maytansinoid, that inhibits microtubule assembly and kills various cancer cells at low nM concentration. However, its application in the clinic has been hampered by severe toxic side effects1. Its trastuzumab conjugate (T-DM1), which was approved by the FDA in 2013, is a promising therapeutic agent for patients harboring ovarian cancers with high Her-2 expression2. However, the general limitation for antibody drug conjugates (ADCs) is low drug content, high clearance by the reticuloendothelial, and high manufacturing cost. To overcome this, we designed and synthesized a novel PEG-based, cholic acid/ DM1 hybrid telodendrimer (PEG5k-CA4-DM1) comprised of one DM1 molecule and three molecules of maleimide per telodendrimer, which self-assembled into 25nm nanomicelles for targeted therapy against ovarian cancer. To enhance the stability of this nanoparticle, PEG5k-Cys4-CA8, which contain 4 thiol groups per telodendrimer is formulated together with PEG5k-CA4-DM1 at a ratio of 2:5, to generate thiol/maleimide crosslinked DM1 micellar prodrug (DM1-nano). To further enhance its tumor-targeting ability, the surface of DM1-nano was decorated with LXY30 via a hydrophilic “stealth” linker (EK)3, using copper-free ‘Click' chemistry. LXY30 is a potent and specific ligand against α3β1 integrin which is overexpressed on the surface of many epithelial cancer cells including a panel of ovarian cancer cell lines (e.g. SKOV-3). Compared with free DM1 and non-targeted DM1-nano, LXY30-EK-DM1-nano not only prevented premature drug release, but also further enhanced tumor targeting ability, drug solubility and in vivo circulation time in blood. When loaded with a fluorescent dye (DiD), LXY30-EK-DM1-nano was found to (i) internalize inside SKOV-3 cells in vitro, (ii) significantly accumulated at the tumor site of SKOV-3 xenograft mice, and (iii) exhibit potent anti-cancer activity in vitro (IC50=26nM with SKOV-3 cells) and in vivo (SKOV-3 xenograft model). In addition, LXY30-EK-DM1-nano was found to be significantly more efficacious and less toxic than free DM1 and non-targeted DM1-nano. In conclusion, the LXY30-DM1-nano offers a promising novel nanotherapeutic agent against ovarian cancer. Citation Format: Xiaocen Li, Wenwu Xiao, Yayu Wang, Xiaojia Chen, Ruiwu Liu, Kit S. Lam. α3β1-Integrin targeted DM1 micellar prodrug for targeted therapy against ovarian 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 3717.
Abstract 2179: Population remodeling in the acquisition of endocrine resistance in breast cancer
Authors: Rong Hu, Surojeet Sengupta, Catherine Sevigny, Zhen Zhang, Yue Wang, Robert Clarke
Journal: Cancer Research (2018)

Abstract The cell-cell interactions that occur within the breast tumor microenvironment are critical determinants of cancer cell fate. In the face of treatment, the theory of clonal evolution dominates current thinking. Thus, individual cells acquire a mutation(s) that provides a selection advantage where Darwinian selection acts at the single-cell level. We studied the effect of antiestrogen treatment on the population remodeling of admixtures of sensitive LCC1 (S) cells and resistant LCC9 (R) human breast cancer cells. R cells were derived from S cells by selection against antiestrogens. We labeled S cells with GFP and R cells with mCherry, mixed the cells in different ratios, and treated with antiestrogen or vehicle. Unlike other resistance phenotypes (e.g., MDR1-driven cytotoxic drug models), R cells do not outcompete S cells, nor do S cells restrain R cell growth. Rather, R cells protect S cells from treatment. Full communication of the resistance phenotype occurs at a 1:1 mixture of S:R; ~75% of the R phenotype transfer is evident at 10:1. These results reflect improved fitness conferred by population interactions, not clonal evolution. SILAC analysis of S and R cells (pure populations) implicate differential regulation of estrogen (E2) response-early; E2 response-late; glycolysis; fatty acid metabolism; mTORC1 signaling; peroxisome; unfolded protein response (UPR); oxidative phosphorylation in S vs. R cells. Clustering of iTRAQ-TAT data from pure and admixed S:R populations shows that the 1:1 and 5:1 treated, and the 1:1 untreated admixtures, cluster with pure R cells. Untreated 5:1 admixed cells cluster with untreated S cells. Thus, R and S cells alter each other's molecular signatures. Studies using scratch labeling and small-molecule inhibitors show that R cells communicate with S cells via both juxtacrine and paracrine interactions mediated by gap junctional intracellular communication and secreted microvesicles, respectively. The molecular features modified reflect our unifying hypothesis of signaling and cell function control in endocrine resistance. Citation Format: Rong Hu, Surojeet Sengupta, Catherine Sevigny, Zhen Zhang, Yue Wang, Robert Clarke. Population remodeling in the acquisition of endocrine resistance in breast 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 2179.
Homocysteine Thiolactone and Protein Homocysteinylation in Human Endothelial Cells
Authors: HieronimJakubowski, LiZhang, ArleneBardeguez, AbramAviv
Journal: Circulation Research (2000)

Abstract—Editing of the nonprotein amino acid homocysteine by certain aminoacyl-tRNA synthetases results in the formation of the thioester homocysteine thiolactone. Here we show that in the presence of physiological concentrations of homocysteine, methionine, and folic acid, human umbilical vein endothelial cells efficiently convert homocysteine to thiolactone. The extent of this conversion is directly proportional to homocysteine concentration and inversely proportional to methionine concentration, suggesting involvement of methionyl-tRNA synthetase. Folic acid inhibits the synthesis of thiolactone by lowering homocysteine and increasing methionine concentrations in endothelial cells. We also show that the extent of post-translational protein homocysteinylation increases with increasing homocysteine levels but decreases with increasing folic acid and HDL levels in endothelial cell cultures. These data support a hypothesis that metabolic conversion of homocysteine to thiolactone and protein homocysteinyla...