tbuckley/cabot-search huggingface dataset:
Abstract 5599: Noninvasive genomic profiling of cerebral spinal fluid in breast cancer patient with leptomeningeal disease
Authors: Masahiro Oikawa, Naveen Ramesh, Emi Sei, Shanshan Bai, Min Hu, de Groot F. John, Murthy Rshmi, Barbara O'Brien, Nicholas Navin
Journal: Cancer Research (2018)

Abstract Leptomeningeal disease (LMD) involves the dissemination of tumor cells from the primary breast tumors into the membranes surrounding the central nervous system and spinal cords. LMD occurs in about 5% of breast cancer patients and is associated with very poor survival. The genomic evolution of LMD in breast cancer patients has remained difficult to study, in part due to technical challenges in collecting longitudinal biopsy samples from the central nervous system. Liquid biopsies of the cerebral spinal fluid (CSF) may provide a unique opportunity to profile circulating tumor DNA (ctDNA) and has not been compared directly to non-invasive monitoring of ctDNA in blood samples. Furthermore, most non-invasive ctDNA profiling methods are limited to a targeted set of genes and have not allowed unbiased whole-genome profiling. To address these limitations, we developed an unbiased method for ctDNA analysis called PEGASUS (Plasma Exome and Genome Analysis by Size-selection and Unbiased Sequencing) that enables whole-genome sequencing of copy number aberrations and somatic mutations from ctDNA. We applied PEGASUS to sequence matched blood samples and CSF from 10 breast cancer patients with LMD. Quantitation of ctDNA levels showed that ctDNA was detected in CSF samples from 9/10 patients, while blood ctDNA was detected in only 1 LMD patient with extensive metastatic disease. Whole-genome copy number profiling at 220kb resolution and mutational profiling of a 2000 cancer gene panel of the matched CSF and blood samples was performed in 10 LMD patients using PEGASUS. Our data identified aneuploid copy number aberrations and somatic mutations (range: 11-25) in the CSF of 7 patients, including mutations in known driver genes such as BRAF, RB1, TP53 and amplifications of MYC and ERBB2. In contrast the matched blood samples showed only diploid copy number profiles and no detectable somatic mutations in 9/10 LMD patients. In one patient with extensive cranial metastatic disease with matched CSF and blood ctDNA, we found a high concordance in copy number profiles (R= 0.75) and modest concordance of somatic mutations (59.5%), but also additional CNAs and mutations that were specific to the CSF. Collectively, these data show that genomic profiling of ctDNA in CSF is technically feasible for patients with LMD, and provides a major advantage over blood ctDNA which cannot be detected in mostcases. Citation Format: Masahiro Oikawa, Naveen Ramesh, Emi Sei, Shanshan Bai, Min Hu, de Groot F. John, Murthy Rshmi, Barbara O'Brien, Nicholas Navin. Noninvasive genomic profiling of cerebral spinal fluid in breast cancer patient with leptomeningeal disease [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 5599.
Abstract 5495: Inhibiting ERRα blocks liver steatosis and tumorigenesis induced by PTEN loss
Authors: Chien-Yu Chen, Yang Li, Jingyu Chen, Lina He, Bangyan Stiles
Journal: Cancer Research (2018)

Abstract Mitochondrial dysfunction has been attributed to be a major cause for fatty liver development and also underlies tumor development. Using a liver-conditional Pten deletion model where the activation of its downstream PI3K/AKT signaling led to fatty liver, steatohepatitis, fibrosis and finally liver cancer development, we reported previously that the fatty liver and liver cancer is accompanied by elevated mitochondrial bioenergetics and a dramatic induction of estrogen-related receptor α (ERRα), a master regulator that orchestrate mitochondria response to modulate metabolism. In this project, we intended to investigate whether blocking ERRα expression and inhibiting mitochondrial respiration can attenuate tumor growth and lipid accumulation in the Pten null livers and human liver cancer cells. Using a genetic knockdown approach with siERRα and chemical genomic approach with a small molecular polyamide compound that binds to the ERRα consensus binding site, we showed that ERRα knockdown suppressed mitochondrial function and impeded cell proliferation in human liver as well as prostate cancer cell lines lacking Pten. In addition, blocking ERRα transcriptional activity with ERRα specific polyamide err-PA significantly reduced tumor growth in xenograft models. Furthermore, err-PA administration in vivo in 1.5-month old liver- specific Pten null mice remarkably prevented the development of fatty liver morphology and quantitatively reduced the hepatic triglyceride level. In summary, our study highlights ERRα's crucial role in regulating mitochondrial bioenergetics and underscores its therapeutic potential in cancer and lipid disorders. Citation Format: Chien-Yu Chen, Yang Li, Jingyu Chen, Lina He, Bangyan Stiles. Inhibiting ERRα blocks liver steatosis and tumorigenesis induced by PTEN loss [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 5495.
Abstract 5193: A subpopulation of circulating epithelial tumor cells positive for fatty acid receptor CD36 is linked to aggressiveness of breast cancer disease
Authors: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann
Journal: Cancer Research (2018)

Abstract Background: Breast cancer is one of the leading causes of cancer death for women worldwide. Major hurdles for a successful treatment are cancer metastases, resistance to therapy and disease recurrence. The presence of circulating epithelial tumor cells (CETCs) is closely related to metastasis formation, but the mechanisms through which CETCs promote recurrence of disease are still unclear. CD36 is found in the cell membrane of tumor cells and responsible for taking up fatty acid. It is known that CD36 is a general marker of metastatic cells and its amplification specifically correlated with metastasis in a large number of human tumors. Therefore, the aim of this study was to determine the metastatic marker CD36 on CETCs and to correlate it's frequency with clinicopathological features in breast cancer patients. Methods: CETCs were determined from blood of 42 patients suffering from breast cancer. The number of vital CETCs and their expression of CD 36 was investigated using the maintrac® method. Results: CD36 expressing CETCs were detected in 95 % of breast cancer patients. Breast cancer patients with metastatic disease had significantly more CD36 positive CETCs as compared to patients without metastases (median 72% vs. 48%; p&amp;lt;0.05). The fraction of CD36 positive CETCs was significantly higher in patients with HER2 positive primary tumor (69% vs. 54%; p&amp;lt;0.05). Furthermore, triple negative breast cancer patients had significantly more CD36 positive CETCs as compared to hormone receptor positive tissue (median 62% vs. 52%; p&amp;lt;0.05). Interestingly, frequency of CD36 positive CETCs correlated significantly with a blinded determination of Ki-67 proliferation index in tumor tissue (r=0.75; p&amp;lt;0.01). We observed a significant heterogeneity in CD36 immunostaining intensity across CETCs from the same patients. Conclusion: We showed for the first time that breast cancer patients have detectable CETCs with a high frequency of CD36 which highly correlated with progression of cancer disease. Our findings suggest that using a CD36 antibody treatment may be an effective strategy to fight cancer. Citation Format: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann. A subpopulation of circulating epithelial tumor cells positive for fatty acid receptor CD36 is linked to aggressiveness of breast cancer disease [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 5193.
Abstract LB-006: Intracellular protein therapy with SOCS3 utilizing aMTD-enabled macromolecule intracellular transduction technology (MITT)
Authors: Youngsil Choi, Seulmee Shin, Kuysook Lee, Daewoong Jo
Journal: Cancer Research (2018)

Abstract Background Macromolecule intracellular transduction technology (MITT), a platform for the discovery/development of new medicinal drugs, is enabled with a new generation of hydrophobic cell-penetrating peptides (CPPs), termed advanced macromolecule transduction domains (aMTDs). Originally derived from the hydrophobic signal peptides of secreted proteins, earlier generations of MTDs were hampered by poor solubility and less efficient cell-permeability. The MITT platform addresses these limitations, first, by the design of synthetic aMTD sequences that incorporate 6 critical factors found to enhance the intracellular delivery of proteins into cells and tissues and second, by the use of humanized solubilization domains to enhance the solubility of aMTD-containing recombinant proteins. Object The goal of this study is to develop and evaluate an aMTD-SOCS3 (suppressor of cytokine signaling 3) protein (iCP-SOCS3) as cell-permeable biotherapeutic to selectively target tumors dependent on JAK/STAT signaling and to compare the cell-/tissue-penetration efficiencies of iCP-SOCS3 with a previous generation of cell-permeable SOCS3 (MTM-SOCS3: CP-SOCS3) enabled by a hydrophobic CPP, termed membrane translocating motif (MTM) derived from the signal peptide of fibroblast growth factor 4 (FGF4). Results Solubility (up to 10 mg/ml) and final yields of E. coli produced iCP-SOCS3 (60 mg/L) were sufficient for clinical development; whereas, CP-SOCS3 suffered from low solubility and yields (0.4 mg/ml and 0.2 mg/L, respectively). Cellular uptake of fluorescent iCP-SOCS3 was enhanced by 25-fold as compared to CP-SOCS3 as assessed by flow cytometry, and delivery and persistence of the protein in a variety of tissues (heart, lung, spleen, kidney, liver and brain) were similarly increased. In addition, aMTD promoted the cell-to-cell transfer of SOCS3 protein, and the transferred iCP-SOCS3 was biochemically active as assessed by inhibition of IFN-γ-induced phosphorylation of STAT1 and STAT3 with concomitant suppression of cancer-associated phenotypes in cultured cells and in mice bearing human tumor xenografts (90% inhibition of proliferation and 84% inhibition of migration in PANC-1 cells, and 85% suppression of pancreatic tumor growth, respectively). Conclusion These results provide further validation of MITT as a platform to develop protein-based biotherapeutics, and suggest the use of iCP-SOCS3 as a novel protein therapy against tumors dependent on JAK/STAT signaling. Citation Format: Youngsil Choi, Seulmee Shin, Kuysook Lee, Daewoong Jo. Intracellular protein therapy with SOCS3 utilizing aMTD-enabled macromolecule intracellular transduction technology (MITT) [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 LB-006.
Global Biventricular Dysfunction in Patients With Asymptomatic Coronary Artery Disease May Be Caused by Myocarditis
Authors: AndreaFrustaci, CristinaChimenti, AttilioMaseri
Journal: Circulation (1999)

Background—The causal role of asymptomatic critical coronary artery obstruction in patients presenting with severe global biventricular dysfunction but no evidence of myocardial infarction is uncertain. Methods and Results—Among 291 patients aged >40 years undergoing a noninvasive (2-dimensional echocardiography) and invasive (catheterization, coronary angiography, and biventricular endomyocardial biopsy, 6 to 8 samples/patient) cardiac study because of progressive heart failure (New York Heart Association functional class III or IV) with global biventricular dysfunction and no history of myocardial ischemic events, 7 patients (2.4%; 7 men; mean age, 49±6.9 years) had severe coronary artery disease (3 vessels in 4 patients; 2 vessels in 1 patient, proximal occlusion of left anterior descending coronary artery in 2 patients). Left ventricular end-diastolic diameter and ejection fraction by 2-dimensional echocardiography were 73±10.5 mm and 23±6.5%, respectively, and right ventricular end-diastolic diameter...
Repression of P66Shc Expression by SIRT1 Contributes to the Prevention of Hyperglycemia-Induced Endothelial Dysfunction
Authors: ShuangZhou, Hou-ZaoChen, Yan-zhenWan, Qing-JunZhang, Yu-ShengWei, ShuaiHuang, Jin-JingLiu, Yun-BiaoLu, Zhu-QinZhang, Rui-FengYang, RanZhang, HuaCai, De-PeiLiu, Chih-ChuanLiang
Journal: Circulation Research (2011)

Rationale:Inactivation of the p66Shc adaptor protein confers resistance to oxidative stress and protects mice from aging-associated vascular diseases. However, there is limited information about the negative regulating mechanisms of p66Shc expression in the vascular system. Objective:In this study, we investigated the role of SIRT1, a class III histone deacetylase, in the regulation of p66Shc expression and hyperglycemia-induced endothelial dysfunction. Methods and Results:Expressions of p66Shc gene transcript and protein were significantly increased by different kinds of class III histone deacetylase (sirtuin) inhibitors in human umbilical vein endothelial cells and 293A cells. Adenoviral overexpression of SIRT1 inhibited high-glucose–induced p66Shc upregulation in human umbilical vein endothelial cells. Knockdown of SIRT1 increased p66Shc expression and also increased the expression levels of plasminogen activator inhibitor-1 expression, but decreased manganese superoxide dismutase expression in high-gl...
Tumor Necrosis Factor Inhibitors and Cancer Recurrence in Swedish Patients With Rheumatoid Arthritis
Authors: Pauline Raaschou, Jonas Söderling, Carl Turesson, Johan Askling
Journal: Annals of Internal Medicine (2018)

Use of tumor necrosis factor inhibitors (TNFi) in patients with a history of cancer remains a clinical dilemma.To investigate whether TNFi treatment in rheumatoid arthritis (RA) is associated with increased risk for cancer recurrence.Population-based cohort study based on linkage of nationwide registers.Sweden.Patients with RA who started TNFi treatment between 2001 and 2015, after being diagnosed with cancer, and matched patients with RA and a history of the same cancer who had never received biologics.The primary outcome was the first recurrence of cancer. Adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs), taking into account time, cancer type, and whether the cancer was invasive or in situ (or tumor, node, metastasis [TNM] classification system stage in a subset of patients).Among 467 patients who started TNFi treatment (mean time after cancer diagnosis, 7.9 years), 42 had cancer recurrences (9.0%; mean follow-up, 5.3 years); among 2164 matched patients with the same cancer history, 155 had recurrences (7.2%; mean follow-up, 4.3 years) (HR, 1.06 [95% CI, 0.73 to 1.54). Hazard ratios were close to 1 in analyses of patient subsets matched on cancer stage or with similar time from index cancer diagnosis to the start of TNFi treatment, as well as in unmatched analyses. Several CIs had upper limits close to 2.The outcome algorithm was partly nonvalidated, and channeling bias was possible if patients with a better index cancer prognosis were more likely to receive TNFi.The findings suggest that TNFi treatment is not associated with increased risk for cancer recurrence in patients with RA, although meaningful risk increases could not be ruled out completely.ALF (an agreement in Stockholm County Council concerning medical education and research in health and medical care), the Swedish Cancer Society, the Swedish Foundation for Strategic Research, and the Swedish Research Council.
Efficacy and safety of subcutaneous immunotherapy with house dust mite for allergic rhinitis: A Meta‐analysis of Randomized Controlled Trials
Authors: Yanran Huang, Chengshuo Wang, Xiangdong Wang, Luo Zhang, Hongfei Lou
Journal: Allergy (2018)

All authors declare no financial or commercial conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Abstract 3833: SEA-BCMA: A highly active enhanced antibody for multiple myeloma
Authors: Heather Van Epps, Martha Anderson, Changpu Yu, Kerry Klussman, Lori Westendorf, Chris Carosino, Luke Manlove, Julia Cochran, Jason Neale, Dennis Benjamin, Maureen Ryan
Journal: Cancer Research (2018)

Abstract Despite a number of new therapies for multiple myeloma (MM) most patients relapse, require multiple lines of therapy, and ultimately succumb to disease. Therapies that are well tolerated and active remain an unmet need. Currently, successful MM therapies combine agents with different mechanisms of action and safety profiles. Therapeutic antibodies have recently altered the MM treatment paradigm, allowing patients to achieve deeper responses with minimal added toxicity. SEA-BCMA is a humanized afucosylated IgG1 antibody targeting BCMA, which shows preclinical evidence of encouraging activity and tolerability. BCMA is expressed at the surface of plasma cells, and induces proliferative signals through the binding of its ligands APRIL and BAFF. SEA-BCMA acts through three mechanisms of action. One, it engages in increased binding to FcγRIII through SEA technology leading to enhanced antibody dependent cellular cytotoxicity. Two, it mediates antibody dependent cellular phagocytosis. Three, it blocks the proliferative signals from BCMA ligand binding. This antibody shows activity in all seven tumor xenograft models tested, inducing tumor delays at doses as low as 0.1mg/kg, and generating prolonged survival and durable regressions with repeat dosing. SEA-BCMA is active on tumor xenografts expressing as few as 2000 surface copies of BCMA antigen. Both effector function and ligand blocking contribute to overall in vivo activity. In the absence of effector cell recruitment, ligand blocking alone can induce prolonged durable regressions. In addition, SEA-BCMA can target MM cells in the presence of soluble BCMA. SEA-BCMA is tolerated up to 100mg/kg in cynomolgus monkey, reflecting lack of toxicity from cellular interactions with the Fc portion of the Ab, since SEA-BCMA does not bind to the cynomolgus monkey antigen. SEA-BCMA displays a 12-day half-life in these animals. In vitro testing with human PBMCs or bone marrow mononuclear cells induced minimal cytokine production in the presence of BCMA target. In summary, SEA-BCMA is highly active and well tolerated in preclinical models and is a strong candidate for treatment of MM patients. Citation Format: Heather Van Epps, Martha Anderson, Changpu Yu, Kerry Klussman, Lori Westendorf, Chris Carosino, Luke Manlove, Julia Cochran, Jason Neale, Dennis Benjamin, Maureen Ryan. SEA-BCMA: A highly active enhanced antibody for multiple myeloma [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 3833.
Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease
Authors: MarcelloTonelli, FrankSacks, MalcolmArnold, LemuelMoye, BarryDavis, MarcPfeffer
Journal: Circulation (2008)

Background— Higher levels of red blood cell distribution width (RDW) may be associated with adverse outcomes in patients with heart failure. We examined the association between RDW and the risk of all-cause mortality and adverse cardiovascular outcomes in a population of people with coronary disease who were free of heart failure at baseline. Methods and Results— We performed a post hoc analysis of data from the Cholesterol and Recurrent Events study. Baseline RDW was measured in 4111 participants who were randomized to receive pravastatin 40 mg daily or placebo and followed for a median of 59.7 months. We used Cox proportional hazards models to examine the association between RDW and adverse clinical outcomes. During nearly 60 months of follow-up, 376 participants died. A significant association was noted between baseline RDW level and the adjusted risk of all-cause mortality (hazard ratio per percent increase in RDW, 1.14; 95% confidence interval, 1.05 to 1.24). After categorization based on quartile of...
Abstract 4226: Association between NSAID, statins, and bisphosphonates and prostate cancer survival during androgen deprivation therapy
Authors: Paavo V. Raittinen, Kirsi Talala, Kimmo Taari, Teuvo L. Tammela, Pauliina Ilmonen, Anssi Auvinen, Teemu J. Murtola
Journal: Cancer Research (2018)

Abstract We study the association between non-steroidal anti-inflammatory drugs (NSAIDs), Statins, and Bisphosphonates (BPs), and prostate cancer (PCa) survival during androgen deprivation therapy (ADT). STAMPEDE trial has demonstrated better PCa-specific survival in men using combination of celecoxib (CEL) and zoledronic acid (ZA) during ADT compared to ADT alone. The mechanism is unclear. ZA inhibits mevalonate pathway (MevP) previously linked with cancer growth. We evaluated PCa survival among men on ADT and simultaneously using BPs including ZA or statins, another drug group inhibiting MevP, and NSAIDs including CEL. We hypothesized that combined use of a MevP inhibitor and NSAID would be associated with improved PCa survival. Our study cohort includes 4,428 men from the Finnish Randomized Study of PCa Screening (FinRSPC) initiating ADT in 1995-2015. Cox proportional hazards model with adjustment for age, FinRSPC study arm, tumor clinical characteristics and co-morbidities (obtained from national registries) was used to calculate HRs and 95% CI for PCa death. Medication use was analyzed as time-dependent variable. Compared to non-users, the risk of PCa death was increased in users of NSAIDs or acetaminophen, and lowered in statin users. Use of BPs or coxibs alone were not associated with the risk. Coxibs and statins together were associated with lowered risk to a similar degree as statins alone. No statistically significant risk differences were observed for other combinations. Statin users with high-risk prostate cancer undergoing ADT have lowered risk of PCa death. NSAID users have increased risk of PCa death, which becomes statistically insignificant when used with statins. Statin and BP use together shows no statistically significant evidence of negating the effects of statin. No clear additive benefit was observed for statins and coxibs together over statins alone. Our findings do not support additive benefits of MevP inhibitor and NSAIDs. Statistical significance codes: *** : p = 0.001, ** : p = 0.01, * : p = 0.1DrugHR95 % CISignificanceStatin0.780.680.90***Acetylsalisylic acid0.900.761.07Coxib1.070.941.22NSAID1.171.041.31**Acetaminophen1.661.511.82***Bisphosphonate0.790.381.64Bisphosphonate and NSAID0.890.551.42Statin and NSAID1.070.901.27Statin and Bisphosphonate1.140.861.50Coxib and Bisphosphonate0.850.421.74Coxib and Statin0.800.621.02*EAU tumor Risk Group2.662.353.00*** Citation Format: Paavo V. Raittinen, Kirsi Talala, Kimmo Taari, Teuvo L. Tammela, Pauliina Ilmonen, Anssi Auvinen, Teemu J. Murtola. Association between NSAID, statins, and bisphosphonates and prostate cancer survival during androgen deprivation therapy [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 4226.