tbuckley/cabot-search huggingface dataset:
Abstract 4261: Pathways of metastatic bladder cancer from a longitudinal patient data set
Authors: Jeremy M. Mason, Zaki Hasnain, Gus Miranda, Karanvir Gill, Paul K. Newton, Inderbir S. Gill, Peter Kuhn
Journal: Cancer Research (2018)

Abstract Bladder cancer (BCa), the 6th commonest cancer in the U.S., is highly lethal when metastatic. Sites and patterns of patient-specific metastatic spread are deemed random and unpredictable. Whether BCa metastatic patterns can be quantified and predicted more accurately is unknown. We used a prospective, longitudinal dataset of 3,505 BCa patients who underwent definitive treatment following diagnosis and were continuously enrolled (1971-2016; mean follow-up 6.13 years). Metastases developed in 30% (n=1,040) of patients, with 5-year survival rate of 18%, compared to 72% in those without metastases (n=2,465). The three commonest metastatic sites at time-of-first progression were pelvis (n=283; 27.2%), bone (n=274; 26.3%), and lung (n=247; 23.8%). We illustrate metastatic pathway progression as color-coded, circular, tree-ring diagrams (primary in the center; metastatic sites outwards). Markov chain modeling, denoting nodes as potential anatomic metastatic sites, indicated higher probability of spread from the bladder to pelvis (15.6%), bone (15.6%), and lung (13.9%), categorizing 4 of 10 anatomical sites as ‘spreaders' and 2 as ‘sponges'. We created a dynamical, data-visualization, web-platform that displays temporal, spatial and Markov modeling figures with predictive capability. For contrasting subgroups, this platform indicated differences in transition probabilities, rank-ordering of metastatic sites, and spreader/sponge node classification. Spatiotemporal patterns of BCa metastasis and sites of spread indicate underlying organotropic mechanisms in the prediction of response. This recognition opens the possibility of organ site-specific therapeutic targeting in the oligo-metastatic disease setting. In the precision medicine era, visualization of complex, time-resolved clinical data will enhance management of post-operative, metastatic BCa patients. Citation Format: Jeremy M. Mason, Zaki Hasnain, Gus Miranda, Karanvir Gill, Paul K. Newton, Inderbir S. Gill, Peter Kuhn. Pathways of metastatic bladder cancer from a longitudinal patient data set [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 4261.
Abstract 13890: Hyperbaric Oxygen Facilitates the Effect of Endothelial Progenitor Cell Therapy on Improving Outcome of Rat Critical Limb Ischemia
Authors: SteveLeu, Hon-KanYip
Journal: Circulation (2017)

Introduction: This study tested the hypothesis that hyperbaric oxygen (HBO) (100% oxygen at 2.4 atmospheres) facilitated the effect of autologous endothelial progenitor cell (EPC) therapy on restoring the blood flow of rat critical limb ischemia (CLI). Methods: Adult-male-SD rats (n=8/each group) were categorized into group 1 (SC), group 2 (CLI treated with culture medium), group 3 [CLI + intermittent HBO (3 h/day for 5 consecutive days after CLI procedure), group 4 [CLI + EPC (2.0x106 cells) (1.2x106 from penis vein injection and 0.8x106 by intramuscular injection three hour after CLI procedure)], and group 5 (CLI-HBO-EPC). Results: By day 14 after LCI procedure, the laser Doppler demonstrated that the ratio of blood flow (i.e., CLI to normal hind-limb) were highest in group 1 and lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but it showed no difference in later two groups (all p<0.0001). Additionally, flow cytometry showed that the number of circulating EPCs were significant...
Abstract 2987: Identification of new combination therapies for lung tumors harboring KRAS mutations
Authors: Miriam Molina-Arcas, Christopher Moore, Sareena Rana, Febe van Maldegem, Stuart Horswell, David Hancock, Julian Downward
Journal: Cancer Research (2018)

Abstract Oncogenic mutations in KRAS are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor prognosis and resistance to existing therapies. Thus, new therapeutic strategies are needed to treat these tumors. We have previously shown that NSCLC cells harboring KRAS mutations are more sensitive to inhibition of KRAS downstream effectors MEK and RAF and to treatment with IGF1R inhibitors than their wild-type counterparts. In order to identify complementary targets for the improvement of IGF1R and/or MEK targeting therapies, we performed a whole-genome shRNA screen in KRAS-mutant NSCLC cells. Interestingly, the list of sensitizers to IGF1R inhibitors included several genes encoding components of the mTOR pathway. Viability assays in a panel of lung cancer cell lines confirmed that combinations of IGF1R inhibitors with mTOR inhibitors, both rapalogs and kinase inhibitors, resulted in a synergistic anti-proliferative effect in KRAS-mutant NSCLC cells. Mechanistic investigations demonstrated some differences between the effects of rapalogs and mTOR kinase inhibitors although, in both cases, mTOR inhibitors increased IGF1R and AKT phosphorylation. Combination with IGF1R inhibitors blocked the reactivation of the PI3K pathway resulting in a robust suppression of PI3K and mTORC1 signaling. Notably, the inhibition of these signaling pathways was stronger in KRAS-mutant cells than in wild-type cells. Addition of a MEK inhibitor to the combination produced a more profound and durable suppression of cell proliferation and a stronger induction of apoptosis. Finally, we validated the different drug combinations in mouse models of KRAS-induced NSCLC. Results showed that the three-drug combination produced a marked tumor regression in a NSCLC mouse model driven by mutant Kras and p53 loss-of-function and also in urethane-induced lung tumors. These findings suggest potential novel therapeutic strategies for NSCLC tumors harboring KRAS mutations. Citation Format: Miriam Molina-Arcas, Christopher Moore, Sareena Rana, Febe van Maldegem, Stuart Horswell, David Hancock, Julian Downward. Identification of new combination therapies for lung tumors harboring KRAS mutations [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 2987.
Abstract 19892: Association Between Estimated-glomerular Filtration Rate and Clinical Outcomes at One Year After Acute Ischemic Stroke
Authors: xiaoqing bu, Yonghong Zhang, Tan Xu, Hao Peng, Jing Chen, Jiang He
Journal: Circulation (2015)

Introduction: The relationship between estimated-glomerular filtration rate (eGFR) and acute ischemic stroke outcomes remains controversial. Hypothesis: We aimed to evaluate the impact of eGFR on all-cause mortality, recurrent stroke, and vascular events in patients with acute ischemic stroke. Methods: 4036 patients with acute ischemic stroke recruited from 26 hospitals across China from August 2009 to May 2013 were included in our study. GFR was estimated by CKD-EPI equations based on serum creatinine and/or cystatin C (CKD-EPIcr, CKD-EPIcys, and CKD-EPIcr-cys). The Cox proportional hazards models were used to examine the relationship between declined eGFR and 1-year all-cause mortality, recurrent stroke, and vascular events. Declined eGFR was defined as &lt;60 mL/min /1.73 m2. Results: Declined eGFR was present in 7.22% (n=281) of patients based on the CKD-EPIcr equation, 3.43% (n=119) based on the CKD-EPIcys equation, and 5.67% (n=170) based on the CKD-EPIcr-cys equation. Compared to patients with an eGFR ≥90 mL/min /1.73 m2, adjusted hazard ratios (95% confidence interval) for all-cause mortality associated with eGFR&lt;60 mL/min /1.73 m2 were 1.68 (1.06 to 2.66, p=0.026), 2.29 (1.29 to 4.06, p=0.005), and 1.79 (1.08 to 2.98, p=0.024) using CKD-EPIcr, CKD-EPIcys, and CKD-EPIcr-cys equations, respectively. For recurrent stroke, adjusted hazard ratios (95% confidence interval) were 0.90 (0.49 to 1.66, p=0.743), 0.60 (0.19 to 1.93, p=0.393), and 0.89 (0.40 to 1.95, p=0.762), respectively. For vascular events, adjusted hazard ratios (95% confidence interval) were 1.33 (0.81 to 2.19, p=0.266), 1.07 (0.46 to 2.47, p=0.880), and 1.31 (0.70 to 2.43, p=0.403), respectively. Conclusion: Our study indicates that declined eGFR is a strong independent risk factor for total mortality among patients with acute ischemic stroke. However, there is no association between low eGFR and recurrent stroke or vascular events among patients with acute ischemic stroke. In addition, the association of eGFR with all-cause mortality among patients with acute ischemic stroke is stronger when eGFR was calculated based on the CKD-EPIcys equation compared to CKD-EPIcr and CKD-EPIcr-cys equations.
Abstract 346: Targeting DNA repair with the combination of p97 and HDAC6 inhibitors in mantle cell lymphoma
Authors: Pratikkumar Vekaria, Anusha Vallurupalli, Dharmalingam Subramaniam, Frank Schoenen, Joseph McGuirk, Rekha M. Rao
Journal: Cancer Research (2018)

Abstract p97 is an ATPase which is involved in remodeling multi-subunit protein complexes. It plays a pivotal role in the retrotranslocation and proteasomal degradation of misfolded ubiquitinated proteins in the endoplasmic reticulum. In association with cytosolic histone deacetylase 6 (HDAC6), p97 promotes the autophagic degradation of polyubiquitylated proteins and damaged organelles. More recently p97 has been implicated in regulating cell division and in facilitating DNA repair by promoting the recruitment of DNA repair proteins to the site of DNA damage. In this study, we determined the molecular mechanisms through which HDAC6 promotes p97 function in mantle cell lymphoma (MCL) cells. We report that treatment of MCL cells with the p97 inhibitors, DBeQ, ML240, NMS-873 and CB-5083 induces ER stress markers GRP78 and CHOP and resulted in dose-dependent apoptosis. Treatment of Z138C xenografts in NSG mice with CB-5083, the first in-class p97 inhibitor, resulted in increased accumulation of polyubiquitylated proteins and improved survival in vivo compared to control mice. Co-treatment with CB-5083 and the HDAC6-selective inhibitor ACY-1215, resulted in accumulation of polyubiquitylated proteins, impaired DNA double-stranded break repair and resulted in the partial depletion of BRCA1 and Cyclin D1 in MCL cells compared to either agent alone. We also demonstrate that shRNA-mediated knockdown of HDAC6 induced enhanced accumulation of H2AX-γ under basal conditions and following treatment with CB-5083 in cultured and primary MCL cells. Finally, treatment of MCL cells with p97 inhibitors and ACY-1215 results in synergistic apoptotic cell death in MCL cells. Collectively our studies create a strong rationale to test efficacy of the combination of p97 inhibitors in combination with HDAC6 inhibitors in MCL. Citation Format: Pratikkumar Vekaria, Anusha Vallurupalli, Dharmalingam Subramaniam, Frank Schoenen, Joseph McGuirk, Rekha M. Rao. Targeting DNA repair with the combination of p97 and HDAC6 inhibitors in mantle cell lymphoma [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 346.
Abstract 2652: Metabolomics biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women
Authors: Yannick Audet-Delage, Lyne Villeneuve, Jean Grégoire, Marie Plante, Chantal Guillemette
Journal: Cancer Research (2018)

Abstract Endometrial cancer (EC) is the most frequent cancer of the female genital tract in developed countries. Most EC occurs after menopause and are diagnosed as endometrioid type I carcinomas that exhibit a favorable prognosis especially for grades 1 and 2. In contrast, type II non-endometrioid carcinomas such as serous tumors have a poor prognosis. The use of small molecule biomarkers may facilitate accurate diagnosis and prognostic predictions. Our goal was to identify novel blood-based markers associated with EC subtypes and recurrence after surgery in postmenopausal women. Using mass spectrometry (MS)-based metabolomics, we examined preoperative serum metabolites of healthy women (n=18), non-recurrent and recurrent cases with type I endometrioid (n=24) and type II serous (n=12) carcinomas, matched for pathological characteristics, body mass index and age. Biochemicals including complex lipids were analyzed by gas chromatography-MS and ultrahigh performance liquid chromatography-tandem MS. A total of 1592 compounds of known identity and 14 different lipid classes were assessed. When comparing EC cases to healthy women, 137 metabolites were significantly different, with spermine as the most altered biochemical, identifying this metabolite as a potential biomarker of EC. Furthermore, recurrent cases of both histological types had higher levels of the monoacylglycerol 1-oleoylglycerol than non-recurrent cases. Type I recurrent cases were also characterized by much lower levels of bile acids and elevated concentrations of phosphorylated fibrinogen cleavage peptide, whereas type II recurrent cases displayed higher levels of ceramides and their derivatives. Our findings provide a first detailed metabolomics study in EC and identify potential non-invasive biomarkers to define clinically relevant risk groups. Citation Format: Yannick Audet-Delage, Lyne Villeneuve, Jean Grégoire, Marie Plante, Chantal Guillemette. Metabolomics biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women [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 2652.
Angina Symptoms Are Associated With Mortality in Older Women With Ischemic Heart Disease
Authors: JannekeBerecki-Gisolf, LindyHumphreyes-Reid, AndrewWilson, AnnetteDobson
Journal: Circulation (2009)

Background— Angina symptoms have been reported to predict mortality in men. The aim of this study was to investigate the association between angina symptoms and mortality in women. Methods and Results— In 2004, 873 older participants in the Australian Longitudinal Study on Women’s Health with self-reported ischemic heart disease participated in a nested substudy. Women were 77 to 83 years of age; 165 (19%) died during the 4.5-year follow-up. Angina symptoms were established with Seattle Angina Questionnaire (SAQ) scores for physical limitation, angina frequency, angina stability, and disease perception. Proportional hazards modeling was used to examine the relationship of SAQ score differences with mortality. Physical limitation scores were associated with mortality, with hazard ratios of 1.1, 1.9, and 3.4 for mild, moderate, and severe versus minimal limitations, respectively (P<0.001). Angina frequency scores were also associated with death, with hazard ratios of 1.2, 1.2, and 4.8 for mild, moderate, an...
Abstract 549: The CUG-translated WT1, not AUG-WT1, is an oncogene
Authors: Kun Yeong Lee, Hong-Gyum Kim, Joohyun Ryu, Do Young Lim, Hanyong Chen, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2018)

Abstract The Wilms' tumor 1 (WT1) gene is believed to act as a canonical tumor suppressor. However, it has also been reported to function as an oncogene. Germline WT1 deletion is associated with Wilms' tumor, and exogenous WT1 cDNA introduction into cells induces the transcriptional suppression of its oncogenic target genes. In contrast, high WT1 expression is associated with poor prognosis in patients with various cancers. Why WT1 acts as a tumor suppressor under certain conditions but as an oncogene under other conditions is unknown. Here, we report that CUG initiation site for WT1 protein synthesis (CUG)-translated WT1 (cugWT1), an N-terminally extended form of canonical AUG initiation site for WT1 protein synthesis (AUG)-translated WT1 (augWT1), was overexpressed in most cancer cell lines and cancer tissues and functioned as an oncogene, whereas the classical augWT1 acted as a tumor suppressor as reported previously and inhibited the function of cugWT1. Translation of cugWT1 is initiated from a CUG codon upstream and in-frame with the coding region of augWT1. cugWT1 induced cell transformation and increased the gene expression of c-myc, bcl-2 and egfr, whereas overexpression of augWT1 repressed colony formation of cancer cells and inhibited the expression of the same target genes by recruiting histone deacetylase 1 (HDAC1). In addition, we found that protein kinase B (AKT)-phosphorylated cugWT1 on Ser62 and protected cugWT1 from proteasomal degradation induced by the F-box/WD repeat-containing protein 8 (FBXW8). These results provide an important breakthrough in the field of cancer biology and contribute significantly to the resolution of the chameleon function of WT1. Citation Format: Kun Yeong Lee, Hong-Gyum Kim, Joohyun Ryu, Do Young Lim, Hanyong Chen, Ann M. Bode, Zigang Dong. The CUG-translated WT1, not AUG-WT1, is an oncogene [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 549.
NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma
Authors: Jenna H. Burton, Christina Mazcko, Amy LeBlanc, Joseph M. Covey, Jiuping Ji, Robert J. Kinders, Ralph E. Parchment, Chand Khanna, Melissa Paoloni, Sue Lana, Kristen Weishaar, Cheryl London, William Kisseberth, Erika Krick, David Vail, Michael Childress, Jeffrey N. Bryan, Lisa Barber, E.J. Ehrhart, Michael Kent, Timothy Fan, Kelvin Kow, Nicole Northup, Heather Wilson-Robles, Joseph Tomaszewski, Julianne L. Holleran, Miguel Muzzio, Julie Eiseman, Jan H. Beumer, James H. Doroshow, Yves Pommier
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics. Experimental Design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined. Results: The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; γH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744. Conclusions: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.
Cycle Length Dynamics and Spatial Stability at the Onset of Postinfarction Monomorphic Ventricular Tachycardias Induced in Patients and Canine Preparations
Authors: AlainVinet, RenéCardinal, PierreLeFranc, FrançoisHélie, PierreRocque, TeresaKus, PierrePagé
Journal: Circulation (1996)

Background The aim of this study was to determine whether cycle length (CL) variations at the onset of monomorphic ventricular tachycardias follow distinctive patterns. Methods and Results We retrospectively analyzed 59 monomorphic ventricular tachycardias induced in 40 patients in whom intraoperative mapping was performed with 63 epicardial and 64 endocardial electrograms recorded simultaneously. Activation times and CL were determined at each electrode site over several beats (36±10 beats, mean±SD) starting with the first after programmed stimulation. In the majority of the tachycardias, CL variations were accounted for by fitting to an exponential function: CL=CLs+Ae−b/τ, where CLs is the stable CL, b is beat number, τ is the time constant (in beat number), and A is the magnitude of CL relaxation. A decelerating trend (with reference to rate) (negative A) accounted for 21 tachycardias, an accelerating trend in rate (positive A) accounted for 12 tachycardias, and 4 others displayed a double dynamic beha...
Adenosine Concentrations in the Interstitium of Resting and Contracting Human Skeletal Muscle
Authors: YlvaHellsten, DaveMaclean, GöranRådegran, BengtSaltin, JensBangsbo
Journal: Circulation (1998)

Background—Adenosine has been proposed to be a locally produced regulator of blood flow in skeletal muscle. However, the fundamental questions of to what extent adenosine is formed in skeletal muscle tissue of humans, whether it is present in the interstitium, and where it exerts its vasodilatory effect remain unanswered. Methods and Results—The interstitial adenosine concentration was determined in the vastus lateralis muscle of healthy humans via dialysis probes inserted in the muscle. The probes were perfused with buffer, and the dialysate samples were collected at rest and during graded knee extensor exercise. At rest, the interstitial concentration of adenosine was 220±100 nmol/L and femoral arterial blood flow (FaBF) was 0.19±0.02 L/min. When the subjects exercised lightly, at a work rate of 10 W, there was a markedly higher (1140±540 nmol/L; P<0.05) interstitial adenosine concentration and a higher FaBF (2.22±0.18 L/min; P<0.05) compared with at rest. When exercise was performed at 20, 30, 40, or 5...