tbuckley/cabot-search huggingface dataset:
Managing Nonmetastatic Castration-resistant Prostate Cancer
Authors: Joaquin Mateo, Karim Fizazi, Silke Gillessen, Axel Heidenreich, Raquel Perez-Lopez, Wim J.G. Oyen, Neal Shore, Matthew Smith, Christopher Sweeney, Bertrand Tombal, Scott A. Tomlins, Johann S. de Bono
Journal: European Urology (2018)

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation.To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients.A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse.Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed.nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future.Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately.
Abstract 14341: Targeted Delivery of Fibroblast Growth Factor-1 by Ultrasound-targeted Microbubble Destruction Reduces Myocyte Apoptosis and Myocardial Fibrosis and Improves Ventricular Systolic and Diastolic Function in Diabetic Cardiomyopathy in Rats
Authors: Xinqiao Tian, Ao Ru, Yingzheng Zhao, Lei Zheng, Xing Li, Jianmin Li, Keke Jin, Shuping Ge
Journal: Circulation (2013)

We sought to pursue the hypothesis that fibroblast growth factor-1 (FGF-1) facilitates tissue repair, angiogenesis, and cardiac functional improvement in diabetic cardiomyopathy (DCM) by targeted d...
Abstract 2614: Macrophage erythroblast attacher (MAEA) polymorphisms are associated with clinical outcome in TRIBE study mCRC patients treated with 5-fluorouracil/bevacizumab-based therapy
Authors: Shivani Soni, Yuji Miyamoto, Wu Zhang, Martin D. Berger, Shu Cao, Elizabeth Melendez, Alberto Puccini, Madiha Naseem, Ryuma Tokunaga, Francesca Battaglin, Michelle Mcskane, Chiara Cremolini, Alfredo Falcone, Fotios Loupakis, Heinz-Josef Lenz
Journal: Cancer Research (2018)

Abstract Background: Macrophage erythroblast attacher (MAEA) also known as Emp (Erythroblast macrophage protein) plays indispensable role in erythroblast and macrophage development and targeted disruption of Emp is embryonically lethal (Soni et al., JBC 2006). Recently, down-regulation of Emp was implicated in abnormal cell motility and higher expression of mitogen-activated protein kinase 1 (MAPK 1) and thymoma viral proto-oncogene 1 (Akt 1) (Gulnaz et. al., BCMD 2016). Our preliminary studies, shows that higher expression of MAEA is associated with longer colorectal cancer (CRC) patient survival. We tested two MAEA polymorphisms (rs13149952 and rs1128427), whether these are correlated with clinical outcome in mCRC treated with 5-Fluorouracil / Bevacizumab based therapy. Methods: Genomic DNA was isolated from blood samples of two cohorts of mCRC patients. Cohort 1 included 227 patients treated with FOLFIRI/BEV (TRIBE trial Arm A, RAS wildtype/mutant=55/116, median age=60 years old, median follow-up period=49.3 months). Cohort 2 had 229 patients treated with FOLFOXIRI/BEV (TRIBE trial Arm B, RAS wildtype/mutant=60/115, median age=60 years old, median follow-up period=46.6 months). PCR-based direct Sanger sequencing was used to determine polymorphism. Results: Our results showed that MAEA rs1128427 in TRIBE arm A patients with RAS mutant tumors having any C genotype was significantly associated with longer overall survival as compared to TT genotype in univariate analysis {25.9 vs 18.8 months, HR(95% CI)=0.61(0.38,0.98), p=0.036}. In TRIBE arm B cohort, MAEA rs1128427 in patients with RAS mutant tumors carrying CC genotype showed significantly longer overall survival than patients with any T allele in both univariate and multivariable analyses {33.4 vs 25 months, uni: HR(95% CI)=0.57(0.34,0.95), p=0.028; multi: HR(95% CI)=0.56(0.32,0.96), p=0.034}. Conclusion: Our findings suggest for the first time, that polymorphisms in MAEA may predict the clinical outcome in Bevacizumab based therapies. Further prospective studies are warranted. Citation Format: Shivani Soni, Yuji Miyamoto, Wu Zhang, Martin D. Berger, Shu Cao, Elizabeth Melendez, Alberto Puccini, Madiha Naseem, Ryuma Tokunaga, Francesca Battaglin, Michelle Mcskane, Chiara Cremolini, Alfredo Falcone, Fotios Loupakis, Heinz-Josef Lenz. Macrophage erythroblast attacher (MAEA) polymorphisms are associated with clinical outcome in TRIBE study mCRC patients treated with 5-fluorouracil/bevacizumab-based 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 2614.
Abstract 15700: L-type Calcium Channels Localization and Function are Affected by Microdomain Remodelling in Human Failing Cardiomyocytes
Authors: Jose L Sanchez-Alonso, Claire E Poulet, Sophie Schobesberger, Navneet Bhogal, Ravi C Balijepalli, Prakash P Punjabi, Julia Gorelik
Journal: Circulation (2015)

Introduction: L-type calcium channels (LTCCs) are essential in determining the electrical and mechanical properties of the cardiac muscle. LTCCs are located in specialized membrane microdomains in cardiac cells. Disruption of their microdomain localization in heart failure may contribute to the pathophysiology of cardiac disease. Methods: We studied isolated ventricular cardiomyocytes from patients with dilated cardiomyopathy with or without Left Ventricular Assistance Device (DCM or DCM+LVAD) versus those with normal ventricular function (nonfailing). Super-resolution scanning patch clamp provided topography images of the cell surface which enabled us to record LTCC current in distinct cellular compartments (T-tubules openings and areas between them, crests). Confocal microscopy was used to score T-tubular density and regularity in Di-8-ANEPPS stained cells. Expression of β2 subunit of LTCC was detected by immunofluorescence, Western blot and qPCR. Results: In failing cells T-tubular density is lower than in normal. The loss of cellular micro-architecture in failing cardiomyocytes leads to a redistribution of functional LTCCs from their usual location (T-tubules) to non-native crests of the sarcolemma. These relocated LTCCs in the crest of DCM cardiomyocytes have increased open probability and lower amplitude as compared with the channels located on the T-tubules. Interestingly, in cardiomyocytes isolated from patients with LVAD the open probability of LTCC is reduced dramatically and the amplitude recovers to the normal level, as does the T-tubular density. Immunostaining of DCM cardiomyocytes shows an increased amount of LTCC β2 subunit in the crest, and Western blot/qPCR shows more abundant expression of LTCC β2 subunit. Conclusion: In DCM cardiomyocytes a considerable amount of LTCCs improperly located on the crest microdomain display a pathologically high activity; this study suggests that the increased expression of LTCC β2-subunit could be responsible. Although LVAD cannot reverse the remodelling in DCM cardiomyocytes it helps to restore part of the microarchitecture of the cells and to normalize the function of the LTCCs.
Abstract 15935: 20,000 Person-Years Later: Long-term Mortality in a Large Drowning Registry
Authors: Erica A Michiels, Joshua C Reynolds, Mat Reeves, Mojdeh N Ahmadabadi
Journal: Circulation (2015)

Objective: Relatively little is known about the long-term outcomes of drowning. There is some evidence of long-term neurocognitive dysfunction among small cohorts, but larger epidemiological studies are lacking. We aimed to assess the long-term mortality of drowning victims from a large registry. Hypothesis: We hypothesized that patients with sequelae of more severe drowning injury are at higher risk of long-term mortality. Methods: Secondary analysis of an existing drowning registry from Seattle, WA. We included the subset of patients that survived to hospital discharge, tabulating Utstein-style drowning variables with descriptive statistics. We used the National Death Index (NDI) to assess long-term mortality beyond the index event through 2012. Wilcoxon rank-sum and chi-square tests assessed differences between long term survivors and non-survivors. We constructed KM curves, stratified by age, sex, drowning-related cardiac arrest, and mRS at hospital discharge, and compared them with the log-rank test. Cox proportional hazard modeling tested variables associated with long-term mortality. Results: Of 2,824 subjects in the registry (submersion 1/74 - 7/96), 776 (27%) survived to hospital discharge and were included in our analyses (median age 5 years, IQR 2-15; 68% male). Long term survivors and non-survivors differed by age (4 years, IQR 2-15 vs. 25 years, IQR 6-46; p&lt;0.0001), recreational substance use (4% vs. 18%; p&lt;0.001), pre-existing comorbidities (16% vs. 38%; p=0.01), drowning-related cardiac arrest (7% vs. 25%; p&lt;0.0001), mechanical ventilation (13% vs. 37%; p&lt;0.0001), and seizures (2% vs. 10%; p&lt;0.0001). Only 63 (8%) subjects died during the 19,699 person-year follow-up period. Subjects with age &gt;40 years (p&lt;0.0001), drowning-related cardiac arrest (p&lt;0.0001), and mRS 4-5 (p&lt;0.0001) were at higher risk of long-term mortality. In adjusted analyses, age (HR 1.05; 95% CI 1.03, 1.07) and mRS 4-5 at hospital discharge (HR 8.2; 95% CI 1.8, 36.4) were associated with long-term mortality. Conclusion: Overall mortality was low during long term follow-up. Age at the index event, drowning-related cardiac arrest, and functional status at hospital discharge were associated with subsequent long term mortality.
Abstract 689: Identification and optimization of novel chemical matter via a structure-based approach resulting in a probe for MTH1
Authors: Marcus Bauser, Anja Giese, Manuel Ellermann, Judith Guenther, Ashley Eheim, Stefanie Bunse, Roland Neuhaus, Joerg Weiske, Maria Quanz, Andrea Glasauer, Katrin Nowak-Reppel, Benjamin Bader, Horst Irlbacher, Hanna Meyer, Nina Queisser, Andrea Haegebarth, Matyas Gorjanacz, Lionel Tresaugues, Tobias Ginman, Fredrik Rahm, Martin Andersson, Ulrica Ericsson, Rickard Forsblom, Johan Lindstroem, Camilla Silvander, Jenny Vicklund
Journal: Cancer Research (2018)

Abstract Cancer cells can form reactive oxygen species (ROS) due to altered redox regulation that affect desoxynucleosides triphosphates (dNTP) in particular. 8-oxo-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP) and 2-hydroxydeoxyadenosine-5'-triphosphate (2-OH-dATP) are the two most abundant oxidative nucleotide lesions in this respect. These undesired nucleoside triphosphates are sanitized by the hydrolase MTH1 (also known as NUDT1) in order to prevent their incorporation into replicating DNA. Sprint Bioscience created a series of drug-like, potent and selective MTH1 inhibitors using fragment-based drug discovery methods. In collaboration with Bayer, these inhibitors were extensively profiled, both in vitro and in vivo, to allow for the selection of a probe molecule with attractive properties for in vivo target validation studies. Herein, we would like to share novel chemical matter and it's binding to MTH1 in protein co-crystal structures. Furthermore, we describe the consecutive, stepwise structure-based optimization process. Extensive SAR elaboration clearly revealed the essential moieties for high potency and favorable ADME properties. We are able to report for the first time how we identified BAY-707 as a very potent and highly selective MTH1 inhibitor representing a potential probe to further evaluate the scope and limitations of MTH1 inhibition for therapeutic applications. Citation Format: Marcus Bauser, Anja Giese, Manuel Ellermann, Judith Guenther, Ashley Eheim, Stefanie Bunse, Roland Neuhaus, Joerg Weiske, Maria Quanz, Andrea Glasauer, Katrin Nowak-Reppel, Benjamin Bader, Horst Irlbacher, Hanna Meyer, Nina Queisser, Andrea Haegebarth, Matyas Gorjanacz, Lionel Tresaugues, Tobias Ginman, Fredrik Rahm, Martin Andersson, Ulrica Ericsson, Rickard Forsblom, Johan Lindstroem, Camilla Silvander, Jenny Vicklund. Identification and optimization of novel chemical matter via a structure-based approach resulting in a probe for MTH1 [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 689.
Urokinase but Not Tissue Plasminogen Activator Mediates Arterial Neointima Formation in Mice
Authors: PeterCarmeliet, LieveMoons, Jean-MarcHerbert, JamesCrawley, FloreaLupu, RogerLijnen, DésiréCollen
Journal: Circulation Research (1997)

Abstract To define the role of the plasminogen activators (PAs) tissue PA (t-PA) and urokinase PA (u-PA) in vascular wound healing, neointima formation and reendothelialization were evaluated after electric or mechanical arterial injury in mice with a single or combined deficiency of t-PA (t-PA−/−) and/or u-PA (u-PA−/−). In both models, neointima formation and neointimal cell accumulation were reduced in u-PA−/− and in t-PA−/−/u-PA−/− arteries but not in t-PA−/− arteries. The electric injury model was used to characterize the underlying cellular mechanisms. Topographic analysis of vascular wound healing in electrically injured wild-type and t-PA−/− arteries revealed a similar degree of migration of smooth muscle cells from the noninjured borders into the necrotic center. In contrast, in u-PA−/− and t-PA−/−/u-PA−/− arteries, smooth muscle cells accumulated at the uninjured borders but failed to migrate into the necrotic center. Cultured u-PA−/− but not t-PA−/− smooth muscle cells also failed to migrate in ...
Extracellular Citrate and Cancer Metabolism—Response
Authors: Maria E. Mycielska, Edward K. Geissler
Journal: Cancer Research (2018)

In response to our recent article showing that cancer cells take up extracellular citrate through the plasma membrane-specific variant (pmCiC) of the mitochondrial citrate transporter and that depriving cancer cells of extracellular citrate by blocking pmCiC activity results in a decreased tumor
Abstract IA14: Exploiting synthetic lethality in the treatment of gynecologic cancers
Authors: Christopher J. Lord
Journal: Clinical Cancer Research (2018)

Abstract PARP inhibitors represent the first synthetic lethal treatment for cancer and are now approved for the treatment of serous ovarian cancers. Despite this advance, drug resistance to PARP inhibitors is a growing problem and in most patients has an unknown etiology. I will discuss efforts to understand PARP inhibitor resistance and to devise therapeutic approaches that limit the impact of revertant BRCA1/2 mutations. I will also discuss recent data describing synthetic lethal interactions between ARID1A defects in gynecologic cancers and novel DNA repair inhibitors, including ATR inhibitors currently undergoing clinical trial assessment. Citation Format: Christopher J. Lord. Exploiting synthetic lethality in the treatment of gynecologic cancers. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA14.
Abstract 15341: Neutrophil Elastase Plays a Pivotal Role in Sepsis-Induced Myocardial Dysfunction
Authors: Kodai Suzuki, Hideshi Okada, Genzou Takemura, Fuminori Yamaji, Chihiro Takada, Kazumasa Oda, Yasuaki Hotta, Nagisa Miyazaki, Tomoaki Doi, Takahiro Yoshida, Shozo Yoshida, Hiroaki Ushikoshi, Shinji Ogura
Journal: Circulation (2017)

Introduction: Myocardial dysfunction often occurs in sepsis, of which underlying mechanism is known to be a burst of several inflammatory mediators that lead to vascular endothelial injuries. Howev...
Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs
Authors: MitsuhoOnimaru, YoshikazuYonemitsu, MitsuguTanii, KazunoriNakagawa, IchiroMasaki, ShinjiOkano, HiroakiIshibashi, KanemitsuShirasuna, MamoruHasegawa, KatsuoSueishi
Journal: Circulation Research (2002)

Hepatocyte growth factor (HGF) is a potent angiogenic polypeptide that stimulates angiogenesis. Transcriptional regulation of HGF, however, has not been fully defined, with the exception of the hypoxia-mediated downregulation in cultured cells. In the present study, we report that angiogenic growth factors, including HGF, were upregulated in a murine model of critical limb ischemia in vivo, a finding that was in conflict with previous in vitro data. Mice deficient in basic fibroblast growth factor-2 (FGF-2) showed reduced induction of HGF protein in ischemic muscles, and overexpression of FGF-2 via gene transfer stimulated endogenous HGF, irrespective of the presence of ischemia. In culture, FGF-2 rapidly stimulated HGF mRNA, and a sustained expression was evident in the time course in vascular smooth muscle cells and fibroblasts. FGF-2–mediated induction of HGF was fully dependent on the mitogen-activated protein kinase pathway yet was not affected by either hypoxia or a protein kinase A inhibitor. In th...
Smooth Muscle Dysfunction in Resistance Arteries of the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα
Authors: SandrineBesnard, JoëlleBakouche, YolandeLemaigre-Dubreuil, JeanMariani, AlainTedgui, DanielHenrion
Journal: Circulation Research (2002)

Retinoic acid receptor–related orphan receptor α (RORα) is a member of the nuclear receptor superfamily. The mouse mutant staggerer (sg/sg) carries a deletion within the RORα gene. RORα plays a major role in cellular differentiation during development and growth. In the present study, we found a lower mean arterial blood pressure in sg/sg than in +/+ mice (80.1±1.2 and 87.0±0.9 mm Hg, respectively; P<0.0002) and a smaller increase in blood pressure after in vivo injections of phenylephrine. To elucidate the mechanisms responsible for this phenotype, we investigated the vascular reactivity of large vessels (aorta and carotid arteries) and small resistance mesenteric arteries in response to mechanical forces or vasoactive agents. Arteries from sg/sg and +/+ mice were studied in vitro in arteriographs. Vascular responses of large vessels to all stimuli were similar in both groups. However, we found a markedly altered vascular function in mesenteric arteries from sg/sg mice. Flow-induced dilation, pressure-in...
Abstract P286: Walking as a Source of Physical Activity for Cardiovascular Disease Prevention
Authors: John D Omura, Emily N Ussery, Fleetwood Loustalot, Janet E Fulton, Susan A Carlson
Journal: Circulation (2018)

Introduction: Increasing physical activity among adults at risk for or with cardiovascular disease (CVD) can help prevent and manage disease. Walking may present an opportunity for promoting physical activity among this high risk group. We hypothesized that in US adults the prevalence of self-reported walking would decrease with increasing CVD risk. Methods: Nationally representative data from the 2015 National Health Interview Survey Cancer Control Supplement (N=28,780) were analyzed. Analyses were repeated after excluding those needing assistance with walking (n=2,192). Walking was defined as engaging in at least one 10-minute bout of transportation or leisure walking in the past seven days. Prevalence estimates of walking (any, transportation, and leisure) are reported overall and by presence of risk factors (overweight or obesity and ≥1 of diabetes, high cholesterol, or hypertension) or CVD (myocardial infarction or stroke). Orthogonal polynomial contrasts were used to identify significant trends. Results: Overall, 64.9% (standard error, SE=0.5) of adults reported any walking (TABLE). This prevalence was highest among those with no CVD or risk factors (67.1%, SE=0.5), decreased with increasing number of risk factors (1 risk factor: 64.0%, SE=1.0; 2 risk factors: 60.3%, SE=1.3; 3 risk factors: 54.8%, SE=2.0), and the lowest was among those with CVD (51.9%, SE=1.7). Similar trends were observed for leisure and transportation walking. To ensure differences in prevalence of walking by risk factor or disease status was not due to functional limitations, repeated analyses that excluded those needing assistance with walking observed similar patterns. Conclusions: Prevalence of any and leisure walking decreased as the presence of CVD risk factors increased and was lowest among those with disease. Promoting walking, especially among adults at higher risk, may present an important opportunity for encouraging an active lifestyle for CVD prevention and management.
Phenotypic Patterns of Mononuclear Cells in Dilated Cardiomyopathy
Authors: ChristophHolzinger, AndreaSchöllhammer, MartinImhof, ChristianReinwald, GeroKramer, AndreasZuckermann, ErnstWolner, GeorgSteiner
Journal: Circulation (1995)

Background Immunological factors in the pathogenesis of idiopathic dilated cardiomyopathy (IDC) were suggested previously on the basis of the demonstration of mononuclear cell infiltrates and autoantibodies against the myocardium. The present study investigated whether tissue leukocyte subpopulations isolated from hearts with IDC (n=6) differ in phenotype from those of tissues without IDC (n=7). Methods and Results Leukocytes were quantified as reactive cells per square millimeter in perivascular, interstitial, and parenchymal tissue sections. Freshly isolated heart-tissue T cells and peripheral-blood T cells from the same patients were analyzed by triple staining and flow cytometry to identify T-cell subpopulations as well as their states of differentiation (expression of CD45RA and Leu-8 versus CD45RO) and activation (IL-2R, IL-7R, very late antigen–1, HLA-DR). All types of infiltrating cells (T cells, B cells, macrophages, granulocytes) are increased in hearts with IDC compared with normal hearts, but ...