tbuckley/cabot-search huggingface dataset:
Vascular Biomarkers and Surrogates in Cardiovascular Disease
Authors: Jean-ClaudeTardif, ThereseHeinonen, DavidOrloff, PeterLibby
Journal: Circulation (2006)

Cardiovascular biomarker research efforts have resulted in the identification of new risk factors and novel drug targets, as well as the establishment of treatment guidelines. Government agencies, academic research institutions, diagnostic industries, and pharmaceutical companies all recognize the importance of biomarkers in advancing therapies to improve public health. In drug development, biomarkers are used to evaluate early signals of efficacy and safety, to select dose, and to identify the target population. The United States Food and Drug Administration has relied on biomarkers to support clinical applications in many therapeutic fields, including cardiovascular disease. The appropriate application of cardiovascular biomarkers requires an understanding of disease natural history, the mechanism of the intervention, and the characteristics and limitations of the biomarker. Channels of communication among researcher, developer, and regulator must remain open to maximize the success of future biomarker ...
Abstract 1340: Assessing autophagic flux in cell culture models with a novel plate-based assay
Authors: Dan F. Lazar, Ryan W. Kessens, Amani A. Gillette, Braeden L. Butler, Christopher T. Eggers, Brock F. Binkowski, Gediminas Vidugiris, Michael R. Slater, Dongping Ma, James J. Cali
Journal: Cancer Research (2018)

Abstract The importance of autophagy in normal cell health and diseased states, including cancer, immunology and inflammation, has become quite clear. Given the growing interest in screening for autophagy modulators, we have developed a homogeneous plate-based assay to measure autophagic flux in cell culture models using NanoLuc® Binary Technology (NanoBiT™). LC3B (Atg8) protein was tagged on its N-terminus with an 11 amino acid peptide, (HiBiT), as well as an intervening “spacer” sequence. When expressed at low-to-moderate levels in mammalian cell lines, this LC3-based reporter is subject to degradation by the autophagic pathway. Changes in reporter levels following cell treatment are determined by addition of a lytic reagent containing Large BiT (LgBiT), which rapidly associates with HiBiT to produce a bright, luciferase activity in the presence of added substrate. In stable U2OS reporter cells, mTORC inhibitor treatment decreased assay signal by 25% (rapamycin) to 60% (PP242, AZD8055), consistent with compound stimulation of autophagic flux and degradation of the autophagy reporter. In contrast, treatment with autophagy inhibitors (bafilomycin A1, chloroquine) produced a 70-80% increase in assay signal, consistent with accumulation of autophagy reporter following blockade of basal autophagy. Similar results were obtained in HEK293 cells stably expressing the reporter, as well as in cells in which autophagy reporter was transiently expressed via simple, one-step transduction with BacMam viral particles. Mechanism of action of autophagy modulators was confirmed through blockade of effects by 50nM bafilomycin A1 cotreatment. Multiplex with a cell necrosis detection agent allowed for same-well determination of cytotoxic effects that might undermine analysis of a compound's discrete effects on autophagic flux. When assayed in 384-well plates with automation, U2OS and HEK293 autophagy reporter cells produced Z' values of 0.6-0.7 in response to autophagy induction (PP242), and Z' values of 0.7-0.8 by subsequent blockade of autophagy (PP242 + bafilomycin A1). Therefore, using this novel plate-based assay system for the determination of autophagic flux, it is possible to screen test agents and quantitatively assess their effects in cell culture models. Citation Format: Dan F. Lazar, Ryan W. Kessens, Amani A. Gillette, Braeden L. Butler, Christopher T. Eggers, Brock F. Binkowski, Gediminas Vidugiris, Michael R. Slater, Dongping Ma, James J. Cali. Assessing autophagic flux in cell culture models with a novel plate-based assay [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 1340.
Esophageal Atresia and Tracheoesophageal Fistula
Authors: Laura Forero Zapata, Mariann Pappagallo
Journal: New England Journal of Medicine (2018)

A newborn baby had copious oral secretions. A nasogastric tube was inserted but met resistance at the T2 level. Esophageal atresia with tracheoesophageal fistula was diagnosed.
Vascular Endothelin-B Receptor System In Vivo Plays a Favorable Inhibitory Role in Vascular Remodeling After Injury Revealed by Endothelin-B Receptor–Knockout Mice
Authors: NobuyukiMurakoshi, TakashiMiyauchi, YoshihikoKakinuma, TakashiOhuchi, KatsutoshiGoto, MasashiYanagisawa, IwaoYamaguchi
Journal: Circulation (2002)

Background— Two subtypes of endothelin (ET) receptors, ETA and ETB, are distributed in vascular smooth muscle cells to cause contraction and proliferation. Vascular endothelial cells express only ETB receptors, which cause NO release. Although ETA receptor blockade is reported to be effective in ameliorating vascular remodeling, there is no report on the long-term effect of ETB receptor blockade on vascular remodeling after injury. Methods and Results— ETB receptor–knockout (KO) mice, which were genetically rescued from lethal intestinal aganglionosis, and wild-type (WT) mice underwent complete ligation of the right common carotid artery, ie, a blood flow cessation model of vascular remodeling. Fourteen days after ligation, the intimal area, the ratio of intimal to medial areas, and the stenotic ratio in the ligated artery of KO mice were significantly increased compared with those of WT mice. The expression level of ET-1 mRNA in the ligated artery of KO mice was increased similarly to that of WT mice, wh...
Atrioventricular Nodal Conduction Gap and Dual Pathway Electrophysiology
Authors: TodorMazgalev, PatrickTchou
Journal: Circulation (1995)

Background The gap phenomenon in atrioventricular (AV) conduction is described as a block that occurs within a range of atrial coupling intervals. This block is assumed to occur between two adjacent parts of the conduction system having different refractory properties; thus, a gap would develop if the functional refractory period of the proximal unit was shorter than the effective refractory period of the distal unit. We describe a new electrophysiological mechanism based on dual pathways electrophysiology of the AV node. Methods and Results In vitro experiments were performed on isolated superfused rabbit hearts. Standard electrophysiological pacing and recording techniques were used to generate conduction curves. The gap phenomenon was documented in 9 of 14 nodal preparations. With shortening of the atrial coupling interval, antegrade conduction block of the “fast” pathway wave front occurred while this impulse was still retrogradely interfering with slow pathway conduction. That is, the fast pathway wa...
Impact of Sex on Cardiovascular Outcome in Patients at High Cardiovascular Risk
Authors: KaiKappert, MichaelBöhm, RolandSchmieder, HelmutSchumacher, KoonTeo, SalimYusuf, PeterSleight, ThomasUnger
Journal: Circulation (2012)

Background—Epidemiological data suggest that sex independently contributes to cardiovascular risk. Clinical trials are often hampered by the enrollment of few female patients. Methods and Results—The Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) included a large proportion of female patients (9378 female versus 22 168 male patients). Differences in male and female patients enrolled in ONTARGET/TRANSCEND were analyzed for the primary 4-fold end point (composite of cardiovascular death, myocardial infarction, stroke, or admission to hospital for heart failure), a secondary 3-fold end point (cardiovascular death, myocardial infarction, stroke), and individual components of the primary composite. Baseline characteristics included age, ethnicity, body mass index, physical activity, tobacco use, alcohol consumption, formal education, clinical ...
Assessment of Changes in Mitral Valve Configuration With Multidetector Computed Tomography
Authors: YasuhiroShudo, GoroMatsumiya, TaichiSakaguchi, ShigeruMiyagawa, YasushiYoshikawa, TakashiYamauchi, KojiTakeda, ShunsukeSaito, SatoshiNakatani, KazuhiroTaniguchi, HironoriIzutani, YoshikiSawa
Journal: Circulation (2010)

Background—The optimal surgical procedures in functional mitral regurgitation remain controversial. We applied papillary muscle imbrication (PMI) combined with undersized mitral annuloplasty (UMAP). Multidetector computed tomography (MDCT) provides images of different phases of the cardiac cycle, allowing an assessment of the geometry. In the present study, we evaluated the mitral valve configuration and subvalvular apparatus before and after UMAP and/or PMI using MDCT imaging. Methods and Results—We studied 26 patients with functional mitral regurgitation (3+ to 4+) with an ejection fraction ≥35% who underwent diagnostic MDCT examinations before and early after the operation. Of these, 15 underwent UMAP and PMI (UMAP+PMI group) and 11 underwent UMAP (UMAP group). The annular anteroposterior diameter, tenting height, tenting area, and interpapillary muscle distance at end-systole were quantified. The annular anteroposterior diameter, tenting height, and tenting area were significantly decreased after the ...
Abstract 2999: Low-dose demethylation therapy for the treatment of cisplatin-resistant testicular cancer
Authors: Andrea Corbet, Costantine Albany, Emmanuel Bikorimana, Ema Khan, Jennifer Rodriguez, Brock C. Christensen, George Sandusky, Lawrence H. Einhorn, Sarah J. Freemantle, Michael J. Spinella
Journal: Cancer Research (2018)

Abstract Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A portion of TGCT patients are refractory to cisplatin. Only 30% of patients refractory to cisplatin respond to salvage therapies while to remainder die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. We have found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). As an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. Together, these preclinical findings provided the rationale for our recently initiated and promising phase I clinical trial using SGI-110 to treat cisplatin refractory TGCT patients. We discuss our recent genome-wide molecular studies aimed to identify potential mechanism(s) to account for the hypersensitivity of TGCTs to 5-aza including promoter demethylation, p53 activation and dsRNA MDA5/MAVS/IRF7 viral mimicry. We also discuss preliminary findings from our ongoing trial. Our findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients. Citation Format: Andrea Corbet, Costantine Albany, Emmanuel Bikorimana, Ema Khan, Jennifer Rodriguez, Brock C. Christensen, George Sandusky, Lawrence H. Einhorn, Sarah J. Freemantle, Michael J. Spinella. Low-dose demethylation therapy for the treatment of cisplatin-resistant testicular 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 2999.
Abstract 390: Genome-wide CRISPR screens in brain tumor initiating cells (BTICs) identify potent sensitizers and resistors of conventional chemoradiotherapy
Authors: Chirayu Chokshi, David Tieu, Kevin Brown, Chitra Venugopal, Parvez Vora, Katherine Chan, Amy Tong, Maleeha Qazi, Mohini Singh, Neil Savage, Andrea Habsid, Jason Moffat, Sheila Singh
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is a highly aggressive and most common form of malignant primary brain tumors in adults (WHO grade IV). Despite surgical and therapeutic interventions, including chemotherapy with the alkylating agent Temozolomide (TMZ) and cranial irradiation, GBM relapse is inevitable with a median survival of &amp;lt;15 months. Extensive intratumoral heterogeneity in GBM is believed to be the leading cause of therapy resistance and disease relapse, suggesting that therapy acts as a bottleneck for tumor evolution. Recently, the advent of CRISPR-Cas9 technology has led to the development of genome-wide libraries of sgRNAs capable of introducing insertion-deletion (indels) within exonic regions of genes, leading to a frameshift mutation two-thirds of the time. Here, we present the first genome-wide CRISPR-Cas9 knockout screen in patient-derived GBM BTICs aimed to discover synthetic lethal sensitizers of conventional chemoradiotherapy. Briefly, we performed genome-wide CRISPR-Cas9 screens in treatment-naïve GBM BTICs subjected to in vitro chemotherapy with TMZ and irradiation. By comparing sgRNA dynamics at each doubling period, we were able to identify potent sensitizer genes exclusive to combined chemoradiotherapy, and not TMZ or irradiation alone. Candidate sensitizer genes were validated in an arrayed format to evaluate impact on GBM BTIC self renewal, proliferation, and sensitivity to TMZ and radiation. We aim to further validate these sensitizers of conventional chemoradiotherapy by performing a focused CRISPR-Cas9 genetic screen in our patient-derived xenograft model of treatment-refractory GBM. Ultimately, adjuvants targeting sensitizer genes could greatly enhance the impact of conventional chemoradiotherapy in GBM patients, leading to an increase in patient survival. Citation Format: Chirayu Chokshi, David Tieu, Kevin Brown, Chitra Venugopal, Parvez Vora, Katherine Chan, Amy Tong, Maleeha Qazi, Mohini Singh, Neil Savage, Andrea Habsid, Jason Moffat, Sheila Singh. Genome-wide CRISPR screens in brain tumor initiating cells (BTICs) identify potent sensitizers and resistors of conventional chemoradiotherapy [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 390.
Abstract 5468: Neratinib significantly inhibits responses to androgen in human prostate cancer cells
Authors: Dafydd A. Dart, Alshad S. Lalani, Francesca Avogadri-Connors, Richard Bryce, Wen G. Jiang
Journal: Cancer Research (2018)

Abstract Background: Prostate cancer (PCa) is the most commonly diagnosed male cancer in the Western world. Tumor growth is initially androgen dependent - and driven by the androgen receptor (AR). The mainstays of prostate cancer treatment are androgen ablation and antiandrogen treatment, which block AR signalling. However, PCa often relapses to an androgen- independent disease. Androgens can transactivate genes directly via the AR-mediated transcription factor and indirectly via less well understood signal transduction pathways. These signal transduction pathways become increasingly relevant as prostate cancer cells progress to anti-androgen resistance, with HER2 being associated with higher relapse rates. Neratinib is an orally available tyrosine kinase inhibitor that irreversibly binds and inhibits EGFR, HER2 and HER4 receptor tyrosine kinases. This study aimed to examine the effect of neratinib on androgen signalling and on the expression of androgen-regulated genes in prostate cancer cells. Methods: Changes in protein phosphorylation after androgen treatment of hormonally starved prostate cancer cells (LNCaP) was assessed using protein microarrays (Kinexus, Canada). Changes in gene expression after neratinib or androgen treatment were ascertained using AmpliSseq® technology or standard qPCR, and analysed via IPA Ingenuity software. Results: Androgen treatment of hormonally starved prostate cancer cells (LNCaP) caused phosphorylation of several members of the signal transduction cascade including HER2 and Src within 2 hours, indicating a role for HER2 in rapid androgen signalling. Additionally, from over 1000 genes upregulated by androgen treatment (&amp;gt;2fold within 2 hours), 87% showed downregulation with neratinib treatment. Ingenuity pathway analysis indicated that STAT3, ETS-family and NF-κB transcription factors may be responsible for the rapid androgen-induced gene upregulation observed, and that these pathways were inhibited by neratinib treatment. Q-Quantitative PCR analysis of PSA expression in LNCaP cells stimulated with androgen in the presence of increasing concentrations of neratinib resulted in a dose-dependent inhibition of androgen activity. Conclusions: These results show that neratinib is able to inhibit the responses of prostate cancer cells to androgens, and that a strong potential signaling cross-talk exists between the androgen receptor and the certain signal transduction pathways - pathways known to be involved in the progression of androgen-independent prostate cancer. Citation Format: Dafydd A. Dart, Alshad S. Lalani, Francesca Avogadri-Connors, Richard Bryce, Wen G. Jiang. Neratinib significantly inhibits responses to androgen in human prostate cancer 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 5468.
Interim PET Analysis in First-Line Therapy of Multiple Myeloma: Prognostic Value of ΔSUVmax in the FDG-Avid Patients of the IMAJEM Study
Authors: Clément Bailly, Thomas Carlier, Bastien Jamet, Thomas Eugene, Cyrille Touzeau, Michel Attal, Cyrille Hulin, Thierry Facon, Xavier Leleu, Aurore Perrot, Laurent Garderet, Margaret Macro, Denis Caillot, Philippe Moreau, Françoise Kraeber-Bodéré, Caroline Bodet-Milin
Journal: Clinical Cancer Research (2018)

Purpose: To assess the prognostic value of interim 18F-fluorodeoxyglucose (FDG)-PET analysis using decrease in maximum standardized uptake value (SUVmax) versus visual analysis in patients with multiple myeloma.Patients and Methods: We evaluated the prognostic value of FDG-PET after three cycles of lenalidomide, bortezomib, and dexamethasone (RVD) in patients with FDG-avid multiple myeloma included in the French prospective multicenter IMAJEM study. All images were centrally reviewed and interpreted using visual criteria and maximal standardized uptake value reduction (ΔSUVmax). Known prognostic factors, such as the revised International Staging System and biochemical response after three cycles of chemotherapy, were also evaluated.Results: In the multivariate analysis, only ΔSUVmax [P < 0.001, HR = 5.56; 95% confidence interval (CI), 1.96-15.81] and biochemical response after three cycles of RVD (P = 0.025, HR = 0.29; 95% CI, 0.1-0.85) appeared as independent prognostic factors, with a more discriminative HR for ΔSUVmax. ΔSUVmax analysis (>-25% vs. ≤-25%) identified patients with improved median progression-free survival (22.6 months and not reached, respectively).Conclusions: ΔSUVmax appears to be a powerful tool for the prediction of long-term outcome in patients with FDG-avid multiple myeloma. Other prospective studies are needed to further validate this prognostic biomarker. Clin Cancer Res; 24(21); 5219-24. ©2018 AACR.
Association of prostate specific-antigen doubling time (PSADT) with metastasis-free survival (MFS) and overall survival (OS) in non-metastatic castration-resistant prostate cancer (nmCRPC).
Authors: Jennifer H Lin, Brian Macomson, Ozgur Tunceli, Chris Pericone, Ajay S. Behl, Siddhant Deshmukh, Neal D. Shore
Journal: Journal of Clinical Oncology (2017)

e16525 Background: For optimal nmCRPC management, it is important to assess the rate of disease progression and its predictors. MFS and OS endpoints are likely to be important determinants in evaluating the relative impact of treatments in nmCRPC patients. This study assessed the association of PSADT with MFS and OS in real world practice. Methods: A retrospective cohort study of men ≥18 years old was conducted using the Optum electronic health record (EHR) database (2007-2016). nmCRPC was defined as a prostate cancer diagnosis, no ICD-9/10 code or therapy indicating metastatic disease, a testosterone (T) level &lt; 50 ng/dL (castrate level) and 2 rising PSAs (relative rise ≥25%; absolute rise ≥2 ng/mL above nadir) ≥1 week apart. Baseline PSADT, calculated from the PSA nadir until 2 nd rise of PSA, was grouped into &lt; 6, 6-18 or &gt; 18 months. A Cox proportional hazard model was used to assess the association of baseline PSADT with MFS and OS, comparing PSADT &lt; 6 and 6-18 months against PSADT &gt; 18 months. Multivariable analysis was adjusted for age, race, comorbidity index score, T levels, therapy and bone scans before nmCRPC. A linear trend was tested by taking PSADT as a continuous variable (median value in each group) in the model. Results: A total of 901 patients were identified. Mean nmCRPC onset age was 76 years and mean follow-up time was 2 years. The median PSADT was 7 months, ranging from 0.5 to 267 months. During follow-up, 477 patients developed metastasis and 384 died. MFS was 89%, 60%, and 47% at year 1, 3 and 5, respectively. Men with PSADT &lt; 6 and 6-18 months had ≥50% increased risk of shorter MFS than men with PSADT &gt; 18 months; hazard ratios (HR) were 1.87 (95% confidence interval [CI]: 1.39-2.54) and 1.50 (95%CI: 1.11-2.04), respectively. OS was 87%, 64% and 57% at year 1, 3 and 5, respectively. Shorter PSADT was associated with shorter OS (p for trend &lt; 0.001). Men with a PSADT &lt; 6 months had a 2-fold increased risk for decreased OS (HR = 2.04, 95% CI: 1.44-2.90). Conclusions: Patients with nmCPRC with shorter PSADT had significantly shorter MFS and OS compared to those with longer PSADT. Baseline PSADT may serve as a predictor for nmCRPC progression.
Radiation Dose Estimates From Cardiac Multislice Computed Tomography in Daily Practice
Authors: JörgHausleiter, TanjaMeyer, MartinHadamitzky, EsterHuber, MariaZankl, StefanMartinoff, AdnanKastrati, AlbertSchömig
Journal: Circulation (2006)

Background— Multislice computed tomography angiography (CTA) is a promising technology for imaging patients with suspected coronary artery disease. Compared with 16-slice CTA, the improved spatial and temporal resolution of 64-slice CTA (0.6- versus 1.0-mm slice thickness and 330- versus 420-ms gantry rotation time) is associated with an increase in radiation dose. The objective of this retrospective investigation was to compare the estimated dose received during 16- and 64-slice CTA in daily practice and to investigate the impact of different scan protocols on dose and image quality. Methods and Results— Radiation dose was estimated for 1035 patients undergoing coronary CTA. Scanning algorithms with and without an ECG-dependent dose modulation and with a reduced tube voltage were investigated on dose estimates and image quality. In the entire patient cohort, radiation dose estimates were 6.4±1.9 and 11.0±4.1 mSv for 16- and 64-slice CTA, respectively (P<0.01). The reduction in radiation dose estimates ra...