tbuckley/cabot-search huggingface dataset:
Abstract 10006: Oxidative Stress Promotes Glucocorticoid-induced Cardiac Fibrosis Mediated by Mineralocorticoid Receptor and Its Co-activator
Authors: Yosuke Omori, Tomohito Ohtani, Yasushi Sakata, Yasuharu Takeda, Shunsuke Tamaki, Yasumasa Tsukamoto, Yukitoshi Ikeya, Takeshi Miwa, Kazuhiro Yamamoto, Toshiaki Mano, Issei Komuro
Journal: Circulation (2012)

Backgrounds: Cardiac fibrosis is considered to be a key determinant in the development of heart failure (HF). We reported that mineralocorticoid receptor (MR) antagonist eplerenone reduced cardiac ...
Abstract 4007: Decipher the myth between progression-free survival and overall survival in HER-2 positive metastatic nreast cancer: Anti-HER2 antibody as the constant winner—A hypothesis-driven meta-regression analysis
Authors: I-Chun Chen, Fu-Chiang Hu, Ching-Hung Lin, Yen-Shen Lu
Journal: Cancer Research (2019)

Abstract Purpose: Traditionally, the predictive value of progression free survival (PFS) hazard ratio (HR) on overall survival (OS) HR in metastatic breast cancer (MBC) was low. We observed that when trials were designed as adding on an anti-HER2 antibody, either trastuzumab or pertuzumab, to the control treatment, the OS increment is usually greater than the PFS increment. We aim to investigate the interaction of increment of median PFS and median OS in HER-2 positive MBC stratified by drug difference patterns between treatment arms using trial-level information. Methods: All randomized phase II or III trials of systematic therapy specifically for HER-2 positive MBC with available OS information were included after a systematic literature review. Treatment arms with shorter PFS were defined as control arm in the analysis. The correlation and interaction of HR for PFS and OS as well as the absolute increment for median PFS and OS were evaluated by fixed-effect or random-effect meta-regression meta-analysis. Drug difference between two treatment arms were specified as a categorical variable in the analysis. Results: A total of 28 trials with 10928 patients published between January 1999 and December 2017 were included in the final analysis. The correlation of median PFS HR (0.73, 95% C.I.= 0.68-078) and median OS HR (0.82, 95% C.I.= 0.77-0.87) was modest as reported by other investigators. However, when the drug difference between treatment arms was anti-HER2 antibody, the absolute increment in median OS is 2 fold of the absolute increment in median PFS (p = 0.0005), showing a linear correlation. This linear correlation was not observed when the drug difference between treatments was non-anti-HER2 antibody. Anti-HER2 antibody as drug difference would translate the absolute increment of median PFS into absolute increment of median OS, suggesting a good predictive value of median PFS on median OS. Conclusion: Anti-HER2 antibody as the drug difference between treatment arms provides consistently longer OS improvement than PFS improvement in HER-2 positive MBCs. Citation Format: I-Chun Chen, Fu-Chiang Hu, Ching-Hung Lin, Yen-Shen Lu. Decipher the myth between progression-free survival and overall survival in HER-2 positive metastatic nreast cancer: Anti-HER2 antibody as the constant winner—A hypothesis-driven meta-regression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4007.
Abstract 1851: Novel roles of DNA-PK in metabolic regulation in prostate cancer
Authors: Emanuela Dylgjeri, Jonathan Goodwin, Ayesha Shafi, Vishal Kothari, Giorgia Zadra, Erin Seifert, Felix Feng, Karen Knudsen
Journal: Cancer Research (2019)

Abstract DNA dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional kinase involved in repairing double-strand DNA breaks through non-homologous end joining (NHEJ), with parallel roles as a master transcriptional regulator of gene networks supporting cell migration and invasion. In prostate cancer (PCa), DNA-PK was found to be highly upregulated and hyperactivated. Strikingly, DNA-PK is the most deregulated kinase in metastatic castration resistant prostate cancer (CRPC), and is independently predictive of metastasis and overall survival in patients with high-risk disease. Combined, these findings highlight the importance of understanding DNA-PK functions beyond DNA repair and transcriptional regulation, which promote the acquisition of aggressive tumor phenotypes. Rapid immunoprecipitation of endogenous proteins (RIME) was performed to identify the DNA-PK interactome, which uncovered novel DNA-PK interactors that play key roles in metabolism. To assess the role of DNA-PK in regulation of metabolism, metabolic profiles of CRPC models were investigated upon DNA-PK modulation. Data presented will describe novel roles of DNA-PK in cancer metabolism and subsequent effects of DNA-PK modulation in key metabolic pathways. Citation Format: Emanuela Dylgjeri, Jonathan Goodwin, Ayesha Shafi, Vishal Kothari, Giorgia Zadra, Erin Seifert, Felix Feng, Karen Knudsen. Novel roles of DNA-PK in metabolic regulation in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1851.
Abstract 400: Digital PCR combined with melting curve analysis for highly multiplexed genotyping
Authors: Junko Tanaka, Tatsuo Nakagawa, Akiko Shiratori, Yuzuru Shimazaki, Kunio Harada, Chihiro Uematsu, Yoshinobu Kohara, Erina Takai, Shinichi Yachida
Journal: Cancer Research (2019)

Abstract Background Digital PCR (dPCR) is a promising method for liquid biopsies and is able to quantify nucleic acids more sensitively than real-time PCR. However, dPCR has a large fluctuation in the fluorescence intensity of the droplets or wells due to insufficient PCR in the small partitions, limiting the multiplexing capability of using the fluorescence intensity. In this study, we propose a new measurement method that combines dPCR with melting curve analysis for highly multiplexed genotyping. Methods A sample is digitized into a silicon chip with up to ~104 wells in which asymmetric PCR was performed to obtain more single-stranded amplicons that are complimentary to molecular beacon probes. Fluorescence images were captured while controlling the temperature of the chip, and melting curve was measured for each well. Then, genotyping was performed by using the fluorescence intensity, dye color of the probe, and melting temperature (Tm). Because the Tm of the PCR products does not considerably depend on the amplification efficiency of PCR, genotyping accuracy is improved by using Tm values, enabling highly multiplexed genotyping. Results The concept was confirmed by measuring wildtype KRAS and its mutants, G12D, G12R, G12V, and G13D. The results showed that the peaks of the Tm distributions of the DNA groups were 69.2°C and 62.8°C for the wildtype and G13D with the first color dye (HEX), in addition to 66.9°C, 63.5°C, and 59.1°C for G12R, G12D, and G12V, respectively, with the second color dye (FAM). By combining the fluorescence intensities for HEX, FAM and the Tm values, the wildtype and mutant groups were clearly identified and able to be quantified. Furthermore, genotyping of cfDNA of pancreatic cancer patients was successfully performed by this method. Conclusion We have proposed a new measurement method that combines dPCR with melting curve analysis, and successfully performed the multiplexed genotyping assay. To our knowledge, this is the first demonstration of genotyping of five DNA groups with a single mutation of cancer-related genes by combining dPCR with melting curve analysis. Citation Format: Junko Tanaka, Tatsuo Nakagawa, Akiko Shiratori, Yuzuru Shimazaki, Kunio Harada, Chihiro Uematsu, Yoshinobu Kohara, Erina Takai, Shinichi Yachida. Digital PCR combined with melting curve analysis for highly multiplexed genotyping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 400.
The Natural History of the Eccrine Miliarias: A Study in Human Ecology
Authors: Frederick Sargent, Herbert L. Slutsky
Journal: New England Journal of Medicine (1957)

THOMAS Sydenham1 taught that there were two conditions necessary for the advancement of medicine: a description of the natural history of disease; and a method of treatment. To prepare such a history he instructed that "every philosophical hypothesis whatsoever that has previously occupied the mind of the author, should lie in abeyance. This being done, the clear and natural phenomena of the disease should be noted — these, and these only ..."1 We were impelled to prepare a study of the natural history of the eccrine miliarias because experience had taught us that these conditions were of great practical importance . . .
Abstract 4900: Dynamic metabolic response of prostate cancer patients treated with ADT and low carb diet
Authors: Stephen Freedland, Pao-Hwa Lin, Emily Y. Chen, Vladimir Tolstikov, Jen-Tsan Chi, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish
Journal: Cancer Research (2019)

Abstract Background: Prostate cancer (PrCa) is one of the most common cancers among men and managed through surgery, hormonal therapy, chemotherapy, radiation, and cryotherapy. Depending on the stage of PrCa, androgen deprivation therapy (ADT) is commonly utilized as an intervention. ADT has proven effective in intervening in PrCa progression, although there are several side effects. Recently, the use of low carb diets has been shown to alter patients’ metabolic phenotype and as such may reduce the side effects of ADT. Methods: In this study 35 men, who were beginning ADT, were randomized to low carb diet intervention with recommended exercise or control (no lifestyle change) for 6 months. Primary results have been reported showing significant weight loss at both 3-month (17lb, p&amp;lt;0.01) and 6-month (23 lbs, p&amp;lt;0.01) and improved insulin control at 3-month (HOMA=-19 as compared to baseline, p=0.02) but not at 6-month (HOMA=-4 as compared to baseline, p=0.13). For this exploratory analysis, sera collected at baseline, 3, and 6 months was used for metabolomics analysis utilizing GC/MS TOF, QqQ LC-HILIC-MS/MS, and TripleTOF 6600 LC-RP-MS and lipidomics analysis using TripleTOF 5600+ MS/MSALL workflows to quantify the chemical diversity of the metabolome and lipidome. Results: Over 450 metabolites and 1000 lipid species were quantified. Metabolomics analysis of sera from the control patients (ADT alone) demonstrated alterations in steroid biosynthesis, androgen/estrogen metabolism, fatty acid metabolism, and lysine degradation. Lipidomics analysis of the control patients demonstrated changes in selective long chain polyunsaturated phosphatidylcholine species. Analysis of the ADT plus low carb patients revealed a change in pyruvate, glucose-alanine cycle, selenoamino acid, phenylalanine/tyrosine, and taurine metabolism. Further, lipidomic analysis revealed changes in several triglycerides, plasmalenylethanolamine, and phosphatidic acid species. Conclusion: In summary, integration of metabolomic and lipidomic analysis in hormonal and metabolic interventions of PrCa patients revealed dynamic changes providing novel insight for tailoring therapeutic intervention and monitoring. Citation Format: Stephen Freedland, Pao-Hwa Lin, Emily Y. Chen, Vladimir Tolstikov, Jen-Tsan Chi, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish. Dynamic metabolic response of prostate cancer patients treated with ADT and low carb diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4900.
The use of AFP and DCP as serum biomarkers to differentiate between hepatocellular carcinoma and intrahepatic cholangiocarcinoma in non-cirrhotic livers.
Authors: Ravindhi Lakmalee Nathavitharana, Mabel Joey Teng, Philip James Johnson, Sarah Berhane, Anna Skowronska, Janet Morse
Journal: Journal of Clinical Oncology (2013)

e15162 Background: Differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) can be challenging in patients without evidence of liver cirrhosis. Definitive diagnosis is based on tissue biopsy. We investigated if the use of serum biomarkers could help differentiate between these two types of malignancies, thereby avoiding the risks associated with biopsy. Methods: Patients with cholangiocarcinoma and HCC were recruited from Queen Elizabeth Hospital, Birmingham, UK; blood samples were collected at time of diagnosis. Two biomarkers, alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were measured in the serum samples from 56 patients with cholangiocarcinoma and 35 patients with HCC without evidence of liver cirrhosis. Of the 56 patients with cholangiocarcinoma, 17 were intrahepatic and 39 were extrahepatic. Results: 17 ICC and 35 HCC were included in the analysis. The levels of AFP and DCP were much higher in HCC as compared to ICC. The median AFP was 64.6 (IQR 10.9, 3564.2) in HCC as compared to 3 (IQR 2.4, 3.9) in ICC. Similarly, the median DCP was 215.41 (IQR 22.46, 692.53) in HCC as compared to 0.33 (IQR 0.16, 1.08) in ICC. Stepwise logistic regression was performed using both biomarkers. Log- DCP remained significant at 95% level in predicting HCC from ICC, giving an AUC of 0.96. Conclusions: In patients with a non-cirrhotic liver and radiological evidence of cancer, measurement of serum AFP and DCP level may help differentiate between HCC and ICC. In this study, DCP is the most useful discriminator between HCC and ICC. Further prospective studies should be done with larger sample sizes to validate the use of AFP and DCP as diagnostic biomarkers in this clinical setting.
Abstract 16378: Clinical Outcomes of Plavix and Generic Clopidogrel for Patients With Hospitalized With an Acute Coronary Syndrome
Authors: Dennis Ko, Jack Tu, Harlan Krumholz, Peter Austin, Therese Stukel, Alice Chong, Maria Koh, Jose de Melo Junior, Cynthia Jackevicius
Journal: Circulation (2016)

Background: Clopidogrel is one of the most commonly prescribed cardiac drugs because of its ability to improve clinical outcomes for cardiovascular conditions. After patent protection of Plavix® ex...
Abstract 2564: Tracing extrachromosomal DNA inheritance patterns in glioblastoma using CRISPR
Authors: Eunhee Yi, Roel Verhaak
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is the most lethal brain tumor; it is characterized by poor response to standard post-resection radiation and cytotoxic therapy, resulting in a dismal prognosis with a five-year survival rate of 10%. Recurrence after therapy for GBM is unavoidable. There are substantial differences among the cells of GBM tumors in the abundance and types of genetic material. This heterogeneity likely is the major cause of therapy failure, the development of treatment resistance, and ultimately recurrence. A recent study has suggested that the majority of GBM activate oncogenes through amplification extrachromosomal DNA (ecDNA). Despite the speculation that ecDNA is a key factor of tumor heterogeneity, how ecDNA is propagated and distributed among—and how it behaves within—cancer cells is completely unknown. To address this gap in knowledge, this study focused on developing a novel cytogenetic tool that enables visualization and tracking ecDNA behavior in live GBM cells. We found breakpoint sequences resulting from genome rearrangements during ecDNA formation by performing computational analysis whole genome sequencing data from a pair of primary/recurrent GBM neurospheres. Each breakpoint represents a unique target sequence for ecDNA-specific labeling. Breakpoint were validated by breakpoint-PCR, focusing on breakpoints shared by the primary and recurrent neurosphere. We determined location and quantity of all ecDNA breakpoints through breakpoint-FISH (BP-FISH) analysis, which showed that all signal was found outside of the conventional chromosomes in the metaphase spread, validating the extrachromosomal nature of the ecDNA breakpoints. The breakpoint quantities, reflecting the number of ecDNA elements per cell, varied between primary and recurrent neurosphere suggesting that ecDNAs quantitatively changed during GBM evolution. These results emphasize the necessity of tracking ecDNA dynamics to answer the question of how ecDNA is distributed into the daughter cells. Our findings will be strong evidence to make ecDNA-specific CRISPR system in further research. Tracing ecDNA dynamics will provide new insight into the impact of ecDNA on cancer evolution. Citation Format: Eunhee Yi, Roel Verhaak. Tracing extrachromosomal DNA inheritance patterns in glioblastoma using CRISPR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2564.
“International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.” Kian Fan Chung, Sally E. Wenzel, Jan L. Brozek, Andrew Bush, Mario Castro, Peter J. Sterk, Ian M. Adcock, Eric D. Bateman, Elisabeth H. Bel, Eugene R. Bleecker, Louis-Philippe Boulet, Christopher Brightling, Pascal Chanez, Sven-Erik Dahlen, Ratko Djukanovic, Urs Frey, Mina Gaga, Peter Gibson, Qutayba Hamid, Nizar N. Jajour, Thais Mauad, Ronald L. Sorkness and W. Gerald Teague. <i>Eur Respir J</i> 2014; …
Journal: European Respiratory Journal (2018)

issue of the European Respiratory Journal was originally published with errors in the criteria used to define severe asthma on page 350 and in table 3.At both aforementioned points in the article, the "poor symptom control" criterion for severe asthma should have been defined as: Asthma Control Questionnaire (ACQ) consistently ⩾1.5 or Asthma Control Test (ACT) <20, rather than as ACQ >1.5 or ACT <20; similarly, the "frequent severe exacerbations" criterion should have been defined as: those requiring two or more bursts of systemic corticosteroids (⩾3 days each) in the previous year, not those requiring two or more bursts of systemic corticosteroids (>3 days each) in the previous year.
Abstract 3806: Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial-mesenchymal transition is critical in conquering ALK-positive lung cancer
Authors: Shinji Nakamichi, Seike Masahiro, Akihiko Miyanaga, Akiko Takahashi, Rintaro Noro, Kaoru Kubota, Akihiko Gemma
Journal: Cancer Research (2019)

Abstract Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib) -resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H2228 cells. Tumor volumes of xenograft mice implanted with established H2228-ceritinib-resistant (H2228-CER) cells were significantly reduced after treatment with ganetespib, or ganetespib in combination with ceritinib. Some ALK-positive NSCLC patients with AXL overexpression showed a poorer response to crizotinib therapy than patients with a low expression of AXL. ALK signaling-independent AXL overexpressed in drug-tolerant cancer cell subpopulations with EMT and CSC features may be commonly involved commonly involved in intrinsic and acquired resistance to ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome drug-tolerant cancer cell subpopulations in ALK-positive NSCLC patients for the reason that ALK-positive NSCLC cells do not live through ALK-TKI therapy. Citation Format: Shinji Nakamichi, Seike Masahiro, Akihiko Miyanaga, Akiko Takahashi, Rintaro Noro, Kaoru Kubota, Akihiko Gemma. Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial-mesenchymal transition is critical in conquering ALK-positive lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3806.
Abstract 12536: Inequities and Outcomes for Patients With ST-Segment Elevation Myocardial Infarction in Brazil - Insights From The ACCEPT Registry
Authors: Antonio Carlos S Sousa, José Augusto S Barreto Filho, Joselina L Oliveira, Marcos Antônio A Santos, Fernando Bacal, Otávio Berwanger, Luiz A Piva e Mattos, Jadelson Andrade
Journal: Circulation (2013)

The public Unified Health System (SUS) was launched in Brazil with the promise to decrease inequities. Whether outcomes of patients with ST-segment elevation myocardial infarction (STEMI) using SUS...
Abstract 10470: Endothelial Dysfunction in Leptomeningeal and Peripheral Arterioles Induced by ß-amyloid Peptides: A Novel Human Model to Study Alzheimer’s Disease
Authors: Seth Truran, Alex E Roher, Thomas G Beach, Daniel A Franco, Camelia Burciu, Geidy Serrano, Chera L Maarouf, Peter Reaven, Raymond Q Migrino
Journal: Circulation (2013)

Background: Treatments effective in transgenic mice have so far failed in human clinical trials to treat Alzheimer’s disease (AD), likely due to deficient recapitulation of human condition by exist...
Abstract 15810: Direct Evidence of Functional Coupling of β2 Adrenergic Receptors With L-type Calcium Channels in Rat Cardiomyocytes and its Loss in Heart Failure
Authors: Jose L Sanchez-Alonso, Julia Gorelik
Journal: Circulation (2015)

Introduction: L-type calcium channels (LTCCs) are crucially involved in excitation-contraction coupling. β1 and β2 adrenergic receptors (βARs) are important mediators of LTCC function via production of the second messenger cAMP. Stimulation of LTCCs through β2AR happens only in the close proximity of the channel suggesting a coupling between LTCC with β2AR rather than with β1AR. We wanted to find out if this coupling is exclusive of the channels located in the t-tubules (TTs) or it can be found in other areas of cell plasma membranes (crests). We also wanted to look at failing cardiomyocytes and see if the coupling is impaired. Method: We applied super-resolution scanning patch-clamp to record functional LTCCs from control and 16-weeks post-MI heart failure rat ventricular cardiomyocytes. Stimulation of β1AR (ISO 1.0μM + ICI 50nM) or β2AR (ISO 1.0μM + CGP 0.3μM), on specific microdomains (TTs or crests) was applied locally though the pipette (350nm tip diameter) in cell-attached mode. Results: In control cells, local stimulation of β2AR increased the occurrence (from 30% to 50% on TTs and from 13% to 27% on crests) and the open probability of LTCCs (0.045±0.007 vs. 0.066±0.007 on TTs, p&lt;0.05 and 0.026±0.008 vs 0.046±0.002 on crest, p&lt;0.05). Surprisingly, local stimulation of β1AR did not increase neither occurrence nor open probability of LTCC both in the TTs and in the crests. In failing cells, a microdomain-specific disruption of signalling was observed, with β2AR stimulation only increasing the occurrence (from 33% to 56%) and the open probability (0.079±0.011 vs 0.0107±0.009, p&lt;0.05) of LTCCs in the crests but not in the TTs. Conclusions: This study provides first direct evidence of the specific coupling of β2ARs with LTCCs that is also dependent on the location and is disrupted in failing cardiomyocytes.