tbuckley/cabot-search huggingface dataset:
Abstract 4018: Mutations of HER2 at L755 residue results in HER2 nuclear accumulation and enhances breast cancer stem cell activity
Authors: Wen-Ling Wang, Lei Nie, Kieu-Thanh Huynh, Jhen-Yu Chen, Jing-Han Yao, Mien-Chie Hung, Wei-Chien Huang
Journal: Cancer Research (2018)

Abstract Background: HER2 plays a critical role in tumor progression and cancer stemness in breast cancer cells. Somatic mutations in HER2 gene have been observed in low HER2-expressing cancer cells and are correlated with insensitization to tyrosine kinase inhibitors. One of the most frequently altered residue is L755, which is located at kinase domain and near a putative nuclear export signal sequence, increasing kinase activity and is associated with lapatinib resistance. Moreover, the correlation between HER2 nuclear localization and drug-resistance and poor clinical outcome has been demonstrated in cancer patients. However, the roles of HER2 mutations in its nuclear distribution and its ability to enhance cancer stemness remain unknown. Methods: We hypothesized that activation of HER2 mutations on amino acid L755 might affect HER2 cellular localization. To investigate the cellular localization of HER2 and the role of L755 mutations in expansion of cancer stem cells, T47D cell line clones expressing wile-type (WT) and mutant HER2 (L755P and L755S) were established. The cellular fractionation, immunofluorescence staining, and western blot analysis were employed to verify the cellular distribution of HER2 L755 mutations. Biochemical strategies were further performed to examine the interaction of HER2 L755 mutant and cellular transporters nuclear importers or exporters. Results: Our results showed that ectopically expressed HER2 L755P and L755S mutants exhibited a higher nuclear retention via interrupting nuclear exporting complex formation. HER2 L755P and HER2 L755S showed higher abilities to associate with CRM1 and RanBP3 but reduced the binding capacity with Ran. The increases in tyrosine phosphorylation of CRM1 and RanBP3 were found by HER2 mutants and cause the defect in the formation of nuclear exporting complex. Additionally, the HER2 L755P and HER2 L755S-expressing cell lines showed higher levels of cancer stem cell markers, CD44 and ALDH1 and increased mammosphere formation. Conclusion: HER2 L755P and L755S mutations enhance the HER2 nuclear localization and breast cancer stemness. This study provided new insight into the role of HER2 mutation in cancer stemness, and was helpful to develop novel prognostic markers for the therapeutic efficacy in breast cancer patients. Citation Format: Wen-Ling Wang, Lei Nie, Kieu-Thanh Huynh, Jhen-Yu Chen, Jing-Han Yao, Mien-Chie Hung, Wei-Chien Huang. Mutations of HER2 at L755 residue results in HER2 nuclear accumulation and enhances breast cancer stem cell activity [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 4018.
Lysophosphatidic Acid Positively Regulates the Fluid Flow–Induced Local Ca2+ Influx in Bovine Aortic Endothelial Cells
Authors: HisayukiOhata, TadahiroIkeuchi, AyaKamada, MasayukiYamamoto, KazutakaMomose
Journal: Circulation Research (2001)

Abstract—Using real-time confocal microscopy, we have demonstrated that lysophosphatidic acid (LPA), a bioactive phospholipid existing in plasma, positively regulates fluid flow–induced [Ca2+]i response in fluo 4–loaded, cultured, bovine aortic endothelial cells. The initial increase in [Ca2+]i was localized to a circular area with a diameter of <4 μm and spread concentrically, resulting in a mean global increase in [Ca2+]i. The local increase often occurred in a stepwise manner or repetitively during constant flow. The percentage of cells that responded and the averaged level of increase in [Ca2+]i were dependent on both the concentration of LPA (0.1 to 10 μmol/L) and the flow rate (25 to 250 mm/s). The response was inhibited by removing extracellular Ca2+ or by the application of Gd3+, an inhibitor of mechanosensitive (MS) channels, but not by thapsigargin, an inhibitor of the endoplasmic reticular Ca2+-ATPase. It was also inhibited by 8-bromo-cGMP, and the inhibition was completely reversed by KT5823, ...
Abstract LB-189: Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer
Authors: Jenna H. Newman, Rachel E. NeMoyer, David Augeri, Jyoti Malhotra, Elaine Langenfeld, Charles B. Chesson, Micheal J. Lee, Saeed Tarabichi, Sachin R. Jhawar, Praveen K. Bommareddy, Sh'rae Marshall, Evita T. Sadimin, John E. Kerrigan, Michael Goedken, Christine Minerowicz, Salma K. Jabbour, Shengguo Li, Natalie Dobias, Mary O. Carayannopolous, Andrew Zloza, John Langenfeld
Journal: Cancer Research (2018)

Abstract Purpose: Studies have shown that bone morphogenetic protein (BMP) signaling is aberrantly expressed in lung and other carcinoma leading to pro-oncogenic effects on tumor growth. The BMP receptor inhibitor DMH2 induces death of lung cancer cells through the downregulation of anti-apoptotic proteins XIAP, TAK1, and Id1-Id3. Since DMH2 does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics better BMP inhibitors are needed. Experimental Design: Here, we identified a site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We examined the effects of JL5 to downregulate BMP signaling and induce cell death of lung cancer cells in vitro and in vivo. We also queried the The Cancer Genome Atlas (TCGA) to assess if genetic alterations in lung cancer would affect drug targetability of the BMP receptors. Results: We show that JL5 has improved pharmacokinetic profile compared to DMH2. JL5 suppresses BMP signaling in lung cancer cells in vitro and in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. The TCBA database analysis suggests that genetic alterations in the BMP signaling cascade will not limit targeting with small molecule inhibitors. Conclusion: Our studies show that the BMP signaling pathway is targetable and BMP receptor inhibitors should be developed as a therapeutic to treat lung and other cancer patients. Citation Format: Jenna H. Newman, Rachel E. NeMoyer, David Augeri, Jyoti Malhotra, Elaine Langenfeld, Charles B. Chesson, Micheal J. Lee, Saeed Tarabichi, Sachin R. Jhawar, Praveen K. Bommareddy, Sh'rae Marshall, Evita T. Sadimin, John E. Kerrigan, Michael Goedken, Christine Minerowicz, Salma K. Jabbour, Shengguo Li, Natalie Dobias, Mary O. Carayannopolous, Andrew Zloza, John Langenfeld. Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung 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 LB-189.
Hydroxy-Methylglutaryl–Coenzyme A Reductase Inhibition Promotes Endothelial Nitric Oxide Synthase Activation Through a Decrease in Caveolin Abundance
Authors: OlivierFeron, ChantalDessy, Jean-PierreDesager
Journal: Circulation (2001)

Background—Hypercholesterolemia is causally associated with defects of endothelial nitric oxide (NO)–dependent vasodilation. Increased uptake of cholesterol by endothelial cells (ECs) upregulates the abundance of the structural protein caveolin-1 and impairs NO release through the stabilization of the inhibitory heterocomplex between caveolin-1 and endothelial NO synthase (eNOS). Therefore, we examined whether the hydroxy-methylglutaryl–coenzyme A reductase inhibitor atorvastatin modulates caveolin abundance, eNOS activity, and NO release through a reduction in endogenous cholesterol levels. Methods and Results—ECs were incubated with increasing doses of atorvastatin in the absence or in the presence of human LDL cholesterol (LDL-Chol) fractions in the presence of antioxidants. Our results show that atorvastatin (10 nmol/L to 1 μmol/L) reduced caveolin-1 abundance in the absence (−75%) and in the presence (−20% to 70%) of LDL-Chol. This was paralleled by a decreased inhibitory interaction between caveolin...
Abstract 14763: Discontinuation of Dofetilide or Qt Prolongation is Much More Common in Real-world Setting Than Reported in Clinical Trials
Authors: VidhuAnand, KairavVakil, SelcukAdabag
Journal: Circulation (2015)

Introduction: Dofetilide is a class III anti-arrhythmic agent approved for achieving and maintaining sinus rhythm in patients with symptomatic atrial fibrillation or flutter (AF). Due to a risk of QT prolongation and ventricular tachycardia (VT) patients initiated on Dofetilide need to be hospitalized for at least 3 days to closely monitor ECG. In large clinical trials 1.8-2.5% of the patients had to discontinue Dofetilide due to QT prolongation. We aimed to evaluate the frequency and correlates of discontinuation of Dofetilide due to QT prolongation (QTc >500 msec) or VT in a real-world, inpatient setting. Methods: We included 100 consecutive patients, hospitalized for Dofetilide initiation at the Minneapolis VA Medical Center from 2011 to 2014. Data was collected retrospectively from electronic medical records. Results: The mean age was 63.8 ± 9.1 years. The indication for Dofetilide was AF (88%) and VT (12%). Dofetilide had to be discontinued in 21% of the patients due to QTc prolongation (17%) or VT (...
Abstract 393: Dynamic networks of transcriptome, DNA methylome, and DNA hydroxymethylome during T-cell lineage commitment
Authors: Byoung-Ha Yoon
Journal: Cancer Research (2018)

Abstract Immunotherapy is a treatment that uses a part of a personal immune system to overcome diseases such as cancer. T cell therapy has been used in a variety of cancer types, including lymphoma, melanoma and colon cancer. There are several strategies used to take advantage of cell-mediated anti-tumor properties of T cells. Cellular immune responses to prevent tumors are typically caused by CD4 and CD8 T cells. The stepwise development of T cells from a multipotent precursor is guided by diverse mechanisms including interactions of lineage specific transcription factors and epigenetic changes and acquires lineage-specific trait. However, in this T-cell development process, a greater understanding of the regulation of genes involved in immunotherapy is needed. To elucidate the transcriptional networks and epigenetic mechanisms underlying T-cell therapy and T cell lineage commitment, we investigated genome-wide changes in gene expression, DNA methylation and hydroxymethylation among five successive populations of T cell development (DN3, DN4, DP, CD4+, and CD8+) using RNA-seq, MBD-seq and hMeDIP-seq, respectively. And investigated interactive networks of transcription factors, chromatin modifiers, and DNA methylation. We found stage specific differentially methylated regions and some of them occurred near the specific differentially expressed genes related to immune cells or cancer immunotherapy such as Cd4, Ccr9 and Pdcd1. Dynamic changes of DNA methylation and hydroxymethylation is associated with the recruitment of the stage specific transcription factors. This study may provide a frame work for understanding the complexity of T cell lineage commitment and immunotherapy-related genes were regulated during T-cell differentiation. Citation Format: Byoung-Ha Yoon. Dynamic networks of transcriptome, DNA methylome, and DNA hydroxymethylome during T-cell lineage commitment [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 393.
Response to: ‘Checkpoint inhibitors and arthritis: seeking balance between victories and defeats’ by Moura and Moura
Authors: Thierry Schaeverbeke, Marie Kostine
Journal: Annals of the Rheumatic Diseases (2018)

We appreciate the very clever analysis by Moura and Moura1 of the numerous questions addressed by the management of immune-related adverse events (irAEs) occurring in patients treated with checkpoint inhibitors, and their citation of a French proverb, although the exact meaning of the proverb « en medecine comme en amour, ni jamais ni toujours » is not that medicine is unpredictable, but that there are always exceptions. Medical doctors must be aware of these exceptions and constantly remain vigilant.

The two first questions addressed by Moura and Moura concern the value of a rheumatologist’s collaboration while guidelines have recently been published to help oncologists in the management of irAEs.2–4 We definitely agree with these authors to consider the strong value added by the rheumatologist’s analysis of musculoskeletal symptoms occurring in patients treated with immune checkpoint inhiboitors (ICIs). To illustrate this point, we will shortly report on three recent patients referred to our rheumatology unit by their oncologist for a suspicion of irAE.

The first patient, an 80-year-old woman, was given nivolumab since 5 …
Rapid and specific labeling of single live <i>Mycobacterium tuberculosis</i> with a dual-targeting fluorogenic probe
Authors: Yunfeng Cheng, Jinghang Xie, Kyung-Hyun Lee, Rajiv L. Gaur, Aiguo Song, Tingting Dai, Hongjun Ren, Jiannan Wu, Zhaogang Sun, Niaz Banaei, Demir Akin, Jianghong Rao
Journal: Science Translational Medicine (2018)

A dual-targeted fluorogenic probe and microfluidic chip enables single-cell labeling and quantification of live Mycobacterium tuberculosis .
Abstract 4251: Neighborhood data system to enable health disparities research in Chicago
Authors: David J. Press, Scarlett Lin Gomez, Briseis Aschebrook-Kilfoy, Habibul Ahsan
Journal: Cancer Research (2018)

Abstract Background: Chicago has become the focus of national concern following findings of striking disparities in cancer incidence and mortality, with worse outcomes for Non-Hispanic Black persons. Chicago also has communities with very high crime rates, racial/ethnic segregation, and resource-poor communities. Social stressors, including crime, social isolation, low socioeconomic status (SES), interpersonal and institutional discrimination, and residence in resource-poor settings intersect at individual- and neighborhood- levels across the lifespan and are associated with poor health outcomes. However, the extent to which these social determinants separately and together contribute to cancer health disparities is unclear. Purpose: To elucidate health disparities attributable to neighborhood social stressors in the Chicago setting, a pilot Chicago Neighborhood Data System (ChNDS) is currently in production, using the Chicago Police Department crimes database, data from the 2010 Census short form, 2008-2012 American Community Survey (ACS), University of Chicago MAPSCorps project, and Environmental Systems Research Institute (ESRI) geodatabases. Approach: We use principal components analysis (PCA) to generate composite indices of neighborhood-level factors at the small area level (census tract or block group): racial/ethnic composition; SES; immigration/ acculturation; other sociodemographic characteristics; crime; and community assets including density/proximity to types of businesses, retail food, and recreational facilities. Future directions: Data record linkages at the small area-level will be performed between the pilot ChNDS and observational and population-based datasets to examine the impact of neighborhood-level characteristics on research study participation, disease occurrence, healthcare utilization, and disease outcomes in Chicago. Citation Format: David J. Press, Scarlett Lin Gomez, Briseis Aschebrook-Kilfoy, Habibul Ahsan. Neighborhood data system to enable health disparities research in Chicago [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 4251.
Abstract 11675: Influence of Donor-Transmitted Lesions on Vessel Remodeling and Plaque Progression in Coronary Artery After Heart Transplant Recipients: Serial Three-Dimensional Intravascular Ultrasound Analysis
Authors: Takuya Watanabe, Osamu Seguchi, Kunihiro Nishimura, Masanobu Yanase, Takuma Sato, Haruki Sunami, Seiko Nakajima, Eriko Hisamatsu, Takamasa Sato, Kensuke Kuroda, Takashi Kobayashi, Yoko Nakao, MIchikazu Nakai, Misa Takegami, Aya Higashiyama, Makoto Watanabe, Yoshihiro Kokubo, Hiroki Hata, Tomoyuki Fujita, Yoshihiro Miyamoto, Takeshi Nakatani
Journal: Circulation (2014)

Introduction: The association between the presence of donor-transmitted lesions (DL) and the progression of cardiac allograft vasculopathy (CAV) including coronary vessel remodeling has been still controversial. The purpose of present study was to elucidate the influence of DL on coronary artery morphology after heart transplantation (HTx). Methods: Serial three-dimensional intravascular ultrasounds (3D-IVUS) analyses were performed in 50 HTx recipients at 9.0±3.6 weeks after HTx and annually thereafter for 5 years. Sites at baseline with maximum intimal thickening≧0.5 mm of anterior descending artery (LAD) were defined as DL. Significant functional narrowing by IVUS was defined as %plaque area (plaque area/vessel area) &gt;40%. A mixed-model repeated-measures analysis was used. Results: DL was present in 54.0% in all recipients. In the first year after HTx, plaque volume significantly increased from 2.04±1.22 to 2.59±1.54 mm 3 /mm (p&lt;0.01) in recipients with DL. Furthermore, the increase of plaque volume during 1 year after HTx was significantly higher in recipients with DL (0.62±0.85 vs 0.16±0.50 mm 3 /mm, p=0.048). Vessel volume in recipients with DL were greater than without DL at 1 year after HTx (12.84±3.15 vs 10.84±2.78 mm 3 /mm, p=0.024). Thereafter, the vessel volume decreased in both groups during 5 years. Consequently, the incidence of functional narrowing up to 5 years was higher in recipients with DL than in without DL (66.7% vs 30.4%, p=0.001). Cox proportional hazard model showed that the presence of DL increased the risk of functional narrowing (hazard ratio:HR3.38, 95% confidence interval 1.35-8.45) after adjusting for donor age, donor sex and the level of high density lipoprotein at 1 year. Conclusions: The presence of DL influenced not only the increase of plaque volume during the first year but also the vessel remodeling during 5 years. Recipients with DL have a higher incidence of significant functional narrowing by IVUS.
Abstract 2250: Tumor mutational burden: Guidelines for derivation and robustness of measurement
Authors: Natalie Mola, Matthew Schu, Suzy Stiegelmeyer, Wendell Jones, Victor J. Weigman
Journal: Cancer Research (2018)

Abstract Tumor mutational burden (TMB) is defined as the number of somatic mutations per Mb of the genome and is used to represent accumulation of somatic mutations over the life of the tumor. Recent evidence has shown that high TMB scores are associated with improved response to immune therapies across multiple indications. However, the derivation of this score is not well characterized, nor is this score universally performed across laboratories. Here we describe our methodology for calculating TMB, which considers an estimation of true germline mutations, the efficacy of different somatic callers, and the identification of regions within a capture panel that most reliably contribute to robust TMB scoring. To accomplish this, we only include positions that fall within high confidence regions of the genome as defined by NIST GIAB datasets HG001-HG005 v3.3.2. The high confidence regions encompass 88% of the exome. Somatic variant calling is performed utilizing the tumor and normal samples using only positions where there is sufficient depth of coverage in both samples. Any remaining germline variants are excluded, leaving only somatic variants in the targeted, high-confidence regions for the final TMB calculation. TMB calculations utilizing high-confidence regions reduce the contribution of false positive variants in the mutational burden estimate. We have compared TMB scores using this approach to those provided from evaluating somatic calls from TCGA, where matched tumor/normal pairs exist. In addition, we introduce a method to determine the effect on TMB scores when in silico determination of germline variants is used to derive somatic calls when matching normal samples are not available. Defining the robustness of this score across and criteria for its derivation will help better position defining analytical range and future utility across indications and NGS panels Citation Format: Natalie Mola, Matthew Schu, Suzy Stiegelmeyer, Wendell Jones, Victor J. Weigman. Tumor mutational burden: Guidelines for derivation and robustness of measurement [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 2250.
Incidence and Prognostic Value of Early Repolarization Pattern in the 12-Lead Electrocardiogram
Authors: DaisukeHaruta, KiyotakaMatsuo, AkiraTsuneto, ShinichiroIchimaru, AyumiHida, NobukoSera, MisaImaizumi, EijiNakashima, KojiMaemura, MasazumiAkahoshi
Journal: Circulation (2011)

Background—Early repolarization pattern is a common ECG finding characterized by J-point elevation and QRS notching or slurring in the inferior and/or lateral leads, yet little is known about its incidence and long-term prognosis in Asian populations. Methods and Results—We reviewed all the ECG records of the 5976 atomic-bomb survivors who were examined at least once during our biennial health examination in Nagasaki, Japan, between July 1958 and December 2004. We defined early repolarization pattern as ≥0.1-mV elevation of the J point or ST segment, with notching or slurring in at least 2 inferior and/or lateral leads. We assessed unexpected, cardiac, and all-cause death risk by Cox analysis. We identified 1429 early repolarization pattern cases (779 incident cases) during follow-up, yielding a positive rate of 23.9% and an incidence rate of 715 per 100 000 person-years. Early repolarization pattern had an elevated risk of unexpected death (hazard ratio, 1.83; 95% confidence interval, 1.12 to 2.97; P=0.0...
Calculating Health Care Waste in Washington State
Authors: David L. Brown, Fiona Clement
Journal: JAMA Internal Medicine (2018)

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