tbuckley/cabot-search huggingface dataset:
A prospective, multi‐center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON‐IDA trial
Authors: Michael Auerbach, David Henry, Richard J. Derman, Maureen M. Achebe, Lars L. Thomsen, John Glaspy
Journal: American Journal of Hematology (2019)

Abstract Iron deficiency anemia (IDA) is prevalent, and intravenous iron, especially if given in a single dose, may result in better adherence compared with oral iron. The present trial (FERWON‐IDA) is part of the FERWON program with iron isomaltoside 1000/ferric derisomaltose (IIM), evaluating safety and efficacy of high dose IIM in IDA patients of mixed etiologies. This was a randomized, open‐label, comparative, multi‐center trial conducted in the USA. The IDA patients were randomized 2:1 to a single dose of 1000 mg IIM, or iron sucrose (IS) administered as 200 mg intravenous injections, up to five times. The co‐primary endpoints were adjudicated serious or severe hypersensitivity reactions, and change in hemoglobin from baseline to week eight. A total of 1512 patients were enrolled. The frequency of patients with serious or severe hypersensitivity reactions was 0.3% (95% confidence interval: 0.06;0.88) vs 0.4% (0.05;1.45) in the IIM and IS group, respectively. The co‐primary safety objective was met, and no risk difference was observed between groups. The co‐primary efficacy endpoint of non‐inferiority in hemoglobin change was met, and IIM led to a significantly more rapid hematological response in the first two weeks. The frequency of cardiovascular events was 0.8% and 1.2% in the IIM and IS group, respectively ( P = .570). The frequency of hypophosphatemia was low in both groups. Iron isomaltoside administered as 1000 mg resulted in a more rapid and more pronounced hematological response, compared with IS, which required multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions and cardiovascular events.
Abstract 391: Serine/threonine kinase LASK2 as a biomarker and therapeutic target for lung cancer
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Cancer Research (2019)

Abstract Since the number of lung cancer patients responding well to standard chemotherapies is still small, further development of new anti-cancer drugs with minimum risk of adverse effects and highly sensitive cancer biomarkers for precision medicine is eagerly required. We have been developing new molecular therapies targeting oncogenic proteins with their companion diagnostics by screening system as follows; i) To identify overexpressed genes in 120 lung cancers by our original gene expression profile database, ii) To confirm the candidate genes for their low expression in 23 normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering hundreds of non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth/invasion of cancer cells by siRNAs. During this process, we selected dozens of druggable oncoproteins with various enzymatic activities, and detected higher expression of serine/threonine kinase LASK2 (lung cancer-associated kinase 2) in the majority of various types of lung cancers, but scarce expression in normal tissues except testis. We further observed much higher expression patterns of LASK2 in brain metastasis as well as advanced primary lung tumors, compared to those in earlier-stage primary lung tumors. Immunohistochemical analysis using tissue microarray showed that strong LASK2 positivity was an independent prognostic factor for NSCLC (P&amp;lt;0.0001). Suppression of LASK2 expression with its siRNAs inhibited growth of lung cancer cells, whereas enhanced cellular proliferation by exogenous expression of LASK2 in mammalian cells also supported its oncogenic function in vitro and in mice model. Invasion of mammalian cells transfected with LASK2-expression vector through Matrigel was significantly enhanced, compared to the control cells transfected with mock or LASK2-kinase dead vector, suggesting that LASK2 could also contribute to the highly malignant phenotype of lung-cancer cells. Induction of LASK2 appeared to activate oncogenic signals for lung cancer such as phosphorylation of MAPK and PCNA. Our data indicate that LASK2 is a promising diagnostic biomarker and therapeutic target for developing precision medicine of lung cancer. Note: This abstract was not presented at the meeting. Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Serine/threonine kinase LASK2 as a biomarker and therapeutic target for 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 391.
Abstract 1260: Inhibition of DOG1, or TMEM16A, results in antitumoral effects in gastrointestinal stromal tumors (GIST) <i>in vitro</i>
Authors: Robin Fröbom, Erik Berglund, Robert Bränström
Journal: Cancer Research (2019)

Abstract DOG1/TMEM16A, over-expressed in &amp;gt;95% of all GISTs, is a calcium-activated chloride channel that has gained attention as a promising drug target due to its involvement in several tumor-physiological processes. Two well-established human GIST cell lines (GIST-T1 and GIST882) were used to study DOG1 inhibitors effect on viability, colony formation, and cell cycle. In this study, we show that specific DOG1/TMEM16A-inhibitors (T16inh-A01 and CaCCinh-A01) decrease chloride currents, and reduces cell viability in GIST cells. However, only CaCCinh-A01 changes the distribution of the cell cycle in GIST cells, putting them into G1 cell cycle arrest, and increases sub-G1 phase population in GIST882 cells. CaCCinh-A01 strongly reduces the colony forming ability of the cells, whereas limited effect by T16inh-A01. Conclusions: DOG1/TMEM16A inhibition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy. CaCCinh-A01 seems to be the more potent inhibitor, presumably due to its effect not only on chloride currents but also on DOG1/TMEM16A expression. Citation Format: Robin Fröbom, Erik Berglund, Robert Bränström. Inhibition of DOG1, or TMEM16A, results in antitumoral effects in gastrointestinal stromal tumors (GIST) in vitro [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 1260.
Abstract P326: Perceived Neighborhood Crime is Associated With Serum Cholesterol Levels Among Females, but Not Males: Santiago Longitudinal Study
Authors: Erin M Delker, Estela Blanco, Patricia East, Raquel Burrows, Jorge Delva, Sheila Gahagan
Journal: Circulation (2018)

Introduction: In a Chilean sample, adolescents’ CVD risk factors were associated with perceived neighborhood crime. To determine if this effect was sustained, we examined associations between adolescents’ perceived neighborhood crime and their serum cholesterol levels in young adulthood. Neighborhood stress has been cross-sectionally related to dyslipidemia in previous studies. Hypothesis: (1) Higher levels of perceived crime will be associated with higher low-density lipoprotein (LDL) cholesterol and lower high-density lipoprotein (HDL). (2) Sex will modify this association. Methods: Data were from adolescent (x =14 yrs) and young adult waves (x =22 yrs) of the Santiago Longitudinal Study (N=645). Perceived neighborhood crime was measured using three scale items about neighborhood drug use, muggings, burglaries and assaults. Crime was analyzed as a continuous and categorical variable. Fasting HDL and LDL cholesterol (mg/dL) were measured at 22 yrs. Associations between crime and HDL and LDL were analyzed by linear regression, adjusting for sex, age and SES. Effect modification by sex was tested with sex*crime interaction. Results: Participants were low-middle income and 55% female. Females perceived slightly more crime than males (F: x =9.1 M: x =8.8, p=0.30). There was a significant sex*crime interaction for HDL (p=0.03) and LDL (p=0.01). Among males, average HDL and LDL were 100±32 and 41±12; crime did not relate to either outcome. Among females, average HDL and LDL were 100±28 and 46±14; neighborhood crime was negatively associated with HDL and positively associated with LDL. For example, females reporting the most crime had, on average, 7.5 mm/dL lower HDL and 12.8 mm/dL higher LDL than females reporting the least amount of crime (Fig. 1). Conclusions: Perceived crime was prospectively associated with worse lipid profiles among females but not males. A sex-specific stress mechanism may be operating. Further study of the physiologic and behavioral mechanisms contributing to these findings is needed.
Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity
Authors: Nikolaos I Panousis, George K Bertsias, Halit Ongen, Irini Gergianaki, Maria G Tektonidou, Maria Trachana, Luciana Romano-Palumbo, Deborah Bielser, Cedric Howald, Cristina Pamfil, Antonis Fanouriakis, Despoina Kosmara, Argyro Repa, Prodromos Sidiropoulos, Emmanouil T Dermitzakis, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Objectives</h3> Systemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the molecular basis for its heterogeneity elusive. We explored the genomic basis for disease susceptibility and severity. <h3>Methods</h3> mRNA sequencing and genotyping in blood from 142 patients with SLE and 58 healthy volunteers. Abundances of cell types were assessed by CIBERSORT and cell-specific effects by interaction terms in linear models. Differentially expressed genes (DEGs) were used to train classifiers (linear discriminant analysis) of SLE versus healthy individuals in 80% of the dataset and were validated in the remaining 20% running 1000 iterations. Transcriptome/genotypes were integrated by expression-quantitative trail loci (eQTL) analysis; tissue-specific genetic causality was assessed by regulatory trait concordance (RTC). <h3>Results</h3> SLE has a 'susceptibility signature' present in patients in clinical remission, an 'activity signature' linked to genes that regulate immune cell metabolism, protein synthesis and proliferation, and a 'severity signature' best illustrated in active nephritis, enriched in druggable granulocyte and plasmablast/plasma–cell pathways. Patients with SLE have also perturbed mRNA splicing enriched in immune system and interferon signalling genes. A novel transcriptome index distinguished active versus inactive disease—but not low disease activity—and correlated with disease severity. DEGs discriminate SLE versus healthy individuals with median sensitivity 86% and specificity 92% suggesting a potential use in diagnostics. Combined eQTL analysis from the Genotype Tissue Expression (GTEx) project and SLE-associated genetic polymorphisms demonstrates that susceptibility variants may regulate gene expression in the blood but also in other tissues. <h3>Conclusion</h3> Specific gene networks confer susceptibility to SLE, activity and severity, and may facilitate personalised care.
Abstract 2904: Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer cell fate and behavior
Authors: Mingchuan Li, Jongdee Nopparat, Jiao Zhang, Byron J. Aguilar, Yan-Hua Chen, Jie Du, Xin Ai, Yong Luo, Yongguang Jiang, Christi Boykin, Qun Lu
Journal: Cancer Research (2019)

Abstract Only a small number of genes are bona fide oncogenes and tumor suppressors such as Ras, Myc, p53 and PTEN. However, targeting these cancer drivers frequently fail to demonstrate sustained cancer remission. Tumor heterogeneity and evolution contribute to cancer resistance and pose challenges for cancer therapy due to differential gene expression profiles driving distinct tumor responses to treatments. Here we report that intratumor heterogeneity of Wnt/β-catenin/armadillo modulator δ-catenin controls individual cell behavior to promote cancer. The differential intratumor subcellular localization of δ-catenin mirrors its compartmentalization in prostate cancer xenograft cultures as a result of mutation-rendered δ-catenin truncations. Wildtype and δ-catenin mutants displayed non-overlapping protein interactomes that highlight rewiring of signal networks. Localization specific δ-catenin mutants influenced p120ctn-dependent Rho GTPase phosphorylation and shifted cells towards bFGF-responsive growth, a known signal to bypass androgen receptor dependence. Mutant δ-catenin promoted Myc-induced prostate tumorigenesis by increasing proliferation over apoptosis as well as β-catenin stabilization and HIF-1α expression. Therefore, intratumor δ-catenin heterogeneity by genetic remodeling promotes prostate cancer expansion towards androgen independence, supporting a neomorphism model paradigm for targeting tumor progression. Citation Format: Mingchuan Li, Jongdee Nopparat, Jiao Zhang, Byron J. Aguilar, Yan-Hua Chen, Jie Du, Xin Ai, Yong Luo, Yongguang Jiang, Christi Boykin, Qun Lu. Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer cell fate and behavior [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 2904.
Association of Coronary Anatomical Complexity With Clinical Outcomes After Percutaneous or Surgical Revascularization in the Veterans Affairs Clinical Assessment Reporting and Tracking Program
Authors: Javier A. Valle, Thomas J. Glorioso, Rory Bricker, Anna E. Barón, Ehrin J. Armstrong, Deepak L. Bhatt, Sunil V. Rao, Mary E. Plomondon, Patrick W. Serruys, Arie P. Keppetein, Joseph F. Sabik, Ovidiu Dressler, Gregg W. Stone, Stephen W. Waldo
Journal: JAMA Cardiology (2019)

Anatomical scoring systems for coronary artery disease, such as the SYNTAX (Synergy Between Percutaneous Coronary Intervention [PCI] With Taxus and Cardiac Surgery) score, are well established tools for understanding patient risk. However, they are cumbersome to compute manually for large data sets, limiting their use across broad and varied cohorts.To adapt an anatomical scoring system for use with registry data, allowing facile and automatic calculation of scores and association with clinical outcomes among patients undergoing percutaneous or surgical revascularization.This cross-sectional observational cohort study involved procedures performed in all cardiac catheterization laboratories in the largest integrated health care system in the United States, the Veterans Affairs (VA) Healthcare System. Patients undergoing coronary angiography in the VA Healthcare System followed by percutaneous or surgical revascularization within 90 days were observed and data were analyzed from January 1, 2010, through September 30, 2017.An anatomical scoring system for coronary artery disease complexity before revascularization was simplified and adapted to data from the VA Clinical Assessment, Reporting, and Tracking Program. The adjusted association between quantified anatomical complexity and major adverse cardiovascular and cerebrovascular events (MACCEs), including death, myocardial infarction, stroke, and repeat revascularization, was assessed for patients undergoing percutaneous or surgical revascularization.A total of 50 226 patients (49 359 men [98.3%]; mean [SD] age, 66 [9] years) underwent revascularization during the study period, with 34 322 undergoing PCI and 15 904 undergoing coronary artery bypass grafting (CABG). After adjustment, the highest tertile of anatomical complexity was associated with increased hazard of MACCEs (adjusted hazard ratio [HR], 2.12; 95% CI, 2.01-2.23). In contrast, the highest tertile of anatomical complexity among patients undergoing CABG was not independently associated with overall MACCEs (adjusted HR, 1.04; 95% CI, 0.92-1.17), and only repeat revascularization was associated with increasing complexity (adjusted HR, 1.34; 95% CI, 1.06-1.70) in this subgroup.These findings suggest that an automatically computed score assessing anatomical complexity can be used to assess longitudinal risk for patients undergoing revascularization. This simplified scoring system appears to be an alternative tool for understanding longitudinal risk across large data sets.
Abstract 14304: Left Atrial Scar Does Not Correlate With Hystory of Stroke: Results From a Prospective Study
Authors: Luigi Di Biase, Pasquale Santangeli, Prasant Mohanty, J. David Burkhardt, Javier Sanchez, Rodney Horton, Rong Bai, Sanghamitra Mohanty, Chintan Trivedi, Dhanunjay Lakkireddy, Madhu Reddy, Francesco Santoro, Richard Hongo, Salwa Beheiry, Claude S Elayi, Viles Gonzalez Juan F, Steven Hao, Robert A Schweikert, Jason Zagrodzky, Andrea Natale
Journal: Circulation (2013)

INTRODUCTION: Atrial fibrillation increases the risk of stroke. Recently DE-MRI detection of left atrial fibrosis has been associated with prior history of strokes. We sought to determine the assoc...
Abstract 4673: DCLK1 promotes hepatocellular carcinoma via atypical β-catenin-regulated signaling and immune suppression
Authors: Naushad Ali, Parthasarathy Chandrakesan, Michael S. Bronze, Courtney W. Houchen
Journal: Cancer Research (2019)

Abstract Introduction: Genetic lineage tracing in mouse model has revealed that mature hepatocytes are the cell of origin of injury-induced hepatocellular carcinoma (HCC), the second most common cause of cancer-related deaths worldwide. Hepatocyte plasticity, defined as the ability to change cellular identity, plays a critical role in the repair process following liver injury. Inflammatory liver diseases often lead to cirrhosis and HCC. The molecular mechanisms that regulate the decision between hepatocyte injury repair and neoplastic initiation are unclear. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated kinase, is expressed during liver injury, cirrhosis, and HCC, but not in normal liver. Here, we demonstrate a novel mechanism by which DCLK1 regulates injury-associated hepatocyte plasticity and immunosuppression in HCC. Methods: Cell culture, DEN/CCl4-induced injury in mouse livers, and humanized mouse model were used for analyzing hepatocyte plasticity and DCLK1+ cells-induced changes in hepatic cells and macrophages. Results: DCLK1-overexpressing primary human hepatocytes formed spheroids in 3D culture. DCLK1-overexpressing hepatoma cells exhibited a 48-kDa active β-catenin with preserved hypophosphorylated N-terminus, which interacted with TCF-4, resulting in enhanced luciferase reporter activity and cyclin D1 expression. Downregulation of DCLK1 using siRNAs inhibited expression of this β-catenin fragment. DCLK1 overexpression increased phosphorylation of GSK-3β at Ser9, thus preventing its complete proteasomal degradation. Liver tissues from patients with cirrhosis and HCC expressed the 48-kDa active β-catenin, DCLK1, cyclin D1, and 80-kDa E-cadherin ectodomain, suggesting a change in epithelial polarity. DCLK1-overexpressing primary human hepatocytes transplanted into FRG mice demonstrated β-catenin activation in the transplanted hepatocytes. Injury-induced DCLK1+ epithelial cells in mouse livers expressed PD-L1. DCLK1+ human hepatoma cells induced CD206 in macrophages in a dual co-culture assay. Conclusions: DCLK1 enhances hepatocyte plasticity, clonogenicity, and tumorigenic signaling via atypical β-catenin-dependent mechanism. DCLK1+ cells show ability to suppress the host anti-tumor immunity by expressing PD-L1 and inducing macrophage polarization. Citation Format: Naushad Ali, Parthasarathy Chandrakesan, Michael S. Bronze, Courtney W. Houchen. DCLK1 promotes hepatocellular carcinoma via atypical β-catenin-regulated signaling and immune suppression [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 4673.
Abstract 13772: Cardiac-Specific Over Expression of Caveolin-3 Protects from Diabetic Cardiomyopathy
Authors: Alice E Zemljic-Harpf, Cameron J Finley, Sarah E Kellerhals, Heidi N Fiedolfsson, Michael Y Migita, Mathivadhani Panneerselvam, Ingrid R Niesman, Sameh S Ali, David M Roth, Hemal H Patel
Journal: Circulation (2012)

Diabetes is a worldwide epidemic currently affecting 366 million people. Diabetic cardiomyopathy is evident as ventricular dysfunction without coronary artery disease or hypertension. Caveolae are ...
Abstract 219: The potential benefit of lower drug-antibody ratio (DAR) on antibody-maytansinoid conjugate <i>in vivo</i> efficacy
Authors: Kerstin W. Sinkevicius, Leanne Lanieri, Jenny Lee, Steven Boule, Nicholas C. Yoder, Stuart W. Hicks, Jan Pinkas, Jose F. Ponte, Richard J. Gregory
Journal: Cancer Research (2019)

Abstract The majority of antibody-drug conjugates (ADCs) with maytansinoid payloads in development are linked via lysine residues and target an average drug-antibody ratio (DAR) of 3.5. These ADCs demonstrate substantial preclinical potency while maintaining good biophysical and pharmacological properties. However, some targets are expressed in normal tissues at levels that result in target-mediated drug disposition (TMDD), which can impact systemic and tumor ADC exposure and tumor penetration. For targets with TMDD, lowering the DAR of the ADCs may be advantageous. Since ADC tolerability is generally determined by the payload dose, lower DAR ADCs can be dosed at a higher antibody concentration, resulting in an increased conjugate exposure which may improve efficacy by saturating TMDD and/or increasing tumor delivery and penetration of the conjugate. In preclinical cell line xenograft studies, lysine-conjugated 2.0 and 3.5 DAR ADCs had comparable efficacy when dosed by payload concentration. However, the effect of TMDD cannot be captured with these models because the antibody in the ADCs does not cross-react with murine target antigen expressed on normal tissues. To supplement our understanding of the factors that influence ADC activity, we generated a cross-reactive model system that utilizes a chimeric anti-murine folate receptor α (FRα) antibody that binds with similar affinity to mouse and human FRα. Using this cross-reactive system, where the target is also expressed in normal tissues, 2.0 DAR conjugates were more efficacious than 3.5 DAR conjugates when dosed at matched payload concentrations in multiple xenograft models, suggesting that lower DAR can be an effective strategy to compensate for TMDD. Additional studies using xenograft models with varying antigen expression levels are ongoing, and studies designed to assess different conjugation methods of generating lower DAR ADCs are planned. This work highlights some of the many factors that impact ADC activity and demonstrates that the DAR of an ADC should be optimized for each target. Citation Format: Kerstin W. Sinkevicius, Leanne Lanieri, Jenny Lee, Steven Boule, Nicholas C. Yoder, Stuart W. Hicks, Jan Pinkas, Jose F. Ponte, Richard J. Gregory. The potential benefit of lower drug-antibody ratio (DAR) on antibody-maytansinoid conjugate in vivo efficacy [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 219.
Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab
Authors: Takaaki Maekawa, Shoichiro Kato, Toshikuni Kawamura, Kohei Takada, Takehiro Sone, Hiraku Ogata, Keita Saito, Takuya Izumi, Shigeki Nagao, Kosuke Takano, Yosuke Okada, Noriaki Tachi, Masahiro Teramoto, Toshikatsu Horiuchi, Reina Hikota-Saga, Kaori Endo-Umeda, Shigeyuki Uno, Yukiko Osawa, Ayako Kobayashi, Shinichi Kobayashi, Ken Sato, Michihiro Hashimoto, Shinya Suzu, Kensuke Usuki, Soji Morishita, Marito Araki, Makoto Makishima, Norio Komatsu, Fumihiko Kimura
Journal: Blood (2019)