tbuckley/cabot-search huggingface dataset:
Abstract 3498: Highly specific macrocyclic ATR inhibitors for the targeted treatment of a broad spectrum of cancers showing lack of anemia or neutropenia in pre-clinical animal models
Authors: Sahithi Pamarthy, Dansu Li, Ekaterine Goliadze, Tina Gill, Lanqi Jia, Erin George, Laura R. Butler, Ryan L. Ragland, Michel Afargan, Fiona A. Simpkins, Eric J. Brown, Oren Gilad
Journal: Cancer Research (2019)

Abstract Ataxia Telangiectasia and Rad3-related (ATR) and its downstream effector Checkpoint Kinase 1 (CHK1) are central to the protection of stalled replication forks.Specific targeting of the ATR is synthetically lethal with multiple cancer-associated changes including oncogenic stress and defects in the DDR pathway and represents an emerging strategy to treat a broad spectrum of cancers. Atrin Pharmaceuticals has rationally designed a novel series of conformationally constrained macrocyclic ATR inhibitors with higher potency and selectivity than other ATR inhibitors currently in clinical development. An in-depth characterization of the ATRN series identified ATRN-119 as our lead compound with an in vitro enzyme IC50 of 20 nM and inhibition of ATR substrate CHK1 Ser345 phosphorylation in cells at an IC50 of 5 nM. ATRN-119 inhibits ATR in cells at much lower concentrations and demonstrates higher selectivity (&amp;gt;2000) for ATR over other closely-related PIK-kinases like ATM, DNA-PK and mTOR. Additionally, ATRN series have favorable ADME properties with increased water solubility and metabolic stability in human serum of up to 4 hours. Oral dosing of ATRN-119 showed significant antitumor effects in human pancreatic and colon cancer xenografts and in orthotopic ovarian Patient Derived Xenograft (PDX) tumors. Notably, hematological analysis of mice treated with daily oral dosing of ATRN-119 indicated no thrombocytopenia, anemia or neutropenia up to 4 weeks of treatment. Exploratory multiple high dosing toxicity studies in rats and dogs indicate significant exposure and good tolerability with lack of anemia or neutropenia. In a series of in-vitro cell viability assays, three dimensional organoid cultures and in-vivo combinationstudies, ATRN-119 showed significant synergism with various PARP inhibitors as well as restoration of PARPi sensitivity in PARPi resistant tumors. Our data suggests a new generation of highly potent and selective ATR inhibitors with favorable safety profile and a broad clinical therapeutic potential either as monotherapy, in combination with PARP inhibitors or as a synthetic lethal approach with key DDR mutations. Citation Format: Sahithi Pamarthy, Dansu Li, Ekaterine Goliadze, Tina Gill, Lanqi Jia, Erin George, Laura R. Butler, Ryan L. Ragland, Michel Afargan, Fiona A. Simpkins, Eric J. Brown, Oren Gilad. Highly specific macrocyclic ATR inhibitors for the targeted treatment of a broad spectrum of cancers showing lack of anemia or neutropenia in pre-clinical animal models [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 3498.
Iatrogenic perforation during colonoscopy in the endoscopic suturing era: surgical emergency or endoscopic clinical practice?
Authors: Antonino Granata, Michele Amata, Alberto Martino, Dario Ligresti, Alessandro Tropea, Serio Calamia, Mario Traina
Journal: Endoscopy (2019)

A 46-year-old man with end-stage renal disease and a surgical history of three kidney transplants underwent colonoscopy to assess eligibility for retransplantation. Water exchange CO2-insufflated colonoscopy was performed under deep sedation.
Abstract LB-290: Telomere dysfunction is a driver of inflammatory bowel disease
Authors: Deepavali Chakravarti, Asha Multani, Prasenjit Dey, Baoli Hu, Di Zhao, Kyle Chang, Mao Xizeng, Guocan Wang, Christoper Terranova, Wen-ting Liao, Denise Spring, Pingping Hou, Jianhua Zhang, Pablo Okhuysen, Eduardo Vilar, Mary K. Estes, Sarah blutt, Alan Wang, Ronald DePinho
Journal: Cancer Research (2019)

Abstract The molecular instigators and therapeutic strategies for inflammatory bowel disease (IBD) are limited. Here, telomere dysfunction is shown to activate pAtm/c-Abl-mediated phosphorylation and stabilization of Yap1 up-regulates pro-IL-18 expression, a major pro-inflammatory factor in IBD. This signaling axis cooperates with gut microbiome which stimulates cytosolic receptors causing activation of caspase-1, which in turn cleaves pro-IL-18 into its mature IL-18 form. Epithelial-derived IL-18 leads to recruitment of IFNγ-secreting T cells and other immunocytes to provoke classical IBD pathology. Consistent with a role for DNA damage signaling as a driver of IBD, newly diagnosed IBD patient samples exhibited elevated expression of pγH2AX, YAP1, Caspase-1 and IL-18 along with significantly reduced telomere lengths compared to healthy tissue controls. Alleviation of IBD pathology can be achieved in mice via telomerase reactivation in intestinal epithelium or pharmacological inhibition of Atm, Yap1, or caspase-1 as well as antibiotic treatment - each intervention dramatically reducing pro-IL-18 cleavage and inflammation. Thus, telomere dysfunction-induced activation of the Atm-Yap1-pro-IL-18 pathway identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating several novel therapeutic strategies for disease interception and management. Note: This abstract was not presented at the meeting. Citation Format: Deepavali Chakravarti, Asha Multani, Prasenjit Dey, Baoli Hu, Di Zhao, Kyle Chang, Mao Xizeng, Guocan Wang, Christoper Terranova, Wen-ting Liao, Denise Spring, Pingping Hou, Jianhua Zhang, Pablo Okhuysen, Eduardo Vilar, Mary K. Estes, Sarah blutt, Alan Wang, Ronald DePinho. Telomere dysfunction is a driver of inflammatory bowel disease [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 LB-290.
RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance
Authors: Daniël A. Lionarons, David C. Hancock, Sareena Rana, Philip East, Christopher Moore, Miguel M. Murillo, Joana Carvalho, Bradley Spencer-Dene, Eleanor Herbert, Gordon Stamp, Djamil Damry, Dinis P. Calado, Ian Rosewell, Ralph Fritsch, Richard R. Neubig, Miriam Molina-Arcas, Julian Downward
Journal: Cancer Cell (2019)

RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.
Abstract 2328: Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York
Authors: Nicolas Robine, Fieke Froeling, Benjamin Hubert, Timothy Chu, Ashlea Chandler, Michael C. Zody, Dayna M. Oschwald, Harold E. Varmus, Charles Sawyers, David Tuveson
Journal: Cancer Research (2020)

Abstract Advances in sequencing technologies have revolutionized our approaches in medicine. However, our current knowledge about the molecular attributes of cancer has primarily been derived from patients of European descent. The overall aims of Polyethnic-1000 are to study the variability of somatic profiles and the effects of genetic ancestry on cancer biology and to bring genomic innovation to under-represented ethnic groups in the diverse patient population of New York City.A dynamic research platform is being created, involving the New York Genome Center, academic centers and partnering hospitals in the New York City region. In an initial retrospective study, the infrastructure, sample workflow, analysis and data sharing policies within the consortium have been developed. Whole-exome and RNA sequencing has been performed on 146 samples from self-identified non-white cancer patients treated at 14 different centers. Genetic ancestry estimation was performed at the super-population and population level using the 1000Genomes references. Data from over 24 tumor types were shared with our collaborators and the somatic variants were made available through our local installation of cBioPortal. Using the knowledge gained during the first stage, we are designing a prospective study to demonstrate our capacity to obtain samples from patients of varied ethnicities and to allow the formation of cohorts of interest for particular cancer types and particular ethnicities, with uniform consent for germline and somatic sequencing and return of results for potentially actionable mutations.By establishing a collaborative network, Polyethnic-1000 will deepen our understanding of the contributions that ethnicities make to the incidence and biology of cancers, potentially improving outcomes for patients who currently lack access to the most recent advances in medical science. Citation Format: Nicolas Robine, Fieke Froeling, Benjamin Hubert, Timothy Chu, Ashlea Chandler, Michael C. Zody, Dayna M. Oschwald, Harold E. Varmus, Charles Sawyers, David Tuveson. Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2328.
Abstract 16775: Severity Assessment of Transcatheter Aortic Valve Paravalvular Regurgitation: A New Approach Based on the Leakage Momentum Flux
Authors: Koohyar Vahidkhah, Mohammed S Barakat, Ali N Azadani
Journal: Circulation (2017)

Introduction: The circumferential extent (CE) of paravalvular regurgitation (PVR) is commonly used for semiquantitative evaluation of transcatheter aortic valve (TAV) PVR severity. This study point...
Abstract LB-252: Group-based smoking cessation treatment for incarcerated men: A pilot study
Authors: Pamela Valera, Nicholas Acuna
Journal: Cancer Research (2019)

Abstract Introduction. Cigarette smoking is the leading cause of morbidity and mortality that contributes to over six million deaths worldwide and is projected to cause more than eight million deaths per year by 2030. Overall cigarette smoking rates in the United States (U.S.) is estimated at 14%, but this number increases to 50-83% of smokers within correctional populations. Methods. Using a cohort study design, sixteen incarcerated male smokers from a Northeastern state maximum prison facility in the U.S. participated in a 4-week group-based smoking cessation treatment program with nicotine replacement therapy and a one-month follow-up period to determine quit behaviors and abstinence. The goal of this pilot study was to explore the feasibility, acceptability, and efficacy of a smoking cessation group treatment intervention for incarcerated smokers where tobacco products are permitted. Results. In this feasibility study, the average age of participants enrolled was 43 (SD = 13.69), and their first incarceration was at 19 (SD = 7.30). The majority of the participants identified as African American/Black (62.5%), 31.3% identified as Caucasian/White, and 6.3% identified as Hispanic/Latino as their race/ethnicity. The average age where individuals started smoking was 13.8 (SD = 3.2) and the total number of years smoked is 25.6 (SD = 14.9). The mean of cigarettes smoked each day was 13.0 (SD = 9.8). More than half of the people in the study indicated that they relight their cigarettes. Additionally, the two brands that participants indicated as their favorite were Kite (18.8%) and Newport (68.8%). Of all the participants, 87.5% indicated that they smoked menthol cigarettes. Majority of the participants indicated the importance of quitting tobacco (8.80 ± 1.82) and that they had a very difficult time during their previous quit attempts (43.8%). Previous quit attempts included forced abstinence while in solitary confinement or administrative segregation. At the 4-week follow up period, half of the participants that were enrolled in the group-based smoking cessation treatment and completed the program indicated that they did not smoke or use tobacco in the past 7-days or since their initial quit date (50.0%). Conclusion. Group-based smoking cessation treatment should be prioritized as an effective intervention to aid incarcerated smokers to quit smoking. This study builds upon our growing knowledge of tobacco dependence and smoking cessation treatment, with a focus on individuals involved in the criminal justice system. Citation Format: Pamela Valera, Nicholas Acuna. Group-based smoking cessation treatment for incarcerated men: A pilot study [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 LB-252.
Two-step endoscopic ultrasound-guided drainage of an isolated posterior bile duct because of an enlarged gallbladder
Authors: Junya Sato, Hirotoshi Ishiwatari, Tatsunori Satoh, Shinya Fujie, Junichi Kaneko, Hiroyuki Matsubayashi, Hiroyuki Ono
Journal: Endoscopy (2019)

An 83-year-old man with hilar cholangiocarcinoma who had undergone multiple metal stent placements for hilar biliary obstruction 15 months previously was admitted to our hospital for treatment of cholangitis. Contrast-enhanced computed tomography revealed dilatation of the right posterior duct, indicating that the isolated posterior duct was causing focal cholangitis.
Abstract 4133: The <i>in vitro</i> melanoma tumor microenvironment conditions macrophages to an immunosuppressive M2-like phenotype, which is reversible by oncolytic virus ORCA-010 with immune modulators
Authors: Ioanna E. Milenova, Rieneke van de Ven, Wenliang Dong, Victor W. van Beusechem, Tanja D. de Gruijl
Journal: Cancer Research (2019)

Abstract The melanoma tumor environment suppresses the immune reaction, favoring tumor escape from the immune system. This suppressive environment is in part sustained by tumor associated M2-like macrophages. In order to activate the immune system, one approach is macrophage-targeted therapies, that repolarize M2-like macrophages to M1-like macrophages. ORCA-010 is a potency enhanced, replication selective oncolytic adenovirus, with strong anti-tumor activity. As a model of macrophage polarization in the tumor microenvironment, human melanoma cell lines were co-cultured in vitro with CD14+ monocytes. The effects to induce M1-like macrophages by addition of lipopolysaccharide (LPS) and interferon (IFN)-gamma, JAK2 or p38 MAPK inhibitors combined with ORCA-010, was assessed in the co-cultures. Cell phenotypes were characterized by flow cytometry. Our data demonstrate that ORCA-010 significantly reduces M2-like macrophage marker CD163 on CD45+ cells in co-cultures, and increases co-stimulatory M1-like macrophage markers CD80 and CD86 expression on macrophages. CD80 is significantly up-regulated by ORCA-010 with LPS and IFN-gamma. Next, the macrophage polarizing effects of combining ORCA-010 with p38 MAPK and JAK2 inhibitors, known for their favorable myeloid M1 and dendritic cell skewing properties, were assessed in the melanoma co-cultures. The inhibitors JAK2 (AG490) and p38 MAPK (LY2228820) both significantly reduced CD163 levels, however did not induce increased CD80 and CD86 by themselves. Only when combining these with ORCA-010 did we observe a CD86 up-regulation. In a B16.OVA immunocompetent mouse model, ORCA-010 appeared to enhance recruitment of CD8+ T cells to the tumor. Interestingly, combining ORCA-010 with anti-PD-1 resulted in a significant increase of recruitment of CD8+ T cells at the tumor, which could be further enhanced by co-treatment with a p38 inhibitor. Our data suggest that ORCA-010 induces a repolarization of the M2-like macrophages to a favorable M1-like phenotype. This can be further enhanced by the combined administration of ORCA-010 with a TLR4 agonist and IFNγ, or with a JAK2 inhibitor. This work is supported by the European Union Horizon2020 ITN-EID grant 643130 “VIRION”. Citation Format: Ioanna E. Milenova, Rieneke van de Ven, Wenliang Dong, Victor W. van Beusechem, Tanja D. de Gruijl. The in vitro melanoma tumor microenvironment conditions macrophages to an immunosuppressive M2-like phenotype, which is reversible by oncolytic virus ORCA-010 with immune modulators [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 4133.
Abstract P014: Association Between Serum Resistin Levels and Coronary Artery Disease: A Meta-analysis
Authors: Pradyumna Agasthi, Sivakanth Aloor, Vivek Yarlagadda, Avantika Chenna, Vivek Menon, Kothandaraman Purushothaman
Journal: Circulation (2016)

Background: Resistin is a cysteine-rich peptide primarily secreted by inflammatory cells and adipocytes. Recent studies have linked resistin to metabolic syndrome and obesity. It is hypothesized that resistin promotes the expression of adhesion molecules on the vascular wall and induces smooth muscle cell proliferation contributing to coronary atherosclerosis. A meta-analysis was performed to evaluate the association between serum resistin levels and coronary artery disease (CAD). Methods: We searched MEDLINE, CINAHL and COCHRANE databases for studies reporting serum-resistin levels in the patients with CAD and healthy controls. Meta-analysis included case controls, cohort and cross-sectional studies. A calculation of weighted standardized mean difference (SMD) in serum resistin level between the CAD and control groups was conducted. Residual maximum likelihood (REML) metaregression was performed on age, body mass index (BMI) and sex covariates. Results: A literature search yielded 158 articles, but only 22 studies enrolling 8364 participants were included in the meta-analysis. The median age and BMI of the CAD group was 62 yrs.(IQR 56-64) and 27 kg/m 2 (IQR 26-30) versus 57 yrs.(IQR 51-62) and 26 kg/m 2 (IQR 24-30) in the control group. There were more females in the control group 41% (IQR 31-54) versus 31% (IQR 24-40) in CAD group. The unweighted median serum resistin levels in the CAD group were 9.6 ng/ml (IQR 6.1-15.6) versus 6.4 ng/ml (IQR 3.9-11.5) in the control group. The SMD of serum resistin level was 1.06 (95% CI 0.74-1.37), P &lt;0.001 comparing those in the CAD group and control group. None of the covariates (age, BMI and sex) accounted for statistical significance. Conclusion: An elevated serum resistin level is significantly and independently associated with presence of CAD. Further studies are needed to confirm this association by adjusting for potential confounders and evaluate the role of resistin in the risk stratifying patients with CAD.
Abstract 4626: Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216
Authors: Ching-Chuan Kuo, Weir-Torn Jiaang, Jing-Jim Ou, Chiung-Tong Chen, Shu-Ching Hsu, Chuan Shih, Li-Mei Lin, Manwu Sun, Yi-Hsin Wang, Zih-Ting Huang, Jang-Yang Chang, Shau-Hua Ueng
Journal: Cancer Research (2019)

Abstract Developing realistic preclinical models using clinical samples that reflect complex tumor biology is critical to advancing cancer research. Patient-derived preclinical tumor models are the optimal tool for understanding drug action patterns and resistance mechanisms. In order to improve the capability of drug R&amp;D in our institute (NHRI-IBPR), we have generated several patient-derived xenograft (PDX) models and characterized the genomic signature and responsiveness to standard-of-care (SOC) therapy. DBPR216, an orally bioavailable multikinase inhibitor, showed potent effect for treatment of gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML) through targeting of c-KIT and FLT-3, respectively. In order to further discover other indications of DBPR216 for clinical application, we investigated the anti-tumor effect of DBPR216 in several in-house PDX models. Among them, we found that DBPR216 was effectively to suppress PDX tumor growth in the immuno-deficient mice in two colorectal adenocarcinoma PDX models, C008 and C015. These PDX models showed similar genomic features with original tumor samples from patients when test using targeted sequencing of cancer related genes. To further identify if DBPR216 is superior to other kinase inhibitors and SOC therapy, we used in vitro PDX cell proliferation assay to quickly examine the anti-tumor effect of DBPR216 compared to a panel of therapeutic drugs. The result demonstrated that DBPR216 appeared to be superior in potency to kinase inhibitors (Regorafenib, Afatinib, Sunitinib, and Imatinib) and SOC therapy (Irinotecan, 5-FU, and Oxaliplatin). Combining the kinase profiling of DBPR216 and mutational analysis of C008 and C015 PDX models, we proposed that DDR2, FLT1, PDGFRα, PDGFRβ, RET, and SRC may be the potential targets of DBPR216 in these PDX models, and need further elucidation. Taken together, we found that DBPR216 exhibits potent anticancer effect against colorectal cancer and may bring the better opportunity than Regorafenib, a therapeutic agent for metastatic colorectal cancer in clinical. DBPR216 is now under preclinical development for further IND submission. Citation Format: Ching-Chuan Kuo, Weir-Torn Jiaang, Jing-Jim Ou, Chiung-Tong Chen, Shu-Ching Hsu, Chuan Shih, Li-Mei Lin, Manwu Sun, Yi-Hsin Wang, Zih-Ting Huang, Jang-Yang Chang, Shau-Hua Ueng. Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216 [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 4626.
Abstract 14865: Intravenous Injection of Liposome-Based Nanoparticles Containing a Novel Prostacyclin Analogue Selectively Targets Ischemia-Reperfused Myocardium to Enhance Angiogenesis and Functional Recovery in Rat
Authors: Shin Yajima, Shigeru Miyagawa, Satsuki Fukushima, Yoshiki Sakai, Akima Harada, Hiroko Iseoka, Motoko Shiozaki, Yuki Mori, Yoshichika Yoshioka, Yoshiki Sawa
Journal: Circulation (2016)

Introduction: Treatment for ischemia reperfusion (I/R) myocardial injury has not been fully established. Nanoparticles (NP) are proposed as an efficient drug delivery system for I/R organ injury. W...