tbuckley/cabot-search huggingface dataset:
Abstract 2368: Risk factors of pancreatic cancer in Vietnam: A matched case-control hospital-based study
Authors: Tu V. Dao, Thuan V. Tran, Dung K. Nguyen, Oanh T. Bui, Quang T. Nguyen, Huong T. Tran
Journal: Cancer Research (2020)

Abstract Background: Data about the risk factors and cancer types in developing countries remains limited. We investigate for the first time the role of a number of risk factors (family cancer history, smoking, alcohol consumption, diabetes, hypertension) associated with pancreatic cancer among Vietnamese patients. Methods: Patients hospitalized at 4 hospitals (K, Bach Mai, Viet Duc, Thai Nguyen) and diagnosed with pancreatic cancer (confirmed by histopathology and/or MRI/CT scan) in the period from January 2017 to May 2019 were included in the study. Some risk factors of the patients were collected and compared with a healthy age- and gender-matched (1:1) control group. Results: We have identified 196 patients with diagnosis of pancreatic cancer of which 114 males and 82 females. The average age of the patient at the time of diagnosis was 58.28 years (standard deviation of 12.94, ranging from 25 to 87). A positive family history, smoking and hypertension disease of pancreatic cancer significantly reduced the risk (OR and 95% CI were 0.06 [0.02 - 0.18], 0.53 [0.27 - 1.00], 0.1 [0.04 - 0.25], respectively). A past or present history of diabetes significantly increased the cancer risk (OR = 2.76 [1.34 - 6.05]), especially in female (OR = 5.68 [1.49 - 28.69]). Current alcohol drinkers showed a significantly increased risk of pancreatic cancer (OR = 2.23 [1.20 - 4.25]). Conclusions: Our finding showed that diabetes significantly increased the risk of pancreatic cancer in Vietnam, especially in women. An alcohol intake habit also increased the risk of pancreatic cancer. Further studies are required for fully understood the other risk factors related to this type of cancer. Citation Format: Tu V. Dao, Thuan V. Tran, Dung K. Nguyen, Oanh T. Bui, Quang T. Nguyen, Huong T. Tran. Risk factors of pancreatic cancer in Vietnam: A matched case-control hospital-based study [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 2368.
Abstract 89: Role of CDK8 and CDK19 in STAT1 phosphorylation at serine 727
Authors: Jing Li, Jiaxin Liang, Lili Wang, Eugenia Broude, Igor Roninson, Mengqian Chen
Journal: Cancer Research (2020)

Abstract Transcription factor STAT1 is part of the JAK/STAT signaling cascade; it plays an essential role in mediating responses to interferons (IFN). STAT1 modulates many cellular processes and has been implicated in both tumor-suppressing and tumor-promoting activities. IFNγ treatment induces STAT1 phosphorylation at tyrosine 701, enabling the translocation of STAT1 from cytoplasm to the nucleus. STAT1 is also phosphorylated at serine 727; S727 phosphorylation modulates the transcriptional activity of STAT1. Transcription-regulating kinase CDK8 was shown to be primarily responsible for IFNγ-induced STAT1 S727 phosphorylation, and serine-phosphorylated form of STAT1 was proposed as a potential pharmacodynamic (PD) marker for the activity of CDK8, an emerging cancer drug target. However, the role of CDK8 in STAT1 S727 phosphorylation in the absence of IFNγ treatment is controversial, as is the role of CDK19, a closely related paralog of CDK8, as well as the relative contributions of kinase-dependent and kinase-independent activities of CDK8 and CDK19. We have found that Senexin B, a selective CDK8/19 inhibitor, decreased both IFNγ-induced and basal STAT1 S727 phosphorylation in all the tested types of tumor cells but some phosphorylation was maintained even at the highest concentrations of Senexin B. We then generated a series of derivatives of human 293 cells with CRISPR-mediated knockout of CDK8, CDK19 and both CDK8 and CDK19 (double knockout, dKO), with subsequent reconstitution of dKO with wild-type (WT) CDK8 or CDK19 or with kinase-dead (KD) mutants of these proteins. The knockout of CDK8 or CDK19 individually had only a moderate effect on IFNγ-induced and basal STAT1 S727 phosphorylation, which remained susceptible to Senexin B. In contrast, such phosphorylation was strongly decreased in dKO cells, where it was unaffected by Senexin B. Senexin B-sensitive STAT1 S727 phosphorylation was restored by re-introduction of WT CDK8 or CDK19 but not of their KD mutants. Hence, both CDK8 and CDK19 mediate STAT1 S727 phosphorylation in kinase-dependent manner. We also tested different cytokines and stress-inducing agents for the ability to induce STAT1 S727 phosphorylation in WT and dKO cells. Several treatments, including serum stimulation, EGF, TNFα, etoposide and taxol, increased this phosphorylation in dKO cells, indicating that STAT1 serine phosphorylation induced by many treatments was CDK8/19-independent. Hence, great caution needs to be utilized in using STAT1 S727 phosphorylation as a PD marker for CDK8 activity. Citation Format: Jing Li, Jiaxin Liang, Lili Wang, Eugenia Broude, Igor Roninson, Mengqian Chen. Role of CDK8 and CDK19 in STAT1 phosphorylation at serine 727 [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 89.
Hemodynamic Response to Treatment and Outcomes in Pulmonary Hypertension Associated With Interstitial Lung Disease Versus Pulmonary Arterial Hypertension in Systemic Sclerosis: Data From a Study Identifying Prognostic Factors in Pulmonary Hypertension Associated With Interstitial Lung Disease
Authors: Louis Chauvelot, Delphine Gamondes, Julien Berthiller, Ana Nieves, Sébastien Renard, Judith Catella‐Chatron, Kais Ahmad, Laurent Bertoletti, Boubou Camara, Emmanuel Gomez, David Launay, David Montani, Jean‐François Mornex, Grégoire Prévot, Olivier Sanchez, Anne‐Marie Schott, Fabien Subtil, Julie Traclet, Ségolène Turquier, Sabrina Zeghmar, Gilbert Habib, Martine Reynaud‐Gaubert, Marc Humbert, Vincent Cottin
Journal: Arthritis & Rheumatology (2020)

Patients with systemic sclerosis and both pulmonary hypertension and interstitial lung disease (SSc-PH-ILD) generally carry a worse prognosis than patients with SSc and pulmonary arterial hypertension (SSc-PAH) without ILD. There is no evidence of the efficacy of PAH therapies in SSc-PH-ILD. We undertook this study to compare survival of and response to treatment in patients with SSc-PH-ILD and those with SSc-PAH.We analyzed 128 patients (66 with SSc-PH-ILD and 62 with SSc-PAH) from 15 centers, in whom PH was diagnosed by right-sided heart catheterization; they were prospectively included in the PH registry. All patients received PAH-specific therapy. Computed tomography of the chest was used to confirm or exclude ILD.At baseline, patients with SSc-PH-ILD had less severe hemodynamic impairment than those with SSc-PAH (pulmonary vascular resistance 5.7 Wood units versus 8.7 Wood units; P = 0.0005) and lower diffusing capacity for carbon monoxide (median 25% [interquartile range (IQR) 18%, 35%] versus 40% [IQR 31%, 51%]; P = 0.0005). Additionally, patients with SSc-PH-ILD had increased mortality (8.1% at 1 year, 21.2% at 2 years, and 41.5% at 3 years) compared to those with SSc-PAH (4.1%, 8.7%, and 21.4%, respectively; P = 0.04). Upon treatment with PAH-targeted therapy, no improvement in the 6-minute walk distance was observed in either group. Improvement in the World Health Organization functional class was observed less frequently in patients with SSc-ILD-PH compared to those with SSc-PAH (13.6% versus 33.3%; P = 0.02). Hemodynamics improved similarly in both groups.ILD confers a worse prognosis to SSc-PH. Response to PAH-specific therapy is clinically poor in SSc-PH-ILD but was not found to be hemodynamically different from the response observed in SSc-PAH.
Abstract 1444: c-FLIP antagonizes the survival of extracellular matrix detached cancer cells
Authors: Matyas Abel Tsegaye, Kyle McGeehan, Mati Nemera, Zachary T. Schafer
Journal: Cancer Research (2020)

Abstract The metastasis of cancer cells to distant sites accounts for over 90% of cancer related deaths. In order to metastasize, cancer cells must be able to survive during extracellular matrix (ECM) detachment, namely by blocking anoikis – caspase dependent cell death – and restoring metabolic deficiencies. Such barriers during tumorigenesis are abrogated through activation of oncogenes, and/or inhibition of tumor suppressors. Elucidating the signaling pathways involved in cancer cell metastasis is a crucial step in designing effective therapeutic interventions. Surprisingly, our investigation has revealed that cellular FLICE-like Inhibitory Protein (c-FLIP), a protein known for its anti-apoptotic function, antagonizes the survival of ECM-detached cancer cells. Additionally, we demonstrated that oncogenic signaling results in the downregulation of c-FLIP expression further suggesting that cancer cells can benefit from diminished FLIP levels. We observed that this repression of c-FLIP expression is a consequence of MEK-ERK signaling. Our study also suggests that the mechanism underlying this paradoxical c-FLIP pathway involves the induction of β-catenin degradation through inhibition of GSK-3β phosphorylation by p38 MAPK. This results in the ubiquitination and subsequent degradation of β-catenin which could contribute to reduced proliferation and migration. Citation Format: Matyas Abel Tsegaye, Kyle McGeehan, Mati Nemera, Zachary T. Schafer. c-FLIP antagonizes the survival of extracellular matrix detached cancer cells [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 1444.
10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial
Authors: Courtney D DiNardo, Abhishek Maiti, Caitlin R Rausch, Naveen Pemmaraju, Kiran Naqvi, Naval G Daver, Tapan M Kadia, Gautam Borthakur, Maro Ohanian, Yesid Alvarado, Ghayas C Issa, Guillermo Montalban-Bravo, Nicholas J Short, Musa Yilmaz, Prithviraj Bose, Elias J Jabbour, Koichi Takahashi, Jan A Burger, Guillermo Garcia-Manero, Nitin Jain, Steven M Kornblau, Philip A Thompson, Zeev Estrov, Lucia Masarova, Koji Sasaki, Srdan Verstovsek, Alessandra Ferrajoli, William G Weirda, Sa A Wang, Sergej Konoplev, Zhining Chen, Sherry A Pierce, Jing Ning, Wei Qiao, Farhad Ravandi, Michael Andreeff, John S Welch, Hagop M Kantarjian, Marina Y Konopleva
Journal: The Lancet Haematology (2020)
Abstract 4113: Discriminatory 11-plex assay designed to monitor estrogen receptor mutations using a novel, melt-analysis capable digital PCR platform
Authors: Jennifer N. Bernier, Johanna E. Takach, Tiffany Wang, Steve Gallagher, Robert Lin, Andrew Zayac, Paul Hung, Matthew Lesho, Douglas Whitman
Journal: Cancer Research (2020)

Abstract In a large fraction of ER+/HER2- metastatic breast cancer (MBC) patients, treatment with aromatase inhibitors fails due to emerging resistance. A key mechanism of this resistance is associated with a limited set of missense mutations in the gene encoding for the estrogen receptor (ESR1). These mutations are primarily found in the ligand binding domain of the protein. They result in a constitutively active estrogen receptor, are infrequently found in primary tumors (&amp;lt;5%) and instead likely coincide with the emergence of an endocrine resistant phenotype. The occurrence of ESR1 mutations following treatment has varied from study to study depending on patient selection and method of detection, but prevalence may be as high as 50%. Because these patients require second line therapies as soon as possible, ESR1 mutations are an area of intense focus in research and clinical trials for ER+/HER2- breast cancer. Studies utilizing droplet digital PCR (ddPCR) assays have correlated an increase of ESR1 mutations in patient liquid biopsy samples with therapeutic resistance approximately 8 months prior to conventional methods, however the number of individual mutations evaluated in these studies was limited due to an inability to accurately and sensitively identify more than one individual mutated SNP allele within a single reaction. We have developed a multiplex digital PCR assay that utilizes melt-based probes to detect and discriminate between 10 unique, clinically relevant ESR1 mutations in circulating tumor DNA (ctDNA) samples while simultaneously quantifying total cell-free DNA (cfDNA). Designed for use with an innovative, array-based dPCR system, the assay requires a hands-on time of only 10-15 minutes and a total run time of 2.5 hours. This assay will allow breast cancer researchers to further refine our understanding of the role ESR1 mutations play in personalized treatment strategies for MBC. Citation Format: Jennifer N. Bernier, Johanna E. Takach, Tiffany Wang, Steve Gallagher, Robert Lin, Andrew Zayac, Paul Hung, Matthew Lesho, Douglas Whitman. Discriminatory 11-plex assay designed to monitor estrogen receptor mutations using a novel, melt-analysis capable digital PCR platform [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 4113.
Abstract 6237: Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis
Authors: Yimin Niu, Cuicui Gao, Hongbin Yang, Qiang Huo, Andrew Wang, Ming Xu, Yang Liu
Journal: Cancer Research (2020)

Abstract Background: Protein drugs are one of the most promising new areas in drug research and development, however, great challenges are still faced in the drug delivery in vivo. Previously, we constructed bone targeted micelles for bone metastases. In order to address the issues of protein delivery in vivo and enhanced cancer bone metastasis treatment, we engineered and evaluated a bone-targeting nanoparticles by using metal organic framework nanoparticles (MOFs), bone-targeting agents (Alendronate) and hyaluronic acid (HA) as materials and a protein toxin as therapeutic. Methods: Alendronate (ALN) were conjugated to HA through PEG as linker and ALN-PEG-HA were obtained. Cytochrome C, as modle proteins, were caged in the MOFs (ZIF-8) by selfassembly of Zn2+ and organic ligands (2-methylimidazole) to form protein-encapsulated nanoparticles (ZIF8-CC). And ALN-PEG-HA were further decorated on the surface of ZIF8-CC nanoparticles via the coordination effect between its carboxyls and metal ions in ZIF-8 to result in active-targeting ALN-HA@ZIF8-CC nanopartilces. The materials and nanoparticles were synthesized and characterized by NMR, FT-IR, TEM, DLS, XRD, TGA and N2 adsorption−desorption isotherms analysis. The in vitro release profiles, stability and cytocompatibility were also studied. Results: The synthesis of ALN-PEG-HA was confirmed by 1H-NMR and FT-IR. TEM, XRD and DLS showed that ALN-HA@ZIF8-CC nanopartilces had been prepared, and the experiment of washing nanoparticles with SDS confirmed that protein was encapsulated in ZIF-8 instead of adsorbed on its surface. TGA and N2 absorption-degradation isotherms analysis also confirmed the formation of the crystal structure and porous structure, respectively. HA coated nanoparticles have good stability while ZIF8-CC were easy to aggregate. The results of in vitro release showed that the nanoparticles have acid sensitive release properties and excellent cell compatibility. In addition, In vitro bone fragment targeting experiment confirmed that nanoparticles have strong bone affinity. Conclusions: Our data demonstrated that bone-targeted protein drug-encapsulated MOFs were constructed. Citation Format: Yimin Niu, Cuicui Gao, Hongbin Yang, Qiang Huo, Andrew Wang, Ming Xu, Yang Liu. Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis [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 6237.
Abstract LB-178: Identification of DNA 5hmC decision signature biomarkers for azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk AML
Authors: Dali HAN, Wei Zhang
Journal: Cancer Research (2020)

Abstract DNA 5hmC biomarkers to predict the outcomes to the of azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy for patients with high-risk AML. Azacitidine (AZA), a DNA methyltransferase inhibitor and epigenetic modulator, has been combined with chemotherapy to treat high-risk AML patients for better clinical outcomes. However, the complete remission (CR) rate and prognosis remains unsatisfactory. Here, we proposed that the use of AZA for high-risk AML patients helped to sensitize leukemia cells to chemotherapy. We analyzed 45 high-risk AML patients who had received AZA treatment followed by High-dose cytarabine and mitoxantrone (AZA-HiDAC-Mito) therapy. We performed RNA-Seq and DNA 5hmC-Seq on available RNA/DNA samples. By comparing differential expressed genes between patients responded to therapy (CR or CRi, responder) and those did not (non-responder), we found that patients with better response had lower expression on ephrin receptor gene and AR pathway related genes. Using XGBoost machine learning model, we developed an 11-gene-5hmC signature to predict treatment outcomes, and it achieved 87.76% sensitivity and 87.10% specificity (AUC=0.911). The signature was also capable of distinguishing which patients would have better response to HiDAC-Mito only treatment, indicating that the signature had a potential to serve as a general predictor for intensive chemotherapy. Our findings show that DNA 5hmC patterns could be used as the prognostic biomarker for AZA-HiDAC-Mito therapy, which could guide further biomarker-based clinical trials. Citation Format: Dali HAN, Wei Zhang. Identification of DNA 5hmC decision signature biomarkers for azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk AML [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 LB-178.
Autoimmune Endocrinopathies: An Emerging Complication of Immune Checkpoint Inhibitors
Authors: Zoe Quandt, Arabella Young, Ana Luisa Perdigoto, Kevan C. Herold, Mark S. Anderson
Journal: Annual Review of Medicine (2020)

Immune checkpoint inhibitors (CPIs) reverse immune suppression that is thought to allow malignant growth. Despite remarkable efficacy in a subset of cancers, their use is accompanied by immune-related adverse events, including endocrinopathies such as hypophysitis, thyroid dysfunction, diabetes, and adrenalitis. These conditions are heterogenous, with differing incidence across CPI types, but are unified by the acuity and extremity of tissue-specific organ failure. Their occurrence may be associated with beneficial tumor control. Further understanding of the risk factors and mechanisms of these endocrine immunotoxicities can help optimize CPI use as well as improve understanding of spontaneous autoimmune diseases.
Abstract 371: A reporter mouse model enabling image-based evaluation of CD8+T cell dynamics in immunocompetent allografts
Authors: Bosong Zhao, Dan Feng, Haiyan Zhu, Lei Ci, Zhipeng Wan, Ruilin Sun
Journal: Cancer Research (2020)

Abstract Immune cell recruitment to tumors is indispensable for the success of immunotherapy. In vivo bioluminescence imaging technology to visualize the location and functionality of immune cells is of great value for immuno-oncology research. Here, we describe the generation of a genetically engineered mouse model “Tluc” in whichall CD8+T cells constitutively express a novel luciferase reporter Akaluc. On the C57/BL6 background, the IRES-Akaluc-EGFP expression cassette was placed downstream of the translation stop codon of the endogenous Cd8a gene, allowing the bioluminescence imaging of CD8+T cell location and function under physiological and pathological conditions. As expected, the engineered mice showed constitutive luciferase expression in lymphoid organs such as thymus, lymph nodes and spleen under normal conditions. We next modeled the T cell dynamics in the context of tumor transplantation. In the case of subcutaneously implanted mouse cancer cells such as MC38 colon cancer cells and antigenic SIY-expressing B16 melanoma cells (but not the regular B16 cells), the reporter mice showed T cell recruitment and infiltration into the tumor mass. This apparent immune response was consistent with the simulation. Our study underscores the utilities of such reporter mice for uncovering the role of immune cells in tumor responses by revealing dynamics, interactions and distribution of various immune cells in tumor settings. Citation Format: Bosong Zhao, Dan Feng, Haiyan Zhu, Lei Ci, Zhipeng Wan, Ruilin Sun. A reporter mouse model enabling image-based evaluation of CD8+T cell dynamics in immunocompetent allografts [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 371.
Squamous Cell Carcinoma of Bladder Diverticulum with Initial Symptoms Produced by Metastasis to Maxillary Sinus
Authors: Akihito Nanbu, Taiji Tsukamoto, Yoshiaki Kumamoto, Masaharu Aoki, Takaoki Hirose, Koji Asakura, Akikatsu Kataura
Journal: European Urology (1988)