tbuckley/cabot-search huggingface dataset:
Abstract 1447: Elucidating the mechanism of Dock7-mediated cellular transformation
Authors: Oriana Y. Teran Pumar, Kristin F. Wilson, Richard A. Cerione
Journal: Cancer Research (2020)

Abstract Akt is a serine/threonine protein kinase that receives signals from a plethora of external and internal stimuli in order to promote survival and regulate cellular growth and metabolism. Akt is part of the highly conserved PI3K/Akt signaling axis and is classically regulated by its interaction with the phosphoinositide, PIP3, and its subsequent phosphorylation at S473 and S308 by the mTOR complex 2 (mTORC2) and 3-Phosphoinositide-dependent protein kinase 1 (PDK1), respectively. Altered Akt activity has been linked to numerous diseases, such as cancer, diabetes and neurodegenerative diseases. Specifically, PI3K/Akt deregulation occurs in approximately one third of human cancers and ~40% of breast cancers. My research focuses on Dock7, a Guanine Nucleotide Exchange Factor (GEF) for the small GTPases Cdc42 and Rac1, and a novel player in the regulation of Akt activity and stability. Dock7 belongs to the Dock family of atypical GEFs and contains two evolutionarily conserved domains, DHR1 (a putative lipid binding domain) and DHR2 (the catalytic GEF domain). The expression level of Dock7 correlates with an unfavorable prognosis in liver cancer patients, and it is highly expressed in triple-negative breast cancers. Studies in our laboratory showed Dock7 is essential for the transformed properties of several cancer cell lines, and that it interacts with Akt in co-immunoprecipitation assays. In order to decipher the mechanism by which Dock7 mediates transformation, I created a Crispr-Cas9 Dock7 Knock-out HeLa cell line. I proceeded to confirm that these cells are not able to grow in an anchorage independent manner nor in serum free conditions, two hallmarks of transformation. Furthermore, in comparison to the phosphorylation status of Akt in parental HeLa cells, I found that in Dock7 KO HeLa cells, Akt is not phosphorylated at the S473 site in the absence of growth factors, indicative of lower basal activity. Accordingly, phosphorylation of downstream effectors of Akt is also downregulated. Besides promoting the phosphorylation state of Akt, Dock7 plays a role in the stability of the Akt protein during certain cellular stresses, highlighting a versatile and important role for Dock7 in Akt regulation and a potential target for therapeutic intervention in tumors where Akt is deregulated. Citation Format: Oriana Y. Teran Pumar, Kristin F. Wilson, Richard A. Cerione. Elucidating the mechanism of Dock7-mediated cellular transformation [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 1447.
Abstract 2159: IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma
Authors: Jilong Yang
Journal: Cancer Research (2020)

Abstract Immunotherapy targeting the PD-1/PD-L1 receptor in melanoma patients has achieved great success. Although many studies have addressed the underlying mechanisms involved in the blockade of PD-1/PD-L1 and the consequent modulation of the immune system, the mechanisms of PD-L1 upregulation and reliable biomarkers to predict the efficacy of anti-PD-1/PD-L1 therapy remain unknown. The present study demonstrates the correlation between IGFBP2 and PD-L1, reveals a novel immune-associated tumour function of IGFBP2 in facilitating nuclear accumulation of EGFR and activation of the EGFR/STAT3/PD-L1 signalling pathway in melanoma cells. Our results also suggest that combined IGFBP2 and PD-L1 expression have the potential to predict the efficacy of anti-PD-1 treatment for malignant melanoma; because the combination of high IGFBP2 and PD-L1 expression characterizes melanoma patients with worse overall survival and is associated with a better immune ecosystem. These characteristics have been confirmed by both in vitro and in vivo data. So, IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signalling pathway and its function as a PD-L1 regulator might suggest novel therapeutic approach for melanoma. Citation Format: Jilong Yang. IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma [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 2159.
Real-world use of workplace based assessments in surgical training: A UK nationwide cross-sectional exploration of trainee perspectives and consensus recommendations from the Association of Surgeons in Training
Authors: Andrew J. Beamish, Maximilian J. Johnston, Rhiannon L. Harries, Helen M. Mohan, J. Edward F. Fitzgerald, Gemma Humm, Mohamed Rabie, Deirdre M. Nally, Vimal J. Gokani, Oroog Ali, Joshua Burke, Joshua M. Clements, Vanessa Cubas, Christina Fleming, Lolade Giwa, James Glasbey, Vimal J. Gokani, Gianluca Gonzi, Rhiannon Harries, Katie Hughes, Elizabeth G. Kane, Kirsty MacLeod, Miriam Manook, Helen Mohan, Deirdre Nally, Philip H. Pucher, Kapil Sahnan, Fenella Shelton, Nisaharan Srikandarajah, Matthew Stovell, Anthony Thaventhiran, Nathan R. Walker, Alex Wilkins
Journal: International Journal of Surgery (2020)
Abstract CT250: A Phase 1a/1b, open-label first-in-human study of the safety, tolerability, and feasibility of gene-edited autologous NeoTCR-T cells (NeoTCR-P1) administered to patients with locally advanced or metastatic solid tumors
Authors: Mihaela Cristea, Bartosz Chmielowski, Roel Funke, Todd Stallings-Schmitt, Mitch Denker, Mark Frohlich, Alex Franzusoff, Mehrdad Abedi, Samuel Ejadi
Journal: Cancer Research (2020)

Abstract Introduction: Neoepitopes (neoE) derived from private tumor-exclusive mutations represent compelling targets for personalized TCR-T cell therapy. An ultra-sensitive and high-throughput process was developed to capture tumor mutation-targeted CD8 T cells from patient blood. NeoTCRs cloned from the captured CD8 T cells, when engineered into fresh CD8 and CD4 T cells, effected killing of patients' autologous tumor cells in vitro. These observations have been leveraged for the development of a fully personalized adoptive T cell therapy (NeoTCR-P1). A Phase 1 clinical trial testing NeoTCR-P1 in subjects with solid tumors is ongoing (NCT03970382). Study Design: During the initial trial phase, escalating doses of NeoTCR-P1 T cells administered without and with IL-2 in the regimen, and following conditioning chemotherapy, will be evaluated in subjects with advanced or metastatic solid tumors (melanoma, urothelial cancer, colorectal cancer, ovarian cancer, HR+ breast cancer, and prostate cancer). The objective of the Phase 1a study is to establish a recommended Phase 2 dose. Primary endpoints include the incidence and nature of DLTs and overall process feasibility. The proliferation, persistence, and trafficking of NeoTCR-T cells will be characterized. In the expansion trial phase, preliminary anti-tumor activity of NeoTCR-P1 will be assessed in selected tumors. The combination of NeoTCR-P1 dosing plus nivolumab will be tested in a Phase 1b study. Conclusion: This is the first clinical study of an autologous, fully personalized adoptive T cell therapy directed against private tumor-exclusive mutations, generated without using recombinant viral vectors. Citation Format: Mihaela Cristea, Bartosz Chmielowski, Roel Funke, Todd Stallings-Schmitt, Mitch Denker, Mark Frohlich, Alex Franzusoff, Mehrdad Abedi, Samuel Ejadi. A Phase 1a/1b, open-label first-in-human study of the safety, tolerability, and feasibility of gene-edited autologous NeoTCR-T cells (NeoTCR-P1) administered to patients with locally advanced or metastatic solid tumors [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 CT250.
Abstract 3838: HDAC5-mediated deacetylation promotes SATB1 oncogenic functions
Authors: Shalakha Sharma, Dr. Sanjeev Das
Journal: Cancer Research (2020)

Abstract HDAC5, a class IIa histone deacetylase is a prominent transcriptional regulator. The functions of HDAC5 have been shown to be regulated via phosphorylation-dependent nuclear-cytoplasmic shuttling. Phosphorylation of two conserved Ser259 and Ser498 residues by calcium/calmodulin dependent protein kinase promotes HDAC5 nuclear export. Dysregulation of HDAC5 has been implicated in development of many pathogenic conditions including cardiac hypertrophy and cancer. However, the mechanisms underlying the role of HDAC5 in tumorigenesis are not well understood. In order to explore the role of HDAC5 in tumorigenesis, we performed a proteomic screen and identified several interacting proteins of HDAC5. In vitro and in vivo studies further confirmed SATB1 as a novel interacting partner of HDAC5. SATB1 (Special AT rich binding protein 1) is a global genome organizer that recruits chromatin remodeling proteins to epigenetically regulate several genes. It has been recently reported to be overexpressed in various cancers and associated with malignant behavior of cancer cells. Our studies revealed SATB1 as a novel substrate of HDAC5-mediated deacetylation during early phase of genotoxic stress. We also mapped the site of deacetylation to the highly conserved K411 residue of SATB1. Upon prolonged genotoxic stress when HDAC5 undergoes nuclear export, SATB1 acetylation was observed. Thus, we screened a shRNA library targeting nuclear histone acetyltransferases and identified Tip60 as the cognate histone acetyltransferase involved in SATB1 acetylation at K411 residue. Next we performed qPCR array and found SATB1 upregulates the expression of genes involved in tumor suppression in acetylation-dependent manner. Increased SATB1 acetylation leads to decreased cell proliferation capacity, migration and invasiveness of tumor cells. Furthermore, studies in mouse tumor models confirmed that HDAC5 promotes SATB1-mediated tumorigenesis. Taken together, our findings add to the substrate repertoire of HDAC5 and provides key insights into SATB1-mediated tumorigenesis. Citation Format: Shalakha Sharma, Dr. Sanjeev Das. HDAC5-mediated deacetylation promotes SATB1 oncogenic functions [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 3838.
HLA‐B*35:01 and Green Tea–Induced Liver Injury
Authors: Jay H. Hoofnagle, Herbert L. Bonkovsky, Elizabeth J. Phillips, Yi‐Ju Li, Jawad Ahmad, Huiman Barnhart, Francisco Durazo, Robert J. Fontana, Jiezhun Gu, Ikhlas Khan, David E. Kleiner, Christopher Koh, Don C. Rockey, Leonard B. Seeff, Jose Serrano, Andrew Stolz, Hans L. Tillmann, Raj Vuppalanchi, Victor J. Navarro
Journal: Hepatology (2020)

Background and Aims Herbal supplements, and particularly multi‐ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea‐associated liver injury. Approach and Results Among 1,414 patients enrolled in the U.S. Drug‐Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea–associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15‐448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re‐exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA‐B*35:01, found in 72% (95% confidence interval [CI], 58‐87) of green tea cases, but only 15% (95% CI, 10‐20) caused by other supplements and 12% (95% CI, 10‐14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5‐11.5). Conclusions Green tea–related liver injury has distinctive clinical features and close association with HLA‐B*35:01, suggesting that it is idiosyncratic and immune mediated.
Abstract 4584: A novel combination of a multipeptide KRAS vaccine and an ACAT1 inhibitor to prevent lung cancer
Authors: Jing Pan, Qi Zhang, Katie Palen, Bryon Johnson, Li Wang, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Ming You
Journal: Cancer Research (2020)

Abstract Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a small GTPase that cycles between GDP and GTP-bound states, which modulates important cell surface receptors essential for cell proliferation and survival. It is one of the most common drivers for many types of cancers, is present in up to 25% all human tumors, and 80% of mutation occurs in codon12. Efforts to target KRAS-driven cancers preventively or therapeutically have been unsuccessful. We recently formulated a multi-peptide KRAS vaccine (KVAX), which targets both wild-type and G12D mutant forms of KRAS and has 100% sequence homology between human and mouse. KVAX elicited strong immunologic response and exhibited striking cancer preventive efficacy when administered prior to KRAS mutation induction. However, clinical high-risk individuals may already express mutant KRAS, which has known to promote an immunosuppressive environment. Therefore, we combined KVAX with avasimibe (AVA), an ACAT1 inhibitor that modulates lipid metabolism in T cells and facilitates better TCR/peptide/MHC interactions, in syngeneic lung cancer mouse model and genetically engineered mouse model, in which mutant KRAS initiated lung tumorigenesis before vaccination. We found that the combination significantly decreased the presence of regulatory T cells in the tumor microenvironment, facilitated CD8+ T cell infiltration in tumor sites, and ultimately led to enhanced anti-cancer efficacy. Using 10X Genomics, we performed single cell RNA-seq on lung tumors from mice treated with KVAX and AVA and found significant increases in APC monocytes and CD4+ Th1 cells, especially increases in the effector/memory T cell population. Meanwhile, KVAX also decreased Tregs and M2 macrophages. These studies include the evaluation of tumor-infiltrating immune cells by single-cell RNA-seq (scRNA-seq) and provide a more detailed mechanisms of action of KVAX alone or in combination with AVA in modulating the tumor immune microenvironment. Citation Format: Jing Pan, Qi Zhang, Katie Palen, Bryon Johnson, Li Wang, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Ming You. A novel combination of a multipeptide KRAS vaccine and an ACAT1 inhibitor to prevent lung cancer [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 4584.
Covid-19: UK studies find gastrointestinal symptoms are common in children
Authors: Susan Mayor
Journal: BMJ (2020)

Covid-19: UK studies find gastrointestinal symptoms are common in children Susan MayorGastrointestinal symptoms are common in children infected with SARS-CoV-2 and should trigger tests for the virus, researchers have said.A prospective study of 992 healthy children (median age 10.1 years) of healthcare workers from across the UK found that 68 (6.9%) tested positive for SARS-CoV-2 antibodies. 1 Half of the children testing positive reported no symptoms, but for those that did the commonest were fever (21 of 68, 31%); gastrointestinal symptoms, including diarrhoea, vomiting, and abdominal cramps (13 of 68, 19%); and headache (12 of 68, 18%).Latest findings from the Covid-19 Symptom Study app, 2 which was launched in late March to track people's symptoms, also show that gastrointestinal symptoms occur frequently in children with positive swab tests.
PB1895 CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS WITH INCREASED SERUM VON WILLEBRAND LEVELS AT DIAGNOSIS HAVE A SHORTER TIME TO TREATMENT
Authors: None Tryfou?., P. Papaioannou, P. Repousis, A.I. Gkioka, E. Koulieris, S. Sachanas, A. Bitsani, M. Dimou, R. Niki, A. Koudouna, A. Kopsaftopoulou, K. Chalmoukou, I. Grafakos, S. Kokkori, A. Tsantes, G. Pangalis, C. Matsouka, P. Panayiotidis, M.-C. Kyrtsonis
Journal: HemaSphere (2019)

Background: CLL is a usually indolent B-cell lymphoproliferative disease that requires only follow-up in about 2/3 of patients while the rest are symptomatic, have a worse outcome and need to be treated. The role of angiogenesis in CLL prognosis’ remains unclear. It has been shown that CLL plasma promotes von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs) [1]. Aims: We investigated whether serum vWF levels in CLL patients at diagnosis could provide prognostic information. Methods: 72 CLL patients were studied of whom 66%, 14% and 10% were Binet staged A, B and C respectively. Thirty-three percent of them never required treatment while 67% required treatment either at the time of diagnosis or during their follow-up. The median time to first treatment (TFT) was 34 months. Serum vWF concentrations were measured by ELISA (R&D Quantiquine, duo Set) in frozen sera drawn at patients’ diagnosis and in 18 healthy individuals (HI). Measurements were performed in duplicate according to the manufacturer's instructions. Statistical analysis was performed by conventional methods, using the SPSS v.22 software. P values below 0,05 were considered statistically significant. Results: Serum vWF levels ranged from 3746 to 14955 pg/ml in HI and from 1785 to 143536 pg/ml (median 5553) in patients. Patients with Serum vWF levels above 5553 pg/ml (median normal value) had a significantly shorter TFT than the others (p = 0,001) as shown in figure. Otherwise, serum vWF levels correlated only with hypogammaglobulinemia (p = 0,04) and to the degree of bone marrow infiltration (p = 0,006).Summary/Conclusion: Increased serum vWF levels correlated with a shorter TFT in CLL patients, suggesting that elevated vWF concentrations reflect active neoangiogenesis that in turn, contributes to a more aggressive disease behavior. 1] Shahidi M et al, Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-κB. Blood Coagul Fibrinolysis. 2016 Sep;27 (6):711-6.
Abstract 6168: Characterization of ATM inhibitor (AZD1390) distribution and pharmacodynamic changes in brain and glioblastoma in preclinical models to inform on mechanism of action
Authors: Lenka Oplustil O'Connor, Gregory Hamm, Maria Udriste, Stephanie Ling, Joanne Wilson, Steve Durant, Gareth Hughes, Sabina Cosulich, Wenlin Shao, Martin Pass, Gemma Jones, Andrew Pierce, Richard Goodwin, Mark O'Connor, Carl Barrett, Elizabeth Harrington
Journal: Cancer Research (2020)

Abstract Ataxia telangiectasia mutated (ATM) kinase is a key factor in DNA double strand break response and is constitutively activated in glioblastoma, leading to marked radioresistance [Bartkova, Carruthers] and therefore an attractive radiosensitisation target in this disease. AZD1390, a potent ATM inhibitor optimized to cross the blood brain barrier, is being evaluated with radiotherapy in Phase 1 (NCT03423628). Positron emission tomography (PET) studies demonstrated AZD1390 brain exposure in healthy human subjects. This study characterises ATM inhibitor penetration and distribution in brain and GBM, as well as pharmacodynamic biomarker changes in human orthotopic GBM patient-derived explant (PDX) models. Radiation +/- AZD1390 treatment was evaluated for compound concentration in plasma and relative abundance in brain/ GBM regions by mass spectrometry imaging (MSI). Parallel samples were analysed by immunohistochemistry for biomarkers of DNA damage response and ATM signalling. We show AZD1390 penetrates brain tissue with preferential compound accumulation into tumour. Higher ratios of AZD1390 in GBM versus normal brain correlate with improved efficacy and greater levels of DNA damage. Moreover, AZD1390 in the GBM region was heterogeneously distributed with MSI characterized specific metabolic clusters having varied AZD1390 intensities. As expected, radiation treatment activated ATM signalling (indicated by increase in pRAD50 and γH2AX positive cells) which was effectively inhibited by AZD1390 co-treatment. Our work provides novel insights into ATM inhibitor pharmacokinetics in brain tumours and demonstrates the benefit of using MSI in conjunction with pharmacodynamic markers to provide a more complete picture of AZD1390 mechanism of action for future translational studies on clinical GBM samples. Citation Format: Lenka Oplustil O'Connor, Gregory Hamm, Maria Udriste, Stephanie Ling, Joanne Wilson, Steve Durant, Gareth Hughes, Sabina Cosulich, Wenlin Shao, Martin Pass, Gemma Jones, Andrew Pierce, Richard Goodwin, Mark O'Connor, Carl Barrett, Elizabeth Harrington. Characterization of ATM inhibitor (AZD1390) distribution and pharmacodynamic changes in brain and glioblastoma in preclinical models to inform on mechanism of action [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 6168.