tbuckley/cabot-search huggingface dataset:
Epigenetic modulation of immunity: towards new therapeutic avenues in hepatocellular carcinoma?
Authors: Angelique Gougelet
Journal: Gut (2019)

Liver cancer is the second leading cause of cancer-related deaths worldwide, for which therapeutic options are very limited and novel strategies alarmingly needed. The leading risk factor for hepatocellular carcinoma (HCC) is cirrhosis due to HBV and HCV viruses, alcohol abuse, genotoxic exposure and metabolic disorders increasingly associated with diabetes and obesity. HCC is the paradigm of inflammation-associated cancer, with >80% of HCC emerging consecutively to a vast remodelling of liver stroma. To restrain inflammatory response, liver parenchyma physiologically harbours a specific microenvironment to prevent the establishment of inflammation. Immune cells largely orchestrate liver protection, in particular Kupffer cells, the liver macrophages, in partnership with fibroblasts. Nevertheless, when it gets into chronicity, liver inflammation sensitises to cancer development, tumor-associated stroma being recognised as a major hallmark of cancer, as described by Hanahan and Weinberg in 2011.1 During hepatocyte transformation, the surrounding cells, including cancer-associated fibroblasts, hepatic stellate cells, tumour-infiltrating leukocytes and tumour-associated macrophages (TAM) are abnormally activated and/or recruited. These cells secrete a cocktail of growth factors, cytokines and chemokines, which exacerbate liver inflammation and injury in favour of hepatocarcinogenesis.2 Macrophages are the major part of immune cell infiltrates in solid tumours, and the density of macrophages is strongly correlated to poor overall survival, including in HCC. Inversely, myeloid-derived suppressor cells (MDSCs) have emerged as central …
Abstract 4313: Identifying and characterizing epigenetic «driver» genes («epidrivers») in regulatory pathways involved in tumorigenesis and tumour cell plasticity
Authors: Andrea Halaburkova, Vincent Cahais, Cyrille Cuenin, Rita Khoueiry, Maria Ouzounova, Akram Ghantous, Zdenko Herceg
Journal: Cancer Research (2019)

Abstract One of the ground-breaking discoveries of the international cancer genome sequencing endeavours is the high frequency of mutational and non-mutational changes in epigenetic regulator genes (ERGs), which constitute a “genetic smoking gun” that epigenetic mechanisms lie in the very heart of cancer biology. However, functional importance of disruption of ERGs in tumorigenesis and cancer phenotype is poorly understood. We hypothesise that these genes are candidates to be drivers («epidrivers») of cancer onset and progression, thus regulating mechanisms underpinning cancer development. Moreover, deregulation of epidrivers may play a role in epithelial-to-mesenchymal transition (EMT) and emergence of cancer resilience. The overarching aim of this study was to identify and functionally characterize “Epidrivers” in tumorigenesis and cancer cell plasticity. To this end, we have set up novel epigenome-wide functional screens in human cultured cells (and organoids) combined with state-of-the-art genome-editing approach (based on CRISPR/Cas9 screen) and multiparametric phenotyping. We designed a custom-made lentiviral CRISPR library that consists of 1,649 gRNAs targeting all known ERGs (426 genes). Lentiviral CRISPR library was used to deliver the ERG gRNAs to target cells expressing the RNA-guided DNA endonuclease Cas9. Independent clones (derived from transduced breast and lung cancer cell lines constitutively expressing Cas9) are screened for acquisition of distinct features of transformed cells. The results of the identification of Epidriver genes based on the analysis of deregulation of core cellular processes, epigenome (ChIP-seq) as well as EMT and multiparametric phenotyping, will be presented. Citation Format: Andrea Halaburkova, Vincent Cahais, Cyrille Cuenin, Rita Khoueiry, Maria Ouzounova, Akram Ghantous, Zdenko Herceg. Identifying and characterizing epigenetic «driver» genes («epidrivers») in regulatory pathways involved in tumorigenesis and tumour cell plasticity [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 4313.
Abstract 5283: Prognostic value of resectable hepatocellular carcinoma: Clinico-pathologic findings
Authors: Jin Young Kim, Mi Hwa Heo, So Jin Shin
Journal: Cancer Research (2019)

Abstract We investigated the prognostic factors of resectable hepatocellular carcinoma (HCC). Preoperative peripheral blood factors, fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and pathologic parameters were investigated for progression free survival (PFS). From February 2008 to December 2012, a retrospective analysis was conducted on 65 patients who had received liver resection. Peripheral blood parameters were collected within 7 days based on operation date. The 18F-FDG uptake was calculated based on the maximum standardized uptake value of the tumor (SUVmax), the liver mean SUV and the tumor-to-normal SUV ratio (TNR). Immuno-histochemical (IHC) stain results were reviewed by a pathologist through specimen. A total of 65 patients were included (46 males, 19 females; average age, 57.5 ± 8.9 years). The median PFS of HCC was 52.9 months. SUVmax was correlated with PFS and the optimal cut off value of SUVmax was 3.25 (p = 0.005). Median PFS of low SUVmax was 76.4 months and high SUVmax was 8.5 months. The optimal cut-off value of TNR was 1.77 for PFS. The median PFS of HCC in patients with low TNR (&amp;lt; 1.77) and high TNR (≥ 1.77) was 82.3 and 7.0 months, respectively (p = 0.002). AST to platelet ratio index (APRI) could be a predictable marker for recurrence of HCC (p = 0.034). The median PFS of high PNI and low PNI were 64.9 and 10.9 months, respectively (p = 0.004). The IHC expression of glucose uptake transporter 2 was correlated with SUVmax. Preoperative SUVmax, TNR, APRI and PNI could predict recurrence after curative resection of HCC. Citation Format: Jin Young Kim, Mi Hwa Heo, So Jin Shin. Prognostic value of resectable hepatocellular carcinoma: Clinico-pathologic findings [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 5283.
Can autologous stem cell transplantation abrogate the poor prognosis associated with high LDH in myeloma patients?
Authors: Osman Ilhan, Guldane Cengiz Seval, Selami Kocak Toprak, Sinem Civriz Bozdag, Meltem Kurt Yuksel, Pervin Topcuoglu, Onder Arslan, Muhit Ozcan, Taner Demirer, Hamdi Akan, Meral Beksac, Gunhan Gurman
Journal: Journal of Clinical Oncology (2019)

e19524 Background: Multiple myeloma (MM) is a plasma cell neoplasia characterized by a diffuse clonal plasma cell infiltration of the bone marrow. Serum lactate dehydrogenase (LDH) is a relevant biomarker in MM and in the era of novel agents, LDH confirmed its negative impact on survival in newly diagnosed setting (Bal et al., presented at ASH2018). Methods: This single center retrospective study included 208 patients with a diagnosis of MM who underwent ASCT at our center between January 2008 - Mart 2018 were prospectively analyzed. We identified patients with baseline serum LDH values (ULN = 247 U/L). We compare baseline characteristics and outcomes of ASCT according to LDH values. Results: All clinical data were available in 208 cases (High LDH: 92 (44.2%), Normal LDH: 116 (55.8%)) There were 87 (41.8 %) female and 87 (41.8 %) male patients. The median age at diagnosis of MM was 63 years (range, 37-77 years). The median time of follow-up was 48 months (range, 2.8-197.5 months). Of the 92 patients with high LDH who underwent ASCT, median age was 65 years and ECOG performance status was 1 and 58.6 % were male. There was no statistically differences in performance status, induction treatment regimens and the number of treatment line prior to ASCT. Induction therapy consisted of 3 drugs in 91.3% and 2 drugs in 8.7 % in high LDH group (p = NS). Forty-eight (53.3%) patients with high LDH received a bortezomib-based induction and 35 patients (40.2 %) achieved ³ very good partial remission (VGPR) after the induction therapy. During follow up, 45 relapses were occurred and all relapsed patients died. According to the long-rank test, estimated 5-year OS was not significantly different between normal and high LDH categories (63.3 %±0.6 % vs. 64.6 %±0.5 %; p = 0.99). Median PFS was 101.4 months (95% CI: 73.7-129) in high LDH group and 92.1 months (95% CI: 71.1-113.1) in normal LDH group (p = 0.99). Conclusions: Elevated LDH was confirmed as a poor prognostic factor in previous reports. In our transplanted patients with high LDH cohort, clinical outcomes are favorable and similar those have normal LDH. Therefore, further studies of larger randomized cohorts are required to clarify the impact of pre-transplant LDH levels on ASCT outcomes.
Abstract 15414: Relations of Orthostatic Hypotension With New-Onset Atrial Fibrillation: The Framingham Heart Study
Authors: Darae Ko, Sarah Preis, Steven Lubitz, David McManus, Ramachandran Vasan, Naomi Hamburg, Emelia Benjamin, Gary Mitchell
Journal: Circulation (2017)

Background: Prior studies have reported that orthostatic hypotension (OH) is associated with increased risk of atrial fibrillation (AF). We sought to determine whether the association persists afte...
Weekly CyborD-DARA Is a Safe and Effective Upfront Treatment for Newly Diagnosed Multiple Myeloma. Preliminary Results of the Early Phase 16-Bcni-001/Ctrial-IE (ICORG) 16-02 Study
Authors: Cian McEllistrim, Mary R Cahill, Philip Murphy, Vitaliy Mykytiv, John Quinn, Amanda Bray, Jessica Walsh, Elizabeth Lenihan, Tara Kenny, Grace Hirakata, Imelda Parker, Andres Hernando, Michael O'Dwyer
Journal: Blood (2017)
The AST/ALT (De Ritis) ratio predicts clinical outcome in pancreatic cancer patients treated with first-line nab-paclitaxel and gemcitabine: post-hoc analysis of an Austrian multicenter, non-interventional study
Authors: J. Riedl, F. Posch, G. Prager, W. Eisterer, L. Öhler, S. Thamer, K. Wilthoner, A. Petzer, P. Pichler, E. Hubmann, T. Winder, S. Burgstaller, M. Korger, J. Andel, R. Greil, M. Pecherstorfer, K. Philipp-Abbrederis, A. Djanani, B. Gruenberger, F. Längle, E. Wöll, A. Gerger
Journal: Annals of Oncology (2019)
Exploratory Study of <i><scp>MYD</scp>88</i> L265P, Rare <i><scp>NLRP</scp>3</i> Variants, and Clonal Hematopoiesis Prevalence in Patients With Schnitzler Syndrome
Authors: Shelly Pathak, Dorota M. Rowczenio, Roger G. Owen, Gina M. Doody, Darren J. Newton, Claire Taylor, Jan Taylor, Catherine Cargo, Philip N. Hawkins, Karoline Krause, Helen J. Lachmann, Sinisa Savic
Journal: Arthritis & Rheumatology (2019)

Objective To assess the prevalence of the MYD 88 L265P mutation and variants within NLRP 3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS). Methods Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin‐associated periodic syndromes ( aCAPS ) were included as controls. Allele‐specific oligonucleotide–polymerase chain reaction was used for the detection of the MYD 88 L265P variant, next‐generation sequencing was applied to analyze NLRP 3 and 28 genes associated with myelodysplastic syndrome, and gene scanning was performed for the detection of X chromosome inactivation. Results Activating NLRP 3 mutations were not present in 11 SchS patients who had not been sequenced for this gene previously. The MYD 88 L265P variant was present in 9 of 30 SchS patients, and somatic mutations associated with clonal hematopoiesis were identified in 1 of 30 patients with SchS and 1 of 6 patients with aCAPS . Evidence of nonrandom X chromosome inactivation was detected in 1 female patient with SchS and 1 female patient with aCAPS . Conclusion A shared molecular mechanism accounting for the pathogenesis of inflammation in SchS remains elusive. Clonal hematopoiesis is not associated with other somatic mutations found in individuals with SchS or aCAPS .
Abstract 713: BBI-608 modulates DNA repair pathways, induces apoptosis and impacts response to 5-Fluorouracil and ionizing radiation in pancreatic cancer cells
Authors: Batoul Farran, Ganji P. Nagaraju, Sneha G. Shipra, Shipra R. Bethi, Gregory B. Lesinski, Bassel El-Rayes
Journal: Cancer Research (2019)

Abstract Background: BBI-608 has been shown to modulate multiple oncogenic cellular pathways which are often constitutively active in pancreatic ductal adenocarcinoma (PDAC). Among these are key mediators of DNA repair and cellular survival pathways. We hypothesized that BBI-608 would sensitize PDAC cells to chemoradiotherapy. Methods: The combined effects of BBI-608 and chemoradiotherapy (5-FU + IR) were evaluated in human (MIA PaCa-2) and murine (PANC-02) PDAC cell lines using a Br-dU cell proliferation assay. To elucidate the mechanism of action, effects on the expression of DNA damage and repair (pATM, γ-H2AX, p53; pATR, and Rad51) molecules were examined by Western blot. Apoptosis was assessed via Annexin V staining and flow cytometric analysis to evaluate mechanism of cell death following treatment of MIA PaCa-2 and PANC-02 cell lines. The in vivo activity of BBI-608, 5-FU + IR, alone and in combination, were evaluated in C57BL/6 mice bearing subcutaneous PANC-02 tumors. Results: The combination of BBI-608 and chemoradiotherapy significantly decreased (p&amp;lt;0.001) cell proliferation and induced Annexin V positive cells in both MIA PaCa-2 and PANC-02 cell lines. BBI-608 and chemoradiotherapy also decreased the activation of pATR, MDM2, and Rad51 and increased pATM, γ-H2AX and p53. Administration of BBI-608 potentiated the effects of chemoradiotherapy in vivo in mice bearing subcutaneous PANC-02 tumors as measured by tumor volume. Conclusion: These data identify a role for BBI-608 as a modulator of DNA damage and apoptosis. These effects enhanced the efficacy of chemoradiotherapy in cell lines and in vivo models of PDAC and provide rationale for continued investigation in the pre-clinical and clinical setting. Note: This abstract was not presented at the meeting. Citation Format: Batoul Farran, Ganji P. Nagaraju, Sneha G. Shipra, Shipra R. Bethi, Gregory B. Lesinski, Bassel El-Rayes. BBI-608 modulates DNA repair pathways, induces apoptosis and impacts response to 5-Fluorouracil and ionizing radiation in pancreatic cancer cells [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 713.
EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses
Authors: Xuexue Liu, Yanli Zhang, Yefang Li, Jianfei Pan, Dandan Wang, Weihuang Chen, Zhuqing Zheng, Xiaohong He, Qianjun Zhao, Yabin Pu, Weijun Guan, Jianlin Han, Ludovic Orlando, Yuehui Ma, Lin Jiang
Journal: Molecular Biology and Evolution (2019)

High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski's horses added for comparison. We find that Tibetan horses do not descend from Przewalski's horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1, also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages.
Abstract 3151: Quantitative measurement of Siglec-15 expression in non-small cell lung cancer and its association with PD-L1, B7-H4 and tumor infiltrating lymphocytes
Authors: Maria Toki, Jon Zugazagoitia, Mehmet Altan, Linda Liu, Nikita Mani, Yuting Liu, Konstantinos Syrigos, Lieping Chen, Solomon Langermann, Roy Herbst, David Rimm
Journal: Cancer Research (2019)

Abstract Introduction: Siglecs are sialic acid-binding transmembrane receptors that regulate the functions of innate and adaptive immune system through the recognition of glycan ligands. Siglec-15 has been recently described as an immune suppressive molecule that shares molecular structure with PD-L1, but its role in NSCLC is still unknown. In this study, we determined Siglec-15 expression in three retrospective NSCLC cohorts and evaluated its association with mutation status, major clinicopathologic characteristics and survival. Experimental procedures: We used multiplexed automated quantitative immunofluorescence (QIF) to develop a validated assay for Siglec-15 measurement and used it to assess Siglec-15 expression and its association to major clinicopathologic variables and survival in three NSCLC cohorts of over 600 patients. Additionally, we investigated the correlation of Siglec-15 expression with tumor-infiltrating lymphocytes, PD-L1, B7-H3 and B7-H4 tumor expression. Results: In our study, Siglec-15 tumor positivity was found in 12.5%, 13.7% and 22.8% of NSCLC cohort patients. Siglec-15 expression was higher in EGFR mutant and EGFR/KRAS wild type tumors compared to KRAS mutants but was not associated with any other major clinicopathological characteristics. Siglec-15 followed a mutually exclusive pattern of expression with PD-L1, B7-H3 and B7-H4 (co-expression in 3.1%, 13.2% and 7.7% of the patients respectively), while high levels were not correlated with lymphocyte infiltration or T-cell activation, suggesting a different upregulation mechanism not mediated by IFN-gamma. Conclusions: Siglec-15 is a protein expressed with high frequency in NSCLC. Co-expression of Siglec-15 with PD-L1, B7-H3 and B7-H4 is relatively rare, suggesting that Siglec-15 has distinct and non-redundant features compared to other B7 family members. Citation Format: Maria Toki, Jon Zugazagoitia, Mehmet Altan, Linda Liu, Nikita Mani, Yuting Liu, Konstantinos Syrigos, Lieping Chen, Solomon Langermann, Roy Herbst, David Rimm. Quantitative measurement of Siglec-15 expression in non-small cell lung cancer and its association with PD-L1, B7-H4 and tumor infiltrating lymphocytes [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 3151.
Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis
Authors: Changwan Ryu, Caitlin Brandsdorfer, Taylor Adams, Buqu Hu, Dylan W. Kelleher, Madeleine Yaggi, Edward P. Manning, Anjali Walia, Benjamin Reeves, Hongyi Pan, Julia Winkler, Maksym Minasyan, Charles S. Dela Cruz, Naftali Kaminski, Mridu Gulati, Erica L. Herzog
Journal: European Respiratory Journal (2019)

Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis. Extracellular mtDNA concentrations were measured using quantitative PCR for the human MT-ATP6 gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort. Relative to controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive MT-ATP6 concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease. Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.
Abstract 292: PTC596 combination therapy for sarcoma
Authors: Marla Weetall, Art Branstrom, John Baird, Liang Cao, Josephine Sheedy, Kylie O'Keefe, Matthew Ingham, Gary K. Schwartz, Robert Spiegel, Edward O'Mara
Journal: Cancer Research (2019)

Abstract Sarcomas are rare cancers derived from mesenchymal tissues. Although rare, there are approximately 15,000 new cases of sarcoma diagnosed each year in the United States. Certain soft tissue sarcomas are treated with doxorubicin and olaratumabas first line, gemcitabine as second line, and often dacarbazine (DTIC) as third line. PTC596 is a first-in-class, oral investigational new drug that reduces levels of BMI1, a protein required for cancer stem cell survival. PTC596 acts by binding to tubulin causing a G2M cell cycle arrest. PTC596 lowers levels of BMI1 in preclinical tumor models and is generally well tolerated as a monotherapy at doses that result in preclinical target plasma concentrations. Efficacy of PTC596 was evaluated in a series of preclinical models. PTC596 delayed tumor growth as monotherapy and significantly enhanced, in combination, the activity of standard chemotherapeutics including gemcitabine, doxorubicin/ doxil, dacarbazine (DTIC), and other tubulin binding agents. Based on these results, a Ph1b clinical trial in patients with relapsed refractory leiomyosarcoma is to be initiated. It is a dose escalation study of a combination regimen of dacarbazine and PTC596 with the dose-limiting toxicity (DLT) to be determined using a continuous reassessment methodology. Previously, a Phase I multi-center dose escalation study was conducted in patients with advanced solid tumors. PTC596 was administered as an oral monotherapy in 4-week cycles using bodyweight-adjusted twice-per-week (biw) dosing. A maximum tolerated dose (MTD) was not determined though a well-tolerated recommended Phase 2 dose of 7mg/kg biw was identified. The most relevant toxicities observed were neutropenia, nausea, and vomiting which were generally mild to moderate, manageable and reversible. Citation Format: Marla Weetall, Art Branstrom, John Baird, Liang Cao, Josephine Sheedy, Kylie O'Keefe, Matthew Ingham, Gary K. Schwartz, Robert Spiegel, Edward O'Mara. PTC596 combination therapy for sarcoma [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 292.