tbuckley/cabot-search huggingface dataset:
Abstract 2775: Investigating myeloid-derived suppressor cells (MDSC) gene expression in predicting outcome in stage matched colorectal cancer patients
Authors: Saleh G. Heneidi, Chance Bloomer, Pankaj Ahluwalia, Ashis Mondal, Ravindra Kolhe
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) has emerged as the third most commonly diagnosed cancer in males and second most common in females. Although surgery, chemotherapy, and emerging immunotherapies have reduced mortality rates, tools that can assist in tailoring individualized treatments are needed. MDSC are immune-suppressive cells that interfere with the functioning of T cells and immune-inflammatory pathways. An extensive literature search identified 8 MDSC-centric genes which were tested for their prognostic significance in CRC. These genes; CEBPB, IL10, NOS2, RORC, S100A8, SOCS1, SOCS3, and TGFB1, along with their expression in tumor microenvironments could give new insights when correlated with clinical-pathologic features of colon cancer patients. The aim of the study is to quantify MDSC gene signatures in colorectal cancer patients. Under an IRB approved protocol, a total of 750 colon cancer patients at the Medical College of Georgia with 5 years of follow-up were initially selected. A total of 88 patients fit in our inclusion criteria, on the basis of survival duration after diagnosis. The FFPE blocks were acquired and patients were stratified on the basis of overall survival in two groups, with higher (&amp;gt;5 years) and lower survival (&amp;lt;1 year), as well as AJCC staging (I to IV), grade, gender and age. Total RNA was isolated and quantified through Nanodrop method. The statistical analysis of data was performed using student t-test and Pearson correlation. SOCS1 (p = 0.00*) was expressed in higher levels in patients with high survival (&amp;gt;5 years). Patients with low expression of TGFB1 survived longer compared to high expression group (p = 0.02*). On race comparison, CEBPA (p = 0.01*) showed significant expression in Caucasian population while NOS2 (p = 0.01*) expressed at higher levels in African Americans. These findings points to the clinical significance of MDSC based genes and tested the utility of a MDSC-related gene expression based prognostic biomarker panel for CRC patients. Citation Format: Saleh G. Heneidi, Chance Bloomer, Pankaj Ahluwalia, Ashis Mondal, Ravindra Kolhe. Investigating myeloid-derived suppressor cells (MDSC) gene expression in predicting outcome in stage matched colorectal cancer patients [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 2775.
Clinical practice use of liquid biopsy to identify RAS/BRAF mutational status in patients with metastatic colorectal cancer: A single institution experience
Authors: V. De Falco, P. Vitiello, E. Giunta, D. Ciardiello, N. Stefania, C. Cardone, P. Vitale, N. Zanaletti, M. Terminiello, L. Poliero, C. Borrelli, V. Caputo, G. Arrichiello, V. Mattera Iacono, F. Marrone, V. Famiglietti, E. Martinelli, F. Ciardiello, T. Troiani
Journal: Annals of Oncology (2019)
Abstract 1754: Monoubiquitinated γ-H2AX - a more specific biomarker of DNA double-strand breaks
Authors: Michal W. Luczak, Anatoly Zhitkovich
Journal: Cancer Research (2019)

Abstract DNA double-strand brakes (DSBs) are a highly toxic form of DNA damage originating from many endogenous and exogenous sources. Cells employ specialized mechanisms for rapid detection and repair of these lesions. Histone H2AX phosphorylated at Ser139 (known as γ-H2AX) acts as a central platform for recruitment of other components of DSB repair. γ-H2AX assessment is currently the most widely used approach for quantitation of DSBs. However, γ-H2AX can be also induced by certain nongenotoxic stressors and during apoptosis, which can lead to false positive observations, especially in prolonged exposures. γ-H2AX undergoes RNF168-mediated K13/K15 monoubiquitination which is necessary for the recruitment of the downstream DSB repair factors. This ubiquitination event is rarely analyzed despite its functional importance. We examined formation and detection of γ-H2AX and its mono- (ub1) and diubiquitinated (ub2) forms in several human cell lines in response to mechanistically distinct inducers of DSBs and false-positive DSBs stressors. We found that γ-H2AX-ub forms were poorly detected using some common blotting procedures and antibodies. Under optimized conditions, γ-H2AX-ub1 was the predominant form accounting up to 80-90% of total γ-H2AX in primary human cells and its formation was strictly associated with the presence of DSBs. γ-H2AX and γ-H2AX-ub1 showed similar dose dependence and disappearance kinetics whereas H2AX-ub2 form was a more stable and dose-independent product. Unlike γ-H2AX, its ubiquitinated forms were not observed in the absence of DSBs (heat-shock or during apoptotic DNA cleavage). Apoptotic cells showed cleavage of the γ-H2AX-targeting E3 ubiquitin ligase RNF168. Our findings demonstrate that the ub1 form is a major fraction in the overall formation of γ-H2AX and its quantitation offers advantage in specificity for nonapoptotic DSBs. Citation Format: Michal W. Luczak, Anatoly Zhitkovich. Monoubiquitinated γ-H2AX - a more specific biomarker of DNA double-strand breaks [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 1754.
Immune modulatory effects of ibrutinib in pancreatic ductal adenocarcinoma
Authors: M. Sinha, M. Griffith, C. Betts, G. Choe, S. Sivagnanam, A. Cheung, W. Tamaki, E. Liu, J. Sudduth-Klinger, G. Vaccaro, C. Lopez, L. Fong, L. Coussens, M. Tempero
Journal: Annals of Oncology (2019)
Bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies: Results of phase I-II trial.
Authors: Veronika Bachanova, Qing Cao, Daniel Jordan Weisdorf, Julie M Curtsinger, Sarah A. Cooley, Jeffrey Miller, Daniel Vallera
Journal: Journal of Clinical Oncology (2019)

e19066 Background: The novel bispecific toxin DT2219 consists of a fusion between the catalytic domain of diphtheria toxin (DT) and single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. Methods: The primary objective of Phase I Dose was to determine DT2219 dose which is well tolerated on an 8 dose schedule (days 1, 3, 5, 8 and day 15, 17, 19 and 22). Phase II Extension aimed to establish a preliminary estimate of overall response at day 29 in patients stratified to Arm A (relapsed/refractory B-cell lymphoma) and Arm B (B-cell leukemia). Baseline serum level of neutralizing antibody (NA) against diphteria toxin below 50% was required for eligibility. Results: Eighteen patients (NHL n = 12; ALL n = 6) at median age 65 years (range 50-83 yrs) with relapse/refractory disease and confirmed expression of CD19 and/or CD22 were enrolled. Treatment was well tolerated at 60 mcg/kg x 8 doses and the most common adverse events included capillary leak sy, elevated AST/ALT, low albumin, weight gain and leukopenia. All were Gr 1-2 and resolved after 3-5 days allowing day 15 DT2219 administration. There were no neutropenic fever or immune mediated adverse events. Four patients experienced dose limiting toxicity at dose 80 μg/kg/day: Gr 4 capillary leak syndrome (n = 1), Gr 3 LFTs abnormalities (n = 2) and Gr 4 thrombocytopenia &gt; 7 days duration (n = 1). Thirteen patients were evaluable for response and 3 experienced objective clinical benefit. One patient with primary refractory pre-B acute lymphoblastic leukemia achieved complete remission after 1 st cycle. Two patients with transformed lymphoma demonstrated transient tumor shrinkage, however, DT2219 therapy was discontinued due to DLT and increased NA titer after 1 st cycle (pre C1 28%, pre C2 108%). Correlative studies showed a low incidence of neutralizing antibody in NHL patients recently exposed to Rituximab. Conclusions: We have established the biologically active dose of DT2219 at 60 μg/kg/day ×8 doses. Further development of DT2219 includes combination with rituximab (to reduce NA formation) and synergistic combinations against B-cell malignancies. Clinical trial information: NCT02370160.
Response to A+CHP by CD30 expression in the ECHELON-2 trial.
Authors: Ranjana H. Advani, Steven M. Horwitz, Swaminathan Padmanabhan Iyer, Nancy L. Bartlett, Won Seog Kim, Herve Tilly, David Belada, Tatyana Feldman, Árpád Illés, Eric D. Jacobsen, Andreas Huettmann, Pier Luigi Zinzani, Owen A. O'Connor, William L. Trepicchio, Harry H. Miao, Shangbang Rao, Matthew Onsum, Thomas John Manley, Tim Illidge
Journal: Journal of Clinical Oncology (2019)

7538 Background: Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free and overall survival with BV plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP in frontline treatment of patients (pts) with CD30+ peripheral T-cell lymphoma (PTCL). Complete remission (CR) rate (A+CHP 68%; CHOP 56%) and objective response rate (ORR) (A+CHP 83%; CHOP 72%) were also significantly increased. Expression of CD30 is universal in systemic anaplastic large-cell lymphoma (sALCL) but variable among non-sALCL subtypes. As ORR is a direct measure of antitumor activity, we examined response to A+CHP by CD30 expression. Methods: Pts with CD30+ (≥10% by local review) PTCL were included in E-2. Eligible histologies included ALK+ sALCL (IPI ≥2), ALK− sALCL, PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma. We analyzed the relationship between CD30 expression (IHC Ber H2 antibody) above and below the median (median CD30=18% PTCL-NOS; 25% AITL) and CR rate, ORR, and duration of CR (DOCR) in pts with AITL and PTCL-NOS treated with A+CHP. Results: Most (26/29, 90%) AITL pts had CD30 expression between 10% and 30%. PTCL-NOS pts were more evenly distributed across levels of CD30 expression ranging from 10% to 100%. CD30 levels were neither predictive of response (Table) nor significantly associated with DOCR in pts with AITL (P=0.30) or PTCL-NOS (P=0.90) (log-rank test). Response by CD30 expression. Clinical trial information: NCT01777152. Conclusions: CD30 expression above vs below median (or at 10%) did not predict response to A+CHP in E-2 non-ALCL subtypes, as responses were seen across CD30 levels. This may be due to intra- and inter-tumoral heterogeneity of CD30 expression, limitations of IHC, the nature of CD30 on the cell surface, and multiple mechanisms of action of BV. Further evaluation of the expression-response relationship in PTCL pts with CD30 &lt;10% is warranted.[Table: see text]
Abstract 3201: Rigosertib, a Ras mimetic, inhibits melanoma cell viability and synergizes with anti-PD1 to promote anti-tumor immune responses
Authors: Chi Yan, Premkumar E. Reddy, Ann Richmond
Journal: Cancer Research (2019)

Abstract Activating mutations in BRAF or NRAS are present in 40% and 21% of melanoma patients, respectively, leading to enhanced cell survival and proliferation. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic that has the potential to block RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways and interfere with CRAF interaction with PLK1 and consequently its centrosomal localization. Here, we demonstrate that RGS inhibits the cell viability at µM levels of human (including A375/SKMel2/SKMel5/HS294T) and murine (including B16F10 and YUMM2.1/3.3/4.1/5.2) melanoma cell lines with a variety of somatic mutational backgrounds. We discovered that RGS treatment immediately (&amp;lt;15mins) and constantly (up to 24hrs) suppresses PI3K-AKTT308 and mTORC2-AKTSer473 phosphorylation. Using the murine melanoma cell line YUMM3.3 (BrafV600E/wtCdkn2-/-), we showed that RGS monotherapy, elevated the production of mitochondrial reactive oxygen species, promoted cellular apoptosis, suppressed mitosis in vitro, and inhibited tumor growth in C57BL/6 mice. The optimal in vivo dose of RGS (300mg/kg), which exhibited &amp;gt;50% inhibition of tumor volume and tumor weight, was well tolerated in mice. RGS-treated tumors exhibited an inflammatory tumor microenvironment (TME) with enrichment of dendritic cells and CD45-MHCII+ cells, elevation in frequency and activation of both CD4+ and CD8+ T cells and NK cells, but a decrease in the level of tumor-infiltrating macrophages. Of note, treatment with RGS plus αPD-1 checkpoint blockade synergistically inhibited tumor growth by ~70%. The RGS + αPD-1 combination treatment, but not the monotherapies, reduced the frequency of exhausted PD-L1+LAG3+TIM3+ CD8+ T cells at the tumor sites, as well as in the tumor-draining lymph nodes. Conclusion: These results suggest that RGS, which is a Ras mimetic, may be used in combination with anti-PD-1 immunotherapies to enhance anti-tumor immunity and optimize the treatment of melanoma. This combination therapy warrants a clinical study. The authors sincerely thank Onconova Therapeutics, Newtown, PA 18940 for kindly supplying Rigosertib for this work. Citation Format: Chi Yan, Premkumar E. Reddy, Ann Richmond. Rigosertib, a Ras mimetic, inhibits melanoma cell viability and synergizes with anti-PD1 to promote anti-tumor immune responses [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 3201.
Abstract 20678: MicroRNA Expression Patterns as Predictor of Patients at Risk for Atrial Fibrillation Following Coronary Artery Bypass Grafting
Authors: John Petronovich, John Braxton, Ingrid Glurich
Journal: Circulation (2017)

Introduction: Post-operative atrial fibrillation (POAF) is a common complication following coronary artery bypass grafting (CABG) contributing to increased morbidity and healthcare costs. MicroRNA ...
Abstract 16506: Right Ventricular Systolic Dysfunction by Speckle-Tracking Echocardiography Improves Risk Prediction in Moderate and Severe Tricuspid Regurgitation: Comparison With Conventional Echocardiographic Parameters
Authors: Edgard A Prihadi, Pieter van der Bijl, Erhan Gursoy, Rachid Abou, E M Vollema, Nina Ajmone Marsan, Victoria Delgado, Jeroen J Bax
Journal: Circulation (2017)

Introduction: Right ventricular (RV) systolic dysfunction developing in presence of significant tricuspid regurgitation (TR) leads to poor outcome. Whereas timely detection of RV dysfunction by con...
Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study
Authors: Mark W Tenforde, Margaret Mokomane, Tshepo B Leeme, Nametso Tlhako, Katlego Tsholo, Tony Chebani, Anya Stephenson, Jemima Hutton, Hannah K Mitchell, Raju KK Patel, William J Hurt, Tlhagiso Pilatwe, Tiny Masupe, Mooketsi Molefi, Brandon L Guthrie, Carey Farquhar, Madisa Mine, Joseph N Jarvis
Journal: The Lancet Infectious Diseases (2019)

BackgroundCNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults.MethodsIn this prevalent cohort study, patient records from 2004–15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per μL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per μL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality.FindingsWe included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with culture-confirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per μL and 1209 with CSF WCC above 20 cells per μL). Median age was 37 years (IQR 31–46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per μL (IQR 63–271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0–20 cells per μL vs >20 cells per μL) was not predictive of mortality (average hazard ratio 0·93, 95% CI 0·80–1·09).InterpretationMortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms.FundingNational Institutes of Health, President's Emergency Plan for AIDS Relief, National Institute for Health Research.
Abstract 14258: Associations of Triglycerides and Mortality Across eGFR strata in the NHANES Cohort
Authors: Taryn Benson-Hernandez, Christina Park, Maria Marroquin, Melissa Soohoo, Hamid Moradi, Carola-Ellen Kleine, Connie M Rhee, Csaba P Kovesdy, Kamyar Kalantar-Zadeh, Elani Streja
Journal: Circulation (2018)

Introduction: Prior studies have shown that while elevated serum triglycerides levels are associated with worse survival in the general population, they may not be associated with worse survival in...
Abstract 4314: Reduced m6A modification predicts malignant phenotypes and augmented tumorigenic signaling in gastric cancer
Authors: Cheng Zhang, Mengqi Zhang, Sai Ge, Xiaotin Lin, Wenwen Huang, Ying Gan, Jing Gao, Lin Shen
Journal: Cancer Research (2019)

Abstract Purposes: As the most abundant epigenetic modification on mRNAs and long non-coding RNAs, N6-methyladenosine (m6A) extensively exists in mammalian cells. Controlled by writers (methyltransferases), readers (signal transducers) and erasers (demethylases), m6A influences mRNA structure, maturation and stability, thus regulating protein expression in a post-transcriptional manner. Nevertheless, current understandings to m6A’s pathological roles in tumorigenesis, especially in gastric cancer (GC) remain to be unveiled. In this study, by incorporating multiple datasets and in vitro experiments, we assessed m6A’s clinical-pathological relevance to GC and explored the underlying mechanisms. Methods: The protein and mRNA expressions of canonical m6A regulators (METTL3/METTL14 as writers, YTHDF1/YTHDF2/YTHDF3 as readers and ALKBH5/FTO as erasers) were merged as signatures to indicate levels of m6A modification. Changes of clinical variables, mutations and molecules were assessed in patients with different m6A indications. Pathway and phenotype changes predicted to be affected by m6A were assessed in vitro with gastric cancer HGC27 and MG803 cell lines. Results: We discovered that writers and readers were potential tumor suppressive, while erasers were potential oncogenic factors in GC. Low-m6A modification was an indication for adverse clinical outcomes and was correlated with specific cancer driving mutations, including CDH1, AR and GLI3. Oncogenic signaling and phenotypes were selectively enriched in m6A groups. Through in vitro experiments, we proved that reduced m6A (represented by METTL14 knockdown) promoted GC proliferation and invasiveness potentially through activating Wnt and PI3K-Akt signaling, while restored m6A (represented by FTO knockdown) reversed these phenotypical and molecular changes. Conclusions: Our work demonstrated that m6A is a potential prognostic predictor in gastric cancer and further reveals the reduction of m6A activates oncogenic signaling and promotes gastric cancer malignancy. Citation Format: Cheng Zhang, Mengqi Zhang, Sai Ge, Xiaotin Lin, Wenwen Huang, Ying Gan, Jing Gao, Lin Shen. Reduced m6A modification predicts malignant phenotypes and augmented tumorigenic signaling in gastric 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 4314.
Detection of novel tick-borne pathogen, Alongshan virus, in Ixodes ricinus ticks, south-eastern Finland, 2019
Authors: Suvi Kuivanen, Lev Levanov, Lauri Kareinen, Tarja Sironen, Anne J. Jääskeläinen, Ilya Plyusnin, Fathiah Zakham, Petra Emmerich, Jonas Schmidt-Chanasit, Jussi Hepojoki, Teemu Smura, Olli Vapalahti
Journal: Eurosurveillance (2019)

The newly identified tick-borne Alongshan virus (ALSV), a segmented Jingmen virus group flavivirus, was recently associated with human disease in China. We report the detection of ALSV RNA in Ixodes ricinus ticks in south-eastern Finland. Screening of sera from patients suspected for tick-borne encephalitis for Jingmen tick virus-like virus RNA and antibodies revealed no human cases. The presence of ALSV in common European ticks warrants further investigations on its role as a human pathogen.