tbuckley/cabot-search huggingface dataset:
Abstract 1041: Casein kinase 2 modulates epithelial mesenchymal transition through <i>Helicobacter pylori</i> CagA dependent pathway in gastric cancer cells
Authors: SoDam Lee, Bo Ram Hwang, Jung Chang Yun, Byeong Min Yu, Yong Chan Lee
Journal: Cancer Research (2019)

Abstract Helicobacter pylori is the most important carcinogen in human gastric cancer. However, the pathogenic molecular mechanism which underlies the carcinogenesis in gastric cancer by H. pylori remains largely unknown. In this study, we understand that molecular biological mechanism related to gastric carcinogenesis by investigating the role of CK2 in EMT. Casein kinase 2 is a serine/threonine protein kinase and consists of two catalytic subunits (α or α’) and regulatory subunits (β). CK2 regulates many substrates and its involved in cell growth, proliferation, survival, angiogenesis, invasion. Epithelial-to-mesenchymal transition (EMT) is involved in many signaling pathways, but the key regulatory kinases in this process have not been clearly identified. In our previous study, we reported the cytotoxin-associated gene A (CagA) protein of H. pylori induces cell migration and invasion through increased CK2α activity in gastric epithelial cells. Although the role of CK2 catalytic subunits has remained largely uncharacterized, several studies have recently focused on regulator subunits in EMT. Here, we analyzed the expression level of CK2α did not altered, whereas CK2β decreased in CagA-dependent pathway. Moreover, expression of ectopic CK2β was downregulated by CagA. This suggests that CagA negatively regulates the stability of CK2β protein. We examined the level of ubiquitinated CK2β were higher in HP60190 infected cells than in control cells. Thus, CK2β is degraded by the proteasomal machinery following CagA of H. pylori. In addition, CagA binds both CK2α and CK2β, which results in suppression of CK2β binding by infected HP60190, but does not suppress CK2α binding. Furthermore, downregulation of CK2β increased Snail such as CK2 target genes, EMT-related marker in H. pylori-infected gastric cancer cells. Therefore, the role of Snail regulated by CK2β should be considered when developing cancer therapeutic. Overall, CK2 tetramer subunits might control the function of CagA and EMT related genes, thereby regulating CagA-dependent pathology. Taken together, the results of the present study suggest that the CK2 regulatory subunit has diverse effect on CagA-dependent cellular processes. A pharmacological activator or activator of CK2β may have potential as a therapeutic agent for gastric cancer associated with CagA. Citation Format: SoDam Lee, Bo Ram Hwang, Jung Chang Yun, Byeong Min Yu, Yong Chan Lee. Casein kinase 2 modulates epithelial mesenchymal transition through Helicobacter pylori CagA dependent pathway in gastric 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 1041.
Prognostic value of baseline SUV<sub>max</sub> in patients with advanced stage follicular lymphoma receiving frontline rituximab-based therapy.
Authors: Paolo Strati, Mohamed Amin Ahmed, Nathan Hale Fowler, Fredrick B. Hagemeister, Luis Fayad, Maria Alma Rodriguez, Felipe Samaniego, Michael Wang, Jason Westin, Jorge Enrique Romaguera, Mansoor Noorani, Karishma Phansalkar, Chan Cheah, Lei Feng, Richard Eric Davis, Loretta J. Nastoupil, Sattva Swarup Neelapu
Journal: Journal of Clinical Oncology (2019)

7540 Background: Positron emission tomography (PET) is recommended in follicular lymphoma (FL) for initial staging, evaluation of potential transformation, and response assessment. The prognostic value of pre-treatment PET scan has not been adequately explored. Methods: We performed a single-institution retrospective analysis of patients with advanced stage FL, without histological evidence of transformation, treated with frontline rituximab-based therapy, and analyzed the prognostic significance of baseline maximum standardized uptake value (SUV max ). Results: The median follow-up for the cohort was 94 months. Of 346 patients, 151 (44%) received R-CHOP and 195 (56%) received non-R-CHOP regimens. Among multiple single unit increments of SUV max , a value of &gt;18 showed the strongest association with progression-free survival (PFS) (hazard ratio [HR] 1.5, 95% confidence interval (CI) 0.95-2.3, p=0.08), and was selected as cut-off for further analysis. Fifty-two (15%) patients had a SUV max &gt; 18. On univariate analysis, factors associated with SUV max &gt; 18 were male sex (67% vs 52%, p=0.05), elevated β2-microglobulin (65% vs 47%, p=0.02), elevated LDH (37% vs 13%, p&lt;0.001), presence of B symptoms (35% vs 14%, p=0.01), and largest lymph node ≥ 6 cm (64% vs 30%, p&lt;0.001). On multivariate analysis, largest lymph node ≥ 6 cm was the only factor maintaining its association with SUV max &gt; 18 (odds ratio [OR] 2.7, 95% CI 1.3-5.3, p=0.006). SUV max &gt; 18 significantly associated with a lower CR rate among patients treated with non-R-CHOP regimens (45% vs 92%) (p&lt;0.001) but not among patients treated with R-CHOP (p=1). SUV max &gt; 18 associated with significantly shorter PFS among patients treated with non-R-CHOP regimens (77 months vs not reached, p=0.02), but not among patients treated with R-CHOP (p=0.73). SUV max &gt; 18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (15 year OS 70% vs 75%, p=0.02) and non-R-CHOP regimens (15 year OS 50% vs 75%, p=0.001). Conclusions: In conclusion, baseline SUV max has prognostic value in patients with advanced stage FL receiving rituximab-based therapies. Evaluation in prospective studies is needed to further confirm these findings.
Abstract 4114: NPM1 upregulates the transcription of PD-L1 and suppresses T-cell activity in triple negative breast cancer
Authors: Qian Long, Yizhuo Li, Ge Qin, Changlin Zhang, Dingbo Shi, Miao Chen, Shuihan Shi, Kefang Zhang, Wuguo Deng
Journal: Cancer Research (2019)

Abstract Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here we verified that triple-negative breast cancer (TNBC) had higher PD-L1 expression than other subtypes. We then discovered that nucleophosmin (NPM1) bound to PD-L1 promoter specifically in TNBC cells and activated PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrated that PARP1 suppressed PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which was required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevated PD-L1 expression in TNBC and exerted a synergistic effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a novel transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy. Citation Format: Qian Long, Yizhuo Li, Ge Qin, Changlin Zhang, Dingbo Shi, Miao Chen, Shuihan Shi, Kefang Zhang, Wuguo Deng. NPM1 upregulates the transcription of PD-L1 and suppresses T-cell activity in triple negative breast 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 4114.
Cognitive Change in Schizophrenia and Other Psychoses in the Decade Following the First Episode
Authors: Jolanta Zanelli, Josephine Mollon, Sven Sandin, Craig Morgan, Paola Dazzan, Izabela Pilecka, Tiago Reis Marques, Anthony S. David, Kevin Morgan, Paul Fearon, Gillian A. Doody, Peter B. Jones, Robin M. Murray, Abraham Reichenberg
Journal: American Journal of Psychiatry (2019)

Schizophrenia is associated with a marked cognitive impairment that is widely believed to remain stable after illness onset. Yet, to date, 10-year prospective studies of cognitive functioning following the first episode with good methodology are rare. The authors examined whether schizophrenia patients experience cognitive decline after the first episode, whether this decline is generalized or confined to individual neuropsychological functions, and whether decline is specific to schizophrenia.Participants were from a population-based case-control study of patients with first-episode psychosis who were followed prospectively up to 10 years after first admission. A neuropsychological battery was administered at index presentation and at follow-up to patients with a diagnosis of schizophrenia (N=65) or other psychoses (N=41) as well as to healthy comparison subjects (N=103).The schizophrenia group exhibited declines in IQ and in measures of verbal knowledge and of memory, but not processing speed or executive functions. Processing speed and executive function impairments were already present at the first episode and remained stable thereafter. The magnitude of declines ranged between 0.28 and 0.66 standard deviations. Decline in measures of memory was not specific to schizophrenia and was also apparent in the group of patients with other psychoses. Healthy individuals with low IQ showed no evidence of decline, suggesting that a decline is specific to psychosis.Patients with schizophrenia and other psychoses experience cognitive decline after illness onset, but the magnitude of decline varies across cognitive functions. Distinct mechanisms consequent to the illness and/or psychosocial factors may underlie impairments across different cognitive functions.
Abstract 1290: Development of anti inflammatory agents targeting TonEBP for treatment of chronic inflammatory diseases
Authors: Byeongjin YE, Hyug Moo Kwon, Soo Youn Choi, Jun Ho Lee, Hyun Je Kang, Cheol-Min Park
Journal: Cancer Research (2019)

Abstract Tonicity-responsive enhancer binding protein (TonEBP), also known as nuclear factor of activated T cells 5 (NFAT5), belongs to the Rel family of transcriptional factors which include NF-κB and NFAT. TonEBP is a key regulator in chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, diabetic nephropathy and hepatocellular carcinoma. TonEBP is a rate-limiting component of “pro-inflammatory enhanceosome” in which TonEBP provides a physical tether between activated transcription factors NF-κB and AP-1 to p300 and RNA polymerase II. Assembled in response to inflammatory signals, the pro-inflammatory enhanceosome drives the transcription of TNF-α, IL-1β, IL-6, MCP-1, iNOS, and COX-2. We discovered a class of compounds (CXs) targeting TonEBP. CXs blocked the assembly of the pro-inflammatory enhancesome and potently suppressed the inflammation-induced expression of TNF-α, IL-1β, IL-6, MCP-1, iNOS, and COX-2. Orally administered CXs exhibited remarkable therapeutic activities in mouse models of inflammatory arthritis. Using an alkynyl derivative of a CX and click reaction, we found that CX was covalently attached to TonEBP by alkylation but not to other components of the enhanceosome. Cells harboring a site-directed mutant TonEBP molecule whose amino acid residues for the alkylation were removed exhibited a markedly reduced sensitivity to CXs. These data demonstrate that CXs are a new class of anti-inflammatory agents with a novel mode of action. Citation Format: Byeongjin YE, Hyug Moo Kwon, Soo Youn Choi, Jun Ho Lee, Hyun Je Kang, Cheol-Min Park. Development of anti inflammatory agents targeting TonEBP for treatment of chronic inflammatory diseases [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 1290.
Abstract 3146: MFG-E8: A novel prognostic marker for gastric cancer
Authors: Sai Ge, Jing Gao, Lin Shen
Journal: Cancer Research (2019)

Abstract Gastric cancer is one of the leading causes of cancer-related death all over the world. Milk fat globule-epidermal growth factor (EGF)-factor VIII (MFG-E8) was found to be highly unregulated in a variety of cancers, could induce phagocytosis of apoptotic cells and a significant factor in immune systems. However, its prognostic potential has not been evaluated in gastric cancer (GC). In our former proteomic study, MFG-E8 was found significantly overexpressed in gastric cancer tissues comparing with paired non-cancerous gastric tissues. This study aimed to analyze the association between the expression of MFG-E8 in GC tissues and clinical outcomes in GC patients. In this study, 3 independent cohorts (GSE15460, n = 192; TCGA, n = 380 and ACRG, n = 300) were used to assess MFG-E8 as a biomarker, Kaplan-Meier survival analysis showed that its overexpression was associated with poor prognosis of GC with good discriminative ability in 3 independent cohorts (GSE15460, P &amp;lt;0.001; TCGA, P &amp;lt;0.001 and ACRG, P &amp;lt;0.001). Multivariate analysis further confirmed its prognostic significance (GSE15460, P =0.028; TCGA, P &amp;lt;0.001 and ACRG, P =0.012). These results suggest MFG-E8 may become a potential prognostic factor for GC. Note: This abstract was not presented at the meeting. Citation Format: Sai Ge, Jing Gao, Lin Shen. MFG-E8: A novel prognostic marker for 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 3146.
Abstract 3538: Analysis of error profiles in deep next-generation sequencing data
Authors: Xiaotu Ma, Jinghui Zhang
Journal: Cancer Research (2019)

Abstract Background Sequencing errors are a key confounding factor for detecting low frequency genetic variants for cancer screening, testing, treatment and surveillance through deep next-generation sequencing (NGS). However, there is a lack of comprehensive understanding of errors introduced at various steps of a conventional NGS workflow, such as sample handling, library preparation, enrichment PCR, and sequencing. In this study we systematically investigated the above question by using the current NGS technology. Results We discovered that the substitution error rate can be computationally suppressed to 10-5~10-4, which is 10~100-fold lower than current reports. We then quantified substitution errors attributable to sample handling, library preparation, enrichment PCR, and sequencing using multiple deep sequencing datasets from multiple sequencing centers. We show that 1) error rate differs by nucleotide substitution types, ranging from 10-5 for A&amp;gt;C/T&amp;gt;G, C&amp;gt;A/G&amp;gt;T, and C&amp;gt;G/G&amp;gt;C changes to 10-4 for A&amp;gt;G/T&amp;gt;C changes; 2) C&amp;gt;T/G&amp;gt;A errors exhibit strong sequence context dependency; 3) sample-specific effects dominate elevated C&amp;gt;A/G&amp;gt;T errors; 4) target enrichment PCR lead to ~6-fold increase of overall error rate; 5) more than 70% of hotspot variants, such as BRAF V600E, can be detected at 0.1%~0.01% frequency with the current NGS technology by applying in-silico error suppression. Conclusions We present the first comprehensive analysis of error sources in conventional NGS workflows. The error profiles revealed by our study highlight new directions for further improving NGS accuracy both experimentally and computationally which will lead to enhanced precision for deep sequencing. Citation Format: Xiaotu Ma, Jinghui Zhang. Analysis of error profiles in deep next-generation sequencing data [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 3538.
Abstract 2344: The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma
Authors: Martin K. Thomsen
Journal: Cancer Research (2019)

Abstract Activation of the STING pathway is currently being explored in cancer immune therapy. The first STING agonist tested was DMXAA, but failed in clinical trial, since it does not bind human STING. The second generation of STING agonists are cyclic di-nucleotides (CDNs), either the naturally produced 2’3’ cyclic GMP-AMP or derivatives, and many of these has proven to have high affinity for all common human variations of STING. In our work, we have focused on 3’3’-cyclic 3’3’-cAIMP (Invivogen) for analysis of anticancer activity in mice. Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. We have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase 3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning, revealed that the majority of tumors regressed in response to CDN, but new tumors were detected, which were unresponsive to CDN treatment. Conclusion: modulation of the STING pathway impacts on development of HCC, and holds promise for use in treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care. Citation Format: Martin K. Thomsen. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma [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 2344.
Abstract 4284: Targeting notch signaling in glioblastoma cancer stem cells through modulation of Connexin43 function
Authors: Michael Lunski, James Smyth, Jennifer Vaughn, Zhi Sheng, Robert Gourdie, Benjamin Purow, Samy Lamouille
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is a highly malignant and lethal cancer of the central nervous system for which there has been limited progress in improving patient outcomes despite intensive research efforts. The current multimodal therapy for newly diagnosed GBM patients includes surgical resection, radiotherapy and cytotoxic chemotherapy with temozolomide (TMZ), conferring a median survival time of just 14.6 months. Failure to generate more effective treatment strategies is due to 1) the infiltrative nature of GBM tumor cells preventing complete surgical resection, and 2) the cellular heterogeneity within GBM tumors, which often comprise a sub-population of GBM cancer stem cells (GSCs) characterized by self-renewal characteristics and resistance to chemotherapeutic alkylating agents including TMZ. Multiple signaling pathways, including Notch, participate to the formation and maintenance of GSCs. Recent studies, including our research, have shown that increased levels of gap junction protein Connexin43 (Cx43) correlate with TMZ resistance in GBM cells and inversely correlated with GBM patient survival. Importantly, Cx43 has also been associated with anti-proliferative effects in glioma, and reduced levels of Cx43 protein occur in high-grade gliomas. Therefore, we hypothesized that altering Cx43 localization and/or activity rather than Cx43 expression represents a potent strategy for GBM treatment. Regulating Cx43 function is primarily associated with the multiple sites for post-translational modifications and protein-protein interactions within the Cx43 carboxy-terminus. Our research identifies crosstalk between Cx43 and Notch signaling in GSCs. Using a Cx43 carboxy-terminus mimetic peptide that modulates non-junctional functions of Cx43, we observe a decrease in Notch1 protein expression and reduced transcription of its downstream targets Hes1 and Hey1 in GSCs derived from patient tumors. Most importantly, our Cx43 mimetic peptide decreases cell survival in TMZ-resistant GSCs, limits GSC neurosphere formation in vitro, and inhibits GSC-derived tumor growth in vivo. Our current research aims at dissecting the molecular mechanisms of Cx43 functions on Notch signaling in GSCs using this Cx43 mimetic peptide. In conclusion, we have identified a novel therapeutic opportunity to decrease the tumorigenic potential of GSCs through altering Cx43 activity and Notch signaling to target chemoresistant GSCs in GBM treatment. Citation Format: Michael Lunski, James Smyth, Jennifer Vaughn, Zhi Sheng, Robert Gourdie, Benjamin Purow, Samy Lamouille. Targeting notch signaling in glioblastoma cancer stem cells through modulation of Connexin43 function [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 4284.
Crenolanib versus midostaurin combined with induction and consolidation chemotherapy in newly diagnosed <i>FLT3</i> mutated AML.
Authors: Richard M. Stone, Eunice S. Wang, Aaron David Goldberg, Kendra Lynn Sweet, Amir Tahmasb Fathi, Hongtao Liu, Boo Messahel
Journal: Journal of Clinical Oncology (2019)

TPS7068 Background: Despite the approval of multi-targeted protein kinase inhibitor midostaurin for use in combination with chemotherapy which improves 5-year survival in newly diagnosed (NDx) acute myeloid leukemia (AML) associated with FLT3 mutations; the cumulative incidence of relapse in FLT3 mutant AML remains high, with progression often characterized by secondary FLT3-TKD mutations. Crenolanib is a potent pan- FLT3 inhibitor that has shown promising efficacy and tolerability in combination with chemotherapy in Phase 1/2 trials for AML patients with FLT3-ITD or - TKD mutations. This is the first globally initiated, randomized Phase 3 trial comparing the efficacy of two FLT3-TKIs, crenolanib and midostaurin, combined with intensive chemotherapy in NDx FLT3-mutated AML patients. Methods: This Phase 3, randomized, multi-center trial will be conducted at multiple sites worldwide, with a target enrollment of 510 subjects. Patient inclusion was modified to match the midostaurin RATIFY criteria to enroll NDx FLT3-mutated AML (18 – 60 yo), who are eligible for intensive chemotherapy; with the addition of any FLT3-ITD and/or -TKD mutations being eligible. All subjects will receive TKI treatment and will be randomized in a 1:1 ratio to receive either crenolanib (arm A) or the active-control, midostaurin (arm B). All patients will be treated with 7+3 (100 mg/m 2 IV cytarabine; 90 mg/m 2 IV daunorubicin) and can initiate treatment while awaiting FLT3 results prior to randomization. Consolidation could include chemotherapy (3000 mg/m 2 IV HiDAC) for up to 4 cycles and/or Allo-HSCT, depending on patient condition. During induction and consolidation patients on arm A will take crenolanib (100 mg TID) from d9 until 72h prior to the next cycle, and patients on arm B will take midostaurin (50 mg BID) on d8 to d21 of each cycle. Following consolidation or HSCT, patients may receive up to 12 months of FLT3-TKI maintenance. Maintenance efficacy will be evaluated over time using single-cell sequencing to assess MRD. Primary endpoint is event-free survival. Interim analyses will occur at approximately 178 and 267 events, and primary analysis at 356 events. Enrollment is underway as of January 31, 2019. Clinical trial information: NCT03258931.