tbuckley/cabot-search huggingface dataset:
Abstract 5215: Inhibition of PIM kinases targets synthetic vulnerabilities and enhances antigen presentation in B cell lymphoma
Authors: Patrizia Mondello, Chiara Tarantelli, Luciano Cascione, Alberto J. Arribas, Andrea Rinaldi, Anas Younes, Francesco Bertoni
Journal: Cancer Research (2020)

Abstract The PIM kinases are highly expressed in activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). Oncogenic cooperation between PIMs and MYC has been demonstrated. Transgenic mice co-expressing Eμ-PIM and Eμ-MYC showed accelerated lymphomagenesis. Conversely, knockdown of PIMs dramatically decreased cMYC levels and lowered tumor incidence. Based on these preclinical data, a treatment strategy aiming at disrupting the oncogenic cooperation between PIMs and MYC may improve the outcome of DLBCL. Therefore, we treated a panel of DLBCL cell lines with increasing dose of the clinically relevant pan-PIM inhibitor (PIMi) AZD1208 (from 0.1 to 10μM) for 48 hours (Hrs), which resulted in a dose-dependent growth inhibition with a stronger efficacy in ABC DLBCL cell lines. The analysis of a CRISPR loss-of-function screening in three ABC (LY3, TMD8, HBL1) and three GCB (SUDHL-4, Pfeiffer, BJAB) DLBCL cell lines (Reddy et al, 2017) showed that PIM2 silencing led to significantly decreased viability irrespective of cell-of-origin, suggesting that this oncogene is essential for cell proliferation in DLBCLs. To identify the genes through which PIMs drive the lymphoma phenotype we performed gene expression profiling using 4 ABC DLBCL cell lines (RIVA, TMD8, SUDHL-2, U2932) treated with either DMSO or AZD1208 at 1μM for 4, 8 and 12 Hrs. We observed induction of 3,439 genes whereas 2,473 genes were downregulated. Gene pathway analysis showed that AZD1208 led to downregulation of genes regulated by MYC, including its known downstream p53 and NFKB target genes. On the other hand, AZD1208 treatment broadly induced MHC class II and antigen presentation genes as well as PI3K/AKT, cell cycle and glutaminase genes. Using a high-throughput screening approach, we found that the inhibitors of cell cycle (such as the BCL2 inhibitor venetoclax/ABT199 and the PLK4 inhibitor CFI-400945) and of glutaminase (CB839) enhanced the antiproliferative effect of AZD1208, whereas combinations with the PI3K/AKT/mTOR inhibitors had negligible synergistic effect. In conclusion, our study revealed previously unknown mechanisms of action of PIM inhibitors and provides a framework for future combination strategies. Citation Format: Patrizia Mondello, Chiara Tarantelli, Luciano Cascione, Alberto J. Arribas, Andrea Rinaldi, Anas Younes, Francesco Bertoni. Inhibition of PIM kinases targets synthetic vulnerabilities and enhances antigen presentation in B cell lymphoma [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 5215.
Incorporating Magnetic Resonance Imaging and Biomarkers in Active Surveillance Protocols - Results From the Prospective Stockholm3 Active Surveillance Trial (STHLM3AS)
Authors: Henrik Olsson, Tobias Nordström, Fredrik Jäderling, Lars Egevad, Hari T Vigneswaran, Magnus Annerstedt, Henrik Grönberg, Martin Eklund, Anna Lantz
Journal: JNCI Journal of the National Cancer Institute (2020)

Active surveillance (AS) for men with low-risk prostate cancer (PC) can lead to patient morbidity and healthcare overutilization. The aim of this study was to evaluate an AS protocol using the Stockholm3 test and magnetic resonance imaging (MRI) to reduce biopsy intensity.We conducted a prospective multicenter study of 280 invited men from a contemporary screening study (STHLM3), with Gleason Score (GS) 3 + 3 PC on a current AS protocol. Patients underwent prostate-MRI and blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic variants, and clinical variables to predict risk of GS ≥3 + 4 PC followed by systematic biopsies and targeted biopsies (for Prostate Imaging Reporting and Data System version 2 ≥3 lesions) in all men. Primary outcomes were reclassification to GS ≥3 + 4 PC and clinically significant PC (csPCa), including unfavorable intermediate risk PC or higher based on National Comprehensive Cancer Network guidelines.Adding MRI-targeted biopsies to systematic biopsies increased sensitivity of GS ≥3 + 4 PC compared with systematic biopsies alone (relative sensitivity [RS] = 1.52, 95% confidence interval [CI] = 1.28 to 1.85). Performing biopsies in only MRI positive increased sensitivity of GS ≥3 + 4 PC (RS = 1.30, 95% CI = 1.04 to 1.67) and reduced number of biopsy procedures by 49.3% while missing 7.2% GS ≥3 + 4 PC and 1.4% csPCa. Excluding men with negative Stockholm3 test reduced the number of MRI investigations at follow-up by 22.5% and biopsies by 56.8% while missing 6.9% GS ≥3 + 4 PC and 1.3% csPCa.Including MRI and targeted/systematic biopsies in the follow-up for men on AS increased sensitivity of PC reclassification. Incorporation of risk prediction models including biomarkers may reduce the need for MRI use in men with low-risk PC.
Abstract 5356: Targeted in vivo delivery of NF-κB decoy oligodeoxynucleotide augments efficacy of radiation therapy against B-cell lymphomas
Authors: Zhuoran zhang, Xingli Zhao, Dayson Moreira, Yu-Lin Su, Piotr Swiderski, Stephen Forman, Larry Kwak, Marcin Kortylewski
Journal: Cancer Research (2020)

Abstract Despite recent advances in the treatment of non-Hodgkin B-cell lymphoma (BCL), significant numbers of patients relapse or remain refractory to current therapies. Treatment resistance in BCL is associated with survival signaling via NF-κB transcription factor. While NF-κB is an attractive molecular target in BCL and many other human cancers, as a transcription factor it remains undruggable. Here, we describe a B-cell-selective NF-κB inhibitor consisting of a NF-κB-specific decoy oligodeoxynucleotide (dODN) conjugated to a type B CpG ODN sequence targeting Toll-like receptor-9 (TLR9)-expressing B-cell lymphoma cells. Bc-NFκBdODN showed efficient uptake by human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), such as U2932, OCI-Ly3 and Jeko1, respectively. In addition, we confirmed that Bc-NFκBdODN inhibited nuclear translocation and DNA-binding activity of NF-κB together with the expression of CCND2 and MYC target genes. In vitro Bc-NFκBdODN enhanced direct and ionizing radiation-induced cytotoxicity in lymphoma cells. In xenotransplanted models of human U2932 and Ly3 lymphomas, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors and effectively arrested lymphoma progression when combined with a single, local 3Gy or 10Gy dose of radiation. In immune-competent mice, intratumoral treatment with Bc-NFκBdODN abrogated growth of directly treated as well as distant A20 lymphomas and triggered CD8+ T cell-mediated anti-tumor immune responses. Bc-NFκBdODN but not control Bc-scrambled oligonucleotides downregulated PD-1 expression on CD8+ and CD4+ T cells, while reducing Treg percentage in tumor draining lymph nodes (TDLN). Bc-NFκBdODN treatment also downregulated PD-L1 on tumor-associated myeloid cells and reduced percentage of tumor-infiltrating M-MDSCs. Our results underscore clinical relevance of NF-κB-specific decoy strategy, which can restore efficacy of standard radiation therapy to benefit patients with resistant or relapsed BCL. Citation Format: Zhuoran zhang, Xingli Zhao, Dayson Moreira, Yu-Lin Su, Piotr Swiderski, Stephen Forman, Larry Kwak, Marcin Kortylewski. Targeted in vivo delivery of NF-κB decoy oligodeoxynucleotide augments efficacy of radiation therapy against B-cell lymphomas [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 5356.
PTU-013 Trends in certification for gastrointestinal endoscopy and variations between trainee specialties: results from the uk jets database
Authors: K Siau, J Anderson, I Beales, R Broughton, M Feeney, N Hawkes, B McKaig, R Pullan, S Thomas-Gibson, R Valori, G Johnson, C Wells, P Dunckley
Journal: Gut (2017)

Introduction  In the UK, endoscopy certification is overseen by the Joint Advisory Group (JAG). Since 2011, e-certification has been awarded for upper and lower GI endoscopy via the JAG Electronic Training System (JETS). We aimed to analyse trends in endoscopy e-certification, and assess for differences between trainees in gastroenterology (GI), surgical (GS) and non-medical endoscopists (NME).  Method  We prospectively identified trainees awarded certification for gastroscopy, flexible sigmoidoscopy (FS) and colonoscopy from the JETS database. For each specialty, we collected data on lifetime procedural counts, formative assessments, and key performance indicators (KPIs) at the time of certification. Comparisons between specialties were analysed using a combination of chi2, Mann-Whitney and median tests  Results  Between June 2011-Dec 2016, 2857 applications were awarded certification. Since 2013, numbers for gastroscopy and provisional colonoscopy have reached steady state, whilst certification for sigmoidoscopy and full colonoscopy continue to increase (Figure 1). Trainees awarded certification comprised mainly of GI (53.2%), GS (28.5%) and NME (15.8%) trainees. GI trainees were awarded the greatest share of certification for each endoscopic modality, except for FS, which was mainly awarded to NME (78.3%). Median procedural numbers (p GI>GS. Caecal intubation rates (CIR) at full certification were similar between GI (95.6%) and GS (95.6%, p=0.81), but lower in NME (93.6%, p=0.02 vs. GS, p=0.006 vs. GI), despite no differences at provisional certification (median CIR 95.6%, p=0.32). Rates of D2 intubation (median 98.7%) varied across groups (GS>GI>NME, p=0.002). Certification awarded at first attempt were similar across specialties (mean 89.4%, p=0.19), but varied for gastroscopy (NME 95.5%, GS 90.1%, GI 89.7%, p=0.01).  Conclusion  Despite variations amongst trainee specialties, endoscopy certification is a transparent and robust benchmark for assessing competency, as evidenced by trainee KPIs. Further studies are required to study the impact of recent changes to certification, and if variations in KPIs exist following certification.  Disclosure of Interest  None Declared
Contributions of alveolar epithelial cell quality control to pulmonary fibrosis
Authors: Jeremy Katzen, Michael F. Beers
Journal: Journal of Clinical Investigation (2020)

Epithelial cell dysfunction has emerged as a central component of the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent a metabolically active lung cell population important for surfactant biosynthesis and alveolar homeostasis. AT2 cells and other distal lung epithelia, like all eukaryotic cells, contain an elegant quality control network to respond to intrinsic metabolic and biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, and dysregulated telomeres. Failed AT2 quality control components (the ubiquitin-proteasome system, unfolded protein response, macroautophagy, mitophagy, and telomere maintenance) result in diverse cellular endophenotypes and molecular signatures including ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory cell recruitment, profibrotic signaling, and altered progenitor function that ultimately converge to drive downstream fibrotic remodeling in the IPF lung. As this complex network becomes increasingly better understood, opportunities will emerge to identify targets and therapeutic strategies for IPF.
Gain of LINC00624 Enhances Liver Cancer Progression by Disrupting the Histone Deacetylase 6/Tripartite Motif Containing 28/Zinc Finger Protein 354C Corepressor Complex
Authors: Zhe Li, Xinyuan Lu, Yanfang Liu, Jingjing Zhao, Shengzhe Ma, Haoxiang Yin, Shenglin Huang, Yingjun Zhao, Xianghuo He
Journal: Hepatology (2020)

Background and Aims Long noncoding RNAs (lncRNAs) are involved in almost every stage of tumor initiation and progression. Here, we have identified an antisense lncRNA, LINC00624, that arises from the antisense strand of chromo‐domain‐helicase‐DNA‐binding protein 1‐like ( CHD1L ), located on chr1q21.1, with significant copy number gain and transcriptional activation of CHD1L and B‐cell CLL/lymphoma 9 protein (BCL9), in hepatocellular carcinoma (HCC). Approach and Results Overexpression of LINC00624 enhances tumor growth and metastasis in vitro and in vivo . Mechanistically, higher levels of LINC00624 strengthen the interaction between histone deacetylase 6 (HDAC6) and tripartite motif containing 28 (TRIM28), which accelerates HDAC6 ubiquitination and degradation. Moreover, LINC00624 binds to the RBCC domain of TRIM28, inhibits trimer formation, and weakens the interaction between TRIM28 and zinc finger protein 354C (ZNF354C). Thus, LINC00624 overexpression disrupts the formation of the HDAC6‐TRIM28‐ZNF354C transcriptional corepressor complex, resulting in the dissociation of the complex from the promoter of CHD1L and BCL9 , thereby removing transcription inhibition. Conclusions Our findings suggest that LINC00624 acts as a molecular decoy that sequesters the HDAC6‐TRIM28‐ZNF354C transcriptional corepressor complex away from the specific genomic loci, and that it can potentially be a therapeutic target in HCC.
Abstract 2335: Heterozygous <i>PALB2</i> mutations cause replication stress and DNA repair defects in carrier derived lymphoblastoid cell lines
Authors: Niina Laurila, Kerstin Borgmann, Muthiah Bose, Felix Meyer, Katri Pylkäs, Bing Xia, William Foulkes, Melissa Southey, Helmut Pospiech, Robert Winqvist
Journal: Cancer Research (2020)

Abstract During the last decade, PALB2 has been defined as a high-risk breast cancer susceptibility gene alongside BRCA1 and BRCA2. Heterozygous mutation in PALB2 increases the lifetime breast cancer risk of female carriers to an average of 53%, but the risk estimate is affected by family history, studied population, and the specific pathogenic variant. We have previously shown that lymphoblastoid cell lines (LCLs) of persons heterozygous for PALB2 c.1592delT, a Finnish founder mutation, show defects in DNA replication and damage response. Now we examine how various heterozygous, protein-truncating PALB2 founder mutations from different populations affect cell function, and whether the observed phenotype correlates with disease risk. The study cohorts come from Canada, Australia, and Finland and consist of 80 LCLs of PALB2 mutation carriers (c.1592delT, c.2323C&amp;gt;T, c.3113G&amp;gt;A or c.3323delA) and suitable population controls. There is some evidence that these variants are associated with different magnitudes of breast cancer risk, and PALB2 c.3113G&amp;gt;A has been associated with an exceptionally high cancer risk of 91% (95% CI 44-100) to age 70. Utilizing these LCLs, we have studied DNA damage response, cell cycle progression, and DNA replication with various methods. DNA fiber assay results show that PALB2 mutation carriers elongate their DNA more slowly during replication, likely due to increased fork stalling, but compensate this by increased dormant origin firing. The strongest replication phenotype was observed for PALB2 c.3113G&amp;gt;A carriers. High content analysis shows that most of the mutation carriers had compromised RAD51 foci formation after DNA damage, whereas 53BP1 foci levels were elevated. These results indicate that during DNA double-strand break repair, heterozygous PALB2 mutation carriers may rely more on alternative, error-prone pathways that are independent of RAD51, thus contributing to genomic instability. Additionally, we are currently performing RNA-Seq to determine if the LCLs show adaptation of their gene expression in response to pathogenic PALB2 variants. Citation Format: Niina Laurila, Kerstin Borgmann, Muthiah Bose, Felix Meyer, Katri Pylkäs, Bing Xia, William Foulkes, Melissa Southey, Helmut Pospiech, Robert Winqvist. Heterozygous PALB2 mutations cause replication stress and DNA repair defects in carrier derived lymphoblastoid cell lines [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 2335.
Abstract 3670: Development of cfDNA-based methylation assay for early cancer detections
Authors: Binggang Xiang, Zhixin Zhao, Maya Stevens, Chao Dai, Feng Xie, Xiaohong Wang, Kemin Zhou, Shidong Jia, Pan Du, Jianjun Yu
Journal: Cancer Research (2020)

Abstract Introduction: DNA methylation is the essential epigenetic mechanism of cell regulation, and one of the earliest signatures in cancer development. Blood-based DNA methylation has been tested for cancer early detection. Several methods have been used for DNA methylation sequencing, which include whole genome bisulfite sequencing (WGBS) and antibody-dependent DNA immunoprecipitation (MeDIP). However, WGBS has known issues of DNA loss and fragmentations, and MeDIP only captures the methylated DNA regions and are biased. Therefore, methods that can accurately quantify DNA methylation status while keeping DNA less damaged and loss are highly needed, especially for liquid biopsy at early cancer stages (due to its low cfDNA amount). Methods: We developed a probe capture-based cfDNA methylation assay using proprietary in-house developed liquid biopsy NGS platform and DeepSEA software algorithm. Analytic assay validation has been conducted using reference materials with known methylation profiles. Both cell line gDNA with known methylation profiles and plasma cfDNA from patients were used for this methylation study. Methylation profiles, DNA damages, and losses were evaluated and compared. Fragment distribution and copy number variations (CNV) were compared between untreated and treated samples. Results: In this study, we developed a cfDNA-based methylation assay that measures DNA methylation status and genomic profiling simultaneously. Using both cell line gDNA and plasma cfDNA, the assay detects both methylation change and genomic alterations, including fragment size distribution and CNV in a single test. Discussion: The successful development of cfDNA methylation assay could help identify cancer at its early stage. It also enables the detection and monitoring of minimal residual disease (MRD) and in obtaining information on therapeutic targets and resistance mechanisms relevant to the management of personalized cancer care. Citation Format: Binggang Xiang, Zhixin Zhao, Maya Stevens, Chao Dai, Feng Xie, Xiaohong Wang, Kemin Zhou, Shidong Jia, Pan Du, Jianjun Yu. Development of cfDNA-based methylation assay for early cancer detections [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 3670.
Abstract 4063: Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells
Authors: Andrew Fesler, Ga-Ram Hwang, John Yuen, Jingfang Ju
Journal: Cancer Research (2020)

Abstract Evasion of apoptosis is one of the major hallmarks of cancer and an important factor in chemoresistance. Thus, targeting apoptosis regulation is an important therapeutic approach. Anti-apoptotic BCL2, an oncogene and therapeutic target, is overexpressed in several different cancer types. There have been various approaches developed to target BCL2 including the FDA approved Venetoclax. In this study we have developed a modified siRNA against BCL2 that has enhanced efficacy and also can be delivered into cancer cells without any vehicle. We developed this siRNA by replacing uracil residues in the siRNA with 5-flurouracil (5-FU). This modification incorporates the effects of both 5-FU and siBCL2, to have an enhanced therapeutic effect. We tested several different modified siBCL2's, one with only the sense strand modified, one with only the antisense strand modified and one with both strands modified. We found the modified siBCL2 with both strands modified with 5-FU was most effective at inhibiting BCL2. Importantly, we were able to demonstrate via qRT-PCR and Western blot, that this modified siBCL2 retains its siRNA function and inhibits BCL2 expression in several different cancer types including colon cancer, lung cancer and lymphoma. In addition, in lymphoma cells, we found that our modified siBCL2 has better efficacy than BCL2 inhibitor Venetoclax. Finally, we were able to demonstrate that modified siBCL2 can be delivered into cancer cells without a delivery vehicle. This unique feature may be significant in overcoming the challenge of delivery, which remains a major obstacle for RNA therapeutics. This modified siBCL2 has therapeutic potential for several different cancers. Beyond BCL2, the modification approach we demonstrated may be applicable to other siRNAs and has potential as a platform technology for siRNA based therapeutics. Citation Format: Andrew Fesler, Ga-Ram Hwang, John Yuen, Jingfang Ju. Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4063.
Pharmacological Approaches to Managing Violence and Aggression in Prison Populations: Clinical and Ethical Issues
Authors: Michael Weightman, Ranjit Kini, Robert Parker, Mrigendra Das
Journal: Drugs (2020)

Violence and aggression are common problems encountered in prison, which frequently require clinical intervention. This increased prevalence is partially attributable to the high morbidity of psychiatric and personality disorders in prison inmates. As prisons are non-therapeutic environments, the provision of clinical care becomes more complex. This article examines the general principles of management of violence and aggression in prison settings, with a particular focus on the clinical and ethical considerations that guide pharmacological approaches. Use of psychotropic medication to address these problems is reserved for situations where there is (i) a diagnosable psychiatric disorder, or (ii) a significant risk of harm to an individual without urgent intervention. Initial focus should be on environmental and behavioural de-escalation strategies. Clear assessment for the presence of major mental illness is crucial, with appropriate pharmacological interventions being targeted and time-limited. Optimising management of any underlying psychiatric conditions is an important preventative measure. In the acute setting, rapid tranquilisation should be performed according to local guidelines with a focus on oral prior to parenteral administration. Clinicians must be mindful of capacity and consent issues amongst prisoners to protect patient rights and guide setting of care.
Timing Is Everything: Misincorporation of 8oxodG during Mitosis Is Lethal
Authors: Khadijeh Alnajjar, Joann B. Sweasy
Journal: Cancer Research (2020)

Abstract Exploiting universal cancer vulnerabilities has been used as an approach for developing targeted therapies. In this issue of Cancer Research, Rudd and colleagues show that the dual-functioning inhibitor TH588 potentiates the accumulation of reactive oxygen species during mitosis in cancer by disturbing mitotic progression and simultaneously inhibiting the hydrolysis of 8oxodGTP. This leads to increased incorporation of 8oxodG into the DNA during mitotic replication and increased toxicity. Understanding the mechanism of this inhibitor lays the groundwork for identifying cancer targets. See related article by Rudd et al., p. 3530