tbuckley/cabot-search huggingface dataset:
Abstract A79: A novel small molecule, LLL12B, inhibits STAT3 Phosphorylation and sensitizes ovarian cancer cell to cisplatin and paclitaxel treatment
Authors: Ruijie Zhang, Xiaozhi Yang, Jiayuh Lin
Journal: Clinical Cancer Research (2020)

Abstract Constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling plays an important role in many malignant progressions: cell viability, cell migration, cell growth, chemotherapy resistance, and so on. We developed a nonpeptide small molecule, LLL12B, though structure-based design, which targets STAT3 and was confirmed to inhibit STAT3 phosphorylation (tyrosine 705) and induce apoptosis as indicated by the increases of cleaved caspase-3 in human ovarian cancer cells. LLL12B, also inhibits the cell viability, cell migration, and cell growth in ovarian cancer cells. In addition, LLL12B combined treatment with paclitaxel or cisplatin exhibited greater inhibition of cell viability, cell migration, and cell growth than monotherapy in ovarian cancer cells. Furthermore, LLL12B and paclitaxel or cisplatin combination also showed greater inhibition of cell viability, cell migration, and cell colony than cisplatin and paclitaxel combinational treatment, which is a current ovarian cancer standard care therapy. Also, LLL12B combined with paclitaxel and cisplatin showed greater inhibition of cell viability and cell colony than each combinational treatment of two drugs. In summary, our results indicated that the novel small molecule LLL12B is a potent STAT3 inhibitor in ovarian cancer cells. Our results also indicate that the combinational treatment of LLL12B with cisplatin or/and paclitaxel exhibits potent inhibitory activity in ovarian cancer cells, supporting this drug combination as a potential therapeutic strategy for ovarian cancer. Citation Format: Ruijie Zhang, Xiaozhi Yang, Jiayuh Lin. A novel small molecule, LLL12B, inhibits STAT3 Phosphorylation and sensitizes ovarian cancer cell to cisplatin and paclitaxel treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A79.
Change in MRI-PDFF and Histologic Response in Patients With Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis
Authors: Jonathan G. Stine, Nagambika Munaganuru, Abbey Barnard, Jennifer L. Wang, Kellee Kaulback, Curtis K. Argo, Siddarth Singh, Kathryn J. Fowler, Claude B. Sirlin, Rohit Loomba
Journal: Clinical Gastroenterology and Hepatology (2020)
A novel antiviral lncRNA, EDAL, shields a T309 O-GlcNAcylation site to promote EZH2 lysosomal degradation
Authors: Baokun Sui, Dong Chen, Wei Liu, Qiong Wu, Bin Tian, Yingying Li, Jing Hou, Shiyong Liu, Juan Xie, Hao Jiang, Zhaochen Luo, Lei Lv, Fei Huang, Ruiming Li, Chengguang Zhang, Yuling Tian, Min Cui, Ming Zhou, Huanchun Chen, Zhen F. Fu, Yi Zhang, Ling Zhao
Journal: Genome biology (2020)

Abstract Background The central nervous system (CNS) is vulnerable to viral infection, yet few host factors in the CNS are known to defend against invasion by neurotropic viruses. Long noncoding RNAs (lncRNAs) have been revealed to play critical roles in a wide variety of biological processes and are highly abundant in the mammalian brain, but their roles in defending against invasion of pathogens into the CNS remain unclear. Results We report here that multiple neurotropic viruses, including rabies virus, vesicular stomatitis virus, Semliki Forest virus, and herpes simplex virus 1, elicit the neuronal expression of a host-encoded lncRNA EDAL. EDAL inhibits the replication of these neurotropic viruses in neuronal cells and rabies virus infection in mouse brains. EDAL binds to the conserved histone methyltransferase enhancer of zest homolog 2 (EZH2) and specifically causes EZH2 degradation via lysosomes, reducing the cellular H3K27me3 level. The antiviral function of EDAL resides in a 56-nt antiviral substructure through which its 18-nt helix-loop intimately contacts multiple EZH2 sites surrounding T309, a known O -GlcNAcylation site. EDAL positively regulates the transcription of Pcp4l1 encoding a 10-kDa peptide, which inhibits the replication of multiple neurotropic viruses. Conclusions Our findings show that a neuronal lncRNA can exert an effective antiviral function via blocking a specific O -GlcNAcylation that determines EZH2 lysosomal degradation, rather than the traditional interferon-dependent pathway.
Abstract 3833: Epigenetic regulation of cell state transitions and the therapeutic implications in breast cancer
Authors: Li Ping Toh, Ser Yue Loo, Wai Leong Tam
Journal: Cancer Research (2020)

Abstract During cancer progression, cells would reversibly transit among different cell states that differ in their competence to contribute towards tumor growth, survival, and metastasis. The activation of epithelial-mesenchymal transition (EMT) program in cancer cells has often been attributed to enhanced tumorigenic potential and a gain of therapeutic resistance. We hypothesized that by promoting mesenchymal-epithelial transition (MET), the reverse process of EMT, it could induce a loss of tumorigenic potential and increase susceptibility to standard chemotherapeutics. As EMT is a dynamic and reversible process, epigenetic regulations such as histone modifications and DNA methylation are important in regulating and reprogramming the expression of EMT-responsive genes. Hence, we seek to understand how the epigenetic landscape is altered during transitions between cell states. To understand the molecular link between epigenetic regulations and cell state transitions in cancer cells, a high-throughput library screen on epigenetic modifiers was performed. Epigenetic modifying compounds that can induce MET in basal-like breast cancer cells were uncovered. In vitro and in vivo data demonstrate that compounds targeting the non-BET bromodomains were able to promote MET, induce a loss of stem-like properties, and decrease the tumorigenicity of basal-like breast cancer cells. Using various next-generation sequencing approaches, we also elucidated the mechanisms of how targeting non-BET bromodomains would regulate cell state transitions in breast cancers. While epigenetic therapies are effective in the treatment of hematological malignancies, its application in solid tumors is still limited. Here, we propose the possible use of an epigenetic MET inducer for differentiation therapy of the aggressive basal-like breast cancers. Citation Format: Li Ping Toh, Ser Yue Loo, Wai Leong Tam. Epigenetic regulation of cell state transitions and the therapeutic implications in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3833.
Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer
Authors: Shuai Gao, Sujun Chen, Dong Han, Zifeng Wang, Muqing Li, Wanting Han, Anna Besschetnova, Mingyu Liu, Feng Zhou, David Barrett, My Phu Luong, Jude Owiredu, Yi Liang, Musaddeque Ahmed, Jessica Petricca, Susan Patalano, Jill A. Macoska, Eva Corey, Sen Chen, Steven P. Balk, Housheng Hansen He, Changmeng Cai
Journal: Nature Genetics (2020)
Left Ventricular Subepicardial Twist Predicts Left Ventricular Remodeling After Acute Myocardial Infarction
Authors: E. Abate, D.P. Leong, M. Bertini, G.E. Hoogslag, M.L. Antoni, V. Delgado, E.R. Holman, H.M.J. Siebelink, M.J. Schalij, J.J. Bax, N.A. Marsan
Journal: Circulation (2011)
Abstract 504: p27 transcriptionally coregulates STAT3 to drive cancer stem cells
Authors: Seyedehfatemeh Razavipour, Kibeom Jang, Hyunho Yoon, Minsoon Kim, Miyoung Shin, Dekuang Zhao, Joyce Slingerland
Journal: Cancer Research (2020)

Abstract p27 is a cell cycle inhibitor and a tumor suppressor. It can also regulate cellular processes including migration and transcription through mechanisms independent of its CDK-inhibitory role. In cancers, p27 C-terminal phosphorylation by PI3K-activated kinases, AKT, RSK1, and SGK1 at T157 and T198 alters p27 protein-protein interactions and shifts p27 from CDK-inhibitor to an oncogene. Previously, our group showed that CDK-binding defective p27pT157pT198 phosphomimetic (p27CK-DD) upregulates epithelial-mesenchymal transition (EMT) and the metastatic potential of cancer cell lines. In addition to its action to promote EMT, p27 appears to promote CSC expansion and or maintenance. Here we demonstrated that C-terminally phosphorylated p27 increases CSC properties, including tumor sphere formation and CSC markers. p27CK-DD increases the expression of several embryonic stem cell transcription factors (ES-TFs), including SOX2, NANOG and cMYC, which are known to drive embryonic stem cell self-renewal and to promote CSC expansion. A human phospho-kinase array showed Pyk2 is activated by p27CK-DD. We demonstrated that Pyk2 activation and its binding to p27 are dependent on phosphorylation of p27 at T198 and T157. Treatment with a Pyk2 inhibitor, and PYK2-knockdown by siRNA or shRNA revealed that Pyk2 is a key mediator of the increase in tumor spheres, ALDH1 activity and ES-TFs in cancer cells expressing abundant C-terminally phosphorylated p27. Pyk2 enhances STAT3 phosphorylation and activation. We identified that C-terminally phosphorylated p27 recruits STAT3 to form p27-Pyk2-STAT3 complex leading to STAT3 activation. p27/STAT3 complexes co-localize to the nucleus and co-occupy chromatin. We confirmed by ChIP-qPCR that p27/STAT3 bind and activate the cMYC promotor. Altogether, in breast cancer cells with high p27pT157pT198 or expressing p27CK−DD, STAT3 is partly activated by Pyk2 and interacts with p27. p27 is a STAT3 coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. These data reveal a novel mechanism whereby p27-driven Pyk2 activation promotes CSC expansion and tumor progression via transcriptionally activation of the STAT3 and its target genes. Citation Format: Seyedehfatemeh Razavipour, Kibeom Jang, Hyunho Yoon, Minsoon Kim, Miyoung Shin, Dekuang Zhao, Joyce Slingerland. p27 transcriptionally coregulates STAT3 to drive cancer stem 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 504.
Abstract 2352: Sexual morbidity and gender disparities among young-onset colorectal cancer patients and survivors
Authors: Tamara Springer, Kimberly Newcomer, Danielle Peterson, Ronit Yarden
Journal: Cancer Research (2020)

Abstract Rectal cancer incidence is rising dramatically among people younger than 50 years old. The risk has doubled four times for individuals born in the 1990s relative to those born in the 1970s. Previously, we and others showed that young-onset patients are more likely to be diagnosed at an advanced stage of colorectal cancer when compared to patients of all ages, which would render aggressive treatments. There is limited data and public discussion on the long-term effects of colorectal cancer treatments on intimacy and sexual morbidity and their long-term impact on the quality of life especially among young cancer survivors who were developing their own social and financial responsibilities and establishing their life-long goals. To explore the unique challenges and unmet needs of the young-adult patient population, a cross-sectional study was conducted. Colorectal cancer patients and survivors (N=885) diagnosed between the ages of 20 to 50 years old (median age 42 ± 7.0) completed an online questionnaire that was based on established instruments including EORTC-QOL-30, EORTC-CR-29, and EORTC-SHC-22. Patients and survivors diagnosed at stage III reported worse outcomes. Patients' comprehension of radiation sexual-side effects was assessed based on self-reported discussions with their physicians. Prior to radiation, providers were significantly less likely to discuss the many sexual side-effects and long-term consequences of radiation and surgery with women than with men. Providers were also less likely to discuss fertility preservation, a notable issue with a strong impact on young cancer patients, with women than men prior to and during treatments, regardless of their parental status. While the majority of patients reported having sexual-dysfunction after treatment, women more frequently classified different aspects of their sexual dysfunction as being 'severe.' and expressed worse body image than men. Women were more likely to experience pain while more men reported reduction in sex drive. Additionally, a strong correlation was noted between sexual dysfunction and emotional exhaustion in all young-onset patients and survivors. Together, our survey demonstrates inadequate communications between patients and providers about the irreversible sexual side-effects of colorectal cancer treatments. Younger patients and survivors are facing unique long-term challenges and require further information about fertility preservation options and emotional support regarding their sexuality post-treatment. Citation Format: Tamara Springer, Kimberly Newcomer, Danielle Peterson, Ronit Yarden. Sexual morbidity and gender disparities among young-onset colorectal cancer patients and survivors [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 2352.
Abstract 1436: Determination of antibody's specificity towards phosphorylated protein targets with automated in-capillary enzyme treatment and immunoassay
Authors: Daryl A. Taketa, Rainer Grant, Tufan Aydogdu
Journal: Cancer Research (2020)

Abstract Protein phosphorylation is a reversible reaction that is integral in numerous signaling cascades. Characterization of signaling cascades has been largely detected by immunoblotting with phospho-specific antibodies, which may or may not have enough specificity or affinity. Currently, a separate lysate without any phosphatase inhibitors or a separate blot is needed to determine an antibody's specificity. Here we describe a simple assay that leverages automation and quantitation with capillary electrophoresis-based immunoassay (CEIA) to assess the specificity of these antibodies with a single lysate preparation. In this study, three lysate models are used: K562 ± TNFα treatment, 50 ng/mL phorbol myristate acetate (PMA) differentiated THP-1 ± 1 μg/mL lipopolysaccharide (LPS) treatment, and cytotoxic T lymphocytes (CTL) ± 10 ng/mL PMA and 500 ng/mL ionomycin treatment. K562 cell lysates are commercially purchased whereas THP-1 lysates are generated in-house. For CTL cells, whole blood cells from a single donor are isolated and expanded with commercially available kits. Expanded CTL cells are then stimulated with PMA and ionomycin for 15 minutes. Untreated and treated lysate samples are separated and captured to the inner lumen of the capillary wall with UV activated crosslink chemistry. Cross-linked proteins are treated with lambda phosphatase for 1 hour followed by the immunoassay to investigate the specificity of antibodies against phosphorylated protein targets respective to each activated pathway using either chemiluminescent or fluorescent detection. Preliminary data suggest phospho-specific signal decreased &amp;gt;90% with no significant changes to the non-specific noise. The method described here eliminates the need for multiple lysate preparations or an additional blot to assess an antibody's specificity to a phosphorylated protein target. Citation Format: Daryl A. Taketa, Rainer Grant, Tufan Aydogdu. Determination of antibody's specificity towards phosphorylated protein targets with automated in-capillary enzyme treatment and immunoassay [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 1436.
Gonorrhoea cases in England hit highest level since records began
Authors: Jacqui Wise
Journal: BMJ (2020)

Cases of gonorrhoea in England increased by 26% last year to the highest level since records began in 1918. Official figures showed 70 936 cases in 2019—up from 56 232 in 2018—prompting Public Health England to urge people to practice safe sex.1

Most gonorrhoea diagnoses were reported in gay, bisexual, and other men who have sex with men (up 26% to 33 853), but diagnoses also increased in heterosexual women (up 26% to 17 826) and heterosexual men (up 17% to 15 253). …
SP0144 Residential workshop for parents of adolescents with juvenile idiopathic arthritis: a preliminary evaluation
Authors: AP Turner, JH Barlow, CC Wright
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Caring for a child who has a chronic health condition can be a difficult and demanding task. Research has shown that some parents are at an increased risk for psychosocial problems. <h3>Objectives</h3> The purpose of this study was to evaluate the effectiveness of a pilot Workshop designed specifically for parents of children with JIA. <h3>Method</h3> 26 parents attended the two-day residential Workshop. The Workshop aimed to provide opportunities for parents to meet and discuss issues pertinent to caring for a disabled child. The Parents of Children With Disabilities Inventory (PCDI) was used to assess perceived disability-related stress. The PCDI comprises 4 subscales: Medical and Legal Concerns, Concerns for the Child, Concerns for the Family, Concerns for the Self. Higher scores indicate greater frequency and worry. Results were compared against a Comparison Group (CG) of 28 parents who expressed an interest in but did not attend the Workshop. <h3>Results</h3> Median decreases in scores were significantly greater for the Workshop Group (WG) compared with the CG for Concerns for the Self (frequency) and Total frequency scores, (p = 0.020, 013, respectively). For the WG there were significant group decreases over time for Concerns for the Child (worried), Concerns for the Self (frequency), Total frequency score and Total worried score, (p = 0.023, 0.044, 0.031, 0.009, respectively). <h3>Conclusion</h3> The finding of statistically significant improvements across a range of parental concerns is encouraging. Workshops for parents of children with JIA appear worthy of continued development and evaluation.
Serum mitochondrial DNA predicts the risk of acute exacerbation and progression of idiopathic pulmonary fibrosis
Authors: Koji Sakamoto, Taiki Furukawa, Yasuhiko Yamano, Kensuke Kataoka, Ryo Teramachi, Anjali Walia, Atsushi Suzuki, Masahide Inoue, Yoshio Nakahara, Changwan Ryu, Naozumi Hashimoto, Yasuhiro Kondoh
Journal: European Respiratory Journal (2020)

<b>Patients with IPF often suffer from acute exacerbation, an unpredictable and deadly complication. This study elucidated the potential of circulating mitochondrial DNA as a predictor of acute exacerbation and disease progression of IPF.</b>https://bit.ly/3i0OSza
Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney
Authors: Yonglun Kong, Weijing Feng, Xiaoduo Zhao, Puhua Zhang, Suchun Li, Zhijian Li, Yu Lin, Boen Liang, Chunling Li, Weidong Wang, Hui Huang
Journal: Theranostics (2020)

Background: Chronic kidney diseases (CKD) are usually associated with dyslipidemia. Statin therapy has been primarily recommended for the prevention of cardiovascular risk in patients with CKD; however, the effects of statins on kidney disease progression remain controversial. This study aims to investigate the effects of statin treatment on renal handling of water in patients and in animals on a high-fat diet. Methods: Retrospective cohort patient data were reviewed and the protein expression levels of aquaporin-2 (AQP2) and NLRP3 inflammasome adaptor ASC were examined in kidney biopsy specimens. The effects of statins on AQP2 and NLRP3 inflammasome components were examined in nlrp3-/- mice, 5/6 nephroectomized (5/6Nx) rats with a high-fat diet (HFD), and in vitro. Results: In the retrospective cohort study, serum cholesterol was negatively correlated to eGFR and AQP2 protein expression in the kidney biopsy specimens. Statins exhibited no effect on eGFR but abolished the negative correlation between cholesterol and AQP2 expression. Whilst nlrp3+/+ mice showed an increased urine output and a decreased expression of AQP2 protein after a HFD, which was moderately attenuated in nlrp3 deletion mice with HFD. In 5/6Nx rats on a HFD, atorvastatin markedly decreased the urine output and upregulated the protein expression of AQP2. Cholesterol stimulated the protein expression of NLRP3 inflammasome components ASC, caspase-1 and IL-1β, and decreased AQP2 protein abundance in vitro, which was markedly prevented by statins, likely through the enhancement of ASC speck degradation via autophagy. Conclusion: Serum cholesterol level has a negative correlation with AQP2 protein expression in the kidney biopsy specimens of patients. Statins can ameliorate cholesterol-induced inflammation by promoting the degradation of ASC speck, and improve the expression of aquaporin in the kidneys of animals on a HFD.
Abstract 810: Beyond genomics - A precision oncology approach utilizing multiplex protein profiling for tumor and tumor organoid samples
Authors: Gerrit Erdmann, Przemylaw Dudys, Anja Arndt, Christian Regenbrecht, Markus Templin, Christoph Sachse
Journal: Cancer Research (2020)

Abstract Precision medicine's goal of achieving a better response rate by avoiding ineffective therapies has sparked new approaches, including the testing of patient-derived 3d (PD3Ds) tumor cultures for modeling individual patient response, and the use of various molecular pathology techniques for advanced tumor profiling. An intrinsic limitation of well-established genomics methodologies is, however, that they cannot directly assess cell-signaling activity within the tumor cells defined by the phosphorylation status of cellular signaling pathway networks. Here we present the development of a robust protein profiling strategy utilizing the DigiWest immuno-assay platform, to obtain data on the activation status of key cellular signaling networks implicated in cancer, and on proteins targeted by FDA-approved drugs. This includes targeted cancer therapies for e.g. EGFR, HER2, PI3K, mTOR, ALK and AKT. Accordingly, we compiled a list of relevant pathway nodes and their phosphorylation sites that yield activity information on RAS/RAF/ERK, PI3K/AKT and mTOR signaling pathways. Based on this, we validated 242 total and phospho antibodies in a pre-set oncoproteomic DigiWest panel that yields information on the activity of all major signaling pathways from the receptor level down to transcription factors, apoptosis and proliferation. This oncoproteomic panel can be utilized for elucidating drug response in pre-clinical cell models, in PD3D organoid models or in clinical tumor samples. Exemplary, we show differential activation states in cancer cell lines representing the most prevalent cancer types and the impact of pathway activation in different models. Finally, we tested this panel in PD3D organoids that were subjected to screening against common targeted therapies. While the initial results are promising, further work on evaluating how such an oncoproteomic panel profiling might contribute to the rationale for personalized therapy decisions is required. Disclosure Statement: NMI TT Pharmaservices offers DigiWest protein profiling as a service. CELLphenomics offers PD3D cell cultures and drug testing as a service. Citation Format: Gerrit Erdmann, Przemylaw Dudys, Anja Arndt, Christian Regenbrecht, Markus Templin, Christoph Sachse. Beyond genomics - A precision oncology approach utilizing multiplex protein profiling for tumor and tumor organoid samples [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 810.