tbuckley/cabot-search huggingface dataset:
Abstract 6557: Aescin, a triterpene saponin induces apoptosis &amp; oxidative damage in human oral &amp; laryngeal cancer cells via notch signaling
Authors: Suresh Kathiresan, Hemavardhini Ramadoss, Sanjay Gupta
Journal: Cancer Research (2020)

Abstract The incidence of Head and Neck cancer in increasing worldwide. The major risk factor for these cancers includes viral infection, smoking, alcohol and tobacco consumption. Natural agents have often exhibited medicinal properties with usefulness in treating various human ailments including cancer. Aescin is one of the most prominent constituent of Aesculus hippocastanum L. (Hippocastanaceae) seeds has been conventionally used as medicinal herb. We determined the anticancer effect of aescin on human oral carcinoma (KB) cells and human laryngeal carcinoma (HEp-2) cells. Treatment of KB cells with 25µM and HEp-2 cells with 22µM aescin for 24 hours suppressed proliferation in these cells and induced morphological changes consistent with apoptosis. Exposure of both cell lines to aescin resulted in marked increase in reactive oxygen species, loss of cell viability, and reduction of cellular glutathione levels resulting in depolarization of mitochondrial membrane potential thereby increasing oxidative DNA damage in KB and HEp-2 cells. Furthermore, aescin-mediated apoptosis in these cells progress via notch signaling as shown by downregulation of Notch1, Notch2, Jagged-1, HES1, and HEY1 expression. Taken together, our results demonstrate that aescin initiate apoptosis in KB and HEp-2 cells by increasing oxidative damage implying that aescin might be developed as a potential chemotherapeutic agent for the treatment of human oral and laryngeal cancer. Key word: Oral carcinoma, Aescin, apoptosis, anti-proliferative, Notch signaling Citation Format: Suresh Kathiresan, Hemavardhini Ramadoss, Sanjay Gupta. Aescin, a triterpene saponin induces apoptosis &amp; oxidative damage in human oral &amp; laryngeal cancer cells via notch signaling [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 6557.
Abstract 2509: Genetic heterogeneity and evolutionary history of high grade ovarian carcinoma and matched distant metastases
Authors: Tariq Masoodi, Sarah Siraj, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Fowzan S. Alkuraya, Khawla S. Al-Kuraya
Journal: Cancer Research (2020)

Abstract BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although, metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated. METHODS: Multi-region whole-exome sequencing was performed on HGSOC primary tumors and their metastases (n=33 tumor regions) from 6 patients. The resulting somatic variants were analyzed to delineate tumor evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis. RESULTS: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination in which the metastatic tumor mostly acquires the same mutational process active in primary tumor, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway. CONCLUSIONS: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets. Citation Format: Tariq Masoodi, Sarah Siraj, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Fowzan S. Alkuraya, Khawla S. Al-Kuraya. Genetic heterogeneity and evolutionary history of high grade ovarian carcinoma and matched distant metastases [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 2509.
Apatinib in patients with advanced chordoma: a single-arm, single-centre, phase 2 study
Authors: Chao Liu, Qi Jia, Haifeng Wei, Xinghai Yang, Tielong Liu, Jian Zhao, Yan Ling, Chenguang Wang, Hongyu Yu, Zhenxi Li, Jian Jiao, Zhipeng Wu, Cheng Yang, Jianru Xiao
Journal: The Lancet Oncology (2020)
Abstract 524: Discovery of NKp46 antibody for NK cell engager using common light chain phage display approach
Authors: Teddy Yang, Seng Zhu, Jing Gao, Jingyun Yao, Xumin Gong
Journal: Cancer Research (2020)

Abstract NK cells express activating receptors such as CD16a (FcγRIIIA), NKG2D, SLAM family members and the natural cytotoxicity receptors (NCRs). Full activation of NK cells require co-engagement of different activating receptors. NKp46, a member of NCRs, is a 46 kDa glycoprotein and belongs to immunoglobulin (Ig) superfamily, NKp46 is frequently expressed on tumor infiltrating lymphocytes. Activation of NKp46 with antibody triggers not only NK cell cytotoxicity but also cytokine release. Taken together, NKp46 is a promising target for anti-tumor therapy. Here we described the discovery of fully human NKp46 antibody by phage display approach with common light chain and naïve human B cell library. Bispecific antibody has been researched for many years and very limited number of bispecific antibodies are currently in the market. Heavy and light chain miss pairing is the bottleneck of bispecific antibody discovery and development. To overcome the hurdle, we generated a fully human common light chain phage display library with two commonly used light chain sequences combined with heavy chain fragment from human naïve scFv library. Two light chain sequences were selected based on the approved antibodies sequences and the expression levels. The phage library was then used for panning against recombinant human NKp46 extracellular domain protein and CHOK1 cells overexpressing human NKp46. After conversion to full IgG format, 4 candidates bind specifically to NKp46 and cross react with both human and cyno NKp46. Affinities of the candidates were comparable to bench mark antibodies as determined by FACS. To summarize, we have generated fully human common light chain phage display library that can be used for bispecific antibody discovery. The anti-NKp46 antibodies discovered can be further developed for NK cell engager and NK cell redirecting bispecific antibody. Citation Format: Teddy Yang, Seng Zhu, Jing Gao, Jingyun Yao, Xumin Gong. Discovery of NKp46 antibody for NK cell engager using common light chain phage display approach [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 524.
Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial
Authors: Shaji K Kumar, Susanna J Jacobus, Adam D Cohen, Matthias Weiss, Natalie Callander, Avina K Singh, Terri L Parker, Alexander Menter, Xuezhong Yang, Benjamin Parsons, Pankaj Kumar, Prashant Kapoor, Aaron Rosenberg, Jeffrey A Zonder, Edward Faber, Sagar Lonial, Kenneth C Anderson, Paul G Richardson, Robert Z Orlowski, Lynne I Wagner, S Vincent Rajkumar
Journal: The Lancet Oncology (2020)
Abstract 2933: KLF5 and its association with HIF-1α promotes PTC progression and metastatic potential through AKT activation
Authors: Pratheeshkumar Poyil, Abdul K Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Saravanan Thangavel, Roxanne Melosantos, Ingrid G. Victoria, Rafia Begum, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2020)

Abstract Thyroid cancer is the second most common malignancy among females in Saudi Arabia, with Papillary thyroid carcinoma (PTC) accounting for 80-90%. Kruppel-like factor 5 (Klf5) is a transcription factor that plays a critical role in cell transformation, proliferation, and oncogenesis. Immunohistochemical analysis of KLF5 was performed in 1219 PTC cases. KLF5 over-expression was noted in 65.1% (793/1219) of PTCs, and was significantly associated with tall-cell variant (p &amp;lt;0.0001), extrathyroidal extension (p = 0.0003), lymph node metastasis (p &amp;lt; 0.0001) and stage IV tumors (p &amp;lt; 0.0001). A significant association was also noted with HIF-1α over-expression (p = 0.0492). Interestingly, KLF5 over-expressing tumors showed poor disease-free survival (p = 0.0066). Functional studies in PTC cell lines showed that KLF5 co-immunoprecipitated with HIF-1α. Knockdown of KLF5 decreased the expression of HIF-1α while KLF5 was not affected by HIF-1α inhibition, suggesting that KLF5 is a functional upstream of HIF-1α. Down-regulation of KLF5 using a specific inhibitor, ML264 or siRNA inhibited cell migration, invasion, and angiogenesis. Also, the treatment of PTC cell lines with ML264 resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Furthermore, the silencing of KLF5 significantly decreased the self-renewal ability of spheroids generated from PTC cells. Our findings confer that KLF5 may be a potential therapeutic target for the treatment of papillary thyroid cancer. Citation Format: Pratheeshkumar Poyil, Abdul K Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Saravanan Thangavel, Roxanne Melosantos, Ingrid G. Victoria, Rafia Begum, Fouad Al-Dayel, Khawla S. Al-Kuraya. KLF5 and its association with HIF-1α promotes PTC progression and metastatic potential through AKT activation [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 2933.
Abstract B47: Physical activity and survival following diagnosis with ovarian cancer
Authors: Tianyi Wang, Mary Townsend, Heather Eliassen, Kathryn Terry, Mingyang Song, Shelley Tworoger
Journal: Clinical Cancer Research (2020)

Abstract Among the limited studies assessing the association between physical activity and ovarian cancer survival, results have been inconsistent. Therefore, we investigated the relation of pre- and postdiagnosis physical activity with risk of death among women with ovarian cancer in two prospective cohort studies, the Nurses’ Health Study (NHS) and NHSII. Analyses included 1,113 women with confirmed invasive, stage I-III epithelial ovarian cancer (611 ovarian cancer specific deaths). We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality by physical activity levels, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index, and nonsteroidal anti-inflammatory use (postdiagnosis models only). Neither prediagnosis physical activity (assessed a median of 12 months before diagnosis) nor postdiagnosis physical activity (assessed a median of 19 months after diagnosis) was significantly associated with risk of ovarian cancer death. For example, comparing women participating in ≥27 vs. &amp;lt;3 MET-hours/week of physical activity, HRs were 1.19 (95%CI: 0.91-1.56) for prediagnosis activity and 0.74 (95%CI: 0.51-1.08) for postdiagnosis activity. In analyses stratified by tumor stage, higher physical activity before and after diagnosis was associated with lower ovarian cancer-specific mortality among stage I/II patients (≥27 vs. &amp;lt;3 MET-hours/week, HR=0.43, 95%CI: 0.21-0.88 for prediagnosis activity, HR=0.31, 95%CI: 0.13-0.72 for postdiagnosis activity), while an increased risk of death or no association was observed among stage III patients (≥27 vs. &amp;lt;3 MET-hours/week, HR=1.37, 95%CI: 1.02-1.84 for prediagnosis activity, HR=0.84, 95%CI: 0.56-1.25 for postdiagnosis activity). Results did not vary significantly by histologic subtype (serous vs. nonserous/unknown). Future analyses will evaluate prediagnosis physical activity reported at least four years prior to ovarian cancer diagnosis and postdiagnosis physical activity within four years after diagnosis. Overall, our analyses suggest that, among all stage I-III ovarian cancer patients, higher levels of physical activity, either before or after diagnosis, are not associated with improved survival. However, physical activity in women with early-stage disease may be related to improved outcomes. Citation Format: Tianyi Wang, Mary Townsend, Heather Eliassen, Kathryn Terry, Mingyang Song, Shelley Tworoger. Physical activity and survival following diagnosis with ovarian cancer [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 B47.
Inhibition of growth and lung metastasis of breast cancer by tumor-homing triple-bioresponsive nanotherapeutics
Authors: Xueqing Zhang, Yamei Huang, Heliang Song, Brandon S.B. Canup, Shuangquan Gou, Zhigang She, Fangyin Dai, Bowen Ke, Bo Xiao
Journal: Journal of Controlled Release (2020)
Response to ‘Impact of COVID-19 pandemic on hospitalisation of patients with systemic lupus erythematosus (SLE): report from a tertiary hospital during the peak of the pandemic’ by Chuah<i>et al</i>
Authors: Alexis Mathian, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2020)

We thank Chuah et al 1 for their interest in our study reporting on the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) in a case series of patients with systemic lupus erythematosus (SLE) under long-term treatment with hydroxychloroquine.2 Chuah et al point to an indirect consequence of the COVID-19 pandemic, the reluctance of patients to come to the hospital because of the fear to contract COVID-19 that is reinforced by the awareness of the contagious nature of SARS-CoV-2. The experience of Chuah et al is instructive in this regard. The authors observed a decline of 65.4% in the SLE hospitalisation rate in their medical centre during the containment period, as compared with the same period in 2019. Moreover, five out of the six new patients with SLE presented to the hospital long after the first clinical manifestations. This finding should be put into perspective with the increase in the number of in-hospital deaths of patients with SLE related to infections apparently independent of SARS-CoV-2, which suggests a harmful increase in the diagnostic delay and/or in the …
Genome-wide association study identifies 48 common genetic variants associated with handedness
Authors: Gabriel Cuellar-Partida, Joyce Y. Tung, Nicholas Eriksson, Eva Albrecht, Fazil Aliev, Ole A. Andreassen, Inês Barroso, Jacques S. Beckmann, Marco P. Boks, Dorret I. Boomsma, Heather A. Boyd, Monique M. B. Breteler, Harry Campbell, Daniel I. Chasman, Lynn F. Cherkas, Gail Davies, Eco J. C. de Geus, Ian J. Deary, Panos Deloukas, Danielle M. Dick, David L. Duffy, Johan G. Eriksson, Tõnu Esko, Bjarke Feenstra, Frank Geller, Christian Gieger, Ina Giegling, Scott D. Gordon, Jiali Han, Thomas F. Hansen, Annette M. Hartmann, Caroline Hayward, Kauko Heikkilä, Andrew A. Hicks, Joel N. Hirschhorn, Jouke-Jan Hottenga, Jennifer E. Huffman, Liang-Dar Hwang, M. Arfan Ikram, Jaakko Kaprio, John P. Kemp, Kay-Tee Khaw, Norman Klopp, Bettina Konte, Zoltan Kutalik, Jari Lahti, Xin Li, Ruth J. F. Loos, Michelle Luciano, Sigurdur H. Magnusson, Massimo Mangino, Pedro Marques-Vidal, Nicholas G. Martin, Wendy L. McArdle, Mark I. McCarthy, Carolina Medina-Gomez, Mads Melbye, Scott A. Melville, Andres Metspalu, Lili Milani, Vincent Mooser, Mari Nelis, Dale R. Nyholt, Kevin S. O’Connell, Roel A. Ophoff, Cameron Palmer, Aarno Palotie, Teemu Palviainen, Guillaume Pare, Lavinia Paternoster, Leena Peltonen, Brenda W. J. H. Penninx, Ozren Polasek, Peter P. Pramstaller, Inga Prokopenko, Katri Raikkonen, Samuli Ripatti, Fernando Rivadeneira, Igor Rudan, Dan Rujescu, Johannes H. Smit, George Davey Smith, Jordan W. Smoller, Nicole Soranzo, Tim D. Spector, Beate St Pourcain, John M. Starr, Hreinn Stefánsson, Stacy Steinberg, Maris Teder-Laving, Gudmar Thorleifsson, Kári Stefánsson, Nicholas J. Timpson, André G. Uitterlinden, Cornelia M. van Duijn, Frank J. A. van Rooij, Jaqueline M. Vink, Peter Vollenweider, Eero Vuoksimaa, Gérard Waeber, Nicholas J. Wareham, Nicole Warrington, Dawn Waterworth, Thomas Werge, H.-Erich Wichmann, Elisabeth Widen, Gonneke Willemsen, Alan F. Wright, Margaret J. Wright, Mousheng Xu, Jing Hua Zhao, Peter Kraft, David A. Hinds, Cecilia M. Lindgren, Reedik Mägi, Benjamin M. Neale, David M. Evans, Sarah E. Medland
Journal: Nature Human Behaviour (2020)
Abstract 3970: Tumor-associated macrophage, angiogenesis and lymphangiogenesis predicts prognosis in patients with non-small cell lung cancer
Authors: Ilseon Hwang, Keun Uk Park, Eun Hee Jung, Hun-Mo Ryoo, Kris Ylaya, Joon-Yong Chung, Stephen M. Hewitt
Journal: Cancer Research (2020)

Abstract Background: The tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcome. Tumor-associated macrophages (TAMs) are a well-recognized core element of the TME, and are generally characterized as M2-like macrophages. TAMs are believed to contribute to tumor progression, but the mechanism behind this remains unclear. We aimed to investigate the clinical value, angiogenic and lymphangiogenic significance of TAMs in non-small cell lung cancer (NSCLC). Methods: We assessed CD68, CD163, VEGF-A, and VEGF-C expression in 349 patients with NSCLC by combined immunohistochemistry and digital image analysis. Subsequently, the potential association between M2 TAMs and angiogenetic VEGF-A and/or lymphangiogenetic VEGF-C was evaluated for its prognostic value. Furthermore, the effects of M2 TAMs on angiogenesis and lymphangiogenesis were explored in vitro co-culture system. Results: Elevated M2 (CD163+/CD68+) ratio was significantly associated with poor overall survival (p=0.023). Dual high expression of M2 ratio and VEGF-C was correlated with worse overall survival (p=0.033). Furthermore, CD68 and CD163 expression are positively associated with VEGF-A and/or VEGF-C expression. Multivariate analysis revealed that M2 ratio was an independent predictor of poor survival [HR (95% CI) = 1.53 (1.01-2.33), p=0.046]. Combined M2+/VEGF-C+ expression was also an independent predictor of poor survival [HR (95% CI) = 2.01 (1.28-3.16), p=0.003]. Notably, we confirmed that M2 macrophages enhanced the protein and mRNA expression of both VEGF-A and VEGF-C significantly, while M1 macrophages induced only mRNA expression of VEGF-A significantly in A549 cells. Conclusions: This study suggests that TAMs are significantly associated with angiogenesis or lymphangiogenesis in the progression of NSCLC. Furthermore, elevated M2 ratio and combined M2 and VEGF-C high expression are strong indicators of poor prognosis in patients with NSCLC. Citation Format: Ilseon Hwang, Keun Uk Park, Eun Hee Jung, Hun-Mo Ryoo, Kris Ylaya, Joon-Yong Chung, Stephen M. Hewitt. Tumor-associated macrophage, angiogenesis and lymphangiogenesis predicts prognosis in patients with non-small cell lung 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 3970.
Assessment of Variation in State Regulation of Generic Drug and Interchangeable Biologic Substitutions
Authors: Chana A. Sacks, Victor L. Van de Wiele, Lisa A. Fulchino, Lajja Patel, Aaron S. Kesselheim, Ameet Sarpatwari
Journal: JAMA Internal Medicine (2020)

Brand-name drugs, including biologics, have been the primary source of increasing prescription drug spending in the US. Each state has drug product selection laws that regulate whether and how pharmacists can substitute prescriptions for brand-name drugs with more affordable equivalents, either small-molecule generic drugs or interchangeable biologics, but the details of these laws can vary.To examine the variation in state drug product selection laws with regard to factors that may affect which version of a drug is dispensed.A cross-sectional analysis was performed, using a legal database, to obtain information on state laws of all states plus Washington, DC, as they existed on September 1, 2019.Whether substitution was mandatory or permissive, patient consent was needed prior to substitution, patient notification of substitution was required independent of the drug's packaging, and/or pharmacists were protected from special risk of liability for substitution.For small-molecule and biologic drugs, descriptive statistics were generated for the 4 exposure variables. In addition, for small-molecule drugs, a generic substitution score with a maximum of 1 point was assigned for each exposure variable (range, 0-4 points), with higher scores indicating regulatory requirements limiting substitution.This cross-sectional analysis of the generic drug substitution regulations in the 50 US states and Washington, DC, found that for small-molecule drugs, 19 states required pharmacists to perform generic substitution; 7 states and Washington, DC, required patient consent; 31 states and Washington, DC, mandated patient notification independent of the drug's packaging, and 24 states did not explicitly protect pharmacists from greater liability. Nine states and Washington, DC, had a generic substitution score for small-molecule drugs of 3 or higher, and 45 states had more stringent requirements for interchangeable biologic substitution, most commonly mandatory physician notification.The findings of this study suggest that there is a need for optimizing state drug product selection laws to promote generic and interchangeable biologic substitution, which may help improve medication adherence and reduce drug spending.