tbuckley/cabot-search huggingface dataset:
Abstract 2842: 6-gingerol attenuates metastasis in aged mice model of colorectal cancer through modulation of epithelial-mesenchymal transition mediators genes and e-cadherin upregulation
Authors: Babajide Oluwaseun Ajayi, Ayomiposi Adenigba, Anuoluwapo Adeshina
Journal: Cancer Research (2021)

Abstract Colorectal cancer (CRC) is the third most common cancer in America, and the third cause of cancer related death. Metastasis is the major cause of death in patient with CRC. Many CRC are likely to spread from primary site to the other parts of the body before and after detection of malignant tumor. 6-gingerol, the bioactive component of fresh ginger have been reported to have myriad of biological activities including anti-inflammatory and antioxidant properties. We have previously reported the anti-CRC effect of 6-gingerol. However there is dearth of information on the anti-metastatic effect 6-gingerol in CRC. Thus, the effect of 6-gingerol on epithelial-mesenchymal transition mediators' genes and E-Cadherin repression in aged mice model of CRC was assessed in this study. Following institutional ethical approval. Aged male BALB/c mice (10 months) were divided into four groups of 10 mice each. Mice were fed with AIN-93 diet and allowed access to water ad libitum. Group 1 mice serve as control, group 2 mice received 6-gingerol 10mg/kg/day by oral gavage for 10 weeks. Group 3 mice received a single dose of azoxymethane (AOM) 10mg/kg (iP) and on the seventh day they received three cycles of dextran sulfate sodium (DSS) 2% (W/V) in drinking water ( each cycle is define as one week of DSS followed by two weeks of plain drinking water) Group 4 mice received 6-gingerol 10mg/kg/day by oral gavage in combination with single dose of azoxymethane 10mg/kg (iP) and on the seventh day they received three cycles of dextran sulfate sodium salt 2% (W/V) in drinking water. Mice were humanely sacrificed under anesthesia and colon tissues were processed for RT-PCR and multiplex immunohistochemistry analysis. Mice that received both 6-gingerol and AOM and DSS showed a significant decreased expression of Lymphocyte function-associated antigen-1, N-cadherin, SNAIL 1, ZEB 1, AP4 and HMGA1 with concomitant Upregulation miR-34, miR-15a, miR-218 and miR-302 expression as compared with the AOM and DSS only group. The result obtained from this study showed 6-gingerol inhibited metastasis through modulation of epithelial-mesenchymal transition mediators' genes and E-Cadherin upregulation, and as such 6-gingerol could be a promising anti-metastatic agent in CRC treatment. Citation Format: Babajide Oluwaseun Ajayi, Ayomiposi Adenigba, Anuoluwapo Adeshina. 6-gingerol attenuates metastasis in aged mice model of colorectal cancer through modulation of epithelial-mesenchymal transition mediators genes and e-cadherin upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2842.
Abstract 2990: In vitro drug sensitivity screening platform for primary chronic lymphocytic leukemia (CLL) patient samples
Authors: Bandana Ajay Vishwakarma, Amy Wesa
Journal: Cancer Research (2021)

Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. It is characterized by proliferation and accumulation of monoclonal, small, mature CD5+ B-cells in peripheral blood, bone marrow and secondary lymphoid organs. The current treatment regimens have improved overall survival but CLL patients will eventually experience relapse. The disease is still incurable making it a necessity to discover and screen for new drugs. Patient derived CLL specimens undergo spontaneous apoptosis when grown in culture and is a major limitation to screening for new therapeutic drugs. We have established an in vitro culture conditions which supports growth and proliferation of patient derived primary CLL cells. Champions has a bank of primary CLL patient samples across different Rai stage, genetic mutations and relapsed and refractory cases. We tested nine CLL samples (models) for proliferation. All nine models proliferated 1.5 to 9.6-fold in the optimized media in 6 days, as measured using CellTiter-Glo. Flow cytometric analysis showed that the CLL cells mostly retained the primary phenotypic characteristic CD5+CD10-Cd19+CD20+ even after being in the culture for 6 days. Next, we screened for sensitivity of primary CLL patient samples (N=9) against known standard of care (SOC) drugs venetoclax, ibrutinib, idelalisib, chlorambucil and cytarabine. Primary PBMC patient samples were seeded in 96 well plates in the enriched media and treated with respective drugs over a concentration range over 5 logs. Drug sensitivity was assessed using CellTiter-Glo® luminescent cell viability assay on day 6. Our in vitro assay indicated varied sensitivity of patient samples to approved standard of care drugs. A relapsed bendamustine pre-treated patient sample was sensitive to all the SOC drugs tested. In addition to drug response, whole exome sequencing and RNAseq are being conducted on these samples, to compare mutational analyses with drug responsiveness. With clinically annotated patient-derived CLL samples, WES and RNAseq plus drug response to standard of care provides a comprehensive ex vivo platform for the preclinical testing of drug candidates, which may not only provide information on agent efficacy, but that can permit potential biomarker mining and exploration of patient selection criteria for investigational new agents in CLL. Citation Format: Bandana Ajay Vishwakarma, Amy Wesa. In vitro drug sensitivity screening platform for primary chronic lymphocytic leukemia (CLL) patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2990.
Abstract 1140: A novel MTA non-competitive PRMT5 inhibitor
Authors: Rohit Malik, Peter K. Park, Christopher M. Barbieri, Yuval Blat, Steven Sheriff, Carolyn A. Weigelt, Lisa M. Kopcho, Muge Celiktas, Max Ruzanov, Joseph G. Naglich, Jennifer L. Price, Mary Harner, Kevin M. Omalley, JIngjing Deng, William Schmitz, Guo Li, Zheming Ruan, Lan-ying Qin, Gerald J. Duke, Iyoncy Rodrigo, Mark R. Witmer, David G. Harden, Shilpa Demes, Brian J. Arey, Matt Soars, Brian E. Fink, Ashvinikumar V. Gavai, Gregory D. Vite, Charles F. Voliva
Journal: Cancer Research (2021)

Abstract The chromosome 9p21 (chr9p21) locus is deleted in almost 10% of all cancer types. This locus includes the CDKN2A gene that encodes the critical tumor suppressors p19-ARF and p16-INK4a. Methylthioadenosine phosphorylase (MTAP), a gene proximal to CDKN2A, is co-deleted in 80%-90% of tumors with CDKN2A deletion. MTAP plays a critical role in the methionine salvage pathway, and the deletion of MTAP results in the accumulation of its substrate methythioadenosine (MTA). Accumulation of MTA partially inhibits the activity of the arginine methyltransferase PRMT5, causing MTAP deficient cancer cells to be more sensitive to the genetic knockdown of PRMT5. In contrast to genetic knockdown, sensitivity to pharmacological inhibition of PRMT5 does not appear to stratify with MTAP status. However, currently known PRMT5 inhibitors all possess SAM competitive or uncompetitive MOIs, which generally require displacement of MTA from the active site for binding. We hypothesize that leveraging the high MTA state induced by MTAP deficiency will require an inhibitor that can bind PRMT5 without disrupting bound MTA. Here we report the discovery of a PRMT5 inhibitor with a novel binding mode that is compatible with MTA binding. While this compound possesses the desired MOI, it shows only modestly increased potency toward MTAP-null cells. Mathematical simulations of different inhibitor mechanisms indicate that the degree of selectivity that can be achieved depends on the difference in MTA levels between MTAP-null and WT cells. Our in vitro data suggest that the elevation in intracellular MTA concentrations that occurs with MTAP deletion is not sufficient to confer significantly increased sensitivity to PRMT5 inhibition. We anticipate that the therapeutic index that can be achieved between MTAP-null tumor cells and PRMT5-sensitive normal tissues will be similarly limited in vivo. Citation Format: Rohit Malik, Peter K. Park, Christopher M. Barbieri, Yuval Blat, Steven Sheriff, Carolyn A. Weigelt, Lisa M. Kopcho, Muge Celiktas, Max Ruzanov, Joseph G. Naglich, Jennifer L. Price, Mary Harner, Kevin M. Omalley, JIngjing Deng, William Schmitz, Guo Li, Zheming Ruan, Lan-ying Qin, Gerald J. Duke, Iyoncy Rodrigo, Mark R. Witmer, David G. Harden, Shilpa Demes, Brian J. Arey, Matt Soars, Brian E. Fink, Ashvinikumar V. Gavai, Gregory D. Vite, Charles F. Voliva. A novel MTA non-competitive PRMT5 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1140.
Diagnostic comorbidity in persons with suicidal ideation and behavior
Authors: M D Rudd, P F Dahm, M H Rajab
Journal: American Journal of Psychiatry (1993)

An initial finding of heightened risk of suicidal ideation or behavior among individuals in a random community sample who met diagnostic criteria for panic disorder or panic attacks was not replicated in later studies of both general and specific groups of psychiatric outpatients. The present study represented another effort to validate the finding.The participants included 209 outpatients who had attempted suicide or were at high risk for continued suicidal behavior or eventual suicide. All subjects were evaluated with a structured clinical interview for assigning DSM-III-R diagnoses, the Modified Scale for Suicidal Ideation, the suicidal ideation subscale of the Suicide Probability Scale, and the Beck Hopelessness Scale.The findings indicated the relative complexity and importance of diagnostic comorbidity among these suicidal subjects. Mood disorders were the most frequent primary diagnoses, followed by phobias, posttraumatic stress disorder (PTSD), generalized anxiety disorder, and panic disorder. Panic disorder was not present as an isolated, independent diagnosis; on the contrary, all of the patients with panic disorder also received at least one additional comorbid diagnosis. Mean scores for suicidal ideation and hopelessness were greatest for patients with current comorbid primary mood disorder and panic disorder. However, a critical and equally important role was played by comorbid PTSD, generalized anxiety disorder, and phobias.The findings represent another failure to validate, with a specific clinical group, panic disorder as an independent risk factor for suicidal ideation or behavior. However, they highlight the possibility that panic disorder and other anxiety disorders are risk factors when they co-occur with a primary mood disorder.
CYB561A3 is the key lysosomal iron reductase required for Burkitt B-cell growth and survival
Authors: Zhonghao Wang, Rui Guo, Stephen J. Trudeau, Emma Wolinsky, Tslil Ast, Jin Hua Liang, Chang Jiang, Yijie Ma, Mingxiang Teng, Vamsi K. Mootha, Benjamin E. Gewurz
Journal: Blood (2021)
Covid-19 vaccination: GPs ruled out of booster campaign at practice level
Authors: Adrian O’Dowd
Journal: BMJ (2021)

<h3>Background</h3> The Claim Evaluation Tools database contains multiple-choice items for measuring people’s ability to apply the key concepts they need to know to be able to assess treatment claims. We assessed items from the database using Rasch analysis to develop an outcome measure to be used in two randomised trials in Uganda. Rasch analysis is a form of psychometric testing relying on Item Response Theory. It is a dynamic way of developing outcome measures that are valid and reliable. <h3>Objectives</h3> To assess the validity, reliability and responsiveness of 88 items addressing 22 key concepts using Rasch analysis. <h3>Participants</h3> We administrated four sets of multiple-choice items in English to 1114 people in Uganda and Norway, of which 685 were children and 429 were adults (including 171 health professionals). We scored all items dichotomously. We explored summary and individual fit statistics using the RUMM2030 analysis package. We used SPSS to perform distractor analysis. <h3>Results</h3> Most items conformed well to the Rasch model, but some items needed revision. Overall, the four item sets had satisfactory reliability. We did not identify significant response dependence between any pairs of items and, overall, the magnitude of multidimensionality in the data was acceptable. The items had a high level of difficulty. <h3>Conclusion</h3> Most of the items conformed well to the Rasch model’s expectations. Following revision of some items, we concluded that most of the items were suitable for use in an outcome measure for evaluating the ability of children or adults to assess treatment claims.
Retzius-sparing vs. conventional robotic assisted radical prostatectomy in a prospective, randomised trial – early functional outcome and quality of life
Authors: V.S. Schütz, M Güttlein, D. Würkner, L. Hofer, P. Reimold, K. Kaltenecker, G. Tosev, M. Görtz, M. Hohenfellner, J. Nyarangi-Dix
Journal: European Urology (2021)
Identifying the optimal candidates for radiation therapy after salvage lymph node dissection for node-only recurrent prostate cancer after radical prostatectomy: Results from a multi-institutional collaboration
Authors: C.A. Bravi, N. Fossati, G. Gandaglia, G. Motterle, R.J. Karnes, D. Pfister, A. Heidenreich, A. Kretschmer, C. Stief, G. Devos, S. Joniau, H. Van Poppel, D. Osmonov, K. Juenemann, B. Grubmüller, S. Shariat, A. Nini, A. Hiester, P. Albers, D. Tilki, M. Graefen, I.S. Gill, A. Mottrie, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Abstract 731: Neurotensin causes tyrosine phosphorylation of HER3
Authors: Terry W. Moody, Irene Ramosalvarez, Robert T. Jensen
Journal: Cancer Research (2021)

Abstract Neurotensin (NTS) is an autocrine growth factor for non-small cell lung cancer cells. NTS stimulates and the NTSR1 antagonist SR48692 inhibits NSCLC growth (Moody et al., Life Sci 2014; 100: 25). NSCLC patients, whose tumors have high NTSR1, have significantly lower relapse-free survival than those with low NTSR1 (Younes et al., Oncotarget 2014; 5: 8252). NTS addition to NSCLC cells increases the tyrosine phosphorylation of the EGFR and HER2 (Moody et al., Eur J Pharmacol 2019; 865:172735). Activation of HER3 in NSCLC mediates aggressive growth and drug resistance. Therefore the ability of NTSR1 to regulate transactivation of HER3 was investigated. By RT-PCR, HER3 and NTSR1 but not NTSR2 mRNA was present in NSCLC cells. NTS addition to NCI-H358 or H441 cells increased HER3 and ERK tyrosine phosphorylation by 210% and 240%, respectively and the increase caused by NTS was antagonized by SR48692 or mAb3481 (HER3 mAb). The increase is phosphorylation of Tyr1289-HER3 caused by NTS or neuregulin-1 addition to NSCLC cells was due to the formation of HER2-HER3 and EGFR-HER3 heterodimers. NTSR1 regulation of HER3 or Akt phosphorylation was impaired by PP2 (Src inhibitor) or GM6001 (MMP inhibitor). Because N-acetylcysteine (antioxidant) or Tiron (superoxide scavenger) inhibited the ability of NTS to increase HER3 phosphorylation, reactive oxygen species (ROS) are essential. Using a clonogenic assay, NTS increased NSCLC colony number whereas SR48692 or mAb3481 reduced colony number. The results indicate that NTS increased HER3 tyrosine phosphorylation in a ROS-/Src-/MMP-dependent manner. In summary, NTSR1 transactivates HER3 resulting in ERK and Akt phosphorylation increasing the proliferation and survival of NSCLC cells. Citation Format: Terry W. Moody, Irene Ramosalvarez, Robert T. Jensen. Neurotensin causes tyrosine phosphorylation of HER3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 731.
Bawa-Garba is free to practise again without restrictions after tribunal ruling
Authors: Clare Dyer
Journal: BMJ (2021)

Hadiza Bawa-Garba has been allowed to practise again without restrictions, 10 years after a 6 year old boy in her care died of septic shock following a mistaken diagnosis of gastroenteritis.

A well regarded trainee paediatrician at the time Jack Adcock died in 2011, Bawa-Garba was later found guilty of gross negligence manslaughter.1 Many doctors saw her as a scapegoat for an overstretched and underfunded NHS.

An investigation at Leicester Royal Infirmary found numerous system failures on the 12 hour shift when she was working under extreme pressure, covering several wards without adequate supervision and with IT problems. She had just returned from 14 months’ …
Abstract 885: A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO
Authors: Amanda L. Blackford, Erica J. Childs, Nancy Porter, Gloria Petersen, Kari Rabe, Steven Gallinger, Ayelet Borgida, Sapna Syngal, Ann Schwartz, Michele Cote, Ralph Hruban, Michael Goggins, Alison P. Klein, Giovanni Parmigiani
Journal: Cancer Research (2021)

Abstract Introduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO), and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. Methods: We expanded the existing framework for PANCPRO and BRCAPRO to model underlying risk of pancreatic, breast, and ovarian cancer. We then validated this model on three datasets each reflecting the target populations for these models, including patients referred to a high-risk genetics clinic, patients with multiple family members with pancreatic cancer who underwent genetic testing for BRCA1/2, as well as a prospective registry of pancreatic cancer families. The new model is designated BRCAPANCPRO. Results: BRCAPANCPRO yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUC = 0.84, 95% CI: 0.78, 0.87) and was reasonably well-calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.82 [0.69, 0.94]). In these families, BRCAPANCPRO outperformed both the prior BRCAPRO and PANCPRO models. Discussion: The BRCAPANCPRO model improves the identification of families with a pathogenic variant in BRCA2 or BRCA1, particularly for families where there is the co-occurrence of pancreatic cancer in addition to breast and/or ovarian cancer. The model also improves the prediction of pancreatic cancer among families with a pancreatic cancer family history, with or without breast and/or ovarian cancer. Citation Format: Amanda L. Blackford, Erica J. Childs, Nancy Porter, Gloria Petersen, Kari Rabe, Steven Gallinger, Ayelet Borgida, Sapna Syngal, Ann Schwartz, Michele Cote, Ralph Hruban, Michael Goggins, Alison P. Klein, Giovanni Parmigiani. A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 885.
Abstract 1932: Talazoparib interacts with oncolytic reovirus to enhance death-inducing signaling complex (DISC)-mediated apoptosis and immune response
Authors: Joan N. Kyula, Victoria Roulstone, Richard Elliott, Harriet Whittock, Galabina Bozhanova, Martin McLaughlin, Malin Pedersen, Dragomir Krastev, Stephen Pettitt, Arnaud Legrand, Tencho Tenev, James Wright, Lu Yu, Jyoti Choudhary, Pascal Meier, Christopher J. Lord, Alan Melcher, Grey Wilkinson, Matt Coffey, Kevin J. Harrington
Journal: Cancer Research (2021)

Abstract Reovirus (RT3D) is a naturally occurring double-stranded RNA oncolytic virus that has shown preclinical efficacy in a wide range of tumor types. Early phase clinical studies have shown that this agent has modest monotherapy efficacy and can safely be combined with cytotoxic chemotherapy regimens. In the current studies, we used a high-throughput drug screen approach of different targeted therapeutic agents with the aim of looking for potential viral sensitizers that could enhance RT3D tumor killing. BMN-673 (talazoparib), a clinically approved poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor was identified as a top hit and found to sensitize profoundly to RT3D both in vitro and in vivo in human xenograft tumors in a nude mouse model. We found that RT3D activated cellular PARP1 and was associated with PARylation of cellular proteins, including components of the DISC-associated cell death machinery. Combined treatment with RT3D and talazoparib enhanced extrinsic apoptosis (amplified by autocrine/paracrine TNF-α and TRAIL signaling), NF-κB pathway activity and pro-inflammatory cytokine production (CCL5/RANTES, CXCL8/IL8, CXCL1/GRO and CXCL10/IP10). Signaling was shown to be dependent on nucleic acid sensing mechanisms mediated by RIG-I and TLR3. We also found anti-tumour efficacy in an immunocompetent mouse model and this correlated with an increase in an immune response following combination treatment of RT3D and talazoparib. Our data provide a strong rationale for the combination of oncolytic RT3D with PARP1 inhibitors to exploit immunogenic response in cancer treatment. Citation Format: Joan N. Kyula, Victoria Roulstone, Richard Elliott, Harriet Whittock, Galabina Bozhanova, Martin McLaughlin, Malin Pedersen, Dragomir Krastev, Stephen Pettitt, Arnaud Legrand, Tencho Tenev, James Wright, Lu Yu, Jyoti Choudhary, Pascal Meier, Christopher J. Lord, Alan Melcher, Grey Wilkinson, Matt Coffey, Kevin J. Harrington. Talazoparib interacts with oncolytic reovirus to enhance death-inducing signaling complex (DISC)-mediated apoptosis and immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1932.