tbuckley/cabot-search huggingface dataset:
Recurrent tumor involving a diverticulum after colonic endoscopic submucosal dissection successfully resected by the double-tunnel method
Authors: Marie Kurebayashi, Ken Ohata, Hideyuki Chiba, Maiko Takita, Takashi Muramoto, Fumiki Toriumi, Eiji Sakai
Journal: Endoscopy (2020)

Repeat endoscopic treatment is challenging for lesions that recur after endoscopic resection and for lesions involving a diverticulum because of the severe fibrosis surrounding such lesions [1] [2]. We report the case of a tumor involving a diverticulum that recurred after colonic endoscopic submucosal dissection (ESD) and was successfully resected by the double-tunnel method.
Abstract 2351: Diabetes and risk of early-onset colorectal cancer
Authors: Zitong Li, Xiaobin Zheng, Katelin B. Nickel, Hanyu Chen, Andrew Tipping, Long H. Nguyen, Andrew T. Chan, Ryan C. Fields, Nicholas O. Davidson, Edward Giovannucci, Margaret A. Olsen, Peter T. Campbell, Graham A. Colditz, Yin Cao
Journal: Cancer Research (2020)

Abstract Introduction: Early-onset colorectal cancer (CRC), as defined by CRC diagnosed before age 50, has been increasing in the past 2 decades, with unidentified reasons. Type 2 diabetes increases risk of CRC with average age of onset, however, epidemiological data linking type 2 diabetes and risk of early-onset CRC is thus far limited. Methods: To examine the association between type 2 diabetes and risk of early-onset CRC, we conducted a nested case-control study of early-onset CRC among participants aged 18-50 years with at least 2 years and 3 months of continuous enrollment in the IBM® MarketScan® Research Databases (2006-2015), the largest database that covers healthcare claims from over 150 million privately insured adults in the US. Incident CRC cases were identified using ICD-9-CM diagnosis codes on pathologists' claims. For cases, the index dates were set at the first pathologist date. Controls without CRC were identified using 1:8 frequency matching on age, sex, and geographical region, duration of insurance enrollment, and Rx coverage. Type 2 diabetes within 2 years of the index dates were identified through the ICD-9-CM and confirmed by Klabunde algorithm. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 5986 early-onset CRC cases were identified. Type 2 diabetes was significantly associated with an increased risk of early-onset CRC (prevalence in cases/controls: 7.2% vs 4.3%; OR: 1.40, 95% CI 1.24-1.56), after adjusting for the matching factors, health care utilization, Charlson Comorbidity Index, obesity, inflammatory bowel disease (IBD), colonoscopy and fecal occult blood test (FOBT), and family history of gastrointestinal neoplasm. Notably, the association between type 2 diabetes and early onset-CRC was similar for colon (OR: 1.44, 95% CI 1.25-1.64) and rectal cancer (OR: 1.30, 95% CI 1.18-1.56) (Pheterogeneity = 0.41). These associations remain similar while we restricted the analyses to individuals without IBD, endoscopy/FOBT, or early symptoms, respectively. In addition, the findings were also similar for women and men, as well as CRC diagnosed before and after age 45. Conclusions: Type 2 diabetes was associated with increased risk of early-onset CRC with similar strength of associations for colon and rectal cancer. Citation Format: Zitong Li, Xiaobin Zheng, Katelin B. Nickel, Hanyu Chen, Andrew Tipping, Long H. Nguyen, Andrew T. Chan, Ryan C. Fields, Nicholas O. Davidson, Edward Giovannucci, Margaret A. Olsen, Peter T. Campbell, Graham A. Colditz, Yin Cao. Diabetes and risk of early-onset colorectal 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 2351.
Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors
Authors: Anthony K. Park, Yuman Fong, Sang-In Kim, Jason Yang, John P. Murad, Jianming Lu, Brook Jeang, Wen-Chung Chang, Nanhai G. Chen, Sandra H. Thomas, Stephen J. Forman, Saul J. Priceman
Journal: Science Translational Medicine (2020)

An effective combination immunotherapy using oncolytic viruses delivers de novo CD19 to promote CD19-CAR T cell therapy against solid tumors in mice.
Large waterborne Campylobacter outbreak: use of multiple approaches to investigate contamination of the drinking water supply system, Norway, June 2019
Authors: Susanne Hyllestad, Arild Iversen, Emily MacDonald, Ettore Amato, Bengt Åge Sørby Borge, Anton Bøe, Aslaug Sandvin, Lin T Brandal, Trude Marie Lyngstad, Umaer Naseer, Karin Nygård, Lamprini Veneti, Line Vold
Journal: Eurosurveillance (2020)

On 6 June 2019, the Norwegian Institute of Public Health was notified of more than 50 cases of gastroenteritis in Askøy. A reservoir in a water supply system was suspected as the source of the outbreak because of the acute onset and geographical distribution of cases. We investigated the outbreak to confirm the source, extent of the outbreak and effect of control measures. A case was defined as a person in a household served by Water Supply System A (WSS-A) who had gastroenteritis for more than 24 h between 1 and 19 June 2019. We conducted pilot interviews, a telephone survey and an SMS-based cohort study of residents served by WSS-A. System information of WSS-A was collected. Whole genome sequencing on human and environmental isolates was performed. Among 6,108 individuals, 1,573 fulfilled the case definition. Residents served by the reservoir had a 4.6× higher risk of illness than others. Campylobacter jejuni isolated from cases (n = 24) and water samples (n = 4) had identical core genome MLST profiles. Contamination through cracks in the reservoir most probably occurred during heavy rainfall. Water supply systems are susceptible to contamination, particularly to certain weather conditions. This highlights the importance of water safety planning and risk-based surveillance to mitigate risks.
Abstract 491: Encapsulation of the stem cell inhibitor Salinomycin in novel QUATRAMER sustained injectable suspension (HSB-1216) for the treatment of small cell lung cancer
Authors: Surender M. Kharbanda, Anees Mohammad, Sireesh Appajosyula, Mark Rosenberg, James Hill, Sandeep Laumas, Donald W. Kufe, Harpal Singh
Journal: Cancer Research (2020)

Abstract Small cell lung cancer (SCLC) represents approximately 15% of all cases of lung cancer. SCLC patients have a poor prognosis and limited treatment options. Conventional chemotherapy can reduce the bulk of SCLC lesions, but cancer stem cells (CSCs) survive, reconstitute the tumor and contribute to metastases. Thus, targeting CSCs, which are resistant to many current treatments, may significantly improve outcomes of SCLC patients. Salinomycin (SAL), a potassium ionophore, preferentially targets CSCs. However, SAL is extensively metabolized in animal models and is associated with substantial toxicity at higher doses, limiting its potential for anti-cancer activity in patients In this study, we report a novel QUATRAMER polymeric nanoparticle (NP)-based formulation, that potentially overcomes toxicity of SAL. SAL was encapsulated in polymeric NPs comprised of a polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG-modified PLA-tetra-block copolymer (SAL-NPs; HSB-1216). SAL release from the NPs was controlled by both PEG/PEG-PPG-PEG chain length and the PLA molecular weight, permitting time-dependent release over sustained periods. Treatment of the human SCLC cell line NCI-H69 with HSB-1216 demonstrated an IC50 of 0.5 uM. Once weekly treatment of BALB/c nu/nu mice harboring NCI-H69 xenografts with HSB-1216 at a dose of 5 mg/kg resulted in substantial tumor growth inhibition The tumor growth inhibition was without any effect on the body weights of the mice. These results demonstrate that a novel formulation for sustained delivery of SAL in a sustained injectable suspension represents an approach for targeting CSCs in SCLCs and potentially other cancer types. Citation Format: Surender M. Kharbanda, Anees Mohammad, Sireesh Appajosyula, Mark Rosenberg, James Hill, Sandeep Laumas, Donald W. Kufe, Harpal Singh. Encapsulation of the stem cell inhibitor Salinomycin in novel QUATRAMER sustained injectable suspension (HSB-1216) for the treatment of 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 491.
Covid-19: does the UK spend a large enough proportion of its national wealth on the provision of healthcare?
Authors: Stephen T Green, Lorenzo Cladi
Journal: BMJ (2020)

Given that the provision of healthcare services to a population will always be costly,1 the proportion of national wealth—represented by gross domestic product (GDP)—that a country chooses to spend on health is essentially a political decision. Does the UK currently spend enough?

Ensuring value for money is laudable and reasonable, but it is not acceptable that, …
Abstract 527: Isolation of large and diverse monoclonal antibody panels against the multipass membrane protein targets Kv1.3, P2X7, and Claudin 18.2
Authors: Lewis J. Stafford, Sharon Willis, Joseph Rucker, Benjamin Doranz, Ross Chambers
Journal: Cancer Research (2020)

Abstract Monoclonal antibodies (MAbs) are a well-established treatment approach in oncology and other diseases. Nevertheless, multipass membrane proteins are largely inaccessible as MAb targets due to their poor expression, membrane-dependent structure, small extracellular regions, and high sequence conservation between humans and rodents. Integral Molecular's MPS Antibody Discovery platform specifically addresses each of these challenges. Using this platform, we have isolated large and diverse panels of functional (agonist/antagonist) MAbs against targets including Claudin 18.2 and the ion channels P2X7 and Kv1.3. A key feature that enables the success of the platform is the use of divergent species for immunization. Chickens are immunized with a combination of DNA and Lipoparticles (high-concentration membrane proteins) to obtain high-titer immune responses against the native membrane protein. Our optimized phage-display protocols allow the isolation of large panels of MAbs against diverse epitopes. The MPS Antibody Discovery platform offers the potential for discovering MAbs against difficult targets in cancer with a success rate over 95%. Citation Format: Lewis J. Stafford, Sharon Willis, Joseph Rucker, Benjamin Doranz, Ross Chambers. Isolation of large and diverse monoclonal antibody panels against the multipass membrane protein targets Kv1.3, P2X7, and Claudin 18.2 [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 527.
Childhood BMI and Fasting Glucose and Insulin Predict Adult Type 2 Diabetes: The International Childhood Cardiovascular Cohort (i3C) Consortium
Authors: Tian Hu, David R. Jacobs, Alan R. Sinaiko, Lydia A. Bazzano, Trudy L. Burns, Stephen R. Daniels, Terry Dwyer, Nina Hutri-Kähönen, Markus Juonala, Kari A. Murdy, Ronald J. Prineas, Olli T. Raitakari, Elaine M. Urbina, Alison Venn, Jessica G. Woo, Julia Steinberger
Journal: Diabetes Care (2020)

OBJECTIVE To examine childhood BMI, fasting glucose, and insulin in relation to incident adult type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS We used data from the International Childhood Cardiovascular Cohort (i3C) Consortium. Data included childhood (age 3–19 years) measurements obtained during the 1970s–1990s; a health questionnaire, including self-report of adult T2DM (occurrence age, medication use) obtained at mean age 40 years; and a medical diagnosis registry (Finland). RESULTS The sample included 6,738 participants. Of these, 436 (6.5%) reported onset of T2DM between ages 20 and 59 (mean 40.8) years, and 86% of them reported use of a confirmed antidiabetic medication. BMI and glucose (age and sex standardized) were associated with incident T2DM after adjustment for cohort, country, sex, race, age, and calendar year of measurement. Increasing levels of childhood BMI and glucose were related to an incrementally increased risk of T2DM beginning at age 30 years, beginning at cut points &amp;lt;95th percentile for BMI and &amp;lt;100 mg/dL for glucose. Insulin was positively associated with adult T2DM after adjustment for BMI and glucose and added to T2DM discrimination. CONCLUSIONS Childhood BMI and glucose are predictors of adult T2DM at levels previously considered to be within the normal range. These easy-to-apply measurements are appealing from a clinical perspective. Fasting insulin has the potential to be an additional predictor.
Abstract 4021: Assessing the sensitivity of LSF inhibitors against liver cancer
Authors: Niranjana Pokharel, John Kavouris, Jessica Biagi, Ulla Hansen, Scott E. Schaus
Journal: Cancer Research (2020)

Abstract Introduction: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer mortality. The transcription factor Late SV40 Factor (LSF) functions as an oncogene in HCC, making it a potential protein target for HCC therapy. LSF overexpression correlates with pathogenesis of liver, colorectal and pancreatic cancers, for which there are limited molecularly targeted therapy options. A library of dihydroquinolinones, termed Factor Quinolinone Inhibitors (FQIs), inhibits LSF-DNA binding and specific LSF-protein interactions in in vitro and in cellular assays. The initial lead compound FQI1 causes dramatic mitotic defects in HCC cell lines but has no toxic consequences on immortalized human hepatocytes or primary mouse hepatocytes. Additionally, FQI1 has proven efficacious in endogenous HCC mouse models, with no evidence of associated toxicity. Methods: A series of dihydroquinolinone compounds were synthesized and tested for potency in two HCC cell lines, Huh7 and SNU423, by a cell proliferation assay. The FQI analogs, FQI34, N-oxide FQI34 and FQI37, were separated by chiral chromatography to the corresponding R and S enantiomers. Direct target engagement of the three lead compounds, FQI1, FQI34 and FQI37, is shown with cellular thermal stability assays on Huh7 cells. Results: More than 20 compounds were synthesized and characterized. Among them, FQI37 showed the most potent activity (GI50 = 70 nM) against Huh7 HCC cells. Structure-activity-relationship studies suggest that the amide portion of quinolinone core is important for optimal activity. Growth inhibition assays revealed enantiomeric specificity; the (S)-enantiomers are more potent than the (R)-compounds and the racemate. The cellular thermal shift assay in Huh7 cells demonstrated the direct target binding of FQIs to LSF in cells at micromolar concentrations. Growth inhibition assays also identified colorectal cancer and pancreatic cancer lines to be sensitive to the dihydroquinolinones treatment. Conclusions: Aryl-dihydroquinolinones are promising small molecule chemotherapies for LSF-driven cancers such as HCC, colorectal cancer, and pancreatic cancer. Citation Format: Niranjana Pokharel, John Kavouris, Jessica Biagi, Ulla Hansen, Scott E. Schaus. Assessing the sensitivity of LSF inhibitors against liver 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 4021.
Abstract LB-343: A Leu(CAG)-tRNA derived small RNA regulates ribosomal protein S28 after translation initiation in both human and mouse liver cancers
Authors: Hak Kyun Kim, Jianpeng Xu, Kirk Chu, Hyesuk Park, Hagoon jang, Pan Li, Paul Valdmanis, Qiangpeng Zhang, Mark Kay
Journal: Cancer Research (2020)

Abstract Transfer-RNA-derived small RNA (tsRNA) is implicated in regulating many cellular processes and is dysregulated in various diseases. We recently revealed that the 3′ end of the LeuCAG tRNA-derived small RNA (LeuCAG3′tsRNA) binds to two target sites in human RPS28 mRNA coding region and 3′ UTR, and unwinds their double-stranded secondary structure, which enhances RPS28 translation and subsequently regulates ribosome biogenesis. Inhibition of this tsRNA suppressed the growth of hepatocellular carcinoma in vivo, making it a bona-fide target for cancer therapeutics1. However, the functional conservation between species and the detailed mechanism by which the tsRNA regulates mRNA translation need to be determined in more detailed. Here, we showed that the target site in RPS28 coding region in human is highly conserved in many vertebrate species. While the 3′ UTR target site forms a double-stranded secondary structure with the translation initiation site (TIS) in human RPS28 mRNA, the functional 3′ UTR target site is not present in the species distantly related to human. We revealed that a conserved target site in the mouse Rps28 coding region was sufficient for tsRNA-regulated enhanced translation of the mRNA and cancer cell viability in mouse cell line. Moreover, we demonstrated that the tsRNA regulates mRNA translation after initiation in both human and mouse. Our results have implications for providing additional insights into the biological role of LeuCAG3'tsRNA in post-transcriptional gene regulation and cancer cell viability.1. Kim, HK, et al. (2017). A transfer-RNA-derived small RNA regulates ribosome biogenesis. Nature: 1-21doi:10.1038/nature25005. Citation Format: Hak Kyun Kim, Jianpeng Xu, Kirk Chu, Hyesuk Park, Hagoon jang, Pan Li, Paul Valdmanis, Qiangpeng Zhang, Mark Kay. A Leu(CAG)-tRNA derived small RNA regulates ribosomal protein S28 after translation initiation in both human and mouse liver cancers [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 LB-343.
Abstract 4198: Role of receptor tyrosine kinase AXL in mediating DNA damage response
Authors: Xun Hui Yeo, Wai Leong Tam, Ruby Yun-Ju Huang
Journal: Cancer Research (2020)

Abstract AXL is a receptor tyrosine kinase that is often overexpressed in many cancers. It contributes to tumor progression, metastasis and drug resistance through activating downstream signaling cascades, making it an emerging therapeutic target. Moreover, the first-in-class AXL inhibitor R428 (BGB321) was lately approved by the FDA for the treatment of relapsed or refractory acute myeloid leukemia. Previously, R428 (BGB321) was also reported to show selective sensitivity towards ovarian cancers with a Mesenchymal molecular subtype. Recently, a novel role of AXL in the regulation of DNA damage responses has been brought to light. Here, we further explored AXL's role in mediating DNA damage responses by using ovarian cancer as a disease model. AXL inhibition using R428 resulted in the increase DNA damage foci in ovarian cancer cells SKOV3 and HeyA8. This occurred concurrently with the upregulation of classic DNA damage response signaling molecules such as γH2Ax, ATM and ATR. RNA sequencing results further validated this observation, that R428-treated cells showed downregulation of genes involved in cell cycle control and DNA replication, suggesting the decrease in proliferation. Through SILAC co-immunoprecipitation mass spectrometry, we uncovered a novel binding partner of AXL that could potentially regulate the DNA damage repair upon the inhibition of AXL, giving us insights to how AXL inhibition might contribute to DNA damage. Furthermore, our results showed that AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress, paving ways to the rationale for potential combinatory use of AXL and DNA damage repair inhibitors. Citation Format: Xun Hui Yeo, Wai Leong Tam, Ruby Yun-Ju Huang. Role of receptor tyrosine kinase AXL in mediating DNA damage response [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 4198.
Abstract 3001: Drug resistant PDX models for new drug discovery
Authors: Feifei Zhang, Yuan Long, Danyi Wen
Journal: Cancer Research (2020)

Abstract Drug resistant is one of the biggest challenge for cancer therapy. How to understand the mechanism and to overcome the drug resistant with new therapeutics represent the hot focus for oncology drug discovery. Drug resistant patient-derived xenograft (PDX) models derived from surgery samples, biopsy samples, hydrothorax or ascetic fluid provides unique tool for new therapeutics R&amp;D. We have successfully established an array of drug resistant PDX models. Representative drug resistant PDX includes: clinically AZD9291-resistant EGFR triple mutant (Ex19del, T790M, C797S) PDX model. In vivo efficacy results show that this triple mutant NSCLC PDX model was resistant to Erlotinib and AZD9291 and sensitive to the combination of Cetuximab and Brigatinib. We also established CD74-ROS1 fusion and G2032R mutant NSCLC PDX model; EML4-ALK fusion and L1196M mutant NSCLC PDX model; Olaparib resistant Ovarian cancer PDX model; Heceptin resistant gastric PDX model; Rituximab and ABT-199 resistant DLBCL PDX model, and so on. In conclusion, these precious PDX models provide insight into resistance mechanisms as well as serve as models to develop new therapeutics drug candidates that overcome the drug resistant. Citation Format: Feifei Zhang, Yuan Long, Danyi Wen. Drug resistant PDX models for new drug discovery [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 3001.