tbuckley/cabot-search huggingface dataset:
Abstract 2099: Assessing cancer drug response prediction from gene expression
Authors: James Talwar, Hannah Carter
Journal: Cancer Research (2020)

Abstract Customizing treatments targeted to a patient specific disease landscape remains an open challenge in precision medicine. Gene expression data, generated through next generation sequencing technologies, has shown significant power for supervised machine learning approaches. Here, we evaluated neural network performance at predicting cancer cell-line specific drug sensitivity. Gene expression data for 17,737 genes across 1014 human cancer cell-lines with IC50 concentrations for 251 anti-cancer drugs were obtained from the Genomics of Drug Sensitivity in Cancer Project. Cell-lines were considered sensitive if IC50 concentration was below maximum drug concentration. For neural network input, gene expression values were scaled to a range of -0.5 to 0.5 through log transformation, z-scoring, subtracting the minimum and dividing by the range. A hyperparameter optimized neural network model consisting of two hidden layers of size 1024 and 512 respectively resulted in a test set accuracy ranging from 60.2% to 67.8% across drugs compared to an average baseline performance of 53.4%. Dimension reduction through clustering and Nearest Neighbor Networks did not result in improved performance. We found that classical machine learning classification methods including support vector machines showed comparable performance to our neural network approach. However, neural network cross-training on drugs sharing the same putative targets (e.g. AURKA) led to a 5.03% improvement in neural network prediction accuracy. Overall, our analysis shows that utilizing gene expression profiles independent of other -omics data for cancer drug response prediction through machine learning frameworks offers modest predictive capabilities. To increase performance, we suggest augmenting training size through shared pathway cross-training, optimizing feature encoding to maximize neural network predictive capabilities, and incorporating other -omics data. Citation Format: James Talwar, Hannah Carter. Assessing cancer drug response prediction from gene expression [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 2099.
Use of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus infection and severe renal impairment
Authors: Desmond Y. H. Yap, Kevin S. H. Liu, Yu-Chun Hsu, Grace L. H. Wong, Ming-Chang Tsai, Chien-Hung Chen, Ching-Sheng Hsu, Yee Tak Hui, Michael K. K. Li, Chen-Hua Liu, Yee-Man Kan, Ming-Lung Yu, Man-Fung Yuen
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: Data on treatment efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) for chronic hepatitis C virus (HCV) infection in Asian patients with severe renal impairment are limited. This study aimed to study the treatment and side effects of GLE/PIB in these patients infected with non-1 genotype (GT) HCV.Methods: We prospectively recruited patients with Child’s A cirrhosis and eGFR &lt;30 mL/min/1.73 m&lt;sup&gt;2&lt;/sup&gt; in Hong Kong and Taiwan during 2017–2018 to receive GLE/PIB treatment.Results: Twenty-one patients (GT2, n=7; GT3, n=6; and GT6, n=8) received GLE/PIB for 11.2±1.8 weeks. All except one were treatment-naïve. GLE/PIB was initiated in 16 patients while on dialysis (seven on peritoneal dialysis [PD] and nine on hemodialysis) and in five patients before dialysis. One patient died of PD-related peritonitis during treatment and two were lost to follow up. The SVR12 rate in the remaining 18 patients was 100%. All patients achieved undetectable levels at 4-, 12-, 24- and 48-week after treatment. Patients with deranged alanine aminotransferase showed normalization after 4 weeks and the response was sustained for 48 weeks. No significant adverse event was observed.Conclusions: GLE/PIB treatment was associated with high efficacy and tolerability in HCV-infected patients with severe renal impairment.
Abstract 3344: The human commensal <i>lactobacillus rhamnosus</i> GG orchestrates an anti-tumor immune response
Authors: Josh Owens, Bejan Saeedi, Crystal Naudin, Sarah Hunter-Chang, Trevor Darby, Brian Robinson, Rheinallt Jones
Journal: Cancer Research (2020)

Abstract Only 10% of patients with colorectal cancer (CRC) are approved for immunotherapy and only 50% of approved patients are responsive to this treatment. The 95% of CRC patients that are refractory to immunotherapy are so because of low anti-tumor immune responses in the gut mucosa. Mucosal immunity is sensitive to changes in the microbiome community structure, and to dietary supplementation with beneficial bacteria, known as ‘probiotics' which are known to augment mucosal immunity. Therefore, we supplemented the murine microbiome by daily oral gavage with the human commensal bacteria, Lactobacillus rhamnosus GG (LGG). We discovered that LGG increases colonic CD8 T cell responses by flow cytometry and immunofluorescence analysis. We did not believe that LGG was having a direct effect on CD8 T-cell function but was being augmented through an innate cell population. Using BATF3-null mice which lack conventional dendritic cells, we did not detect LGG-induced CD8 T-cell changes determining that this response is dendritic cell dependent. In addition, we sought to determine how LGG was being sensed by dendritic cells. Based off preliminary data and published reports, we utilized Toll like Receptor 2 (TLR2)-null mice and found that LGG-induced CD8 T cell induction also required TLR2 signaling. These data describe a novel mechanism whereby LGG induces colonic CD8 T cells activation through a dendritic cell and TLR2-dependent manner. As CD8 T-cells are critical in the anti-tumor response, we induced colonic tumors in mice by performing the DSS-AOM model. After tumors were established, we administered LGG daily by oral gavage. LGG supplementation resulted in significantly reduced tumor burden compared to control mice fed vehicle or a non-probiotic bacterium. Furthermore, this reduction in tumor burden was CD8 T cell dependent, as depletion of CD8 T cells abrogated this effect. In summary, oral supplementation with LGG may hold clinical promise in augmenting colonic anti-tumor immune responses and may increase immunotherapy response rates in patients. Citation Format: Josh Owens, Bejan Saeedi, Crystal Naudin, Sarah Hunter-Chang, Trevor Darby, Brian Robinson, Rheinallt Jones. The human commensal lactobacillus rhamnosus GG orchestrates an anti-tumor immune 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 3344.
Abstract A23: Ultrarapid total abdominal FLASH irradiation in a preclinical model of ovarian cancer
Authors: Karen Levy, Jinghui Wang, Joshua Eggold, Suchitra Natarajan, Peter Maxim, Bill Loo, Erinn Rankin
Journal: Clinical Cancer Research (2020)

Abstract Introduction: Ultrahigh dose-rate irradiation (FLASH RT) is rapidly emerging as new strategy to enhance the therapeutic index of radiotherapy by protecting normal tissues from radiation-induced toxicity while maintaining tumor control. In mice, FLASH has been shown to protect the lung, skin, and brain against radiation-induced toxicity. A recent study has utilized FLASH radiotherapy in preclinical models of lung cancer to demonstrate that FLASH RT radiotherapy achieves similar tumor control to conventional RT. While these findings identify an important role for FLASH RT in the protection of multiple tissues, the role of FLASH in enhancing the therapeutic index of abdominal and pelvic tumors located near the highly radiosensitive intestine is not known. For this purpose, we have developed an experimental platform using a clinical linear accelerator that enables total abdominal FLASH RT where rapid delivery of a single fraction of high-dose radiotherapy is performed in less than one second (200 Gy/sec). Methods: For the tumor model, ID8 cells were injected intraperitoneally into female mice. Radiation was delivered 10 days post-ID8 injection. Tumor burden was assessed at 28 days following tumor injection. Flow cytometry was used to profile infiltrating immune cells. Normal tissue toxicity was assessed through survival, total body weight, solid stool production, complete blood count, and histologic analysis. Results: In ID8 tumor-bearing mice, 14 Gy FLASH promotes GI function with a 2-fold increase in solid stool production at 5 days post-TAI. Both modalities extended median overall survival in the ID8 model by 5 days and reduced tumor burden by 50% relative to unirradiated controls. Irradiated cohorts also demonstrated an increase in the number of proliferating CD8+ and CD4+ T cells present in the ascites. Conclusion: We demonstrate that FLASH RT protects the gastrointestinal (GI) tract from lethal radiation-induced toxicity, improves epithelial integrity and GI function, enhances crypt survival, and provides efficient tumor control in a preclinical model of ovarian peritoneal metastasis. Here we present the first data supporting the potential for tumor control and GI protection using FLASH-TAI in a syngeneic orthotopic preclinical model of ovarian cancer. Citation Format: Karen Levy, Jinghui Wang, Joshua Eggold, Suchitra Natarajan, Peter Maxim, Bill Loo, Erinn Rankin. Ultrarapid total abdominal FLASH irradiation in a preclinical model of 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 A23.
FRI0054 A long-term, open-label trial of the safety and efficacy of etanercept (25 mg twice weekly) in patients with rheumatoid arthritis (interim analysis)
Authors: RF Willis, R Pedersen
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Several double-blind, placebo-controlled studies previously demonstrated that etanercept was safe and efficacious in treating rheumatoid arthritis (RA) patients who had an inadequate response to disease-modifying antirheumatic drugs (DMARDs). <h3>Objectives</h3> To evaluate the long-term safety and efficacy of etanercept in patients who completed prior double-blind clinical studies comparing etanercept to placebo. <h3>Methods</h3> As reported in previous updates, 549 patients entered this 4-year, open-label study and began treatment with etanercept 25 mg twice weekly at 58 centres in Europe following completion of double-blind clinical studies. All patients previously had inadequate responses to DMARDs. Safety assessments were performed at regular intervals to determine the incidence of treatment emergent adverse events including malignancies and serious infections (those associated with hospitalisation and/or the administration of intravenous antibiotics). The numbers of painful and swollen joints were predefined as primary efficacy endpoints; other efficacy measures included ACR response rates and acute phase reactants. Efficacy was analysed with the last observation carried forward (LOCF). <h3>Results</h3> Of the 549 patients initially enrolled, 437 (80%) are currently active, 479 (87%) completed 1 year, and 94 (17%) completed 2 years. A total exposure of 927 patient-years has been accrued. The rate of withdrawal from the study was similar for efficacy- and tolerance-related reasons (7% and 8%, respectively). Adjusted for patient exposure, the most frequent adverse events were injection site reactions and upper respiratory infections. Rates of serious infections and malignancies have remained unchanged over the course of the study. Maintained efficacy was observed as demonstrated by a mean 71% and 72% reduction in painful and swollen joint counts, respectively. Similar to results measured at the early time points of this open-label trial, ACR 20, 50, and 70 response rates were determined to be 79%, 47%, and 25%, respectively, as patients approached two years of treatment. <h3>Conclusion</h3> Following the accumulation of substantial exposure in patients with RA, etanercept demonstrates an acceptable safety profile and continues to provide significant and maintained clinical benefit.
Abstract 4949: Essential role of arachidonic acid metabolism in prostate cancer stem cell survival
Authors: Jitender Monga, Brendan Carney, Sejal Patil, Jagadananda Ghosh
Journal: Cancer Research (2020)

Abstract Background: Cancer stem cells (CSC) are rare group of neoplastic cells with features that include, self-renewal, pluripotency and tumorigenicity, and are thought to be responsible for tumor recurrence and metastasis. Thus, a lot of excitement surrounds the idea of going right to the root of the tumor and target the stem cells to eradicate cancer permanently. A hierarchically organized CSC model in prostate cancer is evident with CD44 (+), CD133 (+) subpopulations isolated from human prostate tumors. While most therapies are directed to the fast-growing tumor mass made of differentiated cells, they cannot target the relatively slow-dividing and resistant cancer stem cells, which may underlie as a mechanism of why the cancer is not permanently eradicated with standard chemotherapy. Thus, an important challenge is to find measures to eliminate the CSCs, which by definition, will stop tumor growth and prevent recurrence. However, knowledge about molecular features critical for prostate cancer stem cells (PCSC) is meager. Thus, we wanted to examine the role of arachidonate 5-lipoxygenase (ALOX5) which plays critical role in the survival of cancer (but not of normal) cells, in the biology of PCSC. Methods: Using an established, clinically-relevant in vitro model of human PCSCs which express both pluripotency markers (Nanog, c-Myc, Sox2) and tumor-progenitor markers (CD44, CD133, ALDH1), we interrogated the role of a fatty acid metabolic pathway in stem cell vulnerability. Especially, our goal was to characterize the effects of targeting ALOX5 to see whether it could be a new target to eliminate PCSCs. Results: Inhibition of ALOX5 by shRNA or MK591 dramatically decreased the protein levels of Nanog and c-Myc, suggesting a role for ALOX5 in prostate cancer stemness. Moreover, ALOX5 inhibition was found to selectively kill PCSCs (but not normal stem cells) by inducing apoptosis via inhibition of survivin, cyclin D1 and CDK4, and activation of c-Jun N-terminal Kinase and caspase 3, suggesting an essential role of ALOX5 in the survival of PCSC. Interestingly, non-cancer parenchyma body cells, including normal stem cells, do not express ALOX5 (presumably because of promoter hypermethylation) and are not affected by ALOX5 inhibitors. Conclusion: Our findings indicate that ALOX5 plays a causal role in maintaining prostate cancer stemness by regulating Nanog and c-Myc oncogenes, and suggest that an effective, long-lasting therapy of prostate cancer may be possible by targeting ALOX5 to kill and eliminate PCSCs to block prostate tumor growth and prevent recurrence. Citation Format: Jitender Monga, Brendan Carney, Sejal Patil, Jagadananda Ghosh. Essential role of arachidonic acid metabolism in prostate cancer stem cell survival [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 4949.
Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in
Authors: Anna K Nowak, W Joost Lesterhuis, Peey-Sei Kok, Chris Brown, Brett GM Hughes, Deme J Karikios, Thomas John, Steven C-H Kao, Connull Leslie, Alistair M Cook, Nick Pavlakis, Karen Briscoe, Kenneth J O'Byrne, Christos S Karapetis, Wei-Sen Lam, Ailsa Langford, Sonia Yip, Martin R Stockler
Journal: The Lancet Oncology (2020)
Comparison of Preoperative Remission Scores and Diabetes Duration Alone as Predictors of Durable Type 2 Diabetes Remission and Risk of Diabetes Complications After Bariatric Surgery: A Post Hoc Analysis of Participants From the Swedish Obese Subjects Study
Authors: Kajsa Sjöholm, Lena M.S. Carlsson, Magdalena Taube, Carel W. le Roux, Per-Arne Svensson, Markku Peltonen
Journal: Diabetes Care (2020)

OBJECTIVE Bariatric surgery is associated with diabetes remission and prevention of diabetes-related complications. The ABCD, DiaRem, Ad-DiaRem, DiaBetter, and individualized metabolic surgery scores were developed to predict short- to medium-term diabetes remission after bariatric surgery. However, they have not been tested for predicting durable remission nor the risk of diabetes complications, nor compared with diabetes duration alone. RESEARCH DESIGN AND METHODS We identified 363 individuals from the surgically treated group in the prospective Swedish Obese Subjects study with preoperative type 2 diabetes and for whom data (preoperative age, BMI, C-peptide, HbA1c, oral diabetes medications, insulin use, and diabetes duration) were available for calculation of remission scores. Partial remission (after 2 and 10 years) was defined as blood glucose &amp;lt;6.1 mmol/L or HbA1c &amp;lt;6.5% (48 mmol/mol) and no diabetes medication. Information on diabetes complications (at baseline and over 15 years of follow-up) was obtained from national health registers. Discrimination was evaluated by area under receiver operating characteristic curves (AUROCs). RESULTS For 2-year diabetes remission, AUROCs were between 0.79 and 0.88 for remission scores and 0.84 for diabetes duration alone. After 10 years, the predictive ability of scores decreased markedly (AUROCs between 0.70 and 0.76), and no score had higher predictive capacity than diabetes duration alone (AUROC = 0.73). For development of microvascular and macrovascular diabetes complications over 15 years, AUROCs for remission scores were 0.70–0.80 and 0.62–0.71, respectively, and AUROCs for diabetes duration alone were 0.77 and 0.66, respectively. CONCLUSIONS Remission scores and diabetes duration are good predictors of short-term diabetes remission. However, for durable remission and risk of complications, remission scores and diabetes duration alone have limited predictive ability.
Abstract B64: Targeting the pH regulators in the tumor microenvironment for ovarian cancer treatment
Authors: Arpita Kulshrestha, Gajendra K. Katara, Sylvia Schneiderman, Valerie E. Riehl, Alexandria N. Young, Shayna Levine, Safaa Ibrahim, Mahmood Bilal, Alice Gilman-Sachs, Kenneth D. Beaman
Journal: Clinical Cancer Research (2020)

Abstract The high mortality rate in ovarian cancer (OVCA) is currently the most pressing concern despite the research advancements. It is still not clear how to effectively treat OVCA patients to prevent a relapse or to treat the relapse tumors that display a drug-resistant profile. To address this issue, this study targets a uniquely expressed pH regulator in the tumor microenvironment as a strategy to treat ovarian cancer. In order to survive the metabolic acidosis, cancer cells overexpress pH regulators on their surface to pump out excess protons/lactic acid. This, in turn, acidifies the tumor microenvironment and promotes tumor invasion/chemoresistance. The a2-Vacuolar-ATPases (V-ATPases) are the major pH-sensing unit of the V-ATPase proton pumps and are abundantly expressed on the surface of ovarian cancer cells. To establish the clinical importance, our findings show that a2-V-ATPases are overexpressed in all morphologic subtypes and stages of human OVCA and are absent on normal ovarian tissues. We further examined the therapeutic potential of monoclonal antibody against a2-V-ATPase (V0a2-mab) in controlling tumor growth in the preclinical mouse model. In vivo V0a2-mab treatment (300μg in PBS; i.p) resulted in a significantly delayed tumor growth compared to control, with no apparent in vivo toxicity in athymic nude mice xenograft model. The delayed tumor growth was attributed to high immune infiltration with increased leukocyte population and an enhanced iNOS expression compared to control mice. These results show that V-ATPases are overexpressed in the tumor microenvironment and their inhibition impairs OVCA growth by interfering with tumor acidification that enhances the antitumor responses. In conclusion, the study demonstrates that targeting V-ATPase pH regulators is an effective treatment strategy in ovarian cancer. Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Sylvia Schneiderman, Valerie E. Riehl, Alexandria N. Young, Shayna Levine, Safaa Ibrahim, Mahmood Bilal, Alice Gilman-Sachs, Kenneth D. Beaman. Targeting the pH regulators in the tumor microenvironment for ovarian cancer 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 B64.
SAT0132 Validation of the `quality of life scale` (qols-g) in patients with fibromyalgia
Authors: M Offenbaecher, M Waltz, G Stucki
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The Quality of Life Scale (QOLS) is a 16 item questionnaire. The QOLS covers a broader perspective of quality of life as it is seen by patients with rheumatic diseases including non-health factors as satisfying relationships with others, material well being, self-fulfilment and leisure activities. <h3>Objectives</h3> Our objective was to translate the QOLS into German and to evaluate its reliability and validity for the use of German speaking patients with fibromyalgia (FM). <h3>Methods</h3> We administered the QOLS to 57 FM patients meeting the ACR criteria (14 patients filled out the questionnaire 1 week later) together with German versions of the FIQ, the SF-36 and a tender point count (TPC). All patients were asked about the severity of pain today (VAS) and the duration of symptoms; pressure pain thresholds (PPT) were assessed by dolorimetry at all tender points with a Fisher Dolorimeter and laboratory tests were obtained. Test-retest reliability was assessed using Spearman correlations. Internal consistency was evaluated with Cronbach's alpha of reliability. Construct validity of the QOLS was evaluated by correlating the QOLS with the FIQ and the SF-36 scores as well as with the pain variables and dolorimetry scores. <h3>Results</h3> Age range was 33–73 years (mean 53,8). Means were for the TPC (maximal achievable score 120) 67, for pain today 6,8 and for duration of symptoms 11,8 years; the mean tenderness threshold was 1,49 kg/cm<sup>2</sup>. Test-retest reliability was for the total QOLS 0,76. Internal consistency was 0,88. As hypothesised, low to moderate correlations (rho) were obtained between the QOLS and the total FIQ (-0,29), the SF-36 (e.g. physical component 0,19, mental component -0,17) as well as the pain variables (VAS -0,18, TPC -0,01) and PPT (0,12). <h3>Conclusion</h3> The QOLS-G is a reliable and valid instrument for measuring quality of life in German patients with FM.