tbuckley/cabot-search huggingface dataset:
Hydrogen peroxide-response nanoprobe for CD44-targeted circulating tumor cell detection and H2O2 analysis
Authors: Chunting Li, Jiexuan Wang, Xinmiao Lu, Huang Ge, Xin Jin, Qinhua Guan, Yue su, Ruijun Pan, Peiyong Li, Wei Cai, Xinyuan Zhu
Journal: Biomaterials (2020)
Plasma IL8 Is a Biomarker for TAK1 Activation and Predicts Resistance to Nanoliposomal Irinotecan in Patients with Gemcitabine-Refractory Pancreatic Cancer
Authors: Valeria Merz, Camilla Zecchetto, Raffaela Santoro, Francesca Simionato, Fabio Sabbadini, Domenico Mangiameli, Geny Piro, Alessandro Cavaliere, Michela Deiana, Maria Teresa Valenti, Diana Bazan, Vita Fedele, Sara Lonardi, Davide Melisi
Journal: Clinical Cancer Research (2020)

Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting.In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients' outcome were obtained on the basis of the maximization of the Youden's statistics.Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39-4.67; P = 0.0017; median overall survival 8.9 months vs 5.3 months; HR, 3.51; 95% CI, 0.84-6.68; P = 4.9e-05). These results were confirmed in a validation cohort of 50 patients.Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer.
Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer
Authors: Dongqiang Zeng, Zilan Ye, Jiani Wu, Rui Zhou, Xinxiang Fan, Gaofeng Wang, Yiqiang Huang, Jianhua Wu, Huiying Sun, Miaohong Wang, Jianping Bin, Yulin Liao, Nailin Li, Min Shi, Wangjun Liao
Journal: Theranostics (2020)

Immune-checkpoint blockades (ICBs) have been routinely implemented to treat metastatic urothelial cancer (mUC), whereas robust biomarkers are urgently warranted. Herein, we explored latent promising biomarkers based on 348 pretreatment mUC samples from IMvigor210.
Biological validation of a linear regression mathematical model of gene expression and radiation response
Authors: Hongling Zhang, Steven Eschrich, Haiyan Zhao, Javier Torres-Roca
Journal: Cancer Research (2007)

3803  Background: In a previous study we showed that a multivariate linear regression model of gene expression and radiation response (as measured by survival fraction at 2Gy, SF2) predicted cellular radiosensitivity and identified at least one novel protein (RbAp48) mechanistically involved in radiation response. The model predicted that three additional known genes (rgs-19, r5pia and topo1) could be involved in regulating radiation response. In this study, we continue the biological testing of the multivariate linear regression model.  Methods: The details of the multivariate linear regression model of gene expression and radioresponse in a 35 cell line database have been published previously (1).RGS-19 (Flag -tag) and R5PIA were transfected into MDA-MB231 and MALME-3M cell lines respectively, using Lipofectamine2000 reagent (Invitrogen). Overexpression of both RGS-19 and R5PIA were confirmed by western blot. Cell survival after 2, 4 6,and 8 Gy radiation were determined by the clonogenic assay. RbAp48 siRNA (100 nM) designed by Dharmacon’s SMARTpool technology or a pool of 4 negative controls siRNA (100 nM) was transfected into HCT116 colon cancer cell lines following the DharmaFECT transfection protocol (Dharmacon). Knockdown of RbAp48 was verified 72 hours after transfection, by Western Blot.  Results: The model predicted that overexpression of RGS-19 and R5PIA should lead to radiosensitization while downregulation of RbAp48 should lead to radioresistance. Indeed, overexpression of RGS-19 resulted in radiosensitization of MDA-MB231 breast cancer cell lines (SF2, Empty Vector: 0.50 ± 0.06 vs. RGS19 plasmid: 0.35 ± 0.06, n=3, p=0.01) (SF8 value, Empty Vector: 0.096 ± 0.053 and RGS19 plasmid: 0.068 ± 0.06, n=3, p=0.06). In contrast, overexpression of R5PIA had no effects on radiosensitivity of SKMEL28 cancer cell lines as measured by SF2 (Empty Vector: 0.64 ± 0.10 and R5PIA plasmid: 0.68 ± 0.09, n=4). Additionally downregulation of RbAp48 resulted in radiation resistance of HCT-116 (SF2, control siRNA: 0.26 ± 0.04, RbAp48 siRNA: 0.37 ± 0.03, n=6) (SF8 control siRNA: 0.00275 ± 0.0002, RbAp48 siRNA: 0.00575 ± 0.0004, n=6), also consistent with the predictions of the model.  Conclusions: These data further confirm the biological validity of the mathematical algorithm applied to this genomic analysis. Two of the three genes tested affected radiation response as predicted by the model. A third gene (top1) is currently a target for radiosensitization in clinical use.  References  1. Torres-Roca JF, Eschrich S, Zhao H, Bloom G, Sung J, McCarthy S, Cantor AB, Scuto A, Li C, Zhang S, Jove R, Yeatman T. (2005) Cancer Res 65:7169-76
Reduction-sensitive platinum (IV)-prodrug nano-sensitizer with an ultra-high drug loading for efficient chemo-radiotherapy of Pt-resistant cervical cancer in vivo
Authors: Kejun Luo, Wenxuan Guo, Yanting Yu, Simeng Xu, Min Zhou, Keqi Xiang, Kun Niu, Xianqi Zhu, Guangying Zhu, Zheng An, Qingsong Yu, Zhihua Gan
Journal: Journal of Controlled Release (2020)
SAT0342 INNATE LYMPHOID CELLS ARE PREDICTORS OF DISEASE PROGRESSION IN SYSTEMIC SCLEROSIS: A 3-YEARS FOLLOW-UP STUDY
Authors: A. Soare, S. Weber, G. Schett, J. Distler, A. Ramming
Journal: Annals of the Rheumatic Diseases (2020)

Background: Activation of the immune system is a characteristic feature of SSc. Numerous studies have suggested that type 2 are key drivers of progressive fibrosis. Recently, innate lymphoid cells (ILC) are emerging as an important cellular source of type 2 cytokines triggering fibrotic tissue remodeling independently of the adaptive immune system. Increased levels of ILC2 were found in patients with SSc. However, the contributive role of ILC2 in pathogenesis of SSc is not completely understood. Objectives: We aim in our 3 years observational study to evaluate the predictive role of ILC2 in SSc patients. Methods: We conducted an observational retrospective study on 52 patients with SSc fulfilling the 2013 ACR/EULAR classification criteria. Yearly clinical, laboratory and investigational data according to EUSTAR recommendations were collected. Blood samples collected between 15.09.2014 and 15.01.2015 were analyzed by flow cytometry and ILC2 counts were measured. The predictive value of ILC2 during a 3-year follow-up was analyzed using SPSS 21.0. Results: 52 patients were included in the study, 78% female, 63% limited cutaneous SSc with a mean follow-up time of 2.85 ± 1.28 years. At baseline we have shown that circulating ILC2s are significantly increased compared to gender and age-matched healthy controls. Increased numbers of ILC2s significantly correlated with worsening of mRSS calculated by five point increase in mRSS or 25% increase from baseline (p &lt; 0.001; 95% CI 1.39 – 3.26). ILC2 counts also correlated with 5% decrease of diffusion capacity of carbon monoxide (DLCO) during the follow-up time (p &lt; 0.0001; 95% CI 1.83 – 3.49). Worsening of forced vital capacity (FVC) assessed as 5% decrease over 2 years was also significantly correlated with an increased number of ILC2s (p &lt; 0.0001; 95% CI 1.27 – 3.04). In contrast, we did not find any correlation regarding increase in pulmonary arterial pressure assessed by echocardiography. Although new appearance of digital ulcers could not be predicted by ILC2 counts, increased numbers of ILC2s were correlated with digital ulcers at follow-up. Conclusion: Here, we provide first evidence for a role of ILC2s as potential prognostic marker of disease progression in SSc. Disclosure of Interests: Alina Soare: None declared, Stefanie Weber: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen
Sequential CRISPR-Based Screens Identify LITAF and CDIP1 as the Bacillus cereus Hemolysin BL Toxin Host Receptors
Authors: Jie Liu, Zehua Zuo, Inka Sastalla, Chengyu Liu, Ji Yong Jang, Yusuke Sekine, Yuesheng Li, Mehdi Pirooznia, Stephen H. Leppla, Toren Finkel, Shihui Liu
Journal: Cell Host & Microbe (2020)
Radiomics Analysis of Computed Tomography helps predict poor prognostic outcome in COVID-19
Authors: Qingxia Wu, Shuo Wang, Liang Li, Qingxia Wu, Wei Qian, Yahua Hu, Li Li, Xuezhi Zhou, He Ma, Hongjun Li, Meiyun Wang, Xiaoming Qiu, Yunfei Zha, Jie Tian
Journal: Theranostics (2020)

Rationale: Given the rapid spread of COVID-19, an updated risk-stratify prognostic tool could help clinicians identify the high-risk patients with worse prognoses.We aimed to develop a non-invasive and easy-to-use prognostic signature by chest CT to individually predict poor outcome (death, need for mechanical ventilation, or intensive care unit admission) in patients with COVID-19.Methods: From November 29, 2019 to February 19, 2020, a total of 492 patients with COVID-19 from four centers were retrospectively collected.Since different durations from symptom onsets to the first CT scanning might affect the prognostic model, we designated the 492 patients into two groups: 1) the early-phase group: CT scans were performed within one week after symptom onset (0-6 days, n = 317); and 2) the late-phase group: CT scans were performed one week later after symptom onset (≥7 days, n = 175).In each group, we divided patients into the primary cohort (n = 212 in the early-phase group, n = 139 in the late-phase group) and the external independent validation cohort (n = 105 in the early-phase group, n = 36 in the late-phase group) according to the centers.We built two separate radiomics models in the two patient groups.Firstly, we proposed an automatic segmentation method to extract lung volume for radiomics feature extraction.Secondly, we applied several image preprocessing procedures to increase the reproducibility of the radiomics features: 1) applied a low-pass Gaussian filter before voxel resampling to prevent aliasing; 2) conducted ComBat to harmonize radiomics features per scanner; 3) tested the stability of the features in the radiomics signature by several image transformations, such as rotating, translating, and growing/shrinking.Thirdly, we used least absolute shrinkage and selection operator (LASSO) to build the radiomics signature (RadScore).Afterward, we conducted a Fine-Gray competing risk regression to build the clinical model and the clinic-radiomics signature (CrrScore).Finally, performances of the three prognostic signatures (clinical model, RadScore, and CrrScore) were estimated from the two aspects: 1) cumulative poor outcome probability prediction; 2) 28-day poor outcome prediction.We also did stratified analyses to explore the potential association between the CrrScore and the poor outcomes regarding different age, type, and comorbidity subgroups. Ivyspring International
Preclinical evaluation of an <sup>111</sup>In/<sup>225</sup>Ac theranostic targeting transformed MUC1 for triple negative breast cancer
Authors: Vanessa J Kelly, Shu-ta Wu, Vijay Gottumukkala, Richard Coelho, Keryn Palmer, Surabhi Nair, Timothy Erick, Rahul Puri, Ohad Ilovich, Pinku Mukherjee
Journal: Theranostics (2020)

Rationale: Transformed MUC1 (tMUC1) is a cancer-associated antigen that is overexpressed in >90% of triple-negative breast cancers (TNBC), a highly metastatic and aggressive subtype of breast cancer.TAB004, a murine antibody targeting tMUC1, has shown efficacy for the targeted delivery of therapeutics to cancer cells.Our aim was to evaluate humanized TAB004 (hTAB004) as a potential theranostic for TNBC.Methods: The internalization of hTAB004 in tMUC1 expressing HCC70 cells was assessed via fluorescent microscopy.hTAB004 was DOTA-conjugated and radiolabeled with Indium-111 or Actinium-225 and tested for stability and tMUC1 binding (ELISA, flow cytometry).Lastly, in vivo biodistribution (SPECT-CT), dosimetry, and efficacy of hTAB004 were evaluated using a TNBC orthotopic mouse model.Results: hTAB004 was shown to bind and internalize into tMUC1-expressing cells.A production method of 225 Ac-DOTA-hTAB004 (yield>97%, RCP>97% SA=5 kBq/µg) and 111 In-DOTA-hTAB004 (yield>70%, RCP>99%, SA=884 kBq/µg) was developed.The labeled molecules retained their affinity to tMUC1 and were stable in formulation and mouse serum.In NSG female mice bearing orthotopic HCC70 xenografts, the in vivo tumor concentration of 111 In-DOTA-hTAB004 was 65 ± 15 %ID/g (120 h post injection).A single 225 Ac-DOTA-hTAB004 dose (18.5 kBq) caused a significant reduction in tumor volume (P<0.001,day 22) and increased survival compared to controls (P<0.007).The human dosimetry results were comparable to other clinically used agents. Conclusion:The results obtained with hTAB004 suggest that the 111 In/ 225 Ac-DOTA-hTAB004 combination has significant potential as a theranostic strategy in TNBC and merits further development toward clinical translation.
SAT0024 JAK-INHIBITION WITH BARICTINIB INHIBITS ACTIVATION OF NLRP1/CASPASE1/GDMSD PYROPTOSIS PATHWAY IN RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS
Authors: W. Xie, Z. Zhang
Journal: Annals of the Rheumatic Diseases (2020)

Background: Synovial fibroblasts (SFs) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASFs. Objectives: We aim to examine the presence of GSDMD-mediated pyroptosis and its role in activated RASFs. Methods: Fibroblasts were isolated from RA synovium obtained from knee replacement surgeries. NLRP1, Caspase-1, GSDMD expression in synovial tissue and TNF-treated RASFs were assessed by qPCR and Western blot. Interleukin (IL)-1 was measured by ELISA in supernatant after pretreated with TNF and barictinib. LDH release was measured using the CytoTox 96 Non-Radioactive Cytotoxicity Assay Kit. Endogenous NLRP1, Caspase-1, and GSDMD was knocked down using small interfering RNA. Results: The expressions of NLRP1, pro-Caspase-1, Caspase-1 p10, GSDMD and its pyroptosis-inducing fragment GSDMD-N were greater in RA synovium than OA synovium. TNF-induced NLRP1, pro-Caspase-1, Caspase-1 p10, GSDMD, and GSDMD-N expression at the transcript and protein level in a time-dependent manner (P &lt; 0.05). Meanwhile, the release of LDH and IL-1 were significantly increased in RASFs after treated with TNF. We also confirmed the presence of pyroptosis in electron microscopy. Furthermore, blocking the JAK pathway with barictinib significantly reduced TNF-induced pyroptosis at the transcriptional, protein and activity levels (P &lt; 0.05). Finally, blocking the JAK pathway, we observed a reduction of IL-1 bioactivity in RASFs (P &lt; 0.05). Conclusion: Our results demonstrate an important role of GSDMD-mediated pyroptosis and shed lights on a potential pyroptosis-targeted treatment. Meanwhile, JAK inhibition alleviates inflammasome-induced pyroptosis by blocking pyroptosis pathway in RASFs. References: [1] Masters, S. L. et al. NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity,2012,37:1009–1023. Disclosure of Interests: None declared
Abstract 14568: Diet, Nutrients, and Symptoms in Persons With Heart Failure
Authors: Erica Davis, Sandra B Dunbar, Melinda Higgins, Carolyn M Reilly
Journal: Circulation (2019)

Introduction: Patients with heart failure (HF) often have high symptom burden, poor quality of life (QOL), depression, and low nutrient intake, including micronutrients. Poor dietary intake has bee...
Clinical predictive factors of unresponsiveness to omalizumab in patients with chronic spontaneous urticaria
Authors: J. Castagna, L. Bernard, F. Hacard, F. Delcroix, A.‐S. Darrigade, J.‐F. Nicolas, E. Decullier, A. Nosbaum, F. Bérard
Journal: British Journal of Dermatology (2020)
Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors
Authors: Sergey Anpilov, Yair Shemesh, Noa Eren, Hala Harony-Nicolas, Asaf Benjamin, Julien Dine, Vinícius E.M. Oliveira, Oren Forkosh, Stoyo Karamihalev, Rosa-Eva Hüttl, Noa Feldman, Ryan Berger, Avi Dagan, Gal Chen, Inga D. Neumann, Shlomo Wagner, Ofer Yizhar, Alon Chen
Journal: Neuron (2020)
A Pharmacokinetic (PK) study of SU-5416 in patients on enzyme-inducing anti-epileptic drugs (EIAED), by the North American Brain Tumor Consortium
Authors: Tanyifor M. Tohnya, Alex Sparreboom, Howard A. Fine, Alfred Yung, Patrick Wen, Timothy Cloughesy, Larry Junck, Frank Lieberman, Michael Prados, William D. Figg
Journal: Cancer Research (2004)

401  In vitro studies suggest SU-5416, an anti-angiogenic agent, has anti-tumor activity in the brain and is metabolized via CYP3A4.This study investigated the effect of enzyme-inducing anti-epileptic drugs on the clinical PK of SU-5416. Eligible patients (pts), diagnosed with recurrent high grade astrocytomas or mixed gliomas, received escalating doses (65-190 mg/m2) of SU-5416 administered as a 1-hr i.v. infusion on days 1 and days 4 of each week for 4 weeks. In the absence of DLTs or significant clinical deterioration patients were treated for another 4 weeks. PK profiles were available for 5 pts in the EIAED group and 7 pts in the control group which was made of patients who were not on EIAED. SU-5416 exhibited apparent linear PK in the dose range investigated. The concentration-time profiles of SU-5416 were very similar between pts regardless of treatment group. Though profiles were similar, there was considerable variability in the PK parameters between pts. No statistical differences were observed between the two treatment groups for either the CL values (P = 0.62) or the Vλz values (P = 0.93). Dose-normalized AUC0-α, dose-normalized Cmax, or T1/2 on day 1 also did not vary between the groups (P ≥ 0.15).The PK parameters of SU-5416 in patients with recurrent high grade astrocytomas and mixed gliomas were similar between patients receiving EIAED and those who were not. This study suggests that the concomitant administration of EIAED does not result in marked increase in the CL of SU-5416.
Evaluation of combined insulin-like growth factor type 1 (IGF1R) and mTOR pathway blockade in sarcoma xenograft models
Authors: Isaac Darko, Choh Yeung, Xiaolin Wan, Lee Helman, Chand Khanna
Journal: Cancer Research (2007)

4760  The insulin-like growth factor and mTOR pathways have been connected to sarcoma development and progression. Preliminary data suggests that mTOR pathway inhibition can slow growth of sarcoma xenografts, including rhabdomyosarcoma. Unfortunately mTOR inhibition alone does not eliminate tumors and appears to secondarily upregulate phosphorylation of phospho-AKT in sarcomas. We therefore hypothesized that using a combination of IGF1R and mTOR pathway blockade using h7C10 (IGF1R antibody) and rapamycin respectively will lead to improved antitumor activity and prevent deleterious upregulation of phospho-AKT. Using rhabdomyosarcoma (RMS) cell lines and xenografts, we found that the IGF-1 receptor antibody (h7C10) alone decreased alveolar RMS (Rh30) cell number by 50% at 48hrs, but had inconsistent effect on an embryonal RMS (RD) cell line as measured by MTT assay (10ug/mL at 48hrs). h7C10 decreased phospho-AKT in Rh30 cell lysates (10ug/mL at 48hrs). Surprisingly, in vivo growth (measured by mean chemiluminescent intensity units) of established Rh30 cells expressing luciferase (Rh30-Luc) in SCID/beige mice was significantly decreased with h7C10 monotherapy (52.2±25.3) compared to mice treated with vehicle control (19mm±0.82) by day 36. The combination of h7C10 and rapamycin yielded results similar to h7C10 (11.9±10.4, p
A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism
Authors: Rossella Alfano, Marc Chadeau-Hyam, Akram Ghantous, Pekka Keski-Rahkonen, Leda Chatzi, Almudena Espin Perez, Zdenko Herceg, Manolis Kogevinas, Theo M. de Kok, Tim S. Nawrot, Alexei Novoloaca, Chirag J. Patel, Costanza Pizzi, Nivonirina Robinot, Franca Rusconi, Augustin Scalbert, Jordi Sunyer, Roel Vermeulen, Martine Vrijheid, Paolo Vineis, Oliver Robinson, Michelle Plusquin
Journal: Metabolism (2020)

Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited.