tbuckley/cabot-search huggingface dataset:
Abstract 3380: Predicting the effects of small molecules on transcriptome of cancer cell lines using deep learning
Authors: Junhyeok Jeon, Sang Mi Lee, GaRyoung Lee, Hyun Uk Kim
Journal: Cancer Research (2020)

Abstract Developing a computational model that can predict the effects of small molecules on biological status of a cell can be very useful for various applications, including candidate drug compound screening and toxicity testing in silico. In this study, we developed a deep learning model that predicts the effects of small molecules on gene expression levels of a cell. This deep learning model takes two inputs: the structure of a chemical, presented in SMILES, and a protein sequence encoded by a gene of interest. The model processes these two input data using a fingerprinting method for the input chemical structure and a convolutional neural network for the input protein sequence. As a result, the model predicts whether a given molecule upregulates or downregulates a gene of interest where the molecule and gene are both provided as inputs. The deep learning model was developed by using so called L1000 profiles covering gene expression levels of various cancer cell lines under a large number of perturbation conditions [1]. L1000 is a cost-effective transcriptome technology that can accurately infer the expression levels of 9,196 genes on the basis of expression levels of 978 ‘landmark' genes that are directly measured. In this study, the deep learning model was developed for three different cancer cell lines, HA1E (kidney), HCC515 (lung), and HEPG2 (liver), by using L1000 profiles covering expression levels of the landmark genes individually perturbed with 5,213 molecules for the HA1E cell line, 5,171 molecules for the HCC515, and 3,529 for HEPG2. The deep learning models developed in this study will be useful for a wide range of studies that examine the effects of small molecules, for example in drug development and toxicity testing. [1] Subramanian et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171, 1437-1452 (2017) Citation Format: Junhyeok Jeon, Sang Mi Lee, GaRyoung Lee, Hyun Uk Kim. Predicting the effects of small molecules on transcriptome of cancer cell lines using deep learning [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 3380.
Ongoing challenges to understanding multidrug- and rifampicin-resistant tuberculosis in children <i>versus</i> adults
Authors: C. Finn McQuaid, Ted Cohen, Anna S. Dean, Rein M.G.J. Houben, Gwenan M. Knight, Matteo Zignol, Richard G. White
Journal: European Respiratory Journal (2020)

Previous analyses suggest that children with tuberculosis (TB) are no more or no less likely to have multidrug (MDR)- or rifampicin-resistant (RR)-TB than adults. However, the availability of new data, particularly for high MDR/RR-TB burden countries, suggest updates of country-specific estimates are warranted.We used data from population-representative surveys and surveillance collected between 2000 and 2018 to compare the odds ratio of MDR/RR-TB among children (aged <15 years) with TB, compared to the odds of MDR/RR-TB among adults (aged ≥15 years) with TB.In most settings (45 out of 55 countries), and globally as a whole, there is no evidence that age is associated with odds of MDR/RR-TB. However, in some settings, such as former Soviet Union countries in general, and Georgia, Kazakhstan, Lithuania, Tajikistan and Uzbekistan in particular, as well as Peru, MDR/RR-TB is positively associated with age ≥15 years. Meanwhile, in Western Europe in general, and the United Kingdom, Poland, Finland and Luxembourg in particular, MDR/RR-TB is positively associated with age <15 years. 16 countries had sufficient data to compare over time between 2000-2011 and 2012-2018, with evidence for decreases in the odds ratio in children compared to adults in Germany, Kazakhstan and the United States of America.Our results support findings that in most settings a child with TB is as likely as an adult with TB to have MDR/RR-TB. However, setting-specific heterogeneity requires further investigation. Furthermore, the odds ratio for MDR/RR-TB in children compared to adults is generally either stable or decreasing. There are important gaps in detection, recording and reporting of drug resistance among paediatric TB cases, limiting our understanding of transmission risks and measures needed to combat the global TB epidemic.
Abstract 2087: Bringing advanced analytics experts to the data: Report of an interdisciplinary machine learning workshop
Authors: Sophia Stahl-Toyota, Katrin Glocker, Analie Pascoe Perez, Alexander Knurr, Alexander Denker, Frank Ückert
Journal: Cancer Research (2020)

Abstract Gaining insights from medical and molecular omics data with advanced statistical learning methods requires the collaboration of experts with foundational knowledge of the data contents and context as well as computational and statistical background. The purpose of the workshop was to derive the key components that are necessary to apply machine learning methods to non-public real-world clinical, genomic and transcriptomic data from heterogeneous sources in a cross-institutional collaborative effort. Machine learning experts were invited to the premises of the institution that held a comprehensive collection of patient data. During the preparation phase, regular virtual meetings took place in order to discuss decisions regarding the research questions to analyze, transformations of the raw file formats and the technical infrastructure. The interdisciplinary group of experts decided to focus on models that would assign patients matching therapy classes based on their molecular variation profile. During the workshop phase, the experts spent several days at the same location working solely on the analysis in question. Here we present the lessons learned from conducting such an interdisciplinary workshop. The key components can be divided into a preparatory and a workshop phase. The first phase lays the foundation for the collaboration, including the formalities, discussion of the data and the applicable methods. It is especially important to involve all domains in decisions regarding the data preprocessing steps. As an example, a method might have particular requirements considering the data dimensions, which is information that the data experts need to know in order to aid with the meaningful reduction of the degrees of freedom, by e.g. aggregation or filtering. Sharing anonymized sample files that represent the data format in a realistic manner and sample scripts for testing the infrastructure helps all parties to set up the analysis pipelines efficiently. In the second phase, the intense working atmosphere allowed for quick iterations of feature engineering, model training and result evaluation. In the common case that a dataset is not yet publicly sharable, we demonstrate that it is a feasible option to invite analysts to the institution holding the data. Additionally, the focused atmosphere that is created by a limited-time workshop setting is advantageous to the motivation of the collaborators. Citation Format: Sophia Stahl-Toyota, Katrin Glocker, Analie Pascoe Perez, Alexander Knurr, Alexander Denker, Frank Ückert. Bringing advanced analytics experts to the data: Report of an interdisciplinary machine learning workshop [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 2087.
Successful treatment by novel endoscopic ultrasound-guided devascularization for refractory splenic artery aneurysm associated with portal hypertension
Authors: Hongtan Chen, Feng Li, Fenming Zhang, Jianan Guo, Chunhui Nie, Junhui Sun, Guoqiang Xu
Journal: Endoscopy (2020)

Splenic artery aneurysm carries significant risk of rupture and life-threatening hemorrhage [1]. Therapy utilizing digital subtraction angiography (DSA) with embolization is usually safe and effective; however, incomplete occlusion can occur and frequently requires surgical repair [2]. We report the case of refractory splenic artery aneurysm associated with portal hypertension that was successfully treated by a novel endoscopic ultrasound (EUS)-guided devascularization technique.
Abstract 2506: Simultaneous DNA, RNA and protein analysis from single cells using a high-throughput microfluidic workflow for resolution of genotype-to-phenotype modalities
Authors: Pedro Mendez, Dalia Dhingra, Aik Ooi, Shu Wang, Saurabh Gulati, Nigel Beard, Manimozhi Manivannan, Jens Björkman, Mikael Kubista, Göran Landberg, David Ruff, Anders Ståhlberg
Journal: Cancer Research (2020)

Abstract The TCGA, ICGC and other research consortiums has shown that an integral, multi-omic analysis of tumors is necessary in order to understand a more complete picture of the signaling pathways involved in development, evolution, prognosis and treatment resistance of tumors. However, in such studies, because different data modalities (“omics”) are analyzed separately, the information on how the co-existence of in the same cell is lacking. We report a new approach to measure multiple modalities simultaneously from up to 10,000 individual cells using high-throughput droplet microfluidics on the Tapestri platform, paired with next generation sequencing. Our triomic methodology evaluates targeted protein levels, mRNA transcript levels and somatic gDNA sequence variations (SNV &amp; CNV) from the same cell. We employ oligonucleotide-conjugated antibody panels to probe cellular surface markers and targeted RNA and DNA amplification to resolve gene expression levels and genomic variants. Cell suspensions are first stained with cocktails of oligonucleotide-antibodies. These cells are loaded onto the Mission Bio Tapestri® microfluidic cartridge for generation of the first droplet. This droplet biochemistry allows for concurrent cell lysis and release of gDNA from chromatin scaffolding. A second droplet formation event brings together a barcoded bead and multiplex PCR amplification reagents. After amplification, the combined libraries are sequenced and demultiplexed bioinformatically yielding a multi-omics readout from the single-cells. Six protein surface markers, 35 transcripts and 88 genomic regions in 68 genes were interrogated with a 50:50 cell mixture of MCF7 and GM12878 cells. These targets play key roles in cellular migration, stemness, differentiation and proliferation. We intend to further explore the relationship between genotype-to-phenotype in breast carcinoma cell lines cultured in patient-derived scaffolds mimicking tumor microenvironments under different drug regimen conditions. We report the dynamic multimodal resolution and demonstrate utility of triomics in further illuminating cellular states and biological responses. Citation Format: Pedro Mendez, Dalia Dhingra, Aik Ooi, Shu Wang, Saurabh Gulati, Nigel Beard, Manimozhi Manivannan, Jens Björkman, Mikael Kubista, Göran Landberg, David Ruff, Anders Ståhlberg. Simultaneous DNA, RNA and protein analysis from single cells using a high-throughput microfluidic workflow for resolution of genotype-to-phenotype modalities [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 2506.
Abstract 3162: Early change in peripheral blood CD4+T cells associated with the clinical outcome in gastrointestinal cancer patients receiving immune checkpoint inhibitors
Authors: Zhi-Hao Lu, Chang Liu, Yan-ni Wang, Shuang Li, Xi Jiao, Jian-ling Zou, Zheng-hang Wang, Chang-song Qi, Xiao-tian Zhang, Jian Li, Lin Shen
Journal: Cancer Research (2020)

Abstract Purpose: Predictive biomarkers for immune checkpoint inhibitors (ICIs) are urgently needed in advanced gastrointestinal (GI) carcinoma. Methods: Peripheral blood lymphocyte, lymphocyte subset and early dynamic changes of them were retrospectively analyzed in patients with GI cancer treated with ICIs. Cox regression and Kaplan-Meier analyses were conducted to analyze survival. Results: Eighty patients were enrolled. According to whether tumor progression occurred by 6 months after the initial ICI, patients were divided into two cohorts, 6m-progressive disease (PD) (N=40) and 6m-non-PD (nPD) (N=40).BaselineCD4+/CD8+ T cell (CD4/CD8) ratio was higher in the 6m-nPD cohort than in the 6m-PD cohort. Lymphocyte subsets were obtained both at baseline and before the second dose of ICIs in 61 patients. In total, 54.1% (33/61) of patients experienced tumor progression within 6 months of the initial ICI treatment, and these patients showed significant declines in CD4+ T cell counts (CD4-C1-decline) (p=0.0002) and the CD8+ T cell counts (CD8-C1-decline) (p=0.045) after the first dose of ICIs. In multivariate analyses, CD4-C1-decline (HR=12.66; 95% CI: 2.17-73.91; p=0.005) was an independent prognostic factor for OS. Furthermore, Stratified analyses indicated that CD4-C1-decline was a poor prognostic factor for tumor progression in patients with a deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H). Conclusion: Early change in CD4+ T cell counts in peripheral blood samples may help as prognostic biomarkers for GI cancer patients treated with ICIs. Further prospective studies are needed to validate this conclusion. Citation Format: Zhi-Hao Lu, Chang Liu, Yan-ni Wang, Shuang Li, Xi Jiao, Jian-ling Zou, Zheng-hang Wang, Chang-song Qi, Xiao-tian Zhang, Jian Li, Lin Shen. Early change in peripheral blood CD4+T cells associated with the clinical outcome in gastrointestinal cancer patients receiving immune checkpoint inhibitors [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 3162.
Abstract 4834: Circulating microRNA-762 promotes colorectal cancer proliferation and invasion by upregulating the Wnt-1/β-catenin pathway
Authors: Ying-Yin Chen, Peng-Sheng Lai, Chung-Yu Chen, Hui-Fen Liao
Journal: Cancer Research (2020)

Abstract Background: A number of microRNAs (miRNAs) have been demonstrated to be associated with the diagnosis, progression and prognosis of colorectal cancer (CRC). However, the function of miRNA-762 (miR-762) in CRC remains unclear, and the molecular mechanisms underlying the effects of miR-762 in CRC require further investigation. Methods: The circulating miRNAs from BALB/c mice with CRC CT26 cell implantation were assayed by microarray. Then, miR-762 mimic and inhibitor were transfected to CT26 cells for analysis of cell viability, invasion, and epithelial-mesenchymal transition (EMT), cell cycle, and regulatory molecule expression. Human subjects were included for comparison the circulating miR-762 levels in CRC patients and control donors, as well as the patients with and without distant metastasis. Results: The screening for miRNA levels in mice with CRC cell implantation indicated that plasma miR-762 was upregulated. Transfection of miR-762 mimic to CT26 cells increased cell viability, invasion, and EMT, whereas transfection of miR-762 inhibitor decreased the above abilities. Western blot analysis showed that miR-762 mimic transfection upregulated the expression of Wnt-1 and β-catenin, as well as increased the nuclear translocation of β-catenin. Further analysis showed that serum miR-762 levels in CRC patients were higher than in control donors. Among the CRC patients (n = 20), six patients with distant metastasis showed higher serum miR-762 levels than the patients without distant metastasis. Conclusions: Circulating miR-762 could promote CRC disease development and progression through the Wnt/β-catenin signaling. miR-762 might be used as a biomarker for CRC diagnosis and targeted therapy. Citation Format: Ying-Yin Chen, Peng-Sheng Lai, Chung-Yu Chen, Hui-Fen Liao. Circulating microRNA-762 promotes colorectal cancer proliferation and invasion by upregulating the Wnt-1/β-catenin pathway [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 4834.
Impact of Omitting Post-Transplant Mini-Methotrexate Doses in Allogeneic Hematopoietic Cell Transplantation: A Single-Center Retrospective Study
Authors: Andrew Lin, Patrick Hilden, Molly Maloy, Ann A. Jakubowski, Esperanza B. Papadopoulos, Craig S. Sauter, Roni Tamari, Doris Ponce, Sergio A. Giralt, Boglarka Gyurkocza
Journal: Blood (2017)
Abstract 4844: CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance
Authors: Juan Zhang, Liang Tang, Zhenhu Li, Liang Lu, Yuanwu Bao, Zhaoxiang Ren, Jingshu Ma, Yaling Huang, Zhaobing Xu, Yuanfeng Xia, Charles Z. Ding, Lihong Hu, Shuhui Chen, Archie N. Xie, Xinzhong Jon Wang
Journal: Cancer Research (2020)

Abstract The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib have been approved by US FDA as single agent or in combination with endocrine therapy to treat patients with HR+/Her2- breast cancer. Here, we disclose the preclinical development of CS3002 and its characterization as a novel CDK4/6 inhibitor with unique kinase inhibition spectrum. Similar to the three approved CDK4/6 inhibitors, CS3002 is highly selective for and potent against CDK 4 and 6, a feature that is expected to overcome the toxicity issues of pan-CDK inhibitors. Cell-based assays confirmed the biological activities of CS3002 by showing anti-proliferative effect, significant Rb phosphorylation inhibition, and G1 cell cycle arrest in a set of Rb-positive cancer lines. Furthermore, CS3002 showed excellent in vivo activity as a single agent, and in combinations with either endocrine therapy (fulvestrant) or PD-1 blockade (CS1003) in a set of tumor models, together with desirable ADME/PK and safety profile. CS3002 was further tested against 196 kinases in a Carna panel. In addition to CDK4 and CDK6, FLT3 and TRKA were also potently inhibited with IC50 values &amp;lt;50nM. To this end, CS3002 demonstrated high activity in cell lines harboring NTRK1 fusion that were otherwise insensitive to CDK4/6 inhibitors. Across a panel of 19 AML cell lines, CS3002 demonstrated a similar sensitivity profile to gilteritinib (an approved FLT-3 inhibitor), but overall higher sensitivity compared to palbociclib. Interestingly, when MCF-7 breast cancer cell line was treated continuously with CS3002 in vitro, the emergence of drug-resistance was much delayed compared to treatment with palbociclib or abemaciclib. Given the encouraging preclinical properties as well as the unique potential in allowing indication expansion and delaying drug resistance to CDK4/6 inhibition, CS3002 is selected for clinical exploration in a Phase 1 study for advanced solid tumors (NCT04162301). Citation Format: Juan Zhang, Liang Tang, Zhenhu Li, Liang Lu, Yuanwu Bao, Zhaoxiang Ren, Jingshu Ma, Yaling Huang, Zhaobing Xu, Yuanfeng Xia, Charles Z. Ding, Lihong Hu, Shuhui Chen, Archie N. Xie, Xinzhong Jon Wang. CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance [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 4844.
Covid-19: re-opening universities is high risk
Authors: Gavin Yamey, Rochelle P Walensky
Journal: BMJ (2020)

Over a third of US colleges and universities fully reopened in August. 1 It was risky: at the beginning of the month, the US had about 55 000 new cases per day 2 and no federal covid-19 control plan or coordinated vision for safely reopening universities.Today, the national reopening experiment already looks to have been a disaster.Major campus outbreaks have led many large universities, including the University of North Carolina Chapel Hill (UNC) and the University of Notre Dame, Indiana, to shut down again.Only a week after classes started on 10 August, most of which were face to face, UNC, home to about 30 000 students, reported 130 new infections in students and five in employees. 3uring 1-27 August, there were 756 confirmed new infections at UNC. 4 This scenario has played out at universities nationwide, 5 and by 26 August, there had been at least 26 000 new infections at over 750 colleges and universities.
Adaptable antigen matrix platforms for peptide vaccination strategies and T cell-mediated anti-tumor immunity
Authors: Sjoerd T.T. Schetters, R.J. Eveline Li, Laura J.W. Kruijssen, Steef Engels, Martino Ambrosini, Juan J. Garcia-Vallejo, Hakan Kalay, Wendy W.J. Unger, Yvette van Kooyk
Journal: Biomaterials (2020)

Injection of antigenic peptides has been widely used as a vaccine strategy to boost T cell immunity. However, the poor immunogenicity of single peptides can potentially be strengthened through modification of the tertiary structure and the selection of the accompanying adjuvant. Here, we generated antigenic peptides into non-linear trimers by solid phase peptide synthesis, thereby enhancing antigen presentation by dendritic cells to CD8+ T cells in vitro and in vivo. CD8+ T cells from mice vaccinated with trimers showed an KLRG1+ effector phenotype and were able to recognize and kill antigen-expressing tumor cells ex vivo. Importantly, trimers outperformed synthetic long peptide in terms of T cell response even when equal number of epitopes were used for immunization. To improve the synthesis of trimers containing difficult peptide sequences, we developed a novel small molecule that functions as conjugation platform for synthetic long peptides. This platform , termed Antigen MAtriX (AMAX) improved yield, purity and solubility of trimers over conventional solid phase synthesis strategies. AMAX outperformed synthetic long peptides in terms of both CD8+ and CD4+ T cell responses and allowed functionalization with DC-SIGN-binding carbohydrates for in vivo dendritic cell targeting strategies, boosting T cell responses even further. Moreover, we show that agonistic CD40 antibody combined with MF59 (AddaVax) emulsion synergistically improves the antigen-specific T cell response of the AMAX in vivo. Also, tumor-associated antigens and neo-antigens could be incorporated in AMAX for tumor-specific CD8+ T cell responses. Importantly, immunization with a mix of neoantigen AMAX could reduce tumor growth in a pre-clinical syngeneic mouse model. Hence, we provide pre-clinical support for the induction of effector CD8+ T cells through the adaptable AMAX platform as easy implementable peptidic vaccination strategy against any antigen of choice, including neoantigens for anti-tumor immunity.