tbuckley/cabot-search huggingface dataset:
Abstract 2587: Investigating the impact of chemotherapy on gut microbiota and microbiota-derived metabolites and their link to inflammation and cardiometabolic disorders in children with cancer
Authors: Abderrahim Benmoussa, Laurence Levasseur, Shuxia Coté-Sergerie, Véronique Bélanger, Emile Levy, Caroline Laverdière, Alain Stintzi, Daniel Sinnett, Valérie Marcil
Journal: Cancer Research (2021)

Abstract Children treated for acute lymphoblastic leukemia (ALL) often suffer serious side-effects, including vomiting, diarrhea, severe infections, and cardiometabolic disorders. We hypothesized that deregulation of the intestinal microbiota, and its metabolites, is related to these side effects, and promotes inflammation and cardiometabolic disorders in this population. To explore this new avenue, we are recruiting 38 children with ALL treated at Sainte-Justine UHC in Montreal. At each treatment cycle, we compile clinical, treatment, and diet data, cardiometabolic status (weight, height, blood lipids, glucose, insulin, blood pressure), and collect blood and stool samples. We use high throughput sequencing to analyze the intestinal microbiota. Bacterial metabolites (SCFA, acyl-carnitines, p-cresol and TMAO) in stool and plasma are measured by GS-MS and HPLC-MS/MS. Biomarkers of inflammation (CRP, leptin, TNF-α, IL-6) and oxidative stress (ox-LDL, MDA, 8-OHdG) are evaluated in plasma or red blood cells by ELISA/Bioplex. On admission, 83% of patients had at least one cardiometabolic risk factor (59% high CRP, 83% pre/hypertriglyceridemia, 51% hypertension, 32.5% overweight/obesity, 27.9% hyperglycaemia) and 49% had a family history. After 31 days of treatment, some of these disorders were stabilized while others persisted or worsened (+7% obesity/overweight, -34% hypertriglyceridemia, -4.5% hypertension, +16% high CRP, -16.6% hyperglycaemia) and were associated with changes in short-chain acyl-carnitines (x1.3 - x3.4) and TMAO (x18.3). The links between these disorders, their temporal variation and inflammation, treatments, and side effects are being investigated. This project will serve as a basis for mechanistic and interventional studies to prevent inflammation and cardiometabolic disorders in children with cancer. Citation Format: Abderrahim Benmoussa, Laurence Levasseur, Shuxia Coté-Sergerie, Véronique Bélanger, Emile Levy, Caroline Laverdière, Alain Stintzi, Daniel Sinnett, Valérie Marcil. Investigating the impact of chemotherapy on gut microbiota and microbiota-derived metabolites and their link to inflammation and cardiometabolic disorders in children with cancer [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 2587.
Abstract 1396: Non-competitive inhibition of proteasome by kinase inhibitors
Authors: Alexei F. Kisselev, Olasubomi Akintola, John Smith
Journal: Cancer Research (2021)

Abstract Inhibitors of Bruton's Tyrosine Kinase (BTK) and inhibitors of the proteasome are currently in use for treatment of hematologic malignancies. While the ubiquitin proteasome system is necessary for protein homeostasis in all mammalian cells, BTK is unique to some B cell malignancies. However, BTK inhibitors and LU-102, a specific inhibitor of the β2 site of the proteasome, have previously been shown to synergize in hematologic malignancies which do not express BTK, at a 100-fold higher concentration than is needed for complete inhibition of BTK, suggesting an off-target effect of these BTK inhibitors. Triple Negative Breast Cancer (TNBC), a cancer with poor prognosis and no current targeted therapy, also does not express BTK. We found that LU-102 and a specific BTK inhibitor, CGI-1764, are de-facto synthetically lethal to TNBC cells, and that effect of other BTK inhibitors varied from similar synergy to no synergy. This data further supports the idea that synergy is due to off-target effects of BTK inhibitors.We have now found that CGI-1764 is a non-competitive, allosteric inhibitor of all catalytic subunits of the proteasome 20S proteolytic core and exerts its effect in a unique, dose-dependent manner. RNA sequencing shows that the Unfolded Protein Response pathway is upregulated in TNBC cells response to treatment with the CGI-1746+LU-102 combination. We also found that accumulation of ubiquitin conjugates is synergistic indicating that the combination treatment has a synergistic effect on the inhibition of proteasome activity. These findings may pave the path to the development of more potent allosteric inhibitors of the proteasome and show that kinase inhibitors should be screened for inhibition of the proteasome as potential off-target effect. Citation Format: Alexei F. Kisselev, Olasubomi Akintola, John Smith. Non-competitive inhibition of proteasome by kinase inhibitors [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 1396.
The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma
Authors: Baptiste Eluard, Stéphanie Nuan-Aliman, Nathalie Faumont, Davi Collares, Didier Bordereaux, Aurélie Montagne, Isabelle Martins, Nicolas Cagnard, Martial Caly, Oussama Taoui, Leonardo Lordello, Jacqueline Lehmann-Che, Bruno Tesson, Jose-Angel Martinez-Climent, Christiane Copie-Bergman, Corinne Haioun, Hervé Tilly, Benjamin Bonsang, Anne Vincent-Salomon, Jean-Philippe Jais, Fabrice Jardin, Karen Leroy, Maria Chiara Maiuri, Guido Kroemer, Thierry Jo Molina, Jean Feuillard, Véronique Baud
Journal: Blood (2021)
Advances in hydrogel-based vascularized tissues for tissue repair and drug screening
Authors: Ying Wang, Ranjith Kumar Kankala, Caiwen Ou, Aizheng Chen, Zhilu Yang
Journal: Bioactive Materials (2021)

The construction of biomimetic vasculatures within the artificial tissue models or organs is highly required for conveying nutrients, oxygen, and waste products, for improving the survival of engineered tissues in vitro. In recent times, the remarkable progress in utilizing hydrogels and understanding vascular biology have enabled the creation of three-dimensional (3D) tissues and organs composed of highly complex vascular systems. In this review, we give an emphasis on the utilization of hydrogels and their advantages in the vascularization of tissues. Initially, the significance of vascular elements and the regeneration mechanisms of vascularization, including angiogenesis and vasculogenesis, are briefly introduced. Further, we highlight the importance and advantages of hydrogels as artificial microenvironments in fabricating vascularized tissues or organs, in terms of tunable physical properties, high similarity in physiological environments, and alternative shaping mechanisms, among others. Furthermore, we discuss the utilization of such hydrogels-based vascularized tissues in various applications, including tissue regeneration, drug screening, and organ-on-chips. Finally, we put forward the key challenges, including multifunctionalities of hydrogels, selection of suitable cell phenotype, sophisticated engineering techniques, and clinical translation behind the development of the tissues with complex vasculatures towards their future development.
Abstract 2291: A novel TGF-βRI inhibitor ASKC852, possessing antitumor and PD-L1 synergistic effect activities
Authors: Tingting Song, Min Sun, Hongyu Chen, Xiangyu Fu, Lihong Hu, Shuhua Han, Haijun Tong, Yuanfeng Xia, Jian Zuo, Shaohua Qin, Ying Chen, Charles Ding, Chichung Chan, Shuhui Chen
Journal: Cancer Research (2021)

Abstract Background: Transforming growth factor-β (TGF-β) plays a significant role in multiple physiological signaling pathways, thus occupies a pivotal position in balancing immunity and antigen tolerance. Activation of TGFβ type I receptor (TGF-βRI) recruits and phosphorylates SMAD transcription factors and promotes EMT gene expression, leading to tumor progression and invasion. Inhibition of this pathway therefore has potential to treat cancer. The preclinical evaluations of a novel TGF-βRI inhibitor ASKC852 is described. Results: ASKC852 has been shown to be a potent and highly selective inhibitor of TGF-βRI. ASKC852 inhibited SMAD phosphorylation in HEK293 cells (IC50 &amp;lt; 0.1 μM), a down-stream PD marker of TGF-β signaling pathway. This compound showed metabolic stability, oral bioavailability in mice and rats, with anti-tumor activity when given alone (TGI: 81.2%) in CT26 colon cancer model. In EMT6 breast carcinoma model, ASKC852 demonstrated significant synergistic effect when combined with a mouse PD-L1 antibody. Greater than 50% p-SMAD inhibition was achieved at low doses in in vivo PD studies. In addition, ASKC852 effectively inhibited tumor metastasis in 4T1-luc2 model. In a 28-days pre-clinical toxicology study, ASKC852 showed no effect on rat cardiovascular system @ 30 mg/kg. Conclusion: Our data demonstrates ASK852 is a potent and highly selective TGF-βRI inhibitor. It effectively blocked the TGF-β-SMAD signal pathway, with anti-tumor effect in syngeneic mouse models. Pharmacokinetic profile and safety properties support ASKC852 as a potential anticancer agent for the clinical treatment of solid tumors. Citation Format: Tingting Song, Min Sun, Hongyu Chen, Xiangyu Fu, Lihong Hu, Shuhua Han, Haijun Tong, Yuanfeng Xia, Jian Zuo, Shaohua Qin, Ying Chen, Charles Ding, Chichung Chan, Shuhui Chen. A novel TGF-βRI inhibitor ASKC852, possessing antitumor and PD-L1 synergistic effect activities [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 2291.
Abstract 2606: A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer
Authors: Ana Giménez Capitán, Jillian Bracht, Nicolas Potie, María González-Cao, Santiago Viteri, Alejandro Martínez-Bueno, Carlos Cabrera-Gálvez, Pablo Rubinstein, Clara Mayo-de-las-Casas, Joselyn Valarezo, Chung-Ying Huang, Carlos Pedraz, Richard Boykind, Sarah Warren, Rafael Rosell, Miguel Ángel Molina-Vilaa, Andrés Aguilar-Hernández
Journal: Cancer Research (2021)

Abstract Background: 80% of non-small cell lung cancer (NSCLC) cases are diagnosed at stages IIIB-IV and have a dismal prognosis with a median life expectancy that does not exceed 2 years. In contrast, patients diagnosed at early and locally advanced stages (I-IIIA) can undergo surgery and have the potential to be totally cured. Imaging technologies often detect lung nodules of unknown significance that pose a diagnostic challenge; some patients with benign nodules are submitted to unnecessary surgical interventions while others with small tumors are just kept in observation, risking a significant delay for treatment. A diagnostic test that could differentiate between benign and malignant masses would be of great help in this setting. Methods: Circulating-free RNA (cfRNA) was isolated from the plasma of healthy individuals (N=21), early(I-II) stage (N=22) and stage IIIA (N=12) NSCLC patients, using an automatic extraction method(Qiasymphony, Qiagen). Purified cfRNA was quantified using Qubit, retrotranscribed and pre-amplified (14cycles) using the Low RNA Input Amplification kit (NanoString Technologies). Gene expression analysis was performed on the nCounter platform using the PanCancer IO360TM (NanoString Technologies), which can detect 770 transcripts related to tumor biology, micro-environment and the immune system. Results: Gene expression analysis revealed differential patterns for some cf-mRNAs from localized stage NSCLC patients versus healthy controls. A bioinformatics recursive feature elimination algorithm selected a 16-gene mRNA signature that was able to distinguish between localized NSCLC and control samples with an area under the ROC curve of 0.91 to 0.95. Furthermore, the signature scores derived from the algorithm were significantly different between the two cohorts. Conclusions: We have found an 16-gene signature that can differentiate between cfRNA of localized stages NSCLC patients and control individuals. Our results warrant validation studies in larger cohorts. Citation Format: Ana Giménez Capitán, Jillian Bracht, Nicolas Potie, María González-Cao, Santiago Viteri, Alejandro Martínez-Bueno, Carlos Cabrera-Gálvez, Pablo Rubinstein, Clara Mayo-de-las-Casas, Joselyn Valarezo, Chung-Ying Huang, Carlos Pedraz, Richard Boykind, Sarah Warren, Rafael Rosell, Miguel Ángel Molina-Vilaa, Andrés Aguilar-Hernández. A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer [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 2606.
Abstract LB190: DNAscopeTM: A novel chromogenic in-situ hybridization technology for high-resolution detection of DNA copy number and structural variations
Authors: Li-Chong Wang, Farzaneh Tondnevis, Courtney Todorov, Jayson Gaspar, Aparna Sahajan, Vasudha Murlidhar, Bingqing Zhang, Xiao-Jun Ma
Journal: Cancer Research (2021)

Abstract Genomic DNA anomalies such as copy number variations (gene duplication, amplification, deletion) and gene rearrangements are important biomarkers and drug targets in many cancer types. DNA in-situ hybridization (ISH) is the gold standard method to directly visualize these molecular alterations in formalin-fixed paraffin-embedded (FFPE) tumor tissues at single-cell resolution within a histological section. However, currently available fluorescent ISH (FISH) assays provide limited morphological detail due to the use of fluorescent nuclear staining compared to chromogenic staining. Furthermore, FISH techniques rely on expensive fluorescence microscopes, risk loss of fluorescent signal over time and involve tedious imaging at high magnifications (100X). There is thus an unmet need for a sensitive and robust chromogenic DNA-ISH assay that can enable high-resolution detection of genomic DNA targets with the ease of bright-field microscopy. We present here DNAscope - a novel chromogenic DNA-ISH assay - for detecting and visualizing genomic DNA targets under a standard light microscope. DNAscope is based on the widely used RNAscope® double-Z probe design and signal amplification technology and provides unparalleled sensitivity and specificity with large signal dots readily visualized at 40X magnification and with full morphological context. Furthermore, DNAscope ensures specific DNA detection without interference from RNA due to the use of a novel RNA removal method. Using a duplex chromogenic detection assay in red and blue, we demonstrate highly specific and efficient detection of gene rearrangements (ALK, ROS1, RET and NTRK1), gene amplification (ERBB2, EGFR, MET) and deletion (TP53 and CDKN2A). The DNAscope assay has been carefully optimized for probe signal size and color contrast to enable easy interpretation of signal patterns under conventional light microscopy or digital pathology. Compared to conventional FISH assays, DNAscope probes are standard oligos that are designed in silico to be free of any repetitive sequences and can be rapidly synthesized for any DNA target. In conclusion, the DNAscope assay provides a powerful and convenient alternative to commonly used FISH assays in many cancer research applications. Citation Format: Li-Chong Wang, Farzaneh Tondnevis, Courtney Todorov, Jayson Gaspar, Aparna Sahajan, Vasudha Murlidhar, Bingqing Zhang, Xiao-Jun Ma. DNAscopeTM: A novel chromogenic in-situ hybridization technology for high-resolution detection of DNA copy number and structural variations [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 LB190.
Abstract 2975: Genome-scale CRISPR screen finds prostate lineage specific dependencies
Authors: Adel Attari, Sean Misek, Pinar Eser, Alexa Yeagley, Yu Chen, Jesse Boehm, Yuen-Yi (Moony) Tseng
Journal: Cancer Research (2021)

Abstract Functional genomics has held great promise for mapping cancer dependencies and identifying new therapeutic targets in cancer cell lines. However, this remains a major challenge for prostate cancer (PCa) due to the lack of cancer cell models and efficient optimization of pooled genetic perturbation screens. The Broad Cancer Cell Line Factory (CCLF) is attempting to fulfill this unmet need by generating novel prostate cancer cell models and uncovering prostate specific lineage dependencies. Encouragingly, Dr. Yu Chen at Memorial Sloan Kettering Cancer Center has developed several 3D cancer organoids from advanced prostate cancer. Although the success rate needs improvement for primary PCa, over 12 long-term models have been established by this group. In collaboration with Chen Lab, we aim to expand the prostate cell model collection by using PCa organoids and patient-derived normal cells. We can then apply these models for genetic perturbation profiling to unravel prostate lineage specific dependencies. Many historical cancer cell lines and cancer organoids were not compatible with genome-scale CRISPR screening due to the slow cellular growth. Here we first optimized the media conditions in these PCa organoids by using empirical media screening assay conditions through our HYBRID technology. The HYBRID technology allows for the systemic evaluation of 64 media conditions at once, so that we can perform RNAseq analysis to identify the conditions most physiologically resembling the PCa environment with the maximum doubling time. We have further developed our high throughput screening strategies for organoid culture using an optimized protocol to study 3D growth patterns in a 96-well format using the Incucyte S3 System. Next, to map out all possible dependencies, we are testing the feasibility of a pooled genome scale CRISPR screen. In our preliminary assay development results, we demonstrated the reproducible viral infectibility in several organoids ranging from 40-70% infection rate. We anticipate that these genome-wide CRISPR data in PCa organoid and normal prostate cell models can be integrated and analyzed with 4 previous PCa cell lines screened in the Broad Dependency Map to point out more prostate lineage specific genetic vulnerabilities and possible therapeutic targets. Citation Format: Adel Attari, Sean Misek, Pinar Eser, Alexa Yeagley, Yu Chen, Jesse Boehm, Yuen-Yi (Moony) Tseng. Genome-scale CRISPR screen finds prostate lineage specific dependencies [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 2975.
MCLSによる冠動脈瘤に対して小切開にてOff-pump CABGと瘤切除を行った1治験例
Authors: 末石通暁, 天野篤, 新浪博, 岩村弘志, 山崎元成, 川崎志保理, 菊地慶太, 塩尻泰宏, 蒔苗永, 仲冨岳, 山岡啓信, 岩村泰
Journal: Circulation (2007)
Defining covid-19 elimination
Authors: David CG Skegg, Philip C Hill
Journal: BMJ (2021)

Speaking about progress towards ending the covid-19 epidemic in the United States, Anthony Fauci said: "We will end the epidemic phase, and we will likely get somewhere between control and elimination, more likely closer to control." 1 Now authorities in England are abandoning most efforts to control, let alone eliminate, the infection. 2Throughout the pandemic, the word "elimination" has been used in different senses.Many confuse elimination with eradication, which normally means permanent reduction to zero of the worldwide incidence of an infection-as was achieved for smallpox. 3This confusion helps to make the idea of eliminating covid-19 seem impossible and not worth pursuing.Elimination is variously defined but stops short of permanent eradication of infection.
Abstract 467: Detecting <i>ALK</i> rearrangement by RT-PCR: A superior approach to next generation sequencing
Authors: Yukun Kuang, Peihang Xu, Jiyu Wang, Yifan Zheng, Xue Sun, Zimu Li, RunJing Gan, Huixia Li, Yubiao Guo, Guanshan Zhu, Changbin Zhu, Zunfu Ke, Kejing Tang
Journal: Cancer Research (2021)

Abstract Background: Precisely detecting anaplastic lymphoma kinase (ALK) rearrangement ensures ideal efficacy of ALK targeted tyrosine kinase inhibitors (ALK-TKIs). Next generation sequencing (NGS) has been widely used in clinics, while, numbers of studies indicated NGS would yield false negative outcome, especially for fusion analysis. Instead, more fusions can be detected by RT-PCR at transcription level. This study aims to compare the capacity of RT-PCR and NGS approach to detect ALK rearrangement in Chinese non-small-cell lung cancer (NSCLC) patients. Methods: Formalin-fixed paraffin-embedded (FFPE) tissues from 153 patients pathologically diagnosed as NSCLC with eligible ALK status given by previous NGS testing (29 patients were ALK positive and 124 patients were ALK negative) were collected from November 2017 to October 2019. RT-PCR were applied to detect ALK rearrangements in both groups. For samples with discordant result of ALK status, fluorescence in situ hybridization (FISH) or Sanger's sequencing were used for validation. Results: One hundred and twenty-four samples (26 of 30 ALK positive samples; 98 of 124 ALK negative samples) were successfully subjected to RT-PCR. Five of 98 ALK negative samples given by NGS test were re-defined as ALK positive by RT-PCR. Meanwhile, in 26 ALK positive samples, RT- PCR yielded acceptable result with 96.15% of concordance rate. Only one NGS-defined ALK positive sample was uncovered by RT-PCR due to a rare ALK rearrangement. Four of 6 RT-PCR defined ALK positive cases (3 RT-PCR positive and 1 NGS positive) were validated by either FISH or sanger's sequencing, which resulted positive result. Conclusions: RT-PCR displays reliable and superior capacity to detect ALK fusion in NSCLC patients. Citation Format: Yukun Kuang, Peihang Xu, Jiyu Wang, Yifan Zheng, Xue Sun, Zimu Li, RunJing Gan, Huixia Li, Yubiao Guo, Guanshan Zhu, Changbin Zhu, Zunfu Ke, Kejing Tang. Detecting ALK rearrangement by RT-PCR: A superior approach to next generation sequencing [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 467.