tbuckley/cabot-search huggingface dataset:
Abstract 365: Detection of homologous recombination deficiency across cancer types by a real-time activity-based functional biomarker
Authors: Chih-Ying Lee, Kai-Hang Lei, Shih-Han Huang, Min-Yu Ko, Ko-Yu Chang, Po-Han Lin, Yu-Li Chen, Wen-Fang Cheng, Peter Chi
Journal: Cancer Research (2021)

Abstract Homologous recombination (HR) is an error-free repair pathway to eliminate DNA double-strand breaks and crucial for maintaining genome stability. Pathogenic mutations in genes involved in HR, such as BRCA1 and BRCA2, lead to homologous recombination deficiency (HRD) and sensitive cells to poly(ADP-ribose) polymerase inhibitors (PARPi). As such, the selection of HRD cancer patients becomes an important clinical need. In addition to sequencing HR-related genes, recent studies have developed several approaches to detect HRD including genomic scar score, mutational signatures analysis, and RAD51 foci formation assay. However, these assays are not on a real-time basis and provide an indirect estimation of HR status. To overcome these limitations, we have successfully developed a virus-based functional assay to directly quantify HR activity in cells. Our method detects HR status in a real-time and tumor-only manner. By using this activity-based functional assay, we reveal a universal activity threshold for identifying HRD across cancer types. Here, we present a promising method to accurately detect primary ovarian cancer cells with HRD. Clinical samples that be quantified as HRD show a significant response to PARPi. Therefore, our method can serve as a functional biomarker and companion diagnostic for PARPi. Citation Format: Chih-Ying Lee, Kai-Hang Lei, Shih-Han Huang, Min-Yu Ko, Ko-Yu Chang, Po-Han Lin, Yu-Li Chen, Wen-Fang Cheng, Peter Chi. Detection of homologous recombination deficiency across cancer types by a real-time activity-based functional biomarker [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 365.
P-56 A multicenter prospective translational study using circulating tumor DNA to identify acquired genomic alterations in recurrent gastric or gastroesophageal junction adenocarcinoma in patients who received curative-intent treatment (Liquid-GEAR)
Authors: H. Takeda, T. Suzuki, A. Okita, A. Ishiguro, H. Yabusaki, J. Matsuyama, M. Takahashi, N. Takegawa, N. Fukushima, S. Nishina, R. Kawabata, Y. Kito, Y. Negoro, M. Takahashi, Y. Sunakawa
Journal: Annals of Oncology (2021)
Abstract 13474: Triple Antithrombotic Therapy With Warfarin or Dual Therapy With Dabigatran According to the Precise-Dapt Score in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: Insights From the Re-Dual Pci Trial
Authors: Francesco Costa, Marco Valgimigli, Philippe G Steg, Deepak L Bhatt, Stefan H Hohnloser, Corinna Miede, Matias Nordaby, Gregory Y Lip, Jonas Oldgren, Christopher P Cannon
Journal: Circulation (2019)

Introduction: The PRECISE-DAPT score estimates bleeding risk after percutaneous coronary intervention (PCI), but patients (pts) with atrial fibrillation are at higher bleeding risk due to the conco...
Identification of the JNK-Active Triple-Negative Breast Cancer Cluster Associated With an Immunosuppressive Tumor Microenvironment
Authors: Takashi Semba, Xiaoping Wang, Xuemei Xie, Evan N Cohen, James M Reuben, Kevin N Dalby, James P Long, Lan Thi Hanh Phi, Debu Tripathy, Naoto T Ueno
Journal: JNCI Journal of the National Cancer Institute (2021)

Although an immunosuppressive tumor microenvironment (TME) is key for tumor progression, the molecular characteristics associated with the immunosuppressive TME remain unknown in triple-negative breast cancer (TNBC). Our previous functional proteomic study of TNBC tumors identified that C-JUN N-terminal kinase (JNK) pathway-related molecules were enriched in a cluster associated with the inflammatory pathway. However, the role of the JNK pathway in the TNBC TME is still unclear.
Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in a <i>TP53-</i> and <i>BAX-</i>Dependent Manner
Authors: Tingting Liu, Vi Lam, Elana Thieme, Duanchen Sun, Xiaoguang Wang, Fei Xu, Lili Wang, Olga V. Danilova, Zheng Xia, Jeffrey W. Tyner, Stephen E. Kurtz, Alexey V. Danilov
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Bcl-2 has been effectively targeted in lymphoid malignancies. However, resistance is inevitable, and novel approaches to target mitochondrial apoptosis are necessary. AZD5991, a selective BH3-mimetic in clinical trials, inhibits Mcl-1 with high potency. Experimental Design: We explored the preclinical activity of AZD5991 in diffuse large B-cell lymphoma (DLBCL) and ibrutinib-resistant mantle cell lymphoma (MCL) cell lines, MCL patient samples, and mice bearing DLBCL and MCL xenografts using flow cytometry, immunoblotting, and Seahorse respirometry assay. Cas9 gene editing and ex vivo functional drug screen assays helped identify mechanisms of resistance to Mcl-1 inhibition. Results: Mcl-1 was expressed in DLBCL and MCL cell lines and primary tumors. Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition. Induction of prosurvival proteins (e.g., Bcl-xL) in stromal conditions that mimic the tumor microenvironment rendered protection of primary MCL cells from Mcl-1 inhibition, while BH3-mimetics targeting Bcl-2/xL sensitized lymphoid cells to AZD5991. Treatment with AZD5991 reduced tumor growth in murine lymphoma models and prolonged survival of MCL PDX mice. Conclusions: Selective targeting Mcl-1 is a promising therapeutic approach in lymphoid malignancies. TP53 apoptotic network and metabolic reprogramming underlie susceptibility to Mcl-1 inhibition.
Spontaneous upper urinary tract rupture caused by ureteric stones: clinical characteristics and external validation of a radiological classification system
Authors: L. Boeri, M.G. Spinelli, G. Lucignani, P. Biondetti, L. Martinelli, E. De Lorenzis, G. Albo, A. Ierardi, G. Carrafiello, E. Montanari
Journal: European Urology (2021)
Abstract 3080: ILEI regulates LIFR expression and CSC self-renewal
Authors: William S. Streitfeld, Annamarie C. Dalton, Philip H. Howe
Journal: Cancer Research (2021)

Abstract Our lab has previously identified a mechanism of transforming growth factor beta (TGFβ)-mediated epithelial-to-mesenchymal transition (EMT) in normal murine mammary gland (NMuMG) cells. Reduced expression of heterogenous nuclear ribonucleoprotein E1 (hnRNP E1, hereafter “E1”) in NMuMG cells induces EMT, tumorigenesis, and metastasis. Our experimental data has revealed that increased expression of interleukin-like EMT inducer (ILEI) and of leukemia inhibitory factor receptor (LIFR) proteins occurs following E1 knockdown (E1KD). ILEI and LIFR have been shown to interact by coimmunoprecipitation/radiography experiments, and there is a correlation between ILEI expression and phosphorylation of the LIFR effector STAT3. ILEI is necessary to induce EMT in NMuMG cells, and spheroid formation capacity in non-adherent serum-depleted cell culture conditions is attenuated following either ILEI or LIFR knockdown. Loss of spheroid formation following ILEI knockdown is rescued by treatment with exogenous recombinant ILEI protein (rILEI); however, spheroid formation is not rescued by rILEI following LIFR knockdown. In immunocompromised mice, orthotopic grafts of NMuMG cells with E1KD (E1KD cells) with additional knockdown of either ILEI or LIFR display a decrease in tumor initiation, growth, and metastasis relative to control cells. These data suggest that ILEI-induced spheroid formation capacity involves LIFR, and that an ILEI/LIFR signaling axis promotes breast cancer stem cell (BCSC) phenotype. Characterization of the mechanisms that allow BCSCs to persist during chemotherapeutic interventions will advance our understanding of drug resistant and dormant breast cancer. The precise mechanisms involved in ILEI-mediated EMT and ILEI/LIFR-mediated BCSC induction are unknown. Semi-quantitative PCR data demonstrates that the increase in LIFR expression in E1KD cells is regulated at the transcriptional level. Additionally, E1KD cells with CRISPR-Cas9-mediated ILEI knockout (E1KD-ILEI-KO cells) show decreased luciferase signal relative to control cells following transfection of LIFR promoter DNA sequences placed upstream of a luciferase gene. Further, E1KD-ILEI-KO cells show attenuation of spheroid formation when compared to unaltered E1KD cells. Our data allow us to conclude that ILEI participates in the regulation of LIFR gene transcription, which plays a role in ILEI-induced maintenance of spheroid formation and self-renewal. Continued investigation will allow development of studies aimed at revealing the mechanisms involved in ILEI/LIFR axis-mediated disease progression in vivo. Citation Format: William S. Streitfeld, Annamarie C. Dalton, Philip H. Howe. ILEI regulates LIFR expression and CSC self-renewal [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 3080.
Comparative study of Adrenal Fast Track and Enhanced Recovery (AFTER) protocol for retroperitoneoscopy in patients with primary aldosteronism
Authors: E. Van de Wiel, J. Mulder, A. Hendriks, I. Booij Liewes-Thelosen, X. Zhu, H. Groenewoud, P. Mulders, J. Deinum, J. Langenhuijsen
Journal: European Urology (2021)
Abstract ND11: The discovery and characterization of ION-537: A next generation antisense oligonucleotide inhibitor of YAP1 in preclinical cancer models
Authors: A. Robert Macleod
Journal: Cancer Research (2021)

Abstract The tumor suppressive Hippo pathway is frequently dysregulated in cancer, resulting in the constitutive activation of YAP1 in a variety of solid cancers including hepatocellular cancer (HCC) and head and neck squamous cell carcinoma (HNSCC) among others. Here, we identified potent next-generation constrained ethyl (cEt) antisense oligonucleotides (ASOs) to selectively target either human or mouse YAP1 and evaluated these in several preclinical models of both HCC and HNSCC. In the genetically engineered mouse (GEM) model of HCC (Salvador KO mice) and in the carcinogen-induced models of HCC (diethylnitrosamine, DEN-induced HCC) systemic treatment with mouse YAP1 ASOs resulted in a marked reduction in YAP1 protein level in (~90% reduction) and strong regressions of established tumors. Interestingly, YAP1 ASO treatment also resulted in significant infiltration of T cells and myeloid lineage cells in the tumors in these immune-competent mouse models of HCC suggesting a role in immune activation. Consistent with this notion, YAP1 ASO treatment in combination with anti-PD1 antibody treatment led to enhanced antitumor activity. In HNSCC, loss of the tumor suppressor FAT1 is a frequent occurrence and results in activation and nuclear localization of YAP1. In a panel of human HNSCC cell lines, proliferation was strongly reduced by human YAP1 ASOs selectively in the cell lines harboring homozygous copy loss or nonsense mutations of FAT1 while minimal antiproliferative activity was observed in cells with wild type FAT1. Importantly, the nuclear localization of YAP1 appeared to be a key determining factor for the sensitivity of human HNSCC cells to YAP1 depletion by ASO. In vivo treatment of mice bearing human CAL33 tumors that harbor FAT1 mutation, YAP1 ASOs greatly reduced YAP1 expression in tumors and suppressed tumor growth in both subcutaneous and orthotopic models. Collectively, these results suggest a potential therapeutic use of YAP1 ASOs in the treatment of both HCC and HNSCC with YAP1 activation as a single agent or in combination with immuno-oncology drugs. Based on these finding broad human ASO clinical candidates screens were performed leading to the selection of ION-537, a potent ASO drug targeting human YAP1 has now advanced into human clinical trials in cancer patients with YAP1 activation. Citation Format: A. Robert Macleod. The discovery and characterization of ION-537: A next generation antisense oligonucleotide inhibitor of YAP1 in preclinical cancer models [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 ND11.
Abstract 2171: Brain cancer map: A neural network-based clustering of brain cancer samples based on genome-wide CNV and LOH patterns
Authors: Megan Roytman, Soheil Shams
Journal: Cancer Research (2021)

Abstract Genomic based classification of cancers has been performed using gene expression and methylation patterns (e.g. well-established gene expression profiles used to sub-classify breast cancer). However, there has been very limited progress on classifying cancers based on their global CNV and/or LOH patterns. In this study, we present a novel neural network algorithm based on Self-Organizing Maps (SOMs) that creates a 2-dimensional map of cancer based on global CNV and LOH patterns. We applied this algorithm to 636 brain tumor samples from the TCGA project as part of the Glioblastoma (GBM) and Low-Grade Glioma (LGG) TCGA data sets. The CNV and LOH profiles for the samples was generated and manually curated to adjust for sample ploidy and call fragmentation due to normal cell contamination. Our algorithm generated a 25-node map of brain tumors, where different nodes represent a unique genome-wide profile and neighboring nodes are more similar to each other than more distant nodes. The generated map included nodes representing already known and prognostically important profiles such as 1p/19q co-deletion and combination of trisomy 7, monosomy 10, and homozygous deletion of p16. This is a significant validation of the approach since these profiles were generated completely automatically. In addition to these, new profiles were generated that were further investigated for prognostic value. We then projected all 636 samples back onto the learned map and were able to detect clusters of samples that generally fell within one cancer type, but also discovered some nodes shared by GBM and LGG samples indicating similarity in the CNV profile between these cancer types. We generated Kaplan-Meier survival plot for samples mapped to each node and were able to show statistically significant differences in survival based on the clustering. This approach has the possibility to create a unique CNV based classification of brain tumors for both prognostic and therapeutic applications. Citation Format: Megan Roytman, Soheil Shams. Brain cancer map: A neural network-based clustering of brain cancer samples based on genome-wide CNV and LOH patterns [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 2171.
Azithromycin: can its benefit be ruled out in mild COVID-19?
Authors: Alejandro Rodríguez-Molinero
Journal: The Lancet Respiratory Medicine (2021)

clearance to improve, thereby reducing relapses. 6his hypothesis is supported by a retrospective review that found an inverse association between the duration of initial antibiotic course and subsequent rates of recurrent PBB. 9 These results raise the possibility that children with PBB might benefit from an initial 6-week antibiotic course to reduce relapses, antibiotic burden, and potentially bronchiectasis.This must be balanced against the risk that inappropriate antibiotic use will promote antimicrobial resistance.A further randomised controlled trial in children with PBB, assessing 2 weeks versus 6 weeks antibiotics using carefully chosen outcomes 10 and follow-up of at least 12 months might provide the final piece of the puzzle.Such a trial, along with other well-designed studies in children with respiratory disease, is vital to optimise children's respiratory health and improve the future respiratory health of the whole population.We declare no competing interests.
Abstract LB232: Imbalance of TGF-β1/BMP-7 pathway induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness
Authors: Junya Ning, Yingnan Ye, Jinpu Yu
Journal: Cancer Research (2021)

Abstract The transforming growth factor-beta (TGF-β) signaling represented the predominant cytokine signaling involved in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of TGF-β superfamily, was frequently found to have cross-talk with TGF-β pathway. However, the complex interaction between TGF-β and BMP pathways has not been fully elucidated in HCC. In this study, we found that the imbalance of TGF-β1/BMP-7 pathway was associated with aggressive pathological features and poor clinical outcome in HCC, and it could significantly promote HCC cells invasion and stemness by increasing inhibitor of differentiation 1 (ID1). Next, we indicated that the miR-17-92 cluster could disrupted the balance of TGF-β1/BMP-7 pathway in HCC cells by inducing TGFBR2 post-transcriptional silence and inhibiting ACVR1 post-translational ubiquitylation via targeting Smurf1. Furthermore, we demonstrated that miR-17-92 cluster was originated from the extracellular vesicles (EVs) of M2-polarized tumor associated macrophages (M2-TAMs) infiltrated in HCC microenvironment and induced the imbalance of TGF-β1/BMP-7 pathway. Finally, we found that sh-MIR17HG lentivirus, TGFBR2 lentivirus and ACVR1 inhibitor could profoundly inhibit M2-TAMs-stimulated the growth and metastasis of HCC xenografts in vivo. We propose that imbalance of TGF-β1/BMP-7 pathway may serve as a prognostic biomarker, M2-TAMs and miR-17-92 cluster could be a therapeutic target for this subtype of HCC. Citation Format: Junya Ning, Yingnan Ye, Jinpu Yu. Imbalance of TGF-β1/BMP-7 pathway induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness [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 LB232.
Lesional activation of T <sub>c</sub> 17 cells in Behçet disease and psoriasis supports HLA class I‐mediated autoimmune responses*
Authors: S. Vural, K. Kerl, P. Ertop Doğan, S. Vollmer, U. Puchta, M. He, Y. Arakawa, A.O. Heper, A. Karal‐Öktem, D. Hartmann, A. Boyvat, J.C. Prinz, A. Arakawa
Journal: British Journal of Dermatology (2021)

Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA‐B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL‐23 regulates IL‐17A, which controls the recruitment and activation of neutrophils. To determine pathological changes in BD skin lesions related to the complex genetic predisposition. We characterized the expression of IL‐17A and IL‐23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA‐class I‐associated T‐cell‐mediated autoimmune disease in which excessive T‐cell‐derived IL‐17A production promotes neutrophil activation. We found that in BD lesions, as in psoriasis, actively expanding CD8+ T cells were the predominant source of IL‐17A. IL‐17A+ CD8+ T (Tc17) cells outnumbered infiltrating IL‐17A+ CD4+ T cells. Unlike the epidermal localization of CD8+ T cells in psoriasis, Tc17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co‐localised with a marked IL‐23A expression by CD11c+ dendritic cells and CD68+ macrophages. IL‐17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). In BD, the genetic predisposition may mediate antigen‐specific activation and differentiation of a Tc17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL‐17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL‐23/IL‐17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen‐specific CD8+ T‐cell response.
Large-Scale Proteomic Assessment of Urinary Extracellular Vesicles Highlights Their Reliability in Reflecting Protein Changes in the Kidney
Authors: Qi Wu, Søren B. Poulsen, Sathish K. Murali, Paul R. Grimm, Xiao-Tong Su, Eric Delpire, Paul A. Welling, David H. Ellison, Robert A. Fenton
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Measurement of urinary extracellular vesicle (uEV) protein abundances is frequently used to reflect ongoing (patho)physiologic processes in the kidney. However, whether protein abundances in uEVs and the kidney directly correlate, or whether (patho)physiologic alterations in protein levels in the kidney can be determined by assessing protein changes in uEVs, has never been comprehensively determined. Here, quantitative proteomic data indicate protein abundances in uEVs and kidney in rats are correlated, with a monotonic relationship between altered transporter protein abundance in uEVs and the kidney after a physiologic stimulation. Therefore, it is valid to draw conclusions from altered protein levels in uEVs for particular protein classes and relate them to changes in the kidney. Background Urinary extracellular vesicles (uEVs) are secreted into urine by cells from the kidneys and urinary tract. Although changes in uEV proteins are used for quantitative assessment of protein levels in the kidney or biomarker discovery, whether they faithfully reflect (patho)physiologic changes in the kidney is a matter of debate. Methods Mass spectrometry was used to compare in an unbiased manner the correlations between protein levels in uEVs and kidney tissue from the same animal. Studies were performed on rats fed a normal or high K + diet. Results Absolute quantification determined a positive correlation (Pearson R =0.46 or 0.45, control or high K + respectively, P &lt;0.0001) between the approximately 1000 proteins identified in uEVs and corresponding kidney tissue. Transmembrane proteins had greater positive correlations relative to cytoplasmic proteins. Proteins with high correlations ( R &gt;0.9), included exosome markers Tsg101 and Alix. Relative quantification highlighted a monotonic relationship between altered transporter/channel abundances in uEVs and the kidney after dietary K + manipulation. Analysis of genetic mouse models also revealed correlations between uEVs and kidney. Conclusion This large-scale unbiased analysis identifies uEV proteins that track the abundance of the parent proteins in the kidney. The data form a novel resource for the kidney community and support the reliability of using uEV protein changes to monitor specific physiologic responses and disease mechanisms.