tbuckley/cabot-search huggingface dataset:
Abstract 2765: The indoleamine 2,3 dioxygenase-1 pathway drives intratumoral B cell maintenance
Authors: Burles Avner Johnson, Adam K. Aragaki, Donna M. Williams, Ophelia Rogers, Li Luo, Lingling Xian, Lionel Chia, Noah M. Hahn, Stephen Desiderio, Theodore S. Johnson, David J. McConkey, Linda M.S. Resar
Journal: Cancer Research (2021)

Abstract Immunotherapy has revolutionized cancer treatment by improving survival in many cancer subtypes. While tumor infiltrating B (TIL-B) cells correlate with response to immunotherapy in selected solid tumors, they portend resistance to BRAF inhibitors in BRAF mutant melanoma. Thus, the mechanisms underlying TIL-B cell function within the tumor microenvironment have remained elusive. Here, we discovered that inhibition of the indoleamine 2,3 dioxygenase-1 (IDO1) pathway with D-1-methyl-tryptophan (D-1MT) markedly decreases TIL-B cells in a preclinical model of melanoma. Single cell RNA sequencing (scRNAseq) of murine melanoma demonstrate TIL-B cells are heterogeneous: while some B cells express markers consistent with an immune stimulatory phenotype, others express markers consistent with immune inhibitory function. D-1MT decreased splenic B cells and bone marrow derived B cell precursors in tumor bearing mice, suggesting that IDO1 pathway inhibition impedes B cell maturation. In four distinct human cancer subtypes, intratumoral IDO1 expression consistently correlates with high expression of a pan-B cell gene signature. Further, analysis of scRNAseq data from a cohort of patients with melanoma revealed that most TIL-B cells express IDO1. In mice, D-1MT also decreases intratumoral myeloid derived suppressor cells (MDSCs), which are essential for maintenance of TIL-B cells. Surprisingly, we found that D-1MT enhanced anti-tumor effects of the BRAF inhibitor, vemurafenib, in a preclinical model of BRAF mutant melanoma, suggesting that targeting B cells in this setting may be beneficial. Together, our data reveal a novel paradigm for the IDO1 pathway in regulating TIL-B cells, and uncovered IDO1 as a potential targetable mechanism of resistance to BRAF inhibition in melanoma. Citation Format: Burles Avner Johnson, Adam K. Aragaki, Donna M. Williams, Ophelia Rogers, Li Luo, Lingling Xian, Lionel Chia, Noah M. Hahn, Stephen Desiderio, Theodore S. Johnson, David J. McConkey, Linda M.S. Resar. The indoleamine 2,3 dioxygenase-1 pathway drives intratumoral B cell maintenance [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 2765.
Abstract 1162: Monitoring COVID-19 RNA methyltransferases activities for developing therapeutic drugs
Authors: Said A. Goueli, Kevin Hsiao
Journal: Cancer Research (2021)

Abstract The recent pandemic outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) was first reported in Wuhan, China in late 2019 resulting in infection of over 20 million and death of over one million world-wide as of October 2020. The infection by this virus is highly transmissible and can lead to severe pneumonia and death. The SARS-CoV-2 is an enveloped virus and belongs to the beta coronavirus family containing a large and complex positive-sense single stranded RNA genome (~30kb).It binds to human ACE2 receptor with high affinity, compared to the other CoVs, via its spike protein (S) and membrane fusion leading to the release of its genomic RNA that replicates and produce higher number of subgenomic RNAs. The viral RNA is then capped by nsp 14 and nsp10/16, two nonstructural proteins that catalyze the methylation of RNA to limit its degradation by cellular 5'-3'exonuclease and evade host immune system. These enzymes play critical role in translation of the viral RNA and its replication and thus leading to viral survival. We have used a bioluminescent high throughput enzyme assay for monitoring the activity of these enzymes in order to develop novel inhibitors which can be advanced for therapeutic treatment. We show that we can determine the activity of nanogram amounts of these enzymes and test the activity of these enzymes using different inhibitors, some of which are competitive with S-adenosyl methionine the canonical substrate for these enzymes. We also show the effect of inhibitors that compete with the oligonucleotide substrate. Finally, we tested the effect of a peptide modulator of COVID-2 on the activity of both nsp10/16 and nsp14. The assay is simple, homogenous, fast, and bioluminescent which provides a very robust platform for testing novel compounds on the viral methyltransferases leading to the generation of new drugs towards inhibiting the replication of COVID19 Citation Format: Said A. Goueli, Kevin Hsiao. Monitoring COVID-19 RNA methyltransferases activities for developing therapeutic drugs [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 1162.
Abstract 1730: Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients
Authors: Ayumi Hashimoto, Debashis Sarker, Vikash Reebye, Sheba Jarvis, Mikael H. Sodergren, Andrew Kossenkov, Nina Raulf, Jenni Vasara, Pinelopi Andrikakou, Tim Meyer, Kai-Wen Huang, Ruth Plummer, Cheng Ean Chee, Duncan Spalding, Madhava Pai, David J. Pinato, Rohini Sharma, Bristi Basu, Daniel Palmer, Yuk-Ting Ma, Robert Habib, Anna Martirosyan, Naouel Elasri, Adeline Reynaud, John Rossi, Mark Cobbold, Nagy Habib, Dmitry Gabrilovich
Journal: Cancer Research (2021)

Abstract Tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are widely implicated in the suppression of immune responses in cancer and are associated with negative clinical outcomes. We report that in mouse tumor models, therapeutic up-regulation of the transcriptional factor C/EBPα with small activating RNA (MTL-CEBPA) blocks the suppressive activity of monocytic (M) MDSC and TAM without affecting polymorphonuclear (PMN) MDSC. MTL-CEBPA treatment demonstrated antitumor activity that was dependent on T cells. Combination of MTL-CEBPA and anti-PD1 antibody or with PMN-MDSC targeted therapy resulted in marked antitumor effect. A phase I trial was conducted in 36 patients with advanced hepatocellular carcinoma (HCC). Marked decrease in M-MDSC and the expression of genes and proteins involved in immune suppressive activity of these cells were observed. Combined treatment with MTL-CEBPA and sorafenib resulted in a 27% objective radiological response and three complete responses in patients with virally associated HCC. Tissue biopsies from these patients demonstrated decrease in M2 polarized macrophages within the tumors. Thus, therapeutic up-regulation of C/EBPα inhibited suppressive myeloid cells that resulted in potent antitumor effect in mice and with encouraging clinical response in cancer patients. We are currently recruiting to a multi-centre study of MTL-CEBPA in combination with a PD-1 inhibitor (pembrolizumab) in adult patients with advanced solid tumors (TIMEPOINT - ClinicalTrials.gov Identifier: NCT04105335). Citation Format: Ayumi Hashimoto, Debashis Sarker, Vikash Reebye, Sheba Jarvis, Mikael H. Sodergren, Andrew Kossenkov, Nina Raulf, Jenni Vasara, Pinelopi Andrikakou, Tim Meyer, Kai-Wen Huang, Ruth Plummer, Cheng Ean Chee, Duncan Spalding, Madhava Pai, David J. Pinato, Rohini Sharma, Bristi Basu, Daniel Palmer, Yuk-Ting Ma, Robert Habib, Anna Martirosyan, Naouel Elasri, Adeline Reynaud, John Rossi, Mark Cobbold, Nagy Habib, Dmitry Gabrilovich. Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients [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 1730.
Abstract 2502: Co-existing P53 and ARID1A mutations promote metastatic endometrial tumorigenesis
Authors: Jake J. Reske, Mike R. Wilson, Jeanne Holladay, John I. Risinger, Ronald L. Chandler
Journal: Cancer Research (2021)

Abstract P53 and ARID1A are frequently mutated across cancer but rarely in the same tumor. Uterine endometrial cancer displays the highest P53-ARID1A mutual exclusivity rate. The genetic basis underlying P53-ARID1A mutual exclusivity and the relationship between molecular programs imposed by either mutation have not been elucidated in vivo mouse models. Here, genetically engineered mice were used to discern both unique and overlapping roles of P53 and ARID1A in the endometrium. Endometrial epithelial hyperplasia is driven by P53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium. Sorted hyperplastic endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A-PIK3CA mutant endometrium. Both P53 and ARID1A mutations lead to activation of inflammatory pathways but differ on other gene expression programs, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with respective genetic alterations. ARID1A co-regulates P53 transcriptional gene targets, and the P53 pathway is activated in ARID1A mutant endometrial tumors. Finally, TP53 and ARID1A mutations co-occur more frequently in metastatic lesions, and co-existing TP53-ARID1A mutations are viable in the endometrium and lead to invasive endometrial cancer. These data suggest P53 and ARID1A mutations stimulate shared and distinct tumorigenic programs in the endometrium and promote metastasis when existing simultaneously. We propose that ARID1A loss in P53 mutant endometrial cancer promotes metastasis. Citation Format: Jake J. Reske, Mike R. Wilson, Jeanne Holladay, John I. Risinger, Ronald L. Chandler. Co-existing P53 and ARID1A mutations promote metastatic endometrial tumorigenesis [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 2502.
Limited efficacy of daratumumab in multiple myeloma with extramedullary disease
Authors: Tomas Jelinek, Tereza Sevcikova, David Zihala, Tereza Popkova, Veronika Kapustova, Lucie Broskevicova, Lenka Capkova, Lucie Rihova, Renata Bezdekova, Sabina Sevcikova, Vladimir Zidlik, Martin Havel, Hana Plonkova, Alexandra Jungova, Jiri Minarik, Martin Stork, Ludek Pour, Petr Pavlicek, Ivan Spicka, Vladimir Maisnar, Jakub Radocha, Michal Simicek, Roman Hajek
Journal: Leukemia (2021)
Prognostic Significance of Medullary Abnormalities of the Appendicular Skeleton Detected By Low-Dose Whole-Body Multidetector Computed Tomography in Patients with Multiple Myeloma
Authors: Hiroki Kobayashi, Yoshiaki Abe, Kentaro Narita, Akihiro Kitadate, Masami Takeuchi, Kosei Matsue
Journal: Blood (2017)
Author Correction: SF3B1 as therapeutic target in FLT3/ITD positive acute myeloid leukemia
Authors: Inge van der Werf, Anna Wojtuszkiewicz, Huilan Yao, Rocco Sciarrillo, Manja Meggendorfer, Stephan Hutter, Wencke Walter, Jeroen Janssen, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach, Gerrit Jansen, Gertjan J. L. Kaspers, Richard Groen, Gert Ossenkoppele, Jacqueline Cloos
Journal: Leukemia (2021)

Despite carefully proofreading our submission, we missed a mistake in the affiliation of Wolfgang Kern, Claudia Haferlach and Torsten Haferlach. Instead of (2) H3 Biomedicine, their affiliation should be (3) MLL Munich Leukemia Laboratory, Munich, Germany.
Increased connectivity of hiPSC-derived neural networks in multiphase granular hydrogel scaffolds
Authors: Chia-Chen Hsu, Julian H. George, Sharlayne Waller, Cyril Besnard, David A Nagel, Eric J Hill, Michael D. Coleman, Alexander M. Korsunsky, Zhanfeng Cui, Hua Ye
Journal: Bioactive Materials (2021)

To reflect human development, it is critical to create a substrate that can support long-term cell survival, differentiation, and maturation. Hydrogels are promising materials for 3D cultures. However, a bulk structure consisting of dense polymer networks often leads to suboptimal microenvironments that impedes nutrient exchange and cell-to-cell interaction. Herein, granular hydrogel-based scaffolds were used to support 3D human induced pluripotent stem cell (hiPSC)-derived neural networks. A custom designed 3D printed toolset was developed to extrude hyaluronic acid hydrogel through a porous nylon fabric to generate hydrogel granules. Cells and hydrogel granules were combined using a weaker secondary gelation step, forming self-supporting cell laden scaffolds. At three and seven days, granular scaffolds supported higher cell viability compared to bulk hydrogels, whereas granular scaffolds supported more neurite bearing cells and longer neurite extensions (65.52 ± 11.59 μm) after seven days compared to bulk hydrogels (22.90 ± 4.70 μm). Long-term (three-month) cultures of clinically relevant hiPSC-derived neural cells in granular hydrogels supported well established neuronal and astrocytic colonies and a high level of neurite extension both inside and beyond the scaffold. This approach is significant as it provides a simple, rapid and efficient way to achieve a tissue-relevant granular structure within hydrogel cultures.
<i>Bcar1</i>/p130Cas is essential for ventricular development and neural crest cell remodelling of the cardiac outflow tract
Authors: Marwa Mahmoud, Ian Evans, Laura Wisniewski, Yuen Tam, Claire Walsh, Simon Walker-Samuel, Paul Frankel, Peter Scambler, Ian Zachary
Journal: Cardiovascular Research (2021)

The adapter protein p130Cas, encoded by the Bcar1 gene, is a key regulator of cell movement, adhesion, and cell cycle control in diverse cell types. Bcar1 constitutive knockout mice are embryonic lethal by embryonic days (E) 11.5-12.5, but the role of Bcar1 in embryonic development remains unclear. Here, we investigated the role of Bcar1 specifically in cardiovascular development and defined the cellular and molecular mechanisms disrupted following targeted Bcar1 deletions.
若い乳児におけるヒト不全ウイルス感染の検出と管理を改善するための戦略【JST・京大機械翻訳】
Authors: Kadambari Seilesh, Harvala Heli, Simmonds Peter, Pollard Andrew J, Sadarangani Manish
Journal: The Lancet Infectious Diseases (2019)
Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations
Authors: Felix C. Saalfeld, Carina Wenzel, Petros Christopoulos, Sabine Merkelbach-Bruse, Timm M. Reissig, Silke Laßmann, Sebastian Thiel, Jan A. Stratmann, Ralf Marienfeld, Johannes Berger, Alexander Desuki, Janna-Lisa Velthaus, Diego Kauffmann-Guerrero, Albrecht Stenzinger, Sebastian Michels, Thomas Herold, Michael Kramer, Sylvia Herold, Amanda Tufman, Sonja Loges, Jürgen Alt, Maria Joosten, Gerlinde Schmidtke-Schrezenmeier, Martin Sebastian, Susann Stephan-Falkenau, Cornelius F. Waller, Marcel Wiesweg, Jürgen Wolf, Michael Thomas, Daniela E. Aust, Martin Wermke
Journal: Journal of Thoracic Oncology (2021)
Abstract 3084: KLF8 is a required downstream effector of OGT/O-GlcNAcylation in regulating breast cancer stem-like cells
Authors: Giang Le Minh, Neha M. Akella, Tejsi Dhameliya, Mauricio J. Reginato
Journal: Cancer Research (2021)

Abstract One of the main challenges in treating breast cancer is the intra-tumor heterogeneity, which, partly, is maintained and promoted by a sub-population of breast cancer cells called breast cancer stem-like cells (BCSCs). BCSCs shares traits of mammary stem cells, capable of self-renewing and differentiating, while promotes invasion, metastasis, drug resistance and relapse. BCSCs are highly adaptive, capable of reprogramming metabolism and signaling activity in response to tumor microenvironment. One key component of cell nutrient sensing mechanism, linking alteration in metabolism to cell signaling, is O-GlcNAc transferase (OGT). OGT is responsible to adding O-GlcNAc moieties to target nuclear, cytoplasmic and mitochondrial proteins from UDP-GlcNAc - final product of the hexosamine biosynthetic pathway. This modification is termed O-GlcNAcylation and both OGT and O-GlcNAcylation are upregulated in many cancers. Recently, we showed that OGT/O-GlcNAcylation is enriched in BCSCs, promoting the stemness and tumorigenesis of breast cancer cells in vitro and in vivo. RNA-seq analysis of BCSC-enriched mammospheres with OGT overexpression revealed Kruppel-like-factor 8 (KLF8) as a downstream target of OGT in promoting BCSCs. Here, we showed that KLF8 expression in breast cancer cells is regulated by OGT at protein and mRNA level. Knockdown of KLF8 reduced mammosphere forming efficiency (MFE) and NANOG expression in breast cancer cells, while overexpressing KLF8 increased MFE, NANOG+ and CD44H/CD24L BCSC population. Importantly, KLF8 knockdown abolished the effect of elevated OGT and O-GlcNAcylation in breast cancer cell MFE and BCSC population, while KLF8 overexpression rescued OGT inhibition in MFE and BCSC population. suggesting that KLF8 is required in promoting BCSCs. Interestingly, KLF8 knockdown in breast cancer cell reduced OGT expression, while KLF8 overexpression increased OGT and O-GlcNAcylation, suggesting a possible feed-forward loop between OGT and KLF8 in promoting BCSCs. Supporting the idea that KLF8 and OGT are critical for breast cancer progression, breast cancer patient survival was lower with high KLF8 or OGT levels. Furthermore, overexpression of KLF8 showed increase in resistance to paclitaxel in triple-negative breast cancer cells in vitro, suggesting a possible role of KLF8 in promoting chemotherapy resistance in breast cancer[LM1] . Together, our results suggested that KLF8 is a downstream target of OGT/O-GlcNAcylation in promoting breast cancer stem-like cells population. Citation Format: Giang Le Minh, Neha M. Akella, Tejsi Dhameliya, Mauricio J. Reginato. KLF8 is a required downstream effector of OGT/O-GlcNAcylation in regulating breast cancer stem-like cells [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 3084.
Hidden link in gut–joint axis: gut microbes promote rheumatoid arthritis at early stage by enhancing ascorbate degradation
Authors: Yan Zhao, Mingyue Cheng, Liang Zou, Luxu Yin, Chaofang Zhong, Yuguo Zha, Xue Zhu, Lei Zhang, Kang Ning, Jinxiang Han
Journal: Gut (2021)

Characteristic (%) Before PS adjustment After PS adjustment Before PS adjustment After PS adjustment PPI (n=1 01 438) Non-PPI (n=3 53 266) SMD PPI (n=11 741) Non-PPI (n=11 741) SMD PPI (n=10 708) H 2 RA (n=1 19 493) SMD PPI (n=5067) H 2 RA (n=5067) SMD Values are presented as proportion of the patients (%).*The applicated raw database was the National Health Insurance Service Common Data Model.GORD, gastro-oesophageal reflux disease; H2RA, histamine 2 receptor antagonist; PPI, proton pump inhibitor; PS, propensity matching; SMD, standard mean difference.Table 1 Continued last day of the eradication treatment as the index date.While the authors have mentioned in the discussion section that they could not determine H. Pylori infection status by a laboratory test, it is important to know if both groups were matched regarding clarithromycin based triple therapy or bismuth-based quadruple therapy, as they might differ in efficacy considering 20% resistance rate to clarithromycin in Korea. 2 The authors also mentioned a cumulative dose-response relationship between increasing PPI duration and the risk of gastric cancer development.Though it is true for PPI≥30 and≥180 days, the same is not true for PPI≥365 days, as the result was not statistically significant (PPI≥365 days, HR 3.5, 95% CI 0.85 to 23.49, p value 0.14).Summarily, the gastric cancer incidence rate is higher in Korean men than women when we compare ≥40 years of age groups. 3Hence, it is important to know if gender was equally distributed for each age range in table 1.Our concern is if the PPI group had more men in ≥40 years age group, it can skew the result in the favour of PPI.
The International Thymic Malignancy Interest Group Classification of Thymoma Recurrence: Survival Analysis and Perspectives
Authors: Marco Chiappetta, Filippo Lococo, Edoardo Zanfrini, Rossana Moroni, Vittorio Aprile, Francesco Guerrera, Dania Nachira, Maria Teresa Congedo, Marcello Carlo Ambrogi, Stylianos Korasidis, Marco Lucchi, Pier Luigi Filosso, Enrico Ruffini, Isabella Sperduti, Elisa Meacci, Stefano Margaritora
Journal: Journal of Thoracic Oncology (2021)
High-dose-rate brachytherapy and hypo-fractionated external beam radiation combined with long-term androgen deprivation for very-high-risk prostate cancer
Authors: K. Mori, H. Sasaki, H. Onuma, J. Miki, T. Kimura, S.F. Shariat, M. Aoki, S. Egawa
Journal: European Urology (2021)
Abstract 602: Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers
Authors: Xi Zhang, Kai Tang, Brett Hughes, Sarj Vasani, Zhen Liu, Majid Warkiani, Gunter Hartel, Rahul Ladwa, Liz Kenny, Chamindie Punyadeera
Journal: Cancer Research (2021)

Abstract Background: Metastases remains the major cause of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) that are shed from primary and metastatic sites and circulate in patients' peripheral blood, represent an important window into disease status. Minimally invasive techniques are required to identify at time of diagnosis, which patients will have worse prognosis due to distant relapse. Method: We collected bloods from treatment naïve, locoregionally advanced HNC patients (n=72) at the time of diagnosis, and CTCs were isolated using a spiral microfluidic device. CTCs were then immobilised onto glass slides and identified by using immunofluorescence staining (Cytokeratin/CD45/DAPI). We then correlated the CTC numbers of each patient to their clinical outcome based on either PET/CT scan and/or clinical assessment after definitive treatment. Results: CTCs were detected in 39/72 (54%) of patients (ranging from 1-18 CTCs/10 mL blood) at diagnosis. CTC numbers were correlated to TNM staging (p&amp;lt;0.01), especially the Node staging (p&amp;lt;0.01). Patients with ≥2 CTCs at baseline showed significantly worse prognosis than those with no CTCs detected (P&amp;lt;0.001). We also found that baseline CTCs is an independent predictor of the adverse clinical outcome (residual disease, recurrence, and equivocal clinical presentation) even after adjusting to other prognostic factors (hazard ratio=4.613, p&amp;lt;0.05). Patients with CTC cluster had poor prognosis compared to patients with single CTCs. Conclusion: We were able to predict disease progression based on CTC numbers, thus providing potential additional prognostic information for locally advanced HNC patients. The ability to detect CTCs at diagnosis allows us to stratify the risk in patients as well as to understand the fundamental mechanisms by which CTCs spread. The clinical benefit of establishing the use of CTCs in HNC is likely to translate into better patient selection for treatment intensification and/or de-intensification strategies. Citation Format: Xi Zhang, Kai Tang, Brett Hughes, Sarj Vasani, Zhen Liu, Majid Warkiani, Gunter Hartel, Rahul Ladwa, Liz Kenny, Chamindie Punyadeera. Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers [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 602.