tbuckley/cabot-search huggingface dataset:
Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19
Authors: Yanchun Peng, Alexander J. Mentzer, Guihai Liu, Xuan Yao, Zixi Yin, Danning Dong, Wanwisa Dejnirattisai, Timothy Rostron, Piyada Supasa, Chang Liu, César López-Camacho, Jose Slon-Campos, Yuguang Zhao, David I. Stuart, Guido C. Paesen, Jonathan M. Grimes, Alfred A. Antson, Oliver W. Bayfield, Dorothy E. D. P. Hawkins, De-Sheng Ker, Beibei Wang, Lance Turtle, Krishanthi Subramaniam, Paul Thomson, Ping Zhang, Christina Dold, Jeremy Ratcliff, Peter Simmonds, Thushan de Silva, Paul Sopp, Dannielle Wellington, Ushani Rajapaksa, Yi-Ling Chen, Mariolina Salio, Giorgio Napolitani, Wayne Paes, Persephone Borrow, Benedikt M. Kessler, Jeremy W. Fry, Nikolai F. Schwabe, Malcolm G. Semple, J. Kenneth Baillie, Shona C. Moore, Peter J. M. Openshaw, M. Azim Ansari, Susanna Dunachie, Eleanor Barnes, John Frater, Georgina Kerr, Philip Goulder, Teresa Lockett, Robert Levin, Yonghong Zhang, Ronghua Jing, Ling-Pei Ho, Eleanor Barnes, Danning Dong, Tao Dong, Susanna Dunachie, John Frater, Philip Goulder, Georgina Kerr, Paul Klenerman, Guihai Liu, Andrew McMichael, Giorgio Napolitani, Graham Ogg, Yanchun Peng, Mariolina Salio, Xuan Yao, Zixi Yin, J. Kenneth Baillie, Paul Klenerman, Alexander J. Mentzer, Shona C. Moore, Peter J. M. Openshaw, Malcolm G. Semple, David I. Stuart, Lance Turtle, Richard J. Cornall, Christopher P. Conlon, Paul Klenerman, Gavin R. Screaton, Juthathip Mongkolsapaya, Andrew McMichael, Julian C. Knight, Graham Ogg, Tao Dong
Journal: Nature Immunology (2020)

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4
Attitudes Toward a Potential SARS-CoV-2 Vaccine
Authors: Kimberly A. Fisher, Sarah J. Bloomstone, Jeremy Walder, Sybil Crawford, Hassan Fouayzi, Kathleen M. Mazor
Journal: Annals of Internal Medicine (2020)

Coronavirus disease 2019 (COVID-19) has rapidly instigated a global pandemic. Vaccine development is proceeding at an unprecedented pace. Once available, it will be important to maximize vaccine uptake and coverage.
Abstract 1395: Hsa_circ_005379 competitively binds to miR-182-5p to mediate PTEN expression in oral squamous cell carcinoma
Authors: Yuehong Shen, Wen Su, Hongyu Yang
Journal: Cancer Research (2020)

Abstract Background: Oral squamous cell carcinoma (OSCC) is an oral and maxillofacial malignancy with a high incidence worldwide. Accumulating evidence indicates that circular RNAs (circRNAs) play a vital role in modulating tumor development. However, the mechanism of circRNA action in human OSCC remains largely unknown. Methods: By using high-throughput transcriptome sequencing technology, we conducted a comprehensive study of circRNAs in human OSCC. The effect of CircRNA hsa_circ_0005379 on OSCC tissues and cell lines were monitored by qRT-PCR, transwell assay and western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. Results: CircRNA hsa_circ_0005379 was found to express significantly lower in OSCC tissue compared to paired non-cancerous matched tissue and is associated with tumor size and differentiation. Overexpression of has_circ_0005379 effectively inhibits migration, invasion, and proliferation of OSCC cells in vitro, and suppresses OSCC growth in nude mice. Mechanistic studies revealed that hsa_circ_0005379 may be involved in the regulation of epidermal growth factor receptor (EGFR) pathway. Conclusions: Our findings provide evidence that hsa_circ_0005379 exerts regulatory functions and may be a new therapeutic target for OSCC treatment. Citation Format: Yuehong Shen, Wen Su, Hongyu Yang. Hsa_circ_005379 competitively binds to miR-182-5p to mediate PTEN expression in oral squamous cell carcinoma [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 1395.
Abstract 6550: WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells
Authors: Wei Wu, Huaiwei Ding, Huiyong Zhang
Journal: Cancer Research (2020)

Abstract Androgen receptor (AR) is a primary target for treatment of prostate cancer (PCa). AR signaling plays a critical function in all stages of PCa. Our previous research demonstrated that decursin and its isomer decursinol angelate, a pair of natural compounds from Angelica gigas Nakai, inhibit AR signaling and suppressed the growth of prostate cancer cells in vitro and in vivo. In this study, we have designed a series of pro-drug conjugates of decursin, based on acid-esterified modification, in order to achieve higher water solubility, stronger cytocidal effect and better AR suppression activity. Twelve novel esterified derivatives of decursin were synthesized from decursinol and characterized by 1H-, 13C-NMR and HR-MS techniques. Among them, WD105 displayed the best solubility. Initial structure-activity relationship (SAR) studies were carried out with a cell growth (CCK8) assay and identifıed WD105 and WD106 as lead compounds with more potency at suppressing LNCaP cell growth than decursin judged by IC50 value. In addition, both WD105 and WD106 induced caspase-mediated cell apoptosis (48h), evidenced by cleavage of PARP, in a concentration-dependent manner. Furthermore, WD105 decreased the transcriptional activity of AR and androgen-induced expression of PSA better than WD106 and decursin when assessed by Western Blot and ELISA. Taken together, these data suggest that WD105 has greater in vitro activity than decursin as an AR targeting lead compound. Future studies will characterize the PK metrics and, if warranted, determine the in vivo antitumor effect of WD105 on the growth of LNCaP-AR xenografts. Citation Format: Wei Wu, Huaiwei Ding, Huiyong Zhang. WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells [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 6550.
Abstract 5306: Clinicopathological significance of KIFC1 in human colorectal cancer
Authors: Shintaro Akabane, Naohide Oue, Yuto Fujiki, Naohiro Uraoka, Naoya Sakamoto, Kazuhiro Sentani, Hiroyuki Egi, Hideki Ohdan, Wataru Yasui
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) ranks third in terms of incidence and second in terms of mortality, more than 1.8 million new colorectal cancer cases and 881,000 deaths are reported in Global Cancer Statistics 2018. Therefore, there is an urgent need for a new molecular target in considering treatment strategy. In recent years, cancer has been recognized as a stem cell disease. Spheroid colony formation has been demonstrated as an effective method to characterize cancer stem cells (CSCs). Previously, we analyzed the gene expression profile of spheroid colonies from the gastric cancer cell lines by microarray analysis and found that expression of Kinesin Family Member C1 (KIFC1) was upregulated in gastric spheroid colonies. The kinesin superfamily is a group of proteins that share a motor domain and participate in several biological functions. KIFC1 (or HSET) has been reported to play a vital role in centrosome clustering in cancer cells and is related to pathogenesis in several kinds of cancers. However, the expression of KIFC1 in CRC has not been investigated. The aim of this study is to investigate the expression and the biological function of KIFC1 in CRC. We analyzed the expression and distribution of KIFC1 in 129 CRC cases by immunohistochemistry. In contrast to weak or no staining of KIFC1 in non-neoplastic mucosa, CRC tissue showed stronger, more extensive KIFC1 staining. In total, 67 (52%) of 129 CRC cases were positive for KIFC1. KIFC1-positive CRC cases were significantly associated with CD44-positive and aldehyde dehydrogenase 1 (ALDH1)-positive CRC cases. In the CRC cell proliferation analysis, KIFC1 siRNA-transfected cells showed significantly reduced cell growth ability relative to negative control siRNA-transfected cells. The expression level of phosphorylated Akt and Erk were lower in KIFC1 siRNA-transfected cells compared to negative control siRNA-transfected cells. In the sphere formation analysis, the number and the size of spheres from CRC cells were significantly reduced in KIFC1 siRNA transfected cells than in negative control siRNA-transfected cells. These results indicate that KIFC1 plays an important role in CRC pathogenesis and might be involved in cancer stemness. Although further in-depth studies to clarify the biological significance of KIFC1 in colorectal CSCs are needed, KIFC1 may be a promising therapeutic target for the treatment of CRC. Citation Format: Shintaro Akabane, Naohide Oue, Yuto Fujiki, Naohiro Uraoka, Naoya Sakamoto, Kazuhiro Sentani, Hiroyuki Egi, Hideki Ohdan, Wataru Yasui. Clinicopathological significance of KIFC1 in human colorectal cancer [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 5306.
Echocardiographic Findings in Pediatric Multisystem Inflammatory Syndrome Associated With COVID-19 in the United States
Authors: Daisuke Matsubara, Hunter L. Kauffman, Yan Wang, Renzo Calderon-Anyosa, Sumekala Nadaraj, Matthew D. Elias, Travus J. White, Deborah L. Torowicz, Putri Yubbu, Therese M. Giglia, Alexa N. Hogarty, Joseph W. Rossano, Michael D. Quartermain, Anirban Banerjee
Journal: Journal of the American College of Cardiology (2020)
Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma
Authors: Philippe Armand, Ann Janssens, Giuseppe Gritti, John Radford, John Timmerman, Antonio Pinto, Santiago Mercadal Vilchez, Peter Johnson, David Cunningham, John P. Leonard, Scott J. Rodig, Patricia Martín-Regueira, Anne Sumbul, Selda Samakoglu, Hao Tang, Stephen M. Ansell
Journal: Blood (2020)
Abstract 3102: Analysis of plasma and serum as a source of circulating tumor DNA for hotspot mutations detection in liquid biopsy
Authors: Fabio Pittella-Silva, Yoon Ming Chin, Hui Ting Chan, Satoshi Nagayama, Eisaku Miyauchi, Siew-Kee Low, Yusuke Nakamura
Journal: Cancer Research (2020)

Abstract Blood-based analysis of ctDNA is a promising tool for cancer screening, drug selection, detection of minimum residual disease, monitoring release/recurrence and response to treatment. Although plasma is widely used to obtain ctDNA, biorepositories worldwide possess highly-valuable serum samples collection and comparative studies on the use of serum vs plasma as ctDNA source are still essential. Here we analyzed cell free DNA (cfDNA) from matched plasma and serum samples from healthy donors, colorectal and lung cancer patients to evaluate the differences of serum and plasma on mutation detection efficacy and reproducibility by targeted NGS. We initially addressed the difference of both analytes on the quality of cfDNA recovery and on sequencing performance. We then compared mutation detection using matched samples from healthy individuals spiked-in with standard oligonucleotides including common mutations. The amount of cfDNA was more abundant in serum than plasma and the presence of longer DNA fragments was significantly higher in serum samples. Spiked-in mutated nucleotides were detected in both plasma and serum samples, but allele frequencies (AF) were approximately half in serum samples compared with plasma samples, suggesting ctDNA from serum is more diluted in DNAs of noncancerous origins. We further confirmed this difference in detection efficiency using matched plasma and serum samples from cancer patients and found that mutations with low AF are more frequently missed in serum samples. In addition, concordance with tissue-biopsy mutations found at diagnosis was better in plasma samples. Finally, we examined the use of fragment size selection as an alternative tool to improve mutation detection in serum samples. Our findings clearly demonstrated that the use of serum in retrospective studies should consider the limitations for detecting low AF mutations and indicate the advantages of plasma samples for prospective clinical applications of liquid biopsy. Citation Format: Fabio Pittella-Silva, Yoon Ming Chin, Hui Ting Chan, Satoshi Nagayama, Eisaku Miyauchi, Siew-Kee Low, Yusuke Nakamura. Analysis of plasma and serum as a source of circulating tumor DNA for hotspot mutations detection in liquid biopsy [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 3102.
Near-infrared fluorescence imaging-guided focused ultrasound-mediated therapy against Rheumatoid Arthritis by MTX-ICG-loaded iRGD-modified echogenic liposomes
Authors: Haohan Wu, Yanni He, Hao Wu, Meijun Zhou, Zhili Xu, Ran Xiong, Fei Yan, Hongmei Liu
Journal: Theranostics (2020)

Rheumatoid arthritis (RA), a common inflammatory disorder of the joints characterized by synovitis and pannus formation, often results in irreversible joint erosion and disability. Methotrexate (MTX) is the first-line drug against RA, but the therapeutic effects are sub-optimal due to its poor retention at the target sites and systemic side effects. Multifunctional nanoparticles are highly promising agents for minimally invasive, traceable and effective targeted therapy. Methods: This study developed iRGD peptide-functionalized echogenic liposomes (iELPs) which encapsulates MTX and indocyanine green (ICG) fluorescent probe through the thin film-hydration method. Results: The resulting iELPs showed high affinity for endothelial cells overexpressing αvβ3 integrin, favorable acoustic response and fluorescence tracking properties. Also, near-infrared (NIR) fluorescence imaging of iELPs and ultrasound-triggered drug release of MTX were proved in a mouse RA model, greatly improving the therapeutic efficacy and reducing MTX side effects. Histological assessment of the articular tissues further revealed significantly lower inflammatory cell infiltration and angiogenesis in the iELPs-treated and sonicated mice. Conclusion: Our study provides a promising nanoplatform for integrating ultrasound-controlled drug release and NIR fluorescence imaging for RA treatment.
Abstract 5287: TGF-β-acetylated KLF5-Bcl-2 signaling mediates docetaxel resistance in prostate cancer cells
Authors: Yixiang Li, Baotong Zhang, Jin-Tang Dong
Journal: Cancer Research (2020)

Abstract Purpose: In this study, we explored the role of KLF5 in TGF-β-induced drug resistance in prostate cancer cells to identify novel therapeutic targets. Procedures: We used DU 145 and PC-3 prostate cancer cell lines in in vitro cell survival assay, colony survival assay, and xenograft mouse model to measure docetaxel (DTX) resistance. TGF-β1, the SB505124 TGF-β receptor I inhibitor, and the ABT-199 Bcl-2 inhibitor were used to determine if Bcl-2 mediates TGFβ induced docetaxel resistance. To measure the function of KLF5 and its acetylation at lysine 369 in drug resistance, stable cell lines were constructed with different forms of KLF5 after the endogenous KLF5 was deleted with the CRISPR-Cas9 system. Results: We found that TGF-β induced DTX resistance depends on KLF5 expression. As a downstream molecule of TGF-β signaling, acetylated KLF5 at lysine 369 mediated TGF-β-induced DTX resistance. Moreover, acetylated KLF5 induced DTX resistance in xenograft mouse model. Mechanistically, we found that TGF-β and acetylated KLF5 upregulated Bcl-2 transcription, and inhibition of Bcl-2 sensitized cells to DTX. In addition, DTX promoted Bcl-2 degradation via a proteasome dependent pathway, and TGF-β signaling stabilized Bcl-2 via inhibition of Bcl-2 ubiquitination. Lastly, the TGF-β/acetylated KLF5/Bcl-2 signaling axis induced survival disadvantage in prostate cancer patients. Conclusions: TGF-β induces transcriptional upregulation of Bcl-2 through acetylated KLF5 at lysine 369, and TGF-β stabilizes Bcl-2 via inhibition of DTX-induced Bcl-2 ubiquitination. The TGF-β-acetylated KLF5-Bcl-2 signaling axis is thus a novel mechanism mediating DTX resistance in prostate cancer. Citation Format: Yixiang Li, Baotong Zhang, Jin-Tang Dong. TGF-β-acetylated KLF5-Bcl-2 signaling mediates docetaxel resistance in prostate cancer cells [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 5287.
Decitabine/Cedazuridine: First Approval
Authors: Sohita Dhillon
Journal: Drugs (2020)

A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy
Authors: Elham Beyranvand Nejad, Camilla Labrie, Ziena Abdulrahman, Marit J van Elsas, Eva Rademaker, Jan Willem Kleinovink, Tetje C van der Sluis, Suzanne van Duikeren, Amina F A.S Teunisse, Aart G Jochemsen, Jan Oosting, Noel F C C de Miranda, Thorbald Van Hall, Ramon Arens, Sjoerd H van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments. Methods We exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance. In depth studies on systemic, local and tumor intrinsic changes were performed with flow and mass cytometry, immunohistochemistry, transcriptomics and several perturbation studies with inhibitors or agonistic antibodies in mice. Main findings were recapitulated in vaccinated patients. Results Full tumor regression and cure of tumor-bearing mice is dependent on the magnitude of the vaccine-induced T-cell response. Recurrence of tumors did not involve classical immune escape mechanisms, such as antigen-presentation alterations, immune checkpoint expression, resistance to killing or local immune suppression. However, the recurrent tumors displayed a changed transcriptome with alterations in p53, tumor necrosis factor-α and transforming growth factor-β signaling pathways and they became immunologically cold. Remarkably, ex vivo cell-sorted recurrent tumors, directly reinjected in naïve hosts retained their resistance to vaccination despite a strong infiltration with tumor-specific CD8 + T cells, similar to that of vaccine-responsive tumors. The influx of inflammatory mature myeloid effector cells in the resistant tumors, however, was impaired and this turned out to be the underlying mechanisms as restoration of inflammatory myeloid cell infiltration reinstated the sensitivity of these refractory tumors to vaccination. Notably, impaired myeloid cell infiltration after vaccination was also associated with vaccine resistance in patients. Conclusion An immunotherapy-induced disability of tumor cells to attract innate myeloid effector cells formed a major mechanism underlying immune escape and acquired resistance. These data not only stresses the importance of myeloid effector cells during immunotherapy but also demands for new studies to harness their tumoricidal activities.
Abstract 1061: Increasing potency of anticancer drugs through Sortilin receptor-mediated cancer therapy: A new targeted approach for the treatment of ovarian cancer
Authors: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Larocque, Alain Zgheib, Sophie Kozelko, Richard Béliveau, Christian Marsolais, Borhane Annabi
Journal: Cancer Research (2020)

Abstract Rational : The development of personalized therapies against ovarian cancer remains highly challenging even in current modern oncology. One strategy to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to peptide ligands that selectively target receptors abundantly and/or exclusively expressed in these tumor cells. Increased expression of Sortilin (SORT1), a scavenging receptor also known as neurotensin receptor-3, has been observed in invasive ovarian cancer biopsies. In addition, increased SORT1 expression correlated with breast tumor grades. Procedures : In light of these observations, we developed a peptide conjugation platform to target SORT1 and to increase cell selectivity and internalization of anticancer agents. As a proof-of-concept, doxorubicin and docetaxel were conjugated to a Sortilin-binding proprietary peptide (TH19P01). Results : In vitro, significant intracellular delivery of the doxorubicin-TH19P01 conjugate (TH1904) and docetaxel-TH19P01 conjugate (TH1902) were observed in a ES-2 ovarian cancer cell line model while preserving efficient doxorubicin or docetaxel cytotoxic mechanism. TH19P01 and drug conjugate uptake in ovarian cancer cells assays were reduced when SORT1 expression was specifically silenced using siRNA or upon competition with the SORT1 ligands neurotensin and progranulin. Importantly, drug-TH19P01 conjugates were found to bypass the P-glycoprotein (P-gp) efflux pump in MDCK-MDR1 cells overexpressing P-gp as the uptake of conjugates was unaffected by the P-gp inhibitor Cyclosporin A. In vivo, TH1904 and TH1902 caused a more potent inhibition of human ovarian tumor xenografts grown in mice and were better tolerated than their unconjugated parent drugs. Conclusion : These results strongly support future clinical development of this targeted technology platform to generate novel personalized therapeutics with specific indications in Sortilin-positive cancers. Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Larocque, Alain Zgheib, Sophie Kozelko, Richard Béliveau, Christian Marsolais, Borhane Annabi. Increasing potency of anticancer drugs through Sortilin receptor-mediated cancer therapy: A new targeted approach for the treatment of ovarian cancer [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 1061.