tbuckley/cabot-search huggingface dataset:
Abstract SY30-02: NK cells remember: Engineering NK cell memory-like responses for cancer immunotherapy
Authors: Todd A. Fehniger
Journal: Cancer Research (2021)

Abstract Natural killer (NK) cells are innate lymphoid cells that protect against infection and mediate anti-tumor immune responses. NK cell immunotherapy is a promising cellular therapy approach for leukemia, lymphoma, and other cancers. Multiple laboratories have advanced our understanding of innate NK cell memory and memory-like responses over the past decade, with a unifying definition of enhanced response to re-stimulation after an initial activation event. We identified that human cytokine-induced memory-like (memory) NK cells differentiate after a brief activation with IL-12, IL-15, and IL-18 and mediate enhanced responses against leukemia and other cancer targets. Pre-clinical studies have demonstrated their enhanced anti-tumor potential in vitro, and in vivo in syngeneic murine models and human xenografts. We translated this concept into a first-in-human clinical trial that demonstrated safe adoptive transfer of donor memory NK cells for patients with relapsed or refractory acute myeloid leukemia (AML) resulting in complete remissions. Correlative mass cytometry from this phase 1 study revealed the memory NK cell multidimensional phenotype and identified NKG2A as a major checkpoint for memory NK cell response to AML. Additional clinical trials of donor memory NK cells the HCT setting have demonstrated safety and anti-leukemia activity the immune compatible setting and has provided insights into persistence. Memory NK cells functionally persist for more than 60 days with a unique multidimensional phenotype in two clinical trials in leukemia patients. Further, CITE-seq single cell profiling reveals a unique memory NK cell transcriptomic signature. We have also developed approaches to gene edit and engineer memory-like NK cells with chimeric antigen receptors, expanding the spectrum of cancers for memory-like NK cellular therapy. CAR memory NK cells exhibit enhanced responses, compared with CAR conventional NK cells. Further, pairing with tumor targeting monoclonal antibodies can result in CAR-like responses via CD16/FcγRIIIa, providing additional activating signals that direct memory NK cell response. These studies identify a promising memory NK cell platform for cancer immunotherapy and highlight the importance of correlative studies during clinical trials to advance our understanding of human immunology. Citation Format: Todd A. Fehniger. NK cells remember: Engineering NK cell memory-like responses for cancer immunotherapy [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 SY30-02.
Hepatic Complications in Children with Sickle Cell Anemia Are Rare but Potentially Lethal
Authors: Mariane De Montalembert, Slimane Allali, Laurent Dupic, Cecile Dumesnil, Annie Kamden, Vincent Gajdos, Audrey Coilly, Christophe Chardot, Martin Chalumeau, Valentine Brousse, Florence Lacaille
Journal: Blood (2017)
The Immunomodulatory Drugs Lenalidomide and Pomalidomide Inhibit Multiple Myeloma-Induced Osteoclast Formation and RANKL/OPG Ratio In Myeloma Microenvironment Targeting the Expression of Adhesion Molecules
Authors: Marina Bolzoni, Manuela Abeltino, Paola Storti, Sabrina Bonomini, Luca Agnelli, Katia Todoerti, Antonino Neri, Vittorio Rizzoli, Nicola Giuliani
Journal: Blood (2010)
Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial
Authors: Christopher Sweeney, Sergio Bracarda, Cora N Sternberg, Kim N Chi, David Olmos, Shahneen Sandhu, Christophe Massard, Nobuaki Matsubara, Boris Alekseev, Francis Parnis, Vagif Atduev, Gary L Buchschacher, Rustem Gafanov, Luis Corrales, Michael Borre, Daniil Stroyakovskiy, Gustavo Vasconcelos Alves, Evangelos Bournakis, Javier Puente, Marie-Laurence Harle-Yge, Jorge Gallo, Geng Chen, Justin Hanover, Matthew J Wongchenko, Josep Garcia, Johann S de Bono
Journal: The Lancet (2021)
Gastrodin modified polyurethane conduit promotes nerve repair via optimizing Schwann cells function
Authors: Hongcai Yang, Qing Li, Limei Li, Shaochun Chen, Yu Zhao, Yingrui Hu, Lu wang, Xiaoqian Lan, Lianmei Zhong, Di Lu
Journal: Bioactive Materials (2021)

Peripheral nerve regeneration and functional recovery remain a major clinical challenge. Nerve guidance conduit (NGC) that can regulate biological behavior of Schwann cells (SCs) and facilitate axonal regeneration through microenvironmental remodeling is beneficial for nerve regeneration and functional recovery. Gastrodin, a main constituent of a Chinese traditional herbal medicine, has been known to display several biological and pharmacological properties, especially antioxidative, anti‐inflammatory and nerve regeneration. Herein, polyurethane (PU) NGCs modified by different weight ratio of Gastrodin (0, 1 and 5 wt%) were designed for sequential and sustainable drug release, that created a favorable microenvironment for nerve regeneration. The scaffold showed suitable pore structure and biocompatibility in vitro, and evidently promoted morphological and functional recovery of regenerated sciatic nerves in vivo. Compared to the PU and 1%Gastrodin/PU scaffolds, the 5%Gastrodin/PU significantly enhanced the proliferation, migration and myelination of SCs and up-regulated expression of neurotrophic factors, as well as induction of the differentiation of PC12 cells. Interestingly, the obvious anti-inflammatory response was observed in 5%Gastrodin/PU by reduced expression of TNF-α and iNOS, which also evidenced by the few fibrous capsule formation in the subcutaneous implantation. Such a construct presented a similarity to autograft in vivo repairing a 10 mm sciatic nerve defects. It was able to not only boost the regenerated area of nerve and microvascular network, but also facilitate functional axons growth and remyelination, leading to highly improved functional restoration. These findings demonstrate that the 5%Gastrodin/PU NGC efficiently promotes nerve regeneration, indicating their potential for use in peripheral nerve regeneration applications.
The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells
Authors: Noortje van Gils, Tania Martiañez Canales, Eline Vermue, Arjo Rutten, Fedor Denkers, Tiem van der Deure, Gert J. Ossenkoppele, Francis Giles, Linda Smit
Journal: HemaSphere (2021)

Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.
An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer
Authors: Paula Voabil, Marjolein de Bruijn, Lisanne M. Roelofsen, Sanne H. Hendriks, Simone Brokamp, Marlous van den Braber, Annegien Broeks, Joyce Sanders, Petra Herzig, Alfred Zippelius, Christian U. Blank, Koen J. Hartemink, Kim Monkhorst, John B.A.G. Haanen, Ton N. Schumacher, Daniela S. Thommen
Journal: Nature Medicine (2021)
Abstract LB140: CNS penetrant, irreversible inhibitors potently inhibit the family of allosteric oncogenic EGFR mutants expressed in GBM and demonstrate efficacy in patient-derived xenograft models
Authors: Matthew O'Connor, Matt Lucas, Darlene Romashko, Sara Rasmussen, Tai-An Lin, Nigel Waters, Raffaele Fiorenza, Iwona Wrona, Deborah Chen, Theodore Nicolaides, David R. Raleigh, Tomoko Ozawa, George Trainor, Luca Arista, Alexander Flohr, Giorgio Ottaviani, Chris Roberts, Elizabeth Buck
Journal: Cancer Research (2021)

Abstract Oncogenic EGFR mutations occur in approximately 50% of glioblastomas (GBM) and largely reside in the extracellular domain. Prior attempts to reposition current generation EGFR inhibitors to treat GBM likely failed due to poor brain penetration and an inability to potently target the full spectrum of oncogenic mutations. As EGFR oncogenic mutations are found to be co-expressed in many GBMs, it is important that an inhibitor be broadly active against the entire family of relevant EGFR mutants. Additionally, a successful inhibitor would require a pharmacokinetic (PK) profile that allows for sufficient penetration of the blood brain barrier to elicit robust target engagement of the brain tumor. Using these design principles, we designed a series of highly potent molecules exemplified by BDTX-507. This molecule is an irreversible inhibitor of EGFR with antiproliferative IC50's less than 10 nM against the spectrum of GBM-relevant EGFR mutations. PK/PD studies demonstrated sustained pERK suppression exceeding 24 hours following a single QD dose. Furthermore, when dosed in GBM xenografts, including an intracranial Viii PDX (GBM6), robust tumor regressions and improved survival were observed. Emerging from this series were two advanced compounds, BDTX-700 and BDTX-1535, which also demonstrated potent inhibition of the GBM EGFR spectrum, selectivity v. wild-type EGFR, and an excellent CNS PK profile. BDTX-1535 is currently being evaluated in IND-enabling studies for future clinical evaluation in GBM patients. Citation Format: Matthew O'Connor, Matt Lucas, Darlene Romashko, Sara Rasmussen, Tai-An Lin, Nigel Waters, Raffaele Fiorenza, Iwona Wrona, Deborah Chen, Theodore Nicolaides, David R. Raleigh, Tomoko Ozawa, George Trainor, Luca Arista, Alexander Flohr, Giorgio Ottaviani, Chris Roberts, Elizabeth Buck. CNS penetrant, irreversible inhibitors potently inhibit the family of allosteric oncogenic EGFR mutants expressed in GBM and demonstrate efficacy in patient-derived xenograft 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 LB140.
Abstract 2451: A novel single domain antibody targeting TIGIT for cancer use in combination therapies
Authors: Botong Hua, Ming Yang, Jie Xue, Chen Dong, Yi-Ting Mao, Ou Li, Eric Cheung, Hassan Issafras, Wenfeng Xu, Weidong Jiang
Journal: Cancer Research (2021)

Abstract T-cell immunoglobulin and ITIM domains (TIGIT) has emerged as another popular checkpoint receptor that negatively regulates T-cell functions. TIGIT is upregulated by immune cells, such as activated T cells, natural killer cells, and regulatory T cells. TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment. Beyond CTLA4 and PD1, TIGIT therapies recently demonstrated great combo potential in the clinic along with well-tolerated toxicity profile. Here we present HLX53, a novel single domain antibody (sdAb) targeting TIGIT with differentiated format, binding epitope, and functional activity. HLX53 binds to TIGIT and blocks CD155 and CD112 with sub-nanomolar affinity. In mixed lymphocyte reaction assay (MLR), HLX53 significantly increased IL2 secretion compared to Tiragolumab and Vibostolimab analogues. HLX53's IL2 induction seems to require an adequate bridging effect between T-cell and antigen-presenting cell via Fc-FcγR engagement, further promoting the maturation of antigen-specific T-cell. In vivo, HLX53 exhibits a better tumor inhibition than Tiragolumab analogue and shows synergy in combination with anti-PD-L1 antibody in MC38 model. In addition to its unique epitope/MOA, HLX53 being a sdAb has a shorter half-life and thus potentially a better tumor penetration and a differentiated PK/PD profile. Understanding pharmacokinetic and pharmacodynamic relationships enables a dosing regimen providing adequate target coverage and superior tumor eradication. Citation Format: Botong Hua, Ming Yang, Jie Xue, Chen Dong, Yi-Ting Mao, Ou Li, Eric Cheung, Hassan Issafras, Wenfeng Xu, Weidong Jiang. A novel single domain antibody targeting TIGIT for cancer use in combination therapies [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 2451.
Integrated Phosphoproteomic and N-Glycoproteomic Landscape of Cutaneous T-Cell Lymphoma Reveals Distinctive Pathogenetic Insights and Therapeutic Vulnerabilities
Authors: John Simon Van Arnam, Delphine C. M. Rolland, Kojo S. J. Elenitoba-Johnson, Megan S. Lim, Özlem Önder, Nathanael G. Bailey, David Bahler
Journal: Blood (2017)
Using machine learning models to predict antimicrobial resistance and assist urologists in decision-making regarding empirical antibiotic treatment
Authors: L. Tzelves, G. Feretzakis, E. Loupelis, D. Kalles, P. Mourmouris, I. Manolitsis, A. Pinitas, M. Zerva, N. Chatzikractis, K. Tsirkas, M. Berdempes, M. Martsoukou, N. Skarmoutsou, E. Milona, D. Adamou, A. Velentza, S. Petropoulou, I. Mitsogiannis, A. Papatsoris, C. Deliveliotis, I. Varkarakis, A. Skolarikos
Journal: European Urology (2021)
Distinct projections from the infralimbic cortex exert opposing effects in modulating anxiety and fear
Authors: Yi-Hua Chen, Jian-Lin Wu, Neng-Yuan Hu, Jia-Pai Zhuang, Wei-Peng Li, Sheng-Rong Zhang, Xiao-Wen Li, Jian-Ming Yang, Tian-Ming Gao
Journal: Journal of Clinical Investigation (2021)

Anxiety-related disorders can be treated by cognitive therapies and transcranial magnetic stimulation, which involve the medial prefrontal cortex (mPFC). Subregions of the mPFC have been implicated in mediating different and even opposite roles in anxiety-related behaviors. However, precise causal targets of these top-down connections among diverse possibilities have not been established. Here, we show that the lateral septum (LS) and the central nucleus of the amygdala (CeA) represent 2 direct targets of the infralimbic cortex (IL), a subregion of the mPFC that modulates anxiety and fear. Two projections were unexpectedly found to exert opposite effects on the anxious state and learned freezing: the IL-LS projection promoted anxiety-related behaviors and fear-related freezing, whereas the IL-CeA projection exerted anxiolytic and fear-releasing effects for the same features. Furthermore, selective inhibition of corresponding circuit elements showed opposing behavioral effects compared with excitation. Notably, the IL-CeA projection implemented top-down control of the stress-induced high-anxiety state. These results suggest that distinct IL outputs exert opposite effects in modulating anxiety and fear and that modulating the excitability of these projections with distinct strategies may be beneficial for the treatment of anxiety disorders.
Pharmacologic Activation of p53 Triggers Viral Mimicry Response Thereby Abolishing Tumor Immune Evasion and Promoting Antitumor Immunity
Authors: Xiaolei Zhou, Madhurendra Singh, Gema Sanz Santos, Vincent Guerlavais, Luis A. Carvajal, Manuel Aivado, Yue Zhan, Mariana M.S. Oliveira, Lisa S. Westerberg, D. Allen Annis, John Inge Johnsen, Galina Selivanova
Journal: Cancer Discovery (2021)

The repression of repetitive elements is an important facet of p53's function as a guardian of the genome. Paradoxically, we found that p53 activated by MDM2 inhibitors induced the expression of endogenous retroviruses (ERV) via increased occupancy on ERV promoters and inhibition of two major ERV repressors, histone demethylase LSD1 and DNA methyltransferase DNMT1. Double-stranded RNA stress caused by ERVs triggered type I/III interferon expression and antigen processing and presentation. Pharmacologic activation of p53 in vivo unleashed the IFN program, promoted T-cell infiltration, and significantly enhanced the efficacy of checkpoint therapy in an allograft tumor model. Furthermore, the MDM2 inhibitor ALRN-6924 induced a viral mimicry pathway and tumor inflammation signature genes in patients with melanoma. Our results identify ERV expression as the central mechanism whereby p53 induction overcomes tumor immune evasion and transforms tumor microenvironment to a favorable phenotype, providing a rationale for the synergy of MDM2 inhibitors and immunotherapy. We found that p53 activated by MDM2 inhibitors induced the expression of ERVs, in part via epigenetic factors LSD1 and DNMT1. Induction of IFN response caused by ERV derepression upon p53-targeting therapies provides a possibility to overcome resistance to immune checkpoint blockade and potentially transform "cold" tumors into "hot." This article is highlighted in the In This Issue feature, p. 2945.
ヒト化抗アミノアシル-tRNAシンテターゼ相互作用多機能蛋白質-1(AIMP1)抗体,アチアリズマブは(NZB/NZW)F1マウスにおける腎炎を有意に改善する【JST・京大機械翻訳】
Authors: Mun Chin Hee, Kim Jin-Ock, Ahn Sung Soo, Yoon Taejun, Kim Su Jeong, Ko Eunhee, Noh Hee-Dong, Park Yong-Beom, Jung Hak-Jun, Kim Tae Sung, Lee Sang-Won, Park Sang Gyu
Journal: Biomaterials (2019)
Potential modulatory mechanisms of action by long-chain polyunsaturated fatty acids on bone cell and chondrocyte metabolism
Authors: Maryam Abshirini, Bolaji Lilian Ilesanmi-Oyelere, Marlena C. Kruger
Journal: Progress in Lipid Research (2021)

Long-chain polyunsaturated fatty acids (LCPUFAs) and their metabolites are considered essential factors to support bone and joint health. The n-6 PUFAs suppress the osteoblasts differentiation via increasing peroxisome proliferator-activated receptor gamma (PPARγ) expression and promoting adipogenesis while n-3 PUFAs promote osteoblastogenesis by down-regulating PPARγ and enhancing osteoblastic activity. Arachidonic acid (AA) and its metabolite prostaglandin E2 (PGE2) are key regulators of osteoclast differentiation via induction of the receptor activator of nuclear factor kappa-Β ligand (RANKL) pathway. Marine-derived n-3 LCPUFAs have been shown to inhibit osteoclastogenesis by decreasing the osteoprotegerin (OPG)/RANKL signalling pathway mediated by a reduction of pro-inflammatory PGE2 derived from AA. Omega-3 PUFAs reduce the expression of cartilage degrading enzyme matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloprotease with thrombospondin motifs-5 (ADAMTS-5) protein, oxidative stress and thereby apoptosis via nuclear factor kappa-betta (NF-kβ) and inducible nitric oxide synthase (iNOS) pathways. In this review, a diverse range of important effects of LCPUFAs on bone cells and chondrocyte was highlighted through different mechanisms of action established by cell cultures and animal studies. This review allows a better understanding of the possible role of LCPUFAs in bone and chondrocyte metabolism as potential therapeutics in combating the pathological complications such as osteoporosis and osteoarthritis.
Abstract 1221: The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications
Authors: Jacob J. Adashek, Alexander Andreev-Drakhlin, Jason Roszik, Aakash P. Desai, Vivek Subbiah
Journal: Cancer Research (2021)

Abstract Background: Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions have been recognized as potent drivers of oncogenesis in multiple malignancies. Recently, highly potent and selective RET inhibitors, selpercatinib and pralsetinib have been FDA approved for RET fusion+ NSCLC and selpercatinib for RET+ thyroid cancers. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Patients and methods: 96,324 samples from 89,754 patients available from AACR Project Genie database version 8 were analyzed for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types accessed July 21, 2020. The races of the samples within the cohort were 69,962 (72.6%) white, 5,388 (5.6%) Black, 4,909 (5.1%) Asian, 163 (0.17%) Native American, 48 (0.05%) Pacific Islander, and 15,854 (16.5%) were unknown. Results: There were 56,382 (58.5%) samples from primary tumors, 24,204 (25.1%) samples from unspecified metastasis sites, 4,798 (5.0%) from distant organ metastasis, 1,379 (1.4%) from lymph node metastasis, 1,279 (1.3%) from local recurrence, and 8,282 (8.6%) unknown. In 96,324 tumor samples there were 2,706 (2.81%) RET alterations. This included 223 (0.23%) fusions, 1,689 RET mutations found (1.75%) in 21 tumor histologies, and 794 (0.82%) RET amplifications identified; where the most abundant tissues harboring RET fusions were NSCLC (n = 121), papillary thyroid cancer (n = 53), breast cancer (n = 8) and colorectal cancer (n = 7) and the most abundant tissues harboring RET missense mutations were NSCLC (n = 355), colorectal cancer (n = 292), melanoma (n = 236), and thyroid cancer (n = 127). NSCLC samples with RET fusions had significantly co-altered KRAS, SETD2, PVRL4, EZH1, and RRAGC. Conclusions: RET fusions represent extremely rate events in multiple cancers. RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted because RET is highly targetable with therapeutics. Citation Format: Jacob J. Adashek, Alexander Andreev-Drakhlin, Jason Roszik, Aakash P. Desai, Vivek Subbiah. The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications [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 1221.
Substratification of Patients with Newly Diagnosed Standard-Risk Multiple Myeloma
Authors: Moritz Binder, S. Vincent Rajkumar, Rhett P. Ketterling, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K Buadi, Suzanne R. Hayman, Yi L. Hwa, Steven R. Zeldenrust, John A Lust, Stephen J. Russell, Nelson Leung, Prashant Kapoor, Ronald S. Go, Wilson I Gonsalves, Robert A. Kyle, Shaji K. Kumar
Journal: Blood (2017)