tbuckley/cabot-search huggingface dataset:
Comparative immunogenicity of decellularized wild type and alpha 1,3 galactosyltransferase knockout pig lungs
Authors: Nathan Gasek, Jacob Dearborn, Sara Rolandsson Enes, Robert Pouliot, Jessica Louie, Zachary Phillips, Sean Wrenn, Franziska E. Uhl, Alexander Riveron, John Bianchi, Scott P. Commins, Nicole Delance, Douglas J. Taatjes, Jonathan E. Boyson, Kelly Guthrie, Thomas H. Petersen, Daniel J. Weiss
Journal: Biomaterials (2021)
Abstract 1516: Inclusion of a Dap10 costimulatory domain enhances anti-tumor efficacy of chimeric PD1-expressing T cells in multiple types of solid tumors
Authors: Amorette E. Barber
Journal: Cancer Research (2021)

Abstract Adoptive transfer of T cells is a promising anti-tumor therapy for many cancers. To enhance tumor recognition by T cells, chimeric antigen receptors (CAR) consisting of signaling domains fused to receptors that recognize tumor antigens can be expressed in T cells. One receptor that is a prospective target for a new chimeric antigen receptor is PD1 because the ligands for the PD1 receptor are expressed on many cancer types. Therefore, we developed a murine chimeric PD1 receptor (chPD1) consisting of the PD1 receptor extracellular domain and the activation domain of CD3 zeta. In addition, current chimeric antigen receptor therapies utilize various costimulatory domains to enhance anti-tumor efficacy. Therefore, we also compared the inclusion of CD28, Dap10, 4-1BB, GITR, ICOS, or OX40 costimulatory domains in the chPD1 receptor to determine which costimulatory domain induced optimal anti-tumor immunity. To determine if this novel CAR could potentially target a wide variety of tumors, the anti-tumor efficacy of chPD1 T cells against murine lymphoma, melanoma, kidney, pancreatic, liver, colon, breast, ovarian, prostate, and bladder cancer cell lines was measured. Of the eighteen cell lines tested, all expressed PD1 ligands on their cell surface, making them potential targets for chPD1 T cells. Regardless of the costimulatory domain in the CAR, all of the chPD1 T cells induced similar levels of T cell proliferation and tumor cell lysis. However, differences were observed in the cytokine secretion profiles depending on which costimulatory receptor was included in the CAR. While most of the chPD1 T cell receptor combinations secreted both pro-inflammatory (IFNγ, TNFα, IL-2, GM-CSF, IL-17, and IL-21) and anti-inflammatory cytokines (IL-10), chPD1 T cells containing a Dap10 costimulatory domain secreted high levels of proinflammatory cytokines but did not secrete a significant amount of anti-inflammatory cytokines. Furthermore, T cells expressing chPD1 receptors with a Dap10 domain also had the strongest anti-tumor efficacy in vivo. ChPD1 T cells did not survive for longer than 14 days in vivo, however treatment with chPD1 T cells induced long-lived protective host-anti-tumor immune responses in tumor-bearing mice. Therefore, adoptive transfer of chPD1 T cells could be a novel therapeutic strategy to treat multiple types of cancer and inclusion of the Dap10 costimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile for anti-tumor therapies. Citation Format: Amorette E. Barber. Inclusion of a Dap10 costimulatory domain enhances anti-tumor efficacy of chimeric PD1-expressing T cells in multiple types of solid tumors [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 1516.
Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes
Authors: Farsad Afshinnia, Thekkelnaycke M. Rajendiran, Chenchen He, Jaeman Byun, Daniel Montemayor, Manjula Darshi, Jana Tumova, Jiwan Kim, Christine P. Limonte, Rachel G. Miller, Tina Costacou, Trevor J. Orchard, Tarunveer S. Ahluwalia, Peter Rossing, Janet K. Snell-Bergeon, Ian H. de Boer, Loki Natarajan, George Michailidis, Kumar Sharma, Subramaniam Pennathur
Journal: Diabetes Care (2021)

OBJECTIVES Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. RESEARCH DESIGN AND METHODS In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as &amp;gt;3 mL/min/1.73 m2 per year decline in estimated glomerular filtration rate (eGFR), while control was defined as &amp;lt;1 mL/min/1.73 m2 per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. RESULTS At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m2. A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 (P = 0.039). Observations were confirmed in the validation subset. CONCLUSIONS Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids’ glycerol backbone as an independent predictor of rapid GFR decline in T1D.
Normothermic regional perfusion vs. super-rapid retrieval in controlled donation after circulatory death: Different outcomes in kidney transplantation?
Authors: R. Chaves Marcos, B.T. Antón Eguía, A. Cuevas Palomino, M.D.L. Parra Lopez, P. Rodriguez Marcos, Z. Ruiz De Azúa-Lopez, E. Leon Dueñas, R.A. Medina Lopez
Journal: European Urology (2021)
Abstract LB101: Mechanism of the growth inhibitory effect of pemetrexed disodium heptahydrate in human PC9 cells (EGFR exon 19 deletion)
Authors: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara
Journal: Cancer Research (2021)

Abstract Background: Pemetrexed disodium heptahydrate (pemetrexed) in combination with another drug, is recommended for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). However, the mechanisms of its anticancer activities have not yet been analyzed. We examined the in vitro effects of pemetrexed and further elucidated a potential underlying molecular mechanism.Methods: PC9 cells were treated with pemetrexed and then evaluated with a cell viability assay, Giemsa staining, DAPI staining, flow cytometry (FCM), SA-β-Gal staining, and Western blotting.Results: We found that pemetrexed reduced the proliferation of PC9 cells. The cells treated with pemetrexed showed morphological signs of apoptosis. The apoptotic effect of pemetrexed was related to the generation of ROS and the loss of mitochondrial membrane potential. A cell cycle analysis showed that pemetrexed arrested PC9 cells in the G1 phase. Cellular senescence was associated with pRb hyperphosphorylation and the overexpression of CDK. Regarding the molecular mechanism of this apoptosis, pemetrexed can induce the phosphorylation of p53 at ser 15 and ser 46. Moreover, the expression of extrinsic apoptotic pathway proteins, such as Fas/FasL, DR4/TRAIL, and FADD, was elevated after pemetrexed treatment. Conclusion: In addition to apoptosis, pemetrexed can also cause specific adverse reactions, thus providing a new target for reducing lung toxicity. Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. Mechanism of the growth inhibitory effect of pemetrexed disodium heptahydrate in human PC9 cells (EGFR exon 19 deletion) [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 LB101.
Accuracy of Koelis fusion biopsy: Improved cancer detection with targeted biopsies only
Authors: M. Oderda, S. Albisinni, D. Benamran, G. Calleris, M. Ciccariello, A. Dematteis, R. Diamand, J. Descotes, G. Fiard, V. Forte, A. Giacobbe, A. Marquis, G. Marra, A. Messas, G. Muto, A. Peltier, L. Rius, G. Simone, T. Roumeguere, P. Gontero
Journal: European Urology (2021)
A cohort study on thromboembolic risk with the use of testosterone therapy in Klinefelter syndrome
Authors: F. Melling, S. Birch, A. Espehana, Y. Kailash, P. Carroll, A. El-Shirif, L. Frodsham, M. Salman, P. Allchorne, K. Briggs, M. Shabbir, R. Sandher, T. Yap
Journal: European Urology (2021)
Abstract 1726: Preclinical evaluation of a novel tumor selectively targeted and activated immunocytokine platform
Authors: Kham R. Trinh, Alex Vasuthaswat, George Ayoub, Sherie L. Morrison, David R. Stover
Journal: Cancer Research (2021)

Abstract Interferon alpha (IFNα) is a potent cytokine with receptors expressed universally on virtually all cells types. Recombinant versions of IFNα have demonstrated efficacy in multiple tumor indications and have been FDA approved for treatment of various cancers. However, the full anti-tumor potential of IFNα is not realized with these therapies due to dose limiting toxicity, primarily represented by severe flu-like symptoms resulting from systemic activation of immune cells. Antibody-cytokine fusion proteins have been evaluated as an approach to enhance tumor delivery of the cytokine and thereby increase the therapeutic window. While this approach has merit and can increase the efficacy of such constructs, it typically does not reduce the systemic toxicity since the cytokine is still free to interact with its receptor in circulation. We have designed a novel fusion protein in which the IFNα is active only after it has entered the tumor environment, thereby preventing toxicity resulting from systemic activation of IFNα receptors. Direct antitumor efficacy of an anti-CD138-IFNα2 fusion protein with a tumor selectively cleaved peptide mask was seen in models of multiple myeloma and ovarian cancer. The mask was also shown to prevent IFN mediated activation of peripheral blood cells. Citation Format: Kham R. Trinh, Alex Vasuthaswat, George Ayoub, Sherie L. Morrison, David R. Stover. Preclinical evaluation of a novel tumor selectively targeted and activated immunocytokine platform [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 1726.
Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease
Authors: Shan H. Siddiqi, Frederic L. W. V. J. Schaper, Andreas Horn, Joey Hsu, Jaya L. Padmanabhan, Amy Brodtmann, Robin F. H. Cash, Maurizio Corbetta, Ki Sueng Choi, Darin D. Dougherty, Natalia Egorova, Paul B. Fitzgerald, Mark S. George, Sophia A. Gozzi, Frederike Irmen, Andrea A. Kuhn, Kevin A. Johnson, Andrew M. Naidech, Alvaro Pascual-Leone, Thanh G. Phan, Rob P. W. Rouhl, Stephan F. Taylor, Joel L. Voss, Andrew Zalesky, Jordan H. Grafman, Helen S. Mayberg, Michael D. Fox
Journal: Nature Human Behaviour (2021)
Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines
Authors: Long Chen, Hao Qin, Ruifang Zhao, Xiao Zhao, Liangru Lin, Yang Chen, Yixuan Lin, Yao Li, Yuting Qin, Yiye Li, Shaoli Liu, Keman Cheng, Hanqing Chen, Jian Shi, Gregory J. Anderson, Yan Wu, Yuliang Zhao, Guangjun Nie
Journal: Science Translational Medicine (2021)

Cancer vaccines based on resected tumors from patients have gained great interest as an individualized cancer treatment strategy. However, eliciting a robust therapeutic effect with personalized vaccines remains a challenge because of the weak immunogenicity of autologous tumor antigens. Utilizing exogenous prokaryotic constituents that act as adjuvants to enhance immunogenicity is a promising strategy to overcome this limitation. However, nonspecific stimulation of the immune system may elicit an undesirable immunopathological state. To specifically trigger sufficient antitumor reactivity without notable adverse effects, we developed an antigen and adjuvant codelivery nanoparticle vaccine based on Escherichia coli cytoplasmic membranes (EMs) and tumor cell membranes (TMs) from resected autologous tumor tissue. Introduction of the EM into the hybrid membrane nanoparticle vaccines (HM-NPs) induced dendritic cell maturation, thus activating splenic T cells. HM-NPs showed efficacy in immunogenic CT26 colon and 4T1 breast tumor mouse models and also efficiently induced tumor regression in B16-F10 melanoma and EMT6 breast tumor mouse models. Furthermore, HM-NPs provoked a strong tumor-specific immune response, which not only extended postoperative animal survival but also conferred long-term protection (up to 3 months) against tumor rechallenge in a CT26 colon tumor mouse model. Specific depletion of different immune cell populations revealed that CD8+ T and NK cells were crucial to the vaccine-elicited tumor regression. Individualized autologous tumor antigen vaccines based on effective activation of the innate immune system by bacterial cytoplasmic membranes hold great potential for personalized treatment of postoperative patients with cancer.
Correction to: Family history assessment significantly enhances delivery of precision medicine in the genomics era
Authors: Yasmin Bylstra, Weng Khong Lim, Sylvia Kam, Koei Wan Tham, R. Ryanne Wu, Jing Xian Teo, Sonia Davila, Jyn Ling Kuan, Sock Hoai Chan, Nicolas Bertin, Cheng Xi Yang, Steve Rozen, Bin Tean Teh, Khung Keong Yeo, Stuart Alexander Cook, Saumya Shekhar Jamuar, Geoffrey S. Ginsburg, Lori A. Orlando, Patrick Tan
Journal: Genome Medicine (2021)
Abstract 275: Lack of electron acceptors contributes to redox stress and growth arrest in asparagine-starved sarcoma cells
Authors: Christoph Bauer, Meret Quante, Carla Regina, Michaela Schneider, Geoffroy Andrieux, Oliver Gorka, Olaf Groß, Melanie Boerries, Bernd Kammerer, Simone Hettmer
Journal: Cancer Research (2021)

Abstract Background. Amino acids are integral components of cancer metabolism. Adequate availability of the non-essential amino acid asparagine is necessary to support growth and survival of various cancer cell types, including sarcoma cells. Methods. Different mass spectrometry approaches were employed to determine changes in the metabolome of asparagine-deprived mouse and human sarcoma cells, which may be responsible for arrested growth and apoptosis due to asparagine depletion. Results. Lower aspartate levels, higher aspartate/glutamine ratios and lower levels of tricarboxylic acid (TCA) cycle metabolites in asparagine-deprived sarcoma cells indicated a redirection of TCA cycle flux and were accompanied by reduced NAD+/NADH ratios, consistent with relative deficiency of electron acceptors in asparagine-starved cells. Elevated lactate/pyruvate ratios may be due to compensatory regeneration of NAD+ through increased pyruvate to lactate conversion by lactate dehydrogenase in asparagine-deprived cells. Supplementation with exogenous pyruvate, which was previously shown to serve as electron acceptor in cells challenged by reductive stress, restored aspartate levels, NAD+/NADH ratios, lactate/pyruvate ratios and cell growth in asparagine-deprived cells. Treatment with chemicals disrupting regeneration of NAD+ in the electron transport chain (e.g. metformin) further enhanced the anti-proliferative and pro-apoptotic effects of asparagine depletion. Conclusions. We conclude that asparagine deprivation, through metabolic reprogramming, causes reductive stress, which, in turn, results in lower aspartate levels in asparagine-starved cells. These changes are major contributors to the growth arrest observed in asparagine-starved cells. Future studies are needed to further elucidate the cellular processes that contribute to lack of electron acceptors in asparagine-starved tumor cells. Citation Format: Christoph Bauer, Meret Quante, Carla Regina, Michaela Schneider, Geoffroy Andrieux, Oliver Gorka, Olaf Groß, Melanie Boerries, Bernd Kammerer, Simone Hettmer. Lack of electron acceptors contributes to redox stress and growth arrest in asparagine-starved sarcoma 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 275.
Abstract LB176: Anti-4-1BB x PD-1, a bispecific anti-cancer therapeutics
Authors: Byoung S. Kwon, Hanna Lee, Jin Sung Park, Yeonji Oh, SeungHee Han, Jin Kyung Choi, Bora Hwang, Sun Woo Im, Seunghyun Lee, HoonSung Jeh
Journal: Cancer Research (2021)

Abstract 4-1BB and PD-1 are both T cell costimulatory receptors/immune checkpoint regulators. 4-1BB/4-1BBL provides stimulatory signals while PD-1/PD-L1, suppressive ones to T lymphocytes. Various forms of agonists to 4-1BB or blockers to PD-1 have shown a potent anti-cancer activity by modulating mainly CD8+ T cells. Thus, synergistic or additive anti-cancer effect may be achieved by combining the agonists to 4-1BB and blockers to PD-1. We have tested various combinations of antibodies and proteins with consideration of overall size of the therapeutic candidates. The best anti-cancer activities were obtained by combination of an agonistic anti-4-1BB antibody and soluble PD-1 that binds to PD-L1 with high affinity. To obtain molecularly-evolved PD-1 we first used the 3D complex between PD-1 and PD-L1 to select the major contributing PD-1 amino acids, a library targeting selected amino acids and random mutations were constructed and screened using yeast surface display. The affinity-matured resulting PD-1 is called euPD-1. We finally constructed EU505 that composed of a scFv of anti-4-1BB and euPD-1. Through cell binding and dual antigen assays, we confirmed that EU505 binds both targets independently at the same time. The result of 4-1BB bioassays, a biologically relevant MOA-based assay, showed that potent PD-L1-dependent T cell activation with EU505. In-vitro killing assays showed that EU505 selectively activated T cells which in turn killed high PD-L1-expressing cells, but not low-PD-L1-expressing ones. EU505 demonstrated much stronger tumor-killing effect compared with each component alone when we tested against human PD-L1-expressing tumor cells in a 4-1BB Knock-in mouse model. Furthermore, it was observed that number of effector CD8+ T cells increased in the peripheral blood upon EU505 injection and consequently tumor size was reduced. EU505, a promising anti-cancer drug, appears to enhance CD8+ T cell infiltration and activate T cells in situ at the tumor sites by binding two different targets of 4-1BB and PD-L1 simultaneously. Citation Format: Byoung S. Kwon, Hanna Lee, Jin Sung Park, Yeonji Oh, SeungHee Han, Jin Kyung Choi, Bora Hwang, Sun Woo Im, Seunghyun Lee, HoonSung Jeh. Anti-4-1BB x PD-1, a bispecific anti-cancer therapeutics [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 LB176.
RETRACTION: Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial
Authors: Xiaofei Zhu, Yangsen Cao, Wenyu Liu, Xiaoping Ju, Xianzhi Zhao, Lingong Jiang, Yusheng Ye, Gang Jin, Huojun Zhang
Journal: The Lancet Oncology (2021)
Abstract 2299: An unbiased in vivo screen for activating EGFR mutations
Authors: Deepankar Chakroborty, Kari J. Kurppa, Klaus Elenius
Journal: Cancer Research (2021)

Abstract Cancer tissues harbor thousands of mutations, and a given oncogene may be mutated at hundreds of sites across different samples. Most of these somatic mutations are expected to be inconsequential passenger mutations that reflect the general instability of the tumors. The discovery of most of the currently known driver mutations has been facilitated by their accumulation in mutation hot-spots within their respective genes. However, a vast majority of mutations in cancer tissues are rare and their functional significance remains unknown. Several lines of in vitro and clinical evidence also indicate that there is a significant number of, as yet unidentified, activating driver mutations which could serve as predictive markers in oncology. We are developing our in vitro Screen for Activating Mutations (“iSCREAM”)[1] further and advancing it to better recapitulate natural intratumor heterogeneity by taking the system in vivo. To establish the in vivo model for screening activating mutations we utilize the SALE-Y cells which are immortalized human small airway epithelial cells harboring an activating YAP1 variant[2]. In immunocompromised mice, SALE-Y cells fail to form tumors up to 120 days, but they become tumorigenic after transduction of mutations activating the EGFR-MAPK signaling pathway[2]. We will use the SALE-Y cell background for transduction of an expression library encoding thousands of different randomly mutated variants of the kinase to be tested. EGFR will be used to set up the model because: i) EGFR mutants are known to of transforming the SALE-Y cells[2] and ii) we have previously used EGFR as a model to set up the in vitro screen[1]. The SALE-Y expressing the random collection of EGFR variants will be inoculated subcutaneously into immunocompromised mice, and the activating mutations will be given an opportunity to outcompete passenger mutations during subsequent expansion and suvival of the xenograft. Genomic DNA will be harvested from the tumor tissue and subjected to targeted next-generation sequencing allowing unbiased identification of enriched activating mutations promoting tumor growth. References:1. Chakroborty D, Kurppa KJ, Paatero I, Ojala VK, Koivu M, Tamirat MZ, et al. An unbiased in vitro screen for activating epidermal growth factor receptor mutations. J Biol Chem. 2019.2. Berger AH, Brooks AN, Wu X, Shrestha Y, Chouinard C, Piccioni F, et al. High-throughput Phenotyping of Lung Cancer Somatic Mutations. Cancer Cell. 2015. Citation Format: Deepankar Chakroborty, Kari J. Kurppa, Klaus Elenius. An unbiased in vivo screen for activating EGFR mutations [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 2299.