tbuckley/cabot-search huggingface dataset:
Abstract 1542: A FasL-targeted immunomodulatory fusion protein replaces a pro-death with a costimulatory signal, enhancing T cell function, adoptive cell therapy, and altering the tumor microenvironment
Authors: Margot McMurray, Shannon Oda
Journal: Cancer Research (2021)

Abstract Improved therapies are urgently needed for several cancers, including acute myeloid leukemia (AML) and pancreatic cancers. Adoptive cell therapy (ACT) with genetically-modified T cells has shown impressive results against B cell malignancies, but limited efficacy in other hematologic and solid tumors. To address this need, we have developed immunomodulatory fusion proteins (IFPs) that combine the ectodomain of an inhibitory receptor with a costimulatory endodomain, providing positive signals exclusively delivered to the T cells concurrently engineered to target tumor-expressed antigens, avoiding the systemic T cell activation seen with immune checkpoint-blocking therapies. We developed an IFP to target Fas ligand (FasL), which is commonly over-expressed in TMEs and induces apoptosis in tumor-infiltrating T cells. We replaced the Fas intracellular tail with the costimulatory, pro-survival 4-1BB signaling domain since both Fas and 4-1BB signal as trimers. After exposure to a murine AML cell line, IFP-transduced murine T cells effectively generated 4-1BB signaling, with metabolic reprogramming, and showed enhanced in vitro proliferation, accumulation and function. IFP T cells resisted exhaustion and effectively eradicated AML, improving survival to 71% in the FBL disseminated AML murine model (vs.11% survival with control T cells). We next engineered T cells with a single-vector that combined the IFP with a tumor-targeted mesothelin-targeted T cell receptor (TCR), for studies with the KPC mouse model of PDA that recapitulates the immunosuppressive characteristics of human disease. TCR/Fas-4-1BB T cells showed increased intratumoral concentration over control TCR-only T cells and increased median survival (65 vs. 37 days, P=0.0042). Human TCR/Fas-4-1BB T cells induced significantly more PDA tumor cell lysis than a dominant negative Fas receptor, supporting the increased benefit of the costimulatory signal. Single-cell RNA sequencing results suggest that IFP-ACT can also improve endogenous antitumor immunity, and Fas-4-1BB primary human T cells showed increased in vitro expansion and cytokine production, relative to TCR-only human T cells. We have now developed a toolbox of IFPs with distinct costimulatory domains and we show that IFPs can substantially improve therapeutic efficacy against liquid and solid tumors, supporting clinical translation. Citation Format: Margot McMurray, Shannon Oda. A FasL-targeted immunomodulatory fusion protein replaces a pro-death with a costimulatory signal, enhancing T cell function, adoptive cell therapy, and altering the tumor microenvironment [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 1542.
Gabファミリー足場アダプター蛋白質は、ニューレグリン-1/ErbBシグナリングを介して、心機能の出産後の保守にとって重要
Authors: Nakaoka Y, Kamiya A, Minami T, Sawa H, Fujio Y, Koyama T, Hirota H, Yamauchi-Takihara K, Otsu K, Hori M, Hirano T, Mochizuki N
Journal: Circulation (2007)
Urological surgery remained safe during the second wave of SARS-CoV-2 pandemic in a high incidence area
Authors: A. González Díaz, R. Santos-Pérez De La Blanca, J. Gil-Moradillo, C. Calzas-Montalvo, M.D.P. Caro-González, S. Juste-Álvarez, A. De La Calle-Moreno, P. Abad-López, E. Peña-Vallejo, N.R. Miranda-Utrera, N. Rosillo-Ramírez, A.M. Brandini-Romersi, C. Varela-Rodríguez, A. Rodríguez-Antolín, Á. Tejido-Sánchez
Journal: European Urology (2021)
A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab
Authors: Prasad S. Adusumilli, Marjorie G. Zauderer, Isabelle Rivière, Stephen B. Solomon, Valerie W. Rusch, Roisin E. O'Cearbhaill, Amy Zhu, Waseem Cheema, Navin K. Chintala, Elizabeth Halton, John Pineda, Rocio Perez-Johnston, Kay See Tan, Bobby Daly, Jose A. Araujo Filho, Daniel Ngai, Erin McGee, Alain Vincent, Claudia Diamonte, Jennifer L. Sauter, Shanu Modi, Devanjan Sikder, Brigitte Senechal, Xiuyan Wang, William D. Travis, Mithat Gönen, Charles M. Rudin, Renier J. Brentjens, David R. Jones, Michel Sadelain
Journal: Cancer Discovery (2021)

Abstract Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for &amp;gt;100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors. Significance: Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors. See related commentary by Aldea et al., p. 2674. This article is highlighted in the In This Issue feature, p. 2659
Nutritional basis of type 2 diabetes remission
Authors: Roy Taylor, Ambady Ramachandran, William S Yancy, Nita G Forouhi
Journal: BMJ (2021)

There is still a substantial knowledge gap on how gender mediates child health in general, and child immunisation outcomes in particular. Similarly, implementation of interventions to mitigate gender inequities that hinder children from being vaccinated requires additional perspectives and research. We adopt an intersectional approach to gender and delve into the social ecology of implementation, to show how gender inequities and their connection with immunisation are grounded in the interplay between individual, household, community and system factors. We show how an ecological model can be used as an overarching framework to support more precise identification of the mechanisms causing gender inequity and their structural complexity, to identify suitable change agents and interventions that target the underlying causes of marginalisation, and to ensure outcomes are relevant within specific population groups.
Abstract 2390: LncRNA PAINT promotes prostate cancer progression through modulation of genes involved in epithelial-mesenchymal transition and apoptosis
Authors: Kavya Ganapathy, Md Faqrul Hasan, Jiao Sun, Ayman Khatib, Thomas Andl, Julia Soulakova, Domenico Coppola, Wei Zhang, Ratna Chakrabarti
Journal: Cancer Research (2021)

Abstract Long non-coding RNAs (LncRNAs) play regulatory roles in cellular processes and their aberrant expression may drive cancer progression. Here we report the function of a LncRNA PAINT (Prostate Cancer-Associated Intergenic Non-Coding Transcript) in promoting prostate cancer (PCa) progression. Upregulation of PAINT expression was noted in the advanced stage and metastatic PCa patient tissues and correlated with poor survival. Inhibition of PAINT decreased cell proliferation, S-phase progression, increased expression of apoptotic markers, and improved sensitivity to docetaxel and Aurora kinase inhibitor VX-680. Inhibition of PAINT also decreased cell migration and reduced expression of mesenchymal markers, Slug, and Vimentin. Ectopic expression of PAINT suppressed E-cadherin, increased S-phase progression, and cell migration. PAINT expression in PCa cells also induced larger colony formation and higher expression of mesenchymal markers. Transcriptome profiling of PCa cells overexpressing PAINT showed differential expression of genes involved in epithelial-mesenchymal transition (EMT), apoptosis, and drug resistance which were further validated by qRT-PCR analysis. Additionally, GO enrichment and KEGG pathway analysis revealed altered expression of multiple pathways including p53 signaling and drug metabolism pathways indicating that PAINT may promote an oncogenic environment by simultaneously regulating various biological processes in PCa. In summary, our findings establish the role of PAINT as an oncogene in PCa and indicate the clinical significance of PAINT as a diagnostic marker and a possible therapeutic target for aggressive PCa. Citation Format: Kavya Ganapathy, Md Faqrul Hasan, Jiao Sun, Ayman Khatib, Thomas Andl, Julia Soulakova, Domenico Coppola, Wei Zhang, Ratna Chakrabarti. LncRNA PAINT promotes prostate cancer progression through modulation of genes involved in epithelial-mesenchymal transition and apoptosis [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 2390.
Abstract 965: The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis
Authors: Xiang Chen, John M. Hicks, Poonam Sarkar, Waleed M. Gaber, Tsz-Kwong MAN
Journal: Cancer Research (2021)

Abstract Despite the use of chemotherapy and surgery, the development of metastasis remains to be the leading cause of death in patients with osteosarcoma. LOX encodes for lysyl oxidase, which is an enigmatic molecule in cancer by acting as a tumor suppressor in certain tumors, but a metastatic promoter in other tumors. To investigate the function of LOX, we generated LOX overexpression mutants in two osteosarcoma cell lines and showed that higher LOX expression promoted tumor cell proliferation and invasiveness. Using an orthotopic xenograft mouse model, we further showed that osteosarcoma cells with higher LOX expression produced a higher number of mice with pulmonary metastases than the parental cell line (n=9). To characterize the mechanism of LOX-mediated metastasis, we examined the protein expression of a panel of potential downstream targets. The results demonstrated that phospho-FAK (focal adhesion kinase) expression was increased in the LOX-overexpression mutant relative to the parental cell line. Using a small molecule inhibitor of FAK, we showed that it significantly reduced the LOX-mediated metastasis in the orthotopic xenograft model. To demonstrate the clinical significance of our findings, we analyzed the expression profiling and RNAseq datasets recently generated from the TARGET osteosarcoma study. A Kaplan-Meier analysis showed that a higher level of LOX expression significantly correlated with a poor outcome (p &amp;lt; 0.05) and a multivariate analysis indicated LOX remained to be significant after controlling for initial metastatic status. In addition, we have previously shown that p27 is frequently mislocalized in the cytoplasm of osteosarcoma cells and drives the development of metastasis through interacting with the PAK1-mediated actin cytoskeleton network. Our results showed that the expression of LOX was upregulated in p27-mislocalized osteosarcoma cell lines with high metastatic potential. A tissue microarray analysis showed that cytoplasmic p27 expression significantly correlated with LOX expression (p = 0.003). Together, our findings suggest that a novel link between p27 mislocalization and LOX expression. LOX plays a pivotal role in osteosarcoma metastasis by upregulating FAK phosphorylation. FAK inhibition is a potential therapeutic strategy to reduce the development of metastasis in osteosarcoma with LOX overexpression. Citation Format: Xiang Chen, John M. Hicks, Poonam Sarkar, Waleed M. Gaber, Tsz-Kwong MAN. The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis [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 965.
P-58 Encorafenib and cetuximab in patients with metastatic, BRAF V600E-mutated, colorectal carcinoma: A multi-centric, multi-national, prospective, longitudinal, non-interventional study in Germany and Austria – BERING CRC
Authors: S. Stintzing, G. Hübner, J. Schröder, J. Kisro, M. Welslau, D. Bürkle, T. Göhler, B. Schmidt, H. Müller-Huesmann, B. Krammer-Steiner, E. von der Heyde, F. Reichenbach, D. Arnold, A. Gerger, S. Hegewisch-Becker, A. Vogel, T. Winder, G. Prager
Journal: Annals of Oncology (2021)
Abstract 1941: The regulation of ATG9A-mediated autophagy by an ULK1-independent ATG13 complex
Authors: Daniel Poole, Ashari Kananngara, Vajira Weerasekara, Colten McEwan, Alexandra Thornock, Misael Lazaro, Joshua Youngs, Joshua Andersen
Journal: Cancer Research (2021)

Abstract Cancer cells rely on autophagy for survival during periods of nutrient stress or chemotherapy. The activation of autophagy in cancer is thought to be regulated by AMPK-dependent activation of the ULK1 complex, consisting of FIP200, ATG13, ATG101, and ULK1. However, the regulation and dynamic cooperation of these proteins to govern autophagy is not completely understood. Our preliminary data suggest that ATG13 and ATG101 exist in an ULK1-independent complex that plays a key role in the regulation of autophagy. In an effort to identify the function of this ULK1-independent ATG13 complex, we discovered that an ULK1 binding-deficient mutant of ATG13 interacts with ATG9A, an apical regulator of autophagy. Using a split-venus approach coupled with confocal imaging, we found that ATG13, ATG101 and ATG9A interact together at sites of autophagosome assembly. This interaction between ATG13 and ATG9A is unaffected by deletion of ULK1 or the canonical ULK1 complex protein, FIP200. Furthermore, we found that CRISPR/Cas9-mediated deletion of ATG13 led to an aberrant accumulation of ATG9A puncta that colocalize with p62/SQSTM1. Importantly, this accumulation of ATG9A in ATG13 KO cells was rescued by expression of the ULK1 binding-deficient mutant of ATG13. Taken together, these data suggest that ATG9A interacts with ATG13 and ULK1 separately, and that ATG101 is part of an ULK1-independent ATG13 complex that controls the trafficking of ATG9A to p62 puncta. We are currently developing approaches to selectively isolate, identify, and characterize additional interacting partners of the ULK1-independent ATG13-ATG101 complex, which will give us new insight into the regulation and broader function of this complex in autophagy. Citation Format: Daniel Poole, Ashari Kananngara, Vajira Weerasekara, Colten McEwan, Alexandra Thornock, Misael Lazaro, Joshua Youngs, Joshua Andersen. The regulation of ATG9A-mediated autophagy by an ULK1-independent ATG13 complex [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 1941.
David Oliver: Hospital bed numbers were inadequate before the pandemic and will continue to be so
Authors: David Oliver
Journal: BMJ (2021)

As we approach the planned end to most covid-19 restrictions in England on 19 July, our general hospitals remain under unprecedented midsummer pressures, even though admissions and beds occupied by people with covid-19 are still way below peak pandemic levels.12 Bed capacity was a glaring problem for the NHS well before covid, and even with no more surges in infections it will remain a huge limiting factor to our health system’s resilience and performance.3

Between 2010-11 and 2019-20 England’s overall number of NHS hospital beds fell by 11%, from 144 455 to 128 943. The number of available general and acute beds fell by 8%, from 110 568 to 102 194.4

Population growth, ageing, and the accompanying frailty, disability, and multiple long term conditions all drive activity and need in health and social care. Despite …
Abstract 954: AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma
Authors: Benjamin J. Capoccia, Michael J. Donio, John O. Richards, Ronald R. Hiebsch, Robyn J. Puro, Arun K. Kashyap, Daniel S. Pereira
Journal: Cancer Research (2021)

Abstract Overexpression of CD47 by tumor cells exploits an immune checkpoint that prevents tumor recognition and destruction by innate immune cells. Binding of tumor CD47 to SIRPα on macrophages and dendritic cells triggers a “don't eat me” signal that inhibits phagocytosis enabling escape from innate immune surveillance. Blockade of the CD47/SIRPα axis enables immune recognition and phagocytic clearance of tumor cells. We have developed a clinical stage CD47 targeting antibody AO-176, that is highly differentiated among agents in this class. AO-176 not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also: a) directly induces solid and hematologic tumor cell cytotoxicity and damage-associated molecular patterns (DAMPs); b) preferentially binds tumor versus normal cells, which is correlated with β1-integrin expression and localization; c) negligibly binds RBC; and d) exhibits improved binding at acidic pH as found in tumor microenvironments.Previously we have shown that AO-176 is efficacious in a variety of solid tumor xenograft models as well as in models of multiple myeloma and AML. Here, we show the therapeutic potential of AO-176 in pre-clinical models of lymphoma where CD47 is upregulated and associated with poor prognosis. Using a variety of cell based and in vivo models we show that AO-176 demonstrates increased binding to lymphoma cells at an acidic versus physiologic pH and that this binding and blocking of the do not eat me signal leads to enhanced phagocytosis of lymphoma cells either alone or in combination with rituximab. In addition, we show that AO-176 induces annexin V positivity in lymphoma cells as well as inducing a variety of DAMPs that ultimately may aid in inducing immunogenic cell death of the lymphoma cells. We also demonstrate that AO-176 is a potent tumor growth inhibitor in lymphoma xenograft models and appears to induce immune infiltrates as well as inflammatory cytokines.Taken together, these data show that AO-176 has strong therapeutic potential in lymphoma. AO-176 is currently being evaluated in clinical trials of select solid tumors (NCT03834948) and multiple myeloma (NCT04445701). Citation Format: Benjamin J. Capoccia, Michael J. Donio, John O. Richards, Ronald R. Hiebsch, Robyn J. Puro, Arun K. Kashyap, Daniel S. Pereira. AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma [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 954.
Prostate cancer topography and tumour conspicuity on multiparametric magnetic resonance imaging: A systematic review and meta-analysis
Authors: P. Satish, A. Freeman, D. Kelly, A. Kirkham, C. Orczyk, B. Simpson, F. Giganti, H.C. Whitaker, M. Emberton, J.M. Norris
Journal: European Urology (2021)
Abstract 247: Identification of an ovarian cancer selective splice variant of mesothelin utilizing the Kiromic proprietary search engine CancerDiff
Authors: Lucia Piccotti, Leonardo Mirandola, Maurizio Chiriva-Internati
Journal: Cancer Research (2021)

Abstract The advancement of cures for cancer needs the development of novel, more efficacious, and more specific immunotherapeutic approaches through the discovery of novel target candidates displaying differential expression between healthy and malignant tissues. CancerDiff is a proprietary software module for the identification of potential new immunotherapeutic cancer targets that originate from differentially expressed, alternatively spliced transcripts. When utilized to analyze Ovarian Cancer (OV) datasets, CancerDiff identified a selectively upregulated mesothelin (MSLN) splice variant translated into a protein isoform (IsoMSLN) bearing a distinct unique peptide absent in the canonical protein sequence. To validate this prediction and to confirm the upregulation of IsoMSLN in OV, datasets from publicly available proteomic repositories were searched for its unique signature peptide. In agreement with CancerDiff prediction, IsoMSLN peptide was detected in 71% of OV samples and 61% of adjacent normal tissues. Molecular modeling tools predicted this peptide to be part of the extracellular portion of the protein in an antibody accessible region. These results indicate IsoMSLN unique peptide as a suitable target for immunotherapy for OV cancer. Citation Format: Lucia Piccotti, Leonardo Mirandola, Maurizio Chiriva-Internati. Identification of an ovarian cancer selective splice variant of mesothelin utilizing the Kiromic proprietary search engine CancerDiff [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 247.
Abstract 2118: Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia
Authors: Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Kathryn Roberts, Mao-xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga lyyanki, Da Kuang, Shalini Reshmi, Julie Gastier-Foster, Colton Smith, Ching-Hon Pui, William Evans, Stephen Hunger, Stephen Hunger, Leonidas Platanias, Mary Relling, Charles Mullighan, Mignon Loh, Feng Yue, Jun Yang
Journal: Cancer Research (2021)

Abstract Inherited non-coding genetic variants confer significant disease susceptibility in many cancers. However, the molecular processes of by which germline variants contribute to somatic lesions are poorly understood. We performed targeted sequencing in 5,008 patients and identified a key regulatory germline variant in GATA3 strongly associated with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). By creating an isogenic cellular model with CRISPR-Cas9 system, we showed that this variant activated a strong enhancer that significantly upregulated GATA3 transcription, which in turn reshaped the global chromatin accessibility and 3D genome organization. Remarkably, this genotype switch induced a chromatin loop between the CRLF2 oncogene and a distal enhancer, similar to the somatically acquired super-enhancer hijacking event in patients. GATA3 genotype-related alterations in transcriptional control and 3D chromatin organization were further validated in Ph-like ALL patients. Finally, we showed that GATA3 directly regulates CRLF2 and potentiates the oncogenic effects of JAK-STAT signaling in leukemogenesis. Altogether, our results provide evidence for a novel mechanism by which a germline non-coding variant contributes to oncogene activation epigenetic regulation and 3D genome reprogramming. Citation Format: Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Kathryn Roberts, Mao-xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga lyyanki, Da Kuang, Shalini Reshmi, Julie Gastier-Foster, Colton Smith, Ching-Hon Pui, William Evans, Stephen Hunger, Stephen Hunger, Leonidas Platanias, Mary Relling, Charles Mullighan, Mignon Loh, Feng Yue, Jun Yang. Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia [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 2118.