tbuckley/cabot-search huggingface dataset:
A randomized clinical trial of intravesical instillation of MMC and combination of MMC and Ara-C in non-muscle invasive bladder cancer
Authors: Y. Miyata, T. Matsuo, K. Ohba, K. Mitsunari, T. Keisuke, Y. Hayashida, T. Tsurusaki, J. Watanabe, N. Nishimura, M. Nishikido, H. Sakai
Journal: European Urology (2021)
Abstract 1907: Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity
Authors: Benjamin Tamas Papp, Máté Manczinger, Gergő Balogh, Balázs Koncz, Leó Asztalos, Lajos Kemény, Balázs Papp, Csaba Pál
Journal: Cancer Research (2021)

Abstract The human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a much wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response is unknown. In this paper, we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles, and found that cancer patients that carry HLA-I alleles with high peptide binding promiscuity are characterized by significantly worse prognosis after immune checkpoint inhibitor treatment. This trend can be explained by a reduced capacity of promiscuous HLA-I molecules to discriminate between human self and tumor peptides, yielding a shift in regulation of T-cells in the tumor microenvironment from activation to tolerance. In summary, HLA-I peptide binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner. It could also underlie a negative trade-off between antitumour immunity and the genetic susceptibility to viral infections. Citation Format: Benjamin Tamas Papp, Máté Manczinger, Gergő Balogh, Balázs Koncz, Leó Asztalos, Lajos Kemény, Balázs Papp, Csaba Pál. Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity [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 1907.
Abstract 2647: HOXB7, a key transcriptional regulator in triple negative breast cancer progression
Authors: Kideok Jin
Journal: Cancer Research (2021)

Abstract Despite major advances in breast cancer treatment and management one-third of women with ER-positive, and nearly 30% of women with ER-negative breast cancer will have recurrent disease within fifteen years. Our laboratory and others have accumulated a large body of evidence for the involvement of HOXB7 in various aspects of breast cancer progression: tamoxifen resistance, DNA repair, epithelial-mesenchymal transition, promotion of metastasis in a transgenic mouse model and human cells as well as angiogenesis suggesting a role for HOXB7 not only in the epithelium but also strongly implicating its control on the microenvironment of the tumor. In this project, we focused on understanding factors driven by HOXB7 that lead to triple-negative breast cancer (TNBC). In the previous studies, we found that HOXB7 expression results in the recruitment of stromal components and enhances the formation of lung metastasis in transgenic crosses of HOXB7xHER2 mice. Interestingly, HOXB7 expression was increased in MDA-MB-231 Bone and Brain metastatic cells. Therefore, we hypothesize that HOXB7, through its ability to mediate EMT and recruit pro-angiogenic molecules, is capable of promoting invasion and metastasis. In this report, we established HOXB7 overexpressing MDA-MD-231 cells. We screened secretomes from MB231-HOXB7 cells using Human Cytokine Array Q440 to quantitatively detect 440 human inflammatory factors, growth factors, chemokines, receptors, and cytokines simultaneously. We identified upregulation of IL-8, IL-6, VEGF, ARG2, CXCL1, CF XIV, Procalcitonin, Syndecan-3, AMICA, IL-11, CXCL14, ROBO3, Follistatin, SOST, and ALCAM in the secretomes from MB231-HOXB7 cells. We ranked the expression level of each factor by real-time qRT-PCR and determined that IL-8 and CXCL1 were the top candidates. We confirmed by ELISA that IL-8 and CXCL1 secreted from tumor conditioned medium (TCM) was upregulated compared to the control cells. Our data showed that the HUVEC tube formation was increased by MDA-MD-231-HOXB7 conditioned media. Furthermore, fibroblast and M2 type macrophage migration were promoted by TCM of MDA-MD-231-HOXB7 cells. Significantly, Depletion of IL-8 and CXCL1 using specific shRNAs in MDA-MD-231-HOXB7 cells decreased the HUVEC tube formation and the cell migration of fibroblast and macrophage. In addition, CXCL1 and IL-8 signaling pathway by Reparixin, an inhibitor of the CXCR1/2 abrogated the tube formation and migration induced by MDA-MD-231-HOXB7 cells. These findings implicate IL-8 and CXCL1 signaling as a critical event in HOXB7 overexpression TNBC growth and metastasis via crosstalk between cancer cells and stromal components. Citation Format: Kideok Jin. HOXB7, a key transcriptional regulator in triple negative breast cancer progression [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 2647.
Abstract 2890: Mitotic inhibitors suppresses tumor formation and metastasis of triple negative breast cancer (TNBC)
Authors: Chaeun Song, SeungBaek Lee
Journal: Cancer Research (2021)

Abstract Cell division cycle 20 (Cdc20) is the main activator of the anaphase-promoting complex (APC/C) and is essential in mitosis regulation. Recently, several papers reported that Cdc20 is highly conserved in various human cancers such as pancreatic, prostate, and lung cancers yet its relation to breast cancer is unclear. Here, we found that Cdc20 gene was highly expressed in three different TNBC cell lines among the mitosis regulator genes through the National Center for Biotechnology Information (NCBI). High Cdc20 level is positively correlated with metastasis-free patient survival and relapse-free patient survival in breast cancer patient database. We also checked that Cdc20 is highly conserved in all TNBC cell lines compared to other subtypes of breast cancer cell lines and the knockdown of this gene decreased cell growth and invasion in TNBC. Furthermore, we investigated that the mitosis-related small molecule protein kinase inhibitors such as VX-680, ZM447439, BI2536, and apcin also inhibit tumor cell proliferation, migration, and invasion. In conclusion, Cdc20 has an important role in TNBC cell growth and metastasis. Cdc20 might serve as a potential marker of disease progression and as a principal potential therapeutic target. Also, mitosis-related protein kinase inhibitors are additional potential therapy to suppress cancer cell progression and invasion in TNBC effectively. Citation Format: Chaeun Song, SeungBaek Lee. Mitotic inhibitors suppresses tumor formation and metastasis of triple negative breast cancer (TNBC) [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 2890.
Significant anti-adenovirus antibody response positively correlates with efficacy in patients treated with nadofaragene firadenovec for high-grade BCG-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)
Authors: V. Narayan, S. Boorjian, M. Alemozaffer, B.R. Konety, L. Gomella, A.M. Kamat, S.P. Lerner, R.S. Svatek, L. Karsh, D. Canter, Y. Lotan, B.A. Inman, M. Yang, V. Garcia-Horton, D. Sawutz, N. Parker, C.P.N. Dinney
Journal: European Urology (2021)
Abstract 2170: Proteogenomic and metabolomic characterization of human glioblastoma
Authors: Liang-Bo Wang, Alla Karpova, Marina A. Gritsenko, Jennifer E. Kyle, Song Cao, Yize Li, Dmitry Rykunov, Antonio Colaprico, Joseph Rothstein, Runyu Hong, Vasileios Stathias, MacIntosh Cornwell, Francesca Petralia, Richard D. Smith, Antonio Iavarone, Milan G. Chheda, Jill S. Barnholtz-Sloan, Karin D. Rodland, Tao Liu, Li Ding
Journal: Cancer Research (2021)

Abstract Glioblastoma (GBM) is the most aggressive nervous system cancer, with median survival under 2 years. Understanding its molecular pathogenesis is crucial for improving diagnosis and treatment. We performed an integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs. We identified key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation as well as potential targets for EGFR-, TP53- and RB1-altered tumors. We detected immune subtypes, driven by the presence of distinct immune cell populations using bulk omics, validated by snRNA-seq, and they were correlated with specific expression and histone acetylation patterns. Acetylation of histone H2B in classical-like and immune-low GBM was driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identified specific lipid distributions across subtypes and distinct global metabolic changes in IDH mutated tumors. By comparing the adult GBM proteomics to the adolescent and young adult (AYA) GBM cohort from the HOPE study, we found downregulated IDH1 expression and up-regulated expression of genes in the NADH dehydrogenase family, including NDUFB1, and NDUFB3 among others, which may be related to high IDH1 mutation frequency in AYA. This work highlights biological relationships which could potentially aid GBM patient stratifications for more effective treatments. Citation Format: Liang-Bo Wang, Alla Karpova, Marina A. Gritsenko, Jennifer E. Kyle, Song Cao, Yize Li, Dmitry Rykunov, Antonio Colaprico, Joseph Rothstein, Runyu Hong, Vasileios Stathias, MacIntosh Cornwell, Francesca Petralia, Richard D. Smith, Antonio Iavarone, Milan G. Chheda, Jill S. Barnholtz-Sloan, Karin D. Rodland, Tao Liu, Li Ding, Clinical Proteomic Tumor Analysis Consortium. Proteogenomic and metabolomic characterization of human glioblastoma [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 2170.
Abstract ND03: PD1-IL2v: A next generation, PD-1-targeted cytokine
Authors: Pablo Umana
Journal: Cancer Research (2021)

Abstract High dose interleukin-2 (IL-2) has been the first effective cancer immunotherapy to treat metastatic melanoma and renal cell carcinoma, but its clinical use is limited due to toxicity and the detrimental expansion of regulatory T cells (Tregs). As both of these issues are compounded by binding to IL-2Ra (CD25), second generation IL-2 and IL-15 molecules ("IL2Rbg-biased agonists"), engineered to bind preferentially or exclusively to the intermediate-affinity IL-2R but not to CD25, are currently in clinical trials. However, reduced CD25 binding limits the ability of these 2nd generation cytokines for expansion of tumor antigen-specific T-cells. We have now generated a novel PD-1-targeted IL-2 variant (IL2v), by fusing a high-affinity anti-PD-1 antibody to an IL2v with abolished binding to CD25. High-affinity PD-1 binding allows IL2v to effectively expand tumor-antigen specific T-cells, and to differentiate those cells towards better, non-dysfunctional immune effectors, to much higher levels vs. anti-PD-1/-L1 antibodies alone or in combination with either tolerable doses of standard IL-2 or with a non-PD-1-targeted 2nd generation IL-2Rbg agonist currently in clinical development, and thus mediate significantly superior anti-tumor efficacy at well tolerated drug doses. PD1-IL2v is currently being tested in a Ph1 clinical trial. Citation Format: Pablo Umana. PD1-IL2v: A next generation, PD-1-targeted cytokine [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 ND03.
The applicability of patient-Specific 3D models in the planning of nerve-sparing robot-assisted radical prostatectomy
Authors: H. Veerman, T.N. Boellaard, C. Hoeks, J.A. Van Eick, J. Sluijter, M. Van Alphen, R. Van Veen, E-J. Rijkhorst, E. Wit, T. Van Der Sluis, J. Nieuwenhuijzen, T.A. Roeleveld, A.N. Vis, H.G. Van Der Poel, P.J. Van Leeuwen
Journal: European Urology (2021)
A yeast-expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates
Authors: Maria Pino, Talha Abid, Susan Pereira Ribeiro, Venkata Viswanadh Edara, Katharine Floyd, Justin C. Smith, Muhammad Bilal Latif, Gabriela Pacheco-Sanchez, Debashis Dutta, Shelly Wang, Sanjeev Gumber, Shannon Kirejczyk, Joyce Cohen, Rachelle L. Stammen, Sherrie M. Jean, Jennifer S. Wood, Fawn Connor-Stroud, Jeroen Pollet, Wen-Hsiang Chen, Junfei Wei, Bin Zhan, Jungsoon Lee, Zhuyun Liu, Ulrich Strych, Neeta Shenvi, Kirk Easley, Daniela Weiskopf, Alessandro Sette, Justin Pollara, Dieter Mielke, Hongmei Gao, Nathan Eisel, Celia C. LeBranche, Xiaoying Shen, Guido Ferrari, Georgia D. Tomaras, David C. Montefiori, Rafick P. Sekaly, Thomas H. Vanderford, Mark A. Tomai, Christopher B. Fox, Mehul S. Suthar, Pamela A. Kozlowski, Peter J. Hotez, Mirko Paiardini, Maria Elena Bottazzi, Sudhir Pai Kasturi
Journal: Science Immunology (2021)

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.
Trajectory of Preserved Ratio Impaired Spirometry: Natural History and Long-Term Prognosis
Authors: Jacob Louis Marott, Truls Sylvan Ingebrigtsen, Yunus Çolak, Jørgen Vestbo, Peter Lange
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Natural history of preserved ratio impaired spirometry (PRISm), often defined as FEV1/FVC ⩾lower limit of normal and FEV1 <80% of predicted value, is not well described. Objectives: To investigate the natural history and long-term prognosis of the following PRISm trajectories: persistent PRISm trajectory (individuals with PRISm both young and middle-aged), normal to PRISm trajectory (individuals developing PRISm from normal spirometry in young adulthood), and PRISm to normal trajectory (individuals recovering from PRISm in young adulthood by normalizing spirometry while middle-aged). Methods: We followed 1,160 individuals aged 20-40 years from the Copenhagen City Heart Study from 1976 to 1983 until 2001 to 2003 to determine their lung function trajectory; 72 had persistent PRISm trajectory, 76 had normal to PRISm trajectory, 155 had PRISm to normal trajectory, and 857 had normal trajectory. From 2001-2003 until 2018, we determined the risk of cardiopulmonary disease and death. Measurements and Main Results: We recorded 198 admissions for heart disease, 143 for pneumonia, and 64 for chronic obstructive pulmonary disease as well as 171 deaths. Compared with individuals with normal trajectory, hazard ratios for individuals with persistent PRISm trajectory were 1.55 (95% confidence interval, 0.91-2.65) for heart disease admission, 2.86 (1.70-4.83) for pneumonia admission, 6.57 (3.41-12.66) for chronic obstructive pulmonary disease admission, and 3.68 (2.38-5.68) for all-cause mortality. Corresponding hazard ratios for individuals with normal to PRISm trajectory were 1.91 (1.24-2.95), 2.74 (1.70-4.42), 7.61 (4.21-13.72), and 2.96 (1.94-4.51), respectively. Prognosis of individuals with PRISm to normal trajectory did not differ from those with normal trajectory. Conclusions: PRISm in middle-aged individuals is associated with increased risk of cardiopulmonary disease and all-cause mortality, but individuals who recover from PRISm during their adult life are no longer at increased risk.
Identifying the differential effects of sperm DNA fragmentation on the reproductive cycle in couples undergoing IVF and ICSI
Authors: M.H Abdallah, T. Tharukan, J. Ramsay, T. Yap, Y. Thum, J. Nicopoullos, S.E.M. Lewis, C. Jayasena, S. Minhas
Journal: European Urology (2021)
Abstract 1892: Proteomic interrogation of the metabolic control of MHC class I antigen presentation in metastatic melanoma
Authors: Alyson McKinnon, Nathan Avaritt, Alan Tackett, Brian Koss
Journal: Cancer Research (2021)

Abstract Since 2014, immune checkpoint inhibitors (ICIs) have led the charge against metastatic melanoma as the most commonly utilized first-line treatment. While ICIs have dramatically increased the 5-year overall survival rate, only half of patients respond to treatment. Recently, a proteomic study correlated high levels of tumor mitochondrial metabolic proteins and MHC-related proteins to responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitor treatment. In a study of 91 melanoma cell lines in the European Searchable Tumor Cell and Databank, 67% of the cell lines exhibited HLA class antigen alterations, most commonly being down-regulation of HLA-B. Loss of MHC expression is a mechanism proposed to aid in evading the immune system by decreasing T-cell recognition and killing. Approaches to reverse tumor MHC loss is needed as it is a known mechanism utilized by melanoma and increased MHC expression has been linked to ICI responders. The connection between metabolism and MHC correlation has not been fully explored, and this study sought to further explore that relationship through a proteomic analysis of a metabolically conditioned B16F10 murine melanoma model. To expand our understanding of the metabolic control of MHC Class I antigen presentation, we cultured B16F10 melanoma cells in galactose media (B16.Gal), forcing the cells into an oxidative phosphorylative state relative to B16F10 melanoma cells cultured in glucose media (B16.Glu) which exhibit a glycolytic metabolic profile. We show that enforcing mitochondrial respiration restores the lost basal MHC expression and enhances the response to interferon gamma. Further, B16.Gal cells show higher rates of T-cell killing and increased PD-L1 expression. This phenotype proved reversible as shown by moving B16.Gal cells back into glucose media (B16.GalGlu), supporting the formation of a metabolically conditioned cell model rather than a favorable selection of compatible cells. We used proteomics to identify the driving forces behind the restoration of MHC expression. The identification of these forces could provide novel therapeutic targets for enhancing immunotherapy of melanoma. Citation Format: Alyson McKinnon, Nathan Avaritt, Alan Tackett, Brian Koss. Proteomic interrogation of the metabolic control of MHC class I antigen presentation in metastatic melanoma [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 1892.
Tulane School of Medicine placed on probation amid reports of racism and lack of diversity
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

Tulane University School of Medicine in New Orleans, Louisiana, was placed on probation by the Accreditation Council of Graduate Medical Education on 2 July after public allegations of racism and lack of diversity.1

The council accredits US graduate medical education—some 11 685 residencies and fellowships in specialties and subspecialties. In its recent report only 159 programmes had a status of continued accreditation with warning and just 21 had the more serious status of probationary accreditation.2

Tulane University was founded in 1834 and has 17 programmes of graduate medical education.3 Its problems became public in February 2021. Princess Dennar, who had sued the university for alleged racism and sexism, was suspended from her position as programme director of …
A Mammalian Target of Rapamycin‐Perilipin 3 (mTORC1‐Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis
Authors: Marina Garcia‐Macia, Adrián Santos‐Ledo, Jack Leslie, Hannah L. Paish, Amy L. Collins, Rebecca S. Scott, Abigail Watson, Rachel A. Burgoyne, Steve White, Jeremy French, John Hammond, Lee A. Borthwick, Jelena Mann, Juan P. Bolaños, Viktor I. Korolchuk, Fiona Oakley, Derek A. Mann
Journal: Hepatology (2021)

Background and Aims NAFLD is the most common hepatic pathology in western countries and no treatment is currently available. NAFLD is characterized by the aberrant hepatocellular accumulation of fatty acids in the form of lipid droplets (LDs). Recently, it was shown that liver LD degradation occurs through a process termed lipophagy, a form of autophagy. However, the molecular mechanisms governing liver lipophagy are elusive. Here, we aimed to ascertain the key molecular players that regulate hepatic lipophagy and their importance in NAFLD. Approach and Results We analyzed the formation and degradation of LD in vitro (fibroblasts and primary mouse hepatocytes), in vivo and ex vivo (mouse and human liver slices) and focused on the role of the autophagy master regulator mammalian target of rapamycin complex (mTORC) 1 and the LD coating protein perilipin (Plin) 3 in these processes. We show that the autophagy machinery is recruited to the LD on hepatic overload of oleic acid in all experimental settings. This led to activation of lipophagy, a process that was abolished by Plin3 knockdown using RNA interference. Furthermore, Plin3 directly interacted with the autophagy proteins focal adhesion interaction protein 200 KDa and autophagy-related 16L, suggesting that Plin3 functions as a docking protein or is involved in autophagosome formation to activate lipophagy. Finally, we show that mTORC1 phosphorylated Plin3 to promote LD degradation. Conclusions These results reveal that mTORC1 regulates liver lipophagy through a mechanism dependent on Plin3 phosphorylation. We propose that stimulating this pathway can enhance lipophagy in hepatocytes to help protect the liver from lipid-mediated toxicity, thus offering a therapeutic strategy in NAFLD.