tbuckley/cabot-search huggingface dataset:
Abstract 167: Multiomics profiling of BAP1 loss in uveal melanoma
Authors: Usman Baqai, Timothy Purwin, Nelisa Bechtel, Vivian Chua, Anna Han, Andrew E. Aplin
Journal: Cancer Research (2021)

Abstract BRCA1 Associated Protein 1 (BAP1) is a tumor suppressor gene with identified mutations in various cancers including uveal melanoma (UM), malignant mesothelioma, renal cell carcinoma, and cutaneous melanoma. The protein forms multicomplexes with various transcription factors and cell cycle regulators. It also functions as a deubiquitylating enzyme primarily located in the nucleus and acts on histone 2A, leading to altered gene transcription. Recently, it was shown to play a role in apoptotic signaling, homologous-directed repair, and ferroptosis regulation. Over 90% of metastatic UM cases report loss-of-function BAP1 mutations. There is a strong association between loss-of-function BAP1 mutations, metastasis, and poor disease prognosis, the mechanisms for which remain unclear. Understanding the role of BAP1 in metastasis may help uncover therapeutic approaches and improve overall survival outcomes for metastatic UM patients. Here we used a multi-omics approach to investigate changes in gene expression in UM with BAP1 loss. Bioinformatics analysis using multiple UM patient and cell line data sets revealed upregulation of key cell-cell adhesion genes, CDH1, CADM1, and SDC2 with loss of BAP1. These adhesion proteins may be involved with facilitating collective migration or enable metastatic seeding. Together, these data prompt further investigation into the specific roles of BAP1 during the metastatic cascade in UM, from primary dissemination in the eye to seeding in the liver. Citation Format: Usman Baqai, Timothy Purwin, Nelisa Bechtel, Vivian Chua, Anna Han, Andrew E. Aplin. Multiomics profiling of BAP1 loss in uveal 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 167.
Automated ex-situ detection of pitting corrosion and its effect on the mechanical integrity of rare earth magnesium alloy - WE43
Authors: Kerstin van Gaalen, Felix Gremse, Felix Benn, Peter E. McHugh, Alexander Kopp, Ted J. Vaughan
Journal: Bioactive Materials (2021)

This study develops a three-dimensional automated detection framework (PitScan) that systematically evaluates the severity and phenomenology of pitting corrosion. This framework uses a python-based algorithm to analyse microcomputer-tomography scans (μCT) of cylindrical specimens undergoing corrosion. The approach systematically identifies several surface-based corrosion features, enabling full spatial characterisation of pitting parameters, including pit density, pit size, pit depth as well as pitting factor according to ASTM G46-94. Furthermore, it is used to evaluate pitting formation in tensile specimens of a Rare Earth Magnesium alloy undergoing corrosion, and relationships between key pitting parameters and mechanical performance are established. Results demonstrated that several of the parameters described in ASTM G46-94, including pit number, pit density and pitting factor, showed little correlation to mechanical performance. However, this study did identify that other parameters showed strong correlations with the ultimate tensile strength and these tended to be directly linked to the reduction of the cross-sectional area of the specimen. Specifically, our results indicate, that parameters directly linked to the loss of the cross-sectional area (e.g. minimum material width), are parameters that are most suited to provide an indication of a specimen's mechanical performance. The automated detection framework developed in this study has the potential to provide a basis to standardise measurements of pitting corrosion across a range of metals and future prediction of mechanical strength over degradation time.
ニッチ特異的MHC IIとPD-L1はCD4+CD8αα+上皮内リンパ球分化を調節する【JST・京大機械翻訳】
Authors: Moon Sookjin, Park Yunji, Hyeon Sumin, Kim Young-Min, Kim Ji-Hae, Kim Hyekang, Park Subin, Lee Kun-Joo, Koo Bon-Kyoung, Ha Sang-Jun, Lee Seung-Woo
Journal: The Journal of Experimental Medicine (2021)
Autocrine GMCSF Signaling Contributes to Growth of HER2+ Breast Leptomeningeal Carcinomatosis
Authors: Khairul I. Ansari, Arunoday Bhan, Mika Saotome, Antariksh Tyagi, Bony De Kumar, Clara Chen, Motoki Takaku, Rahul Jandial
Journal: Cancer Research (2021)

Abstract Leptomeningeal carcinomatosis (LC) occurs when tumor cells spread to the cerebrospinal fluid–containing leptomeninges surrounding the brain and spinal cord. LC is an ominous complication of cancer with a dire prognosis. Although any malignancy can spread to the leptomeninges, breast cancer, particularly the HER2+ subtype, is its most common origin. HER2+ breast LC (HER2+ LC) remains incurable, with few treatment options, and the molecular mechanisms underlying proliferation of HER2+ breast cancer cells in the acellular, protein, and cytokine-poor leptomeningeal environment remain elusive. Therefore, we sought to characterize signaling pathways that drive HER2+ LC development as well as those that restrict its growth to leptomeninges. Primary HER2+ LC patient-derived (“Lepto”) cell lines in coculture with various central nervous system (CNS) cell types revealed that oligodendrocyte progenitor cells (OPC), the largest population of dividing cells in the CNS, inhibited HER2+ LC growth in vitro and in vivo, thereby limiting the spread of HER2+ LC beyond the leptomeninges. Cytokine array–based analyses identified Lepto cell–secreted GMCSF as an oncogenic autocrine driver of HER2+ LC growth. LC/MS-MS-based analyses revealed that the OPC-derived protein TPP1 proteolytically degrades GMCSF, decreasing GMCSF signaling and leading to suppression of HER2+ LC growth and limiting its spread. Finally, intrathecal delivery of neutralizing anti-GMCSF antibodies and a pan-Aurora kinase inhibitor (CCT137690) synergistically inhibited GMCSF and suppressed activity of GMCSF effectors, reducing HER2+ LC growth in vivo. Thus, OPC suppress GMCSF-driven growth of HER2+ LC in the leptomeningeal environment, providing a potential targetable axis. Significance: This study characterizes molecular mechanisms that drive HER2+ leptomeningeal carcinomatosis and demonstrates the efficacy of anti-GMCSF antibodies and pan-Aurora kinase inhibitors against this disease.
Effect of general practitioner-led versus surgeon-led colon cancer survivorship care, with or without eHealth support, on quality of life (I CARE): an interim analysis of 1-year results of a randomised, controlled trial
Authors: Julien A M Vos, Laura A M Duineveld, Thijs Wieldraaijer, Jan Wind, Wim B Busschers, Edanur Sert, Pieter J Tanis, Irma M Verdonck-de Leeuw, Henk C P M van Weert, Kristel M van Asselt
Journal: The Lancet Oncology (2021)
Development and Validation of a Risk Prediction Model for Second Primary Lung Cancer
Authors: Eunji Choi, Nilotpal Sanyal, Victoria Y Ding, Rebecca M Gardner, Jacqueline V Aredo, Justin Lee, Julie T Wu, Thomas P Hickey, Brian Barrett, Thomas L Riley, Lynne R Wilkens, Ann N Leung, Loïc Le Marchand, Martin C Tammemägi, Rayjean J Hung, Christopher I Amos, Neal D Freedman, Iona Cheng, Heather A Wakelee, Summer S Han
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background With advancing therapeutics, lung cancer (LC) survivors are rapidly increasing in number. Although mounting evidence suggests LC survivors have high risk of second primary lung cancer (SPLC), there is no validated prediction model available for clinical use to identify high-risk LC survivors for SPLC. Methods Using data from 6325 ever-smokers in the Multiethnic Cohort (MEC) study diagnosed with initial primary lung cancer (IPLC) in 1993-2017, we developed a prediction model for 10-year SPLC risk after IPLC diagnosis using cause-specific Cox regression. We evaluated the model’s clinical utility using decision curve analysis and externally validated it using 2 population-based data—Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and National Lung Screening Trial (NLST)—that included 2963 and 2844 IPLC (101 and 93 SPLC cases), respectively. Results Over 14 063 person-years, 145 (2.3%) ever-smoking IPLC patients developed SPLC in MEC. Our prediction model demonstrated a high predictive accuracy (Brier score = 2.9, 95% confidence interval [CI] = 2.4 to 3.3) and discrimination (area under the receiver operating characteristics [AUC] = 81.9%, 95% CI = 78.2% to 85.5%) based on bootstrap validation in MEC. Stratification by the estimated risk quartiles showed that the observed SPLC incidence was statistically significantly higher in the 4th vs 1st quartile (9.5% vs 0.2%; P &amp;lt; .001). Decision curve analysis indicated that in a wide range of 10-year risk thresholds from 1% to 20%, the model yielded a larger net-benefit vs hypothetical all-screening or no-screening scenarios. External validation using PLCO and NLST showed an AUC of 78.8% (95% CI = 74.6% to 82.9%) and 72.7% (95% CI = 67.7% to 77.7%), respectively. Conclusions We developed and validated a SPLC prediction model based on large population-based cohorts. The proposed prediction model can help identify high-risk LC patients for SPLC and can be incorporated into clinical decision making for SPLC surveillance and screening.
Abstract 2077: Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC
Authors: Stefan Kaulfuss, Andreas Janzer, Gerhard Siemeister, Renan Borowicz, Katrin Jaensch, Katrin Gutberlet, Ricarda Schlenz, Andrea Triller, Ashley Eheim, Michael Jeffers, Sven Christian
Journal: Cancer Research (2021)

Abstract Introduction: BAY2402234 is a potent and specific orally administered inhibitor of dihydroorotate dehydrogenase (DHODH) which showed anti-tumor activity in preclinical models of AML and is under clinical evaluation in myeloid malignancies (NCT03404726). Small cell lung cancer (SCLC) is a highly metastatic malignancy (the brain being a frequent metastatic site), which carries a dismal clinical prognosis. Previous preclinical research indicated that SCLC was particularly sensitive to DHODH inhibition, and in the current investigation the activity of BAY2402234 in this tumor indication was evaluated. Experimental Procedures: A variety of in vivo models derived from human SCLC samples were evaluated: (1) cell-line derived xenograft (CDX) subcutaneous models; (2) a CDX intracranial model; and (3) patient-derived xenograft (PDX) subcutaneous models. As is typical for SCLC, most of these models harbored mutations in both p53 and Rb1. BAY2402234 was administered orally either once daily or on an intermittent schedule (4 days on/3 days off). Standard-of-care (SoC) therapies were included in some experiments. Tumor tissue and plasma were collected for pharmacodynamic analyses. Results: In subcutaneous CDX models, BAY2402234 exhibited robust anti-tumor activity, including tumor regressions in some models. Strong anti-tumor activity was also observed in various subcutaneous PDX models, including activity in a model resistant to SoC therapy. In an intracranial tumor model, BAY2402234 significantly enhanced survival compared to the vehicle-treated cohort. Both dosing schedules tested were well-tolerated and highly active. Pharmacodynamic analyses to quantify the level of target inhibition observed in the various models are ongoing. Conclusions: The results of this investigation confirm and extend previous preclinical results and indicate that BAY2402234 may represent a novel treatment for SCLC, including patients with brain metastases. RESTRICTED Citation Format: Stefan Kaulfuss, Andreas Janzer, Gerhard Siemeister, Renan Borowicz, Katrin Jaensch, Katrin Gutberlet, Ricarda Schlenz, Andrea Triller, Ashley Eheim, Michael Jeffers, Sven Christian. Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC [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 2077.
Incidence and risk factor analysis of complications after sentinel node biopsy for penile cancer: Evaluation at a single high-volume center
Authors: L. Wever, H.M. De Vries, B.W.G. Van Rhijn, H.G. Van Der Poel, M.L Donswijk, K. Sikorska, S. Horenblas, F.W.B. Van Leeuwen, O.R. Brouwer
Journal: European Urology (2021)
Abstract 2701: Molecular profiling to assess the immune response to neoadjuvant SABR in early breast cancer
Authors: Melanie Spears, Vida Talebian, Linda Liao, Megan Hopkins, Kalan Lynn, Michael Lock, Anat Kornecki, John M. Bartlett, Muriel Brackstone
Journal: Cancer Research (2021)

Abstract Radiation therapy is used successfully in the treatment of breast cancer. Stereotactic radiation therapy (SBRT) is well established in the treatment of lung cancer, brain metastases and various other metastatic sites. Localized radiotherapy can promote dendritic cells maturations and activation and enhances phagocytosis of cells by antigen-presenting cells (APCs) increased presentation of tumor-associated antigenic peptides, and T cells being primed from naïve towards memory phenotypes In this study we evaluated the ability to implement a three fraction SBRT regimen for low-risk primary carcinoma of the breast prior to lumpectomy and profiled the immune microenvironment using NanoString's GeoMx Digital Spatial Profiling (DSP) platform and we performed NanoString gene expression profiling using the Human v.1.1 PanCancer immune profiling panel. NanoString's DSP platform was used to analyze 25 patient samples from the SIGNAL 2.0 clinical trial. For analysis, region of interest were selected comparing the tumor microenvironment (TME, CD45+ve) and tumor (pan cytokeratin) in pre and post treated FFPE slides. A panel of 60-antibodies were analyzed in each region. For gene expression profiling total RNA was extracted from the frozen tissue and the human V.1.1 PanCancer Immune Profiling Panel was used. We observed notable differences in the immune microenvironment gene expression patterns in samples pre- and post-treatment. We identified a total of 175 differentially expressed genes (DEGs) using a 5% adjusted p-value across the entire patient population regardless of which radiation arm. Pathway analysis identified genes associated with activation of immune response, signaling by interleukins and adaptive immune response were significantly changed in the post treatment samples. Deconvolution of the immune cell mRNA gene expression data demonstrated that there were significant changes in the cellular composition after radiotherapy. There were significant increase in expression levels of macrophages, dendritic cells, neutrophils and CD8 T cells post radiation treatment. In conclusion we have demonstrated through proteomic and transcriptomic profiling, SBRT elicits an immune response with increases in the innate response. Citation Format: Melanie Spears, Vida Talebian, Linda Liao, Megan Hopkins, Kalan Lynn, Michael Lock, Anat Kornecki, John M. Bartlett, Muriel Brackstone. Molecular profiling to assess the immune response to neoadjuvant SABR in early breast cancer [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 2701.
Abstract 414: Efficacy of Balixafortide (POL6326) and Paclitaxel alone and in combination in humanized breast cancer PDX
Authors: Daniel Obrecht, Johann Zimmermann
Journal: Cancer Research (2021)

Abstract Despite availability of new therapies, outcomes for patients with relapsed metastatic breast cancer is poor with moderate median overall survival. High CXCR4 levels correlate with aggressive metastatic phenotypes and poor prognosis in breast cancer (BC). Anti-cancer mechanisms of CXCR4 antagonists include inhibition of angiogenesis and metastasis, activation of immunosurveillance and chemo sensitization. Balixafortide (POL6326) is a potent, selective inhibitor of the chemokine receptor CXCR4 in PhIII for metastatic HER2-negative breast cancer (BC) in combination with tubulin-binding eribulin (NCT03786094). Clinical proof-of-concept in combination with eribulin was demonstrated in a PhI single arm dose-escalation trial in patients with metastatic HER2-negative BC (NCT01837095). The objective response rate for a dose of 5.5mg/kg balixafortide and 1.4mg/m2 eribulin) was 38% (median duration 4.4 months), and the clinical benefit rate was 63% (median duration 8.1 months). Tolerability and safety of eribulin in combination with balixafortide was comparable to that of eribulin monotherapy. Balixafortide was combined with paclitaxel in a humanized BC patient-derived xenograft (PDX) model to explore the efficacy in combination with another tubulin-binding drugs. Human immunophenotyping confirmed successful human CD34+ cell engraftment and expansion of human immune cells prior implantation of an invasive ductal carcinoma (ypT1a ypN1a R0 G3 L1 V1), ER/PR/Her-2 negative tumor. 10mg/kg paclitaxel was given 2x weekly iv. Dosing of balixafortide was 20mg/kg bid sc for 5 days with 2 days break. Total treatment duration was 28 days. Partial remission was achieved in the combination arm balixafortide+paclitaxel (T/C 13%, 87% inhibition of tumor volume vs vehicle control) which was stat. significantly better than paclitaxel monotherapy (T/C 42%). There was no decrease in tolerability in balixafortide combination vs paclitaxel alone. This data suggests combination with balixafortide is more efficacious and equally tolerated to paclitaxel single agent treatment. Citation Format: Daniel Obrecht, Johann Zimmermann. Efficacy of Balixafortide (POL6326) and Paclitaxel alone and in combination in humanized breast cancer PDX [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 414.
Abstract 1210: NFX1-123: A potential therapeutic target in cancer
Authors: Sreenivasulu Chintala, Anand Anbarasu, Rachel A. Katzenellenbogen
Journal: Cancer Research (2021)

Abstract Background: NFX1-123 is the longer splice variant isoform of the NFX1 gene and is highly expressed in cervical cancer. Cervical cancer is caused by high-risk HPV infections, and NFX1-123 is a protein partner with the HPV oncoprotein E6. Together, NFX1-123 and E6 affect cellular growth, longevity, differentiation, and the immune response. The expression status of NFX1-123 in cancers beyond cervical cancer, and its potential as therapeutic target, has not been investigated. Methods: TSVdb of TCGA was used to quantify NFX1-123 expression in 25 primary cancers tissues compared to adjacent normal tissues. The NFX1-123 protein structure was predicted using I-TASSER: Interactive Threading ASSEmbly Refinement tool. The modeled structure was submitted to the MTi-Openscreen Virtual screening web-server using ZINC-Database to retrieve suitable drug molecules, and further screening was evaluated by PyRx interphase and AutoDock Vina. The top four compounds, found to bind in silico to NFX1-123, were tested experimentally to determine their inhibitory effects on NFX1-123-related cellular growth and survival by MTT assay. Results: 44% of cancers (11 of 25) had significant differences in NFX1-123 expression when compared to adjacent normal solid tissues. Nine of 11 cancers (88%) had greater NFX1-123 expression: breast invasive carcinoma, cholangiocarcinoma, colon adenocarcinoma, renal cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, sarcoma, and stomach adenocarcinoma. Two of 11 cancers (18%) had reduced NFX1-123 expression: lung squamous cell carcinoma, and pheochromocytoma and paraganglioma. Additionally, HPV+ head and neck cancers had greater expression of NFX1-123 compared to HPV- head and neck cancers. Bioinformatics and proteomic predictive analysis revealed the 3-D structure of the NFX1-123; with this structure, drug libraries were screened for high binding affinity compounds. 17 drugs with binding energies range from -11.3 to -10 Kcal/mol. were found. The top four compounds were used to treat HPV- and HPV+ cervical and head and neck cancer cell lines in culture, and two (R428 and Ketoconazole) were found to reduce NFX1-123 protein levels and inhibit cell growth and survival. R428 was also found to inhibit NFX1-123 and regulate autophagy and autophagy-mediated cell death. Conclusion: Nine out of 25 (36%) cancers expressed high levels of NFX1-123, and drug targeting of NFX1-123 can lead to cell growth inhibition. NFX1-123 may be a potential novel therapeutic target in cancers that highly express NFX1-123. Citation Format: Sreenivasulu Chintala, Anand Anbarasu, Rachel A. Katzenellenbogen. NFX1-123: A potential therapeutic target in cancer [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 1210.
Osteoblastoma of the Lumbar Spine: Findings in SPECT/CT.
Authors: Alfredo Laverde Mächler, Juan Pablo Suárez Fernández, María Luz Domínguez Grande, Carmen Vigil Díaz, Francisco Manuel González García
Journal: Clinical Nuclear Medicine (2021)

ABSTRACT Osteoblastoma is an uncommon benign osteoid tissue-forming bone tumor. We present the case of a 16-year-old adolescent boy with lower back pain that radiated down the right thigh. Lumbar MRI and CT findings were consistent with a long-standing osteoid osteoma located in the right laminae and pedicle of L3. SPECT/CT with 99mTc-DPD showed a highly increased osteogenic activity within the lesion, especially in the core region, also suggesting an osteoid osteoma. Surgical en bloc resection was performed with a final histological diagnosis of osteoblastoma.