tbuckley/cabot-search huggingface dataset:
Abstract NG10: A metastasis map of human cancer cell lines
Authors: Xin Jin, Zelalem Demere, Karthik Nair, Ahmed Ali, Gino B. Ferraro, Ted Natoli, Amy Deik, Lia Petronio, Andrew A. Tang, Cong Zhu, Li Wang, Danny Rosenberg, Vamsi Mangena, Jennifer Roth, Kwanghun Chung, Rakesh K. Jain, Clary B. Clish, Matthew G. Vander Heiden, Todd R. Golub
Journal: Cancer Research (2021)

Abstract Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical due to the inherent scale limitation of the in vivo models. Here we introduce an in vivo barcoding strategy capable of determining the metastatic potential of human cancer cell lines in murine xenografts at scale. We validated the robustness, scalability and reproducibility of the method, and applied it to 500 cell lines spanning 21 solid cancer types. We created a first-generation Metastasis Map (MetMap) that reveals organ-specific patterns of metastasis and allows relating those patterns to clinical and genomic features. We demonstrated the utility of MetMap by exploring the molecular basis of breast cancers capable of metastasizing to the brain - a principal cause of death in these patients. Breast cancers that were brain metastatic had unexpected genetic, expression, and metabolic evidence of altered lipid metabolism. Perturbing lipid metabolism curbed brain metastasis development and limited the outgrowth of cancer cells in the brain, suggesting a therapeutic strategy to combat the disease. These results illustrated the utility of MetMap as a step towards next-generation approach for high-throughput metastasis research. Citation Format: Xin Jin, Zelalem Demere, Karthik Nair, Ahmed Ali, Gino B. Ferraro, Ted Natoli, Amy Deik, Lia Petronio, Andrew A. Tang, Cong Zhu, Li Wang, Danny Rosenberg, Vamsi Mangena, Jennifer Roth, Kwanghun Chung, Rakesh K. Jain, Clary B. Clish, Matthew G. Vander Heiden, Todd R. Golub. A metastasis map of human cancer cell lines [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 NG10.
Abstract 1573: Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models
Authors: Mary Ellen Molloy, Laura B. Valenzuela, Priyanka E. Basak, Che-Leung Law
Journal: Cancer Research (2021)

Abstract Tri-specific T Cell-Activating Constructs (TriTACs) are T-cell engagers that have been developed to redirect T cells to kill tumor cells. TriTAC molecules are currently being investigated in multiple phase 1/2 clinical trials in solid tumors, including HPN424 targeting prostate-specific membrane antigen (PSMA) in prostate cancer (NCT03577028), HPN536 targeting mesothelin (MSLN) in multiple malignancies (NCT03872206) and HPN328 targeting Delta Like Canonical Notch Ligand 3 (DLL3) in small cell lung cancer (SCLC) (NCT04471727). TriTAC molecules consist of a single domain antibody (sdAb) specific for a tumor antigen, a sdAb specific for serum albumin for half-life extension, and a single chain Fv (scFv) specific for the CD3ϵ subunit of the T cell receptor (TCR) complex for T cell engagement. In the presence of antigen expressing tumor cells, TriTAC treatment leads to potent T cell activation, production of proinflammatory cytokines, and re-directed tumor cell killing. Upregulation of co-stimulatory and/or inhibitory receptors during activation can potentially affect the cytolytic functions of TriTAC-activated T cells. We demonstrate that PD-1 can be readily detected on T cells subsequent to the engagement of the TCR by the TriTAC molecules HPN424, HPN536, and HPN328 in the presence of tumor cells expressing the target antigens PSMA, MSLN, and DLL3, respectively. We also demonstrate that TriTAC molecules upregulate PD-L1 on T cells in a dose-dependent manner. While induction of PD-1 on T cells suggests that cytolytic activity of TriTAC-activated T cells may be down-modulated by PD-L1-expressed by target tumor cells, simultaneous upregulation of PD-L1 on T cells suggests a second mechanism through which the functions of TriTAC-activated T cells could be further regulated by the PD1/PD-L1 axis in the tumor microenvironment through T cell-T cell interactions. In addition, in the MSLN-expressing NCI-H292 lung cancer model that co-expresses constitutive, high levels of PD-L1, both anti-PD1 and anti-PDL1 antibodies significantly enhanced the antitumor effects of the MSLN-targeting TriTAC HPN536 in vivo. Together these results demonstrate the potential utility of PD1/PDL1 blockade to enhance the potency of TriTAC-mediated tumor cell killing, supporting further investigation of these combinatorial approaches in patients. Citation Format: Mary Ellen Molloy, Laura B. Valenzuela, Priyanka E. Basak, Che-Leung Law. Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1573.
Doctors question NICE recommendation to induce labour at 39 weeks in ethnic minority women
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Doctors and campaigners have raised concerns over proposed NICE guidance that recommends that inducing labour should be considered at 39 weeks in women from an ethnic minority family background, even if their pregnancies are considered uncomplicated.1

The draft guidance, under consultation until 6 July, has advised healthcare professionals to consider induction of labour from 39 weeks in “women with otherwise uncomplicated singleton pregnancies who are at a higher risk of complications associated with continued pregnancy . . . for example with a black, Asian, or minority ethnic family background.”

Black women are four times as likely as white women to die in pregnancy or childbirth, and women from Asian ethnic backgrounds have a twofold higher risk. Women living in the UK’s most deprived areas are almost three times as likely to die as those in the richest areas.2

However, …
OLIGOPELVIS GETUG P07, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer
Authors: Stéphane Supiot, Loig Vaugier, David Pasquier, Xavier Buthaud, Nicolas Magné, Didier Peiffert, Paul Sargos, Gilles Crehange, Pascal Pommier, Genevieve Loos, Ali Hasbini, Igor Latorzeff, Marlon Silva, Fabrice Denis, Jean-Léon Lagrange, Cyrille Morvan, Loic Campion, Audrey Blanc-Lapierre
Journal: European Urology (2021)
Abstract 2713: Preclinical models for translational immuno-oncology research: patient-derived xenografts on humanized mice
Authors: Maria Stecklum, Annika Wulf-Goldenberg, Bernadette Brzezicha, Konrad Klinghammer, Korinna Jöhrens, Wolfgang Walther, Jens Hoffmann
Journal: Cancer Research (2021)

Abstract Background: The preclinical evaluation of novel immune checkpoint modulators is dependent on models with functional human immune cells. In previous experiments, we have demonstrated, that we can use either peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells (HSC) to establish a humanized immune system on highly immunodeficient mice with functional T, B or NK cells. Furthermore, we determined PD-L1 expression as a predictive marker and target for immunotherapy on different patient-derived xenografts (PDX). By co-transplantation of PDX, we successfully generated a fully human tumor-immune-cell model in mice. Finally, we evaluated the functionality of the model by the treatment with checkpoint inhibitors and for combination therapies i.e. with chemotherapy or radiation. Methods: HSC-humanized mice (HIS) were generated by i.v. transplantation of HSC. Engraftment of immune cells was monitored by FACS analysis. For PBMC-humanized mice, immune cells were implanted i.v. PD-L1 expression on PDX was determined by FACS and immunohistochemistry (IHC). PDX from 13 different entities (i.e. melanoma, lymphoma) were transplanted on HIS mice and treated with Ipilimumab (Ipi) and Nivolumab (Nivo) alone or in combination with radiation. Results: 14 weeks after HSC transplantation up to 20% of the human immune cells in the blood were T-cells. We have transplanted more than 40 different PDX from 13 different tumor entities on HIS mice. Most of the investigated PDX (&amp;gt;70%) successfully engrafted and showed no significant difference in tumor growth compared non-humanized mice. However, for some PDX we observed a delayed tumor growth or a complete rejection. Engraftment delay seems to correlate with the PD-L1 expression of PDX (the higher PD-L1, then the higher growth delay). Treatment with Ipi or Nivo alone or in combination led to a minor tumor growth delay and an increased percentage of T-cells in the blood and the tumor. Response showed a correlation to innate immune response and PD-L1 expression of PDX and could further be increased by combination with radiotherapy. Conclusions: Our humanized immune-PDX models enable appropriate preclinical translational research on tumor immune biology and the evaluation of new therapies and combinations, as well as the identification and validation of biomarkers for immune therapy. Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Bernadette Brzezicha, Konrad Klinghammer, Korinna Jöhrens, Wolfgang Walther, Jens Hoffmann. Preclinical models for translational immuno-oncology research: patient-derived xenografts on humanized mice [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 2713.
The Exosomes-Derived EGFR Ligand Amphiregulin (AREG) Is a New Pro-Osteoclastogenic Factor in Multiple Myeloma
Authors: Emanuela Vicario, Stefania Raimondo, Laura Saieva, Federica Costa, Vincenza Tinnirello, Fabrizio Accardi, Franco Aversa, Nicola Giuliani, Riccardo Alessandro
Journal: Blood (2017)
Abstract 1976: Ras-Raf-MEK-ERK signaling pathway: a novel target of ERRα and tamoxifen in TNBC cells
Authors: David Musheyev, Adi Ronen, Miriam T. Lattin, Anya Alayev
Journal: Cancer Research (2021)

Abstract TNBC, or triple-negative breast cancer, is an aggressive type of breast cancer that is associated with a worse prognosis, higher rates of metastases, and a poorer outcome. Historically, TNBC has been proven challenging to treat, due to disease heterogeneity and the fact that the breast cancer tests negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) protein, and thus does not respond to traditional therapies. As such, treatment options for TNBC patients are extremely limited and there is a tremendous need to identify molecular targets and biomarkers that can offer novel targeted approaches. Additionally, due to disease heterogeneity in TNBC, it is important to subclassify TNBC based on prognostic markers and create tailored targeted therapies. ERRα, an orphan nuclear receptor, is an example of a prognostic marker that is correlated with a more aggressive disease progression and a worse outcome. However, ERRα is also a predictive marker for patient response to tamoxifen treatment of ER-negative and TNBC patients, indicating that there may be an alternative use for the selective estrogen modulator (SERM) tamoxifen in the context of TNBC. This led us to investigate whether there is a common pathway that is regulated by both ERRα and tamoxifen that would explain tamoxifen response in the context of TNBC cells. We performed a phosphoproteomic analysis of MDA-MB-231 cells, treated with either tamoxifen or XCT-790, an inverse agonist of ERRα, to identify common downstream targets of both ERRα and tamoxifen. Our findings indicate that the Ras-Raf-MEK-ERK signaling pathway is a common target of both XCT-790 and tamoxifen. This provides a novel treatment strategy that should be investigated for the treatment of TNBC patients, opens the door for investigation of novel targeted therapies, and highlights the need for the use of prognostic markers to identify sub-populations that benefit from individualized treatment strategies. Citation Format: David Musheyev, Adi Ronen, Miriam T. Lattin, Anya Alayev. Ras-Raf-MEK-ERK signaling pathway: a novel target of ERRα and tamoxifen in TNBC 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 1976.
Changes in Ascitic Fluid Polymorphonuclear Cell Count After Antibiotics Are Associated With Mortality in Spontaneous Bacterial Peritonitis
Authors: Saad Saffo, Uyen K. To, Phillip P. Santoiemma, Marcela Laurito, Lamia Haque, Anahita Rabiee, Elizabeth C. Verna, Michael P. Angarone, Guadalupe Garcia-Tsao
Journal: Clinical Gastroenterology and Hepatology (2021)
Very long-term outcomes, time patterns of recurrence and other-cause mortality in patients treated with salvage radiation therapy for recurrent prostate cancer after radical prostatectomy: Implications for risk tailored follow-up strategies
Authors: E. Mazzone, N. Fossati, A. Stabile, A. Martini, R.J. Karnes, S.A. Boorjan, A. Bossi, N. Di Muzio, C. Cozzarini, G. Gandaglia, D. Bartkowiak, D. Böhmer, S. Shariat, G. Goldner, G. Devos, S. Joniau, C. Berghen, G. De Meerleer, H. Van Poppel, A. Necchi, F. Montorsi, T. Wiegel, A. Briganti
Journal: European Urology (2021)
Treatment options and outcomes of men with Penile Intraepithelial Neoplasia (PeIN): A systematic review
Authors: A. Issa, E. Lee, P. Oliveira, M. Lau, A. Parnham, V. Sangar, M. Lucky, N. Grossmann, J. Fronzaroli, F. Janisch, A. Kwok, K. Sebro, C.D. Fankhauser
Journal: European Urology (2021)
Abstract 19254: Engineering a Bioactive Pulmonary Valve using Patient-Specific Valvular Cells
Authors: David Simpson, Vasil Galat, Yekaterina Galat, Sunjay Kaushal
Journal: Circulation (2012)

Background: Valvular heart disease is an unfortunate part of the natural history of many congenital heart patients. Even with surgical interventions that use valvular replacements, pediatric patients with valvular dysfunction will likely require reoperations due to a progressive deterioration of graft durability and limited repair/growth potential. In order to address these concerns we sought to generate a biologically active pulmonary valve using patient-specific valvular cells and decellularized human pulmonary grafts. Methods and Results: Mesenchymal stem cells (MSCs) were generated from patient derived induced pluripotent stem (iPS) cells using culture conditions that favored an epithelial to mesenchymal transition. iPS-MSCs displayed CD105 and CD90 expression &gt; 90% after four passages and could differentiate into osteocytes, chondrocytes and adipocytes (N=4). iPS-MSCs lacked expression of CD45 and CD34. Additionally, compared to bone marrow MSCs, iPS-MSC proliferated more readily (43 ± 1 vs 87 ± 1, p &lt; 0.001) but maintained a gene expression profile &gt;80% identical to bone marrow MSCs. Next, decellularized human pulmonary heart valves (provided by CryoLife®, Inc.) were seeded with iPS-MSCs using a combination of static and dynamic culture conditions. Repopulated pulmonary grafts were cultured up to 30 days. Immunohistochemistry demonstrated increased cellularity and presence of extracellular matrix components such as vimentin, proteoglycans and glycosaminoglycans in repopulated pulmonary valves compared to decellularized pulmonary valves, suggesting sustained cell function and maturation. Conclusions: Our results demonstrate the feasibility of constructing a biologically active human pulmonary valve using a sustainable and potent cell source. It is expected that once implanted, the bioactive pulmonary valve will have advantages over existing valvular replacements by its ability to remodel and grow in the repair of congenital defects.
Artificial intelligence in computed tomography for quantifying lung changes in the era of CFTR modulators
Authors: Gael Dournes, Chase S. Hall, Matthew M. Willmering, Alan S. Brody, Julie Macey, Stephanie Bui, Baudouin Denis de Senneville, Patrick Berger, François Laurent, Ilyes Benlala, Jason C. Woods
Journal: European Respiratory Journal (2021)

Background Chest computed tomography (CT) remains the imaging standard for demonstrating cystic fibrosis (CF) airway structural disease in vivo . However, visual scoring systems as an outcome measure are time consuming, require training and lack high reproducibility. Our objective was to validate a fully automated artificial intelligence (AI)-driven scoring system of CF lung disease severity. Methods Data were retrospectively collected in three CF reference centres, between 2008 and 2020, in 184 patients aged 4–54 years. An algorithm using three 2D convolutional neural networks was trained with 78 patients’ CT scans (23 530 CT slices) for the semantic labelling of bronchiectasis, peribronchial thickening, bronchial mucus, bronchiolar mucus and collapse/consolidation. 36 patients’ CT scans (11 435 CT slices) were used for testing versus ground-truth labels. The method's clinical validity was assessed in an independent group of 70 patients with or without lumacaftor/ivacaftor treatment (n=10 and n=60, respectively) with repeat examinations. Similarity and reproducibility were assessed using the Dice coefficient, correlations using the Spearman test, and paired comparisons using the Wilcoxon rank test. Results The overall pixelwise similarity of AI-driven versus ground-truth labels was good (Dice 0.71). All AI-driven volumetric quantifications had moderate to very good correlations to a visual imaging scoring (p&lt;0.001) and fair to good correlations to forced expiratory volume in 1 s % predicted at pulmonary function tests (p&lt;0.001). Significant decreases in peribronchial thickening (p=0.005), bronchial mucus (p=0.005) and bronchiolar mucus (p=0.007) volumes were measured in patients with lumacaftor/ivacaftor. Conversely, bronchiectasis (p=0.002) and peribronchial thickening (p=0.008) volumes increased in patients without lumacaftor/ivacaftor. The reproducibility was almost perfect (Dice &gt;0.99). Conclusion AI allows fully automated volumetric quantification of CF-related modifications over an entire lung. The novel scoring system could provide a robust disease outcome in the era of effective CF transmembrane conductance regulator modulator therapy.
Abstract 1534: Mesothelin isoform 2 is a novel target for allogenic CARγδT cell therapy in solid tumors
Authors: Xiaohong Wang, Yibin Chen, Anupama Gopisetty, Leonardo Mirandola, Lucia Piccotti, Quynh Nguyen, Maurizio Chiriva-Internati
Journal: Cancer Research (2021)

Abstract Mesothelin (MSLN) is a tumor-associated antigen over-expressed on the cell surface of various malignant tumor cells, including majority of mesothelioma and ovarian cancer. MSLN-directed therapy has been intensively studied in preclinical and clinical settings. However, the clinical efficacy and safety of mesothelin-targeted therapy remains to be demonstrated. To identify a safe and effective target for CAR-T cell therapy in solid tumors, we used artificial intelligent platform developed with public and private RNA transcription database to identify cancer-associated antigens caused by alternative spicing. One of interesting targets is an alternative spicing isoform from MSLN. Human MSLN transcript has at least three isoforms. The isoform 1 is the predominant transcript detected in normal and tumor tissues and has been a promising target for cancer immunotherapy. The isoform 2 is the minor transcript using alternatively spliced exons producing 8 additional amino acids insertion compared to isoform 1. The isoform 3 produces a truncated and soluble MSLN. Our data demonstrated that MSLN isoform 2 is specifically expressed in ovarian cancers but not normal tissues, confirmed by Q-PCR studies. Furthermore, we generated mouse hybridoma antibodies specifically targeting MSLN isoform 2. The antibody specificity was screened and confirmed by ELISA-based reaction to MSLN isoform 2-specific peptide and flow cytometry-based binding to 293T cells overexpressing MSLN isoform 2 but not isoform 1 proteins. We further detected the endogenous MSLN isoform 2 expression in human mesothelioma cell line NCI H226 and further confirmed MSLN isoform 2 expression on human primary mesothelioma and ovarian cancer tissue but not normal tissues by immunohistochemistry staining. To study if targeting MSLN isoform 2 with chimeric antigen receptor (CAR) can control the tumor growth, we made CAR retrovirus construct and showed that genetically modified allogenic gamma-delta T cells expressing CAR for MSLN isoform 2 can kill human mesothelioma cells in vitro and in vivo. In summary, we have demonstrated that MSLN isoform 2 is a tumor-specific antigen, which can be targeted for CAR-T cell therapy. Citation Format: Xiaohong Wang, Yibin Chen, Anupama Gopisetty, Leonardo Mirandola, Lucia Piccotti, Quynh Nguyen, Maurizio Chiriva-Internati. Mesothelin isoform 2 is a novel target for allogenic CARγδT cell therapy in 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 1534.
Rising Rates and Widening Socioeconomic Disparities in Diabetic Ketoacidosis in Type 1 Diabetes in Scotland: A Nationwide Retrospective Cohort Observational Study
Authors: Joseph E. O’Reilly, Anita Jeyam, Thomas M. Caparrotta, Joseph Mellor, Andreas Hohn, Paul M. McKeigue, Stuart J. McGurnaghan, Luke A.K. Blackbourn, Rory McCrimmon, Sarah H. Wild, John R. Petrie, John A. McKnight, Brian Kennon, John Chalmers, Sam Phillip, Graham Leese, Robert S. Lindsay, Naveed Sattar, Fraser W. Gibb, Helen M. Colhoun
Journal: Diabetes Care (2021)

Whether advances in the management of type 1 diabetes are reducing rates of diabetic ketoacidosis (DKA) is unclear. We investigated time trends in DKA rates in a national cohort of individuals with type 1 diabetes monitored for 14 years, overall and by socioeconomic characteristics.All individuals in Scotland with type 1 diabetes who were alive and at least 1 year old between 1 January 2004 and 31 December 2018 were identified using the national register (N = 37,939). DKA deaths and hospital admissions were obtained through linkage to Scottish national death and morbidity records. Bayesian regression was used to test for DKA time trends and association with risk markers, including socioeconomic deprivation.There were 30,427 DKA admissions and 472 DKA deaths observed over 393,223 person-years at risk. DKA event rates increased over the study period (incidence rate ratio [IRR] per year 1.058 [95% credibility interval 1.054-1.061]). Males had lower rates than females (IRR male-to-female 0.814 [0.776-0.855]). DKA incidence rose in all age-groups other than 10- to 19-year-olds, in whom rates were the highest, but fell over the study. There was a large socioeconomic differential (IRR least-to-most deprived quintile 0.446 [0.406-0.490]), which increased during follow-up. Insulin pump use or completion of structured education were associated with lower DKA rates, and antidepressant and methadone prescription were associated with higher DKA rates.DKA incidence has risen since 2004, except in 10- to 19-year-olds. Of particular concern are the strong and widening socioeconomic disparities in DKA outcomes. Efforts to prevent DKA, especially in vulnerable groups, require strengthening.