tbuckley/cabot-search huggingface dataset:
Abstract IA11: Reversal of immunotherapy resistance through hypoxia reduction
Authors: Priyamvada Jayaprakash, Midan Ai, Michael A. Curran
Journal: Clinical Cancer Research (2020)

Abstract Across multiple cancers, we find that T cells fail to accumulate in regions of hypoxia that can occupy as much as 50% of the volume of some solid tumors. In mouse models of both prostate cancer and head and neck cancer, we find that the hypoxia-activated prodrug TH-302 (evofosfamide) can reduce hypoxia by triggering a tissue-remodeling process that culminates in revascularization with organized, functional vessels. In the TRAMP-C2 model of prostate cancer, combining TH-302 with blockade of the T-cell immune checkpoint receptors CTLA-4 and PD-1 cures nearly all mice of 7-day established tumors and the majority of larger, 2-week established malignancy. TRAMP transgenic mice, which do not respond at all to immunotherapy alone, treated with the combination of TH-302 and either CTLA-4 and PD-1 blockade or CTLA-4 blockade and 4-1BB agonist show exceptional tumor control at 36 weeks of age. Mechanistically, hypoxia favors accumulation of myeloid-derived suppressor cells (MDSC), and reduction of hypoxia using TH-302 significantly decreases both their frequency and density in prostate tumors. In addition, the capacity of MDSC from mice receiving hypoxia reduction and checkpoint blockade to suppress T-cell proliferation is significantly diminished. Tumor-infiltrating T cells benefit both directly and indirectly from hypoxia reduction as evidenced by increased proliferation, cytotoxicity, effector cytokine production, and survival. Immunofluorescence reveals a lack of T-cell infiltration of hypoxic zones even in the context of CTLA-4 and PD-1 blockade. In contrast, coadministration of TH-302 with checkpoint blockade promotes nearly equivalent T-cell densities across normoxic and hypoxic tumor areas. Clinically, we are evaluating the combination of TH-302 and ipilimumab in patients with checkpoint refractory melanoma, HPV- head and neck cancer, metastatic prostate cancer, and pancreatic cancer (NCT03098160). Correlative studies in these patients reveal advantageous skewing of the tumor immune microenvironment in tumors where hypoxia is reduced on therapy. Further studies of the response of patient cancers to this therapy are ongoing. In addition, we seek to understand the molecular mechanisms linking hypoxia to impaired suppression in stromal myeloid and fibroblast compartments, and to identify additional pharmacologic interventions capable of disrupting hypoxia. Citation Format: Priyamvada Jayaprakash, Midan Ai, Michael A. Curran. Reversal of immunotherapy resistance through hypoxia reduction [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA11.
Abstract 1611: MYB and the MYB-NFIB fusion induce adenoid cystic carcinoma
Authors: Yuan Hu, Xiaoyuan Zhu, Han Luo, Adel El-Naggar, Carlos Caulin
Journal: Cancer Research (2020)

Abstract Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands, also found at lower frequency rates in other secretory glands such as the mammary and lacrimal glands. Salivary ACCs are slow-growing but aggressive neoplasms, with propensity to perineural invasion and high recurrence rates. MYB is the most frequently altered gene in ACCs, as approximately 40% of the ACCs contain MYB-NFIB gene fusions, and the full-length MYB is overexpressed in over 50% of the fusion-negative ACCs. However, it is still unclear whether MYB activities promote ACC development. To assess the oncogenic potential of MYB in vivo, we generated transgenic mice that overexpress MYB using the TetO system. In these mice, focal MYB overexpression was directed to salivary and mammary glands using the activator line MMTV-tTA. We found that 25% of these mice developed tumors with an average latency of 23 months. Remarkably, all the tumors that developed in these mice were ACCs, and the three main phenotypic variants of human ACCs (cribriform, tubular and solid) were represented in this cohort. Using the same transgenic system, we found that the MYB-NFIB fusion also induced ACCs, with similar incidence and lower latency. Immunohistochemical analysis of these mouse ACCs for several biomarkers of human ACC, including p63 and c-kit, provided additional evidence of the similarity of the mouse ACCs that developed in these models, and human ACCs. RNAseq global expression profiling uncovered the activation of several cancer-associated pathways in MYB-induced mouse ACCs. Most notably, activation NOTCH signaling was highly enriched in these tumors. Additional analysis for the presence of the NOTCH intracellular domain demonstrated that all of the MYB- and MYB-NFIB-induced ACCs contain NOTCH activation. These findings, and the recent identification of activating mutations in NOTCH1 and NOTCH2 in human ACCs, suggest that NOTCH activities may contribute to ACC development. To test this hypothesis, ongoing studies in the lab are directed to assess the role of NOTCH signaling in ACC development, by generating mouse models in which constitutive activation of NOTCH is induced in mice alone or in combination with MYB alterations. Overall, these studies demonstrate that MYB activities are the main oncogenic driver of ACC. Genomic rearrangements that result in MYB-NFIB fusions may enhance the oncogenic potential of MYB. Citation Format: Yuan Hu, Xiaoyuan Zhu, Han Luo, Adel El-Naggar, Carlos Caulin. MYB and the MYB-NFIB fusion induce adenoid cystic carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1611.
Abstract 5266: Continuous trifluridine treatment in colorectal cancer cell lines- investigating its potential
Authors: Kenta Tsunekuni, Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi, Hidetoshi Eguchi, Masaki Mori, Yuichiro Doki, Hideshi Ishii
Journal: Cancer Research (2020)

Abstract Background: Trifluridine (FTD) is a key component of the novel, orally-administered, antitumor drug trifluridine/tipiracil, and is approved for treatment of patients with metastatic colorectal and gastric/GEJ cancers refractory to standard chemotherapy. FTD, an antineoplastic thymidine analogue, is incorporated into the genomic DNA of tumor cells, thereby triggering cell death. An international, double-blind, placebo-controlled Phase III study confirmed the efficacy of trifluridine/tipiracil in patients previously treated with standard chemotherapy. However, the clinical benefit of trifluridine/tipiracil in the first-line metastatic setting still remains unknown. Therefore, we analyzed the sensitivity for FTD, 5-FU, L-OHP, and SN-38 in parental and three FTD long-term treated cell lines. Methods: Three human colorectal cancer cell lines (DLD-1, HCT-116, and RKO) and their respective FTD long-term treated cell lines (treated by step-wise increase in concentrations of FTD starting at 1 µM and ending at 400 µM over a 5 month period) were used. Sensitivity assays using crystal violet staining for FTD, 5-FU, L-OHP, and SN-38 and wound healing assay to assess the migration capacity were performed in these cell lines. Further, mRNA was purified and the resulting microarray was utilized to analyze expression profiles. Results: Continuous FTD long-term treated cell lines were resistant to FTD. In the sensitivity assays, the IC50 values in all three continuously FTD treated cell lines increased by &amp;gt;22-fold for FTD, by &amp;lt;2-fold for 5-FU and L-OHP, and by &amp;lt;9-fold for SN-38 (2 to 8.2-fold in three cell lines) compared to those in parental cell lines. We found that FTD long-treated cells had weaker migration ability than parental cells in all three cell lines. Additionally, HIF1A related glycolytic mRNA was downregulated in FTD long-treated cell lines compared to that in parental cell lines. Conclusions: Although long-term treatment with FTD induced resistance in colorectal cancer cell lines, no cross-resistance to other drugs (5-FU, L-OHP) and partial resistance to SN-38 that are used in standard chemotherapy was observed. Therefore, FTD is expected to be effective even after treatment with standard chemotherapy. Although FTD/TPI is currently used in the later line, it is suggested from this basic study that FTD/TPI may be applicable to take to the front line therapy. Citation Format: Kenta Tsunekuni, Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi, Hidetoshi Eguchi, Masaki Mori, Yuichiro Doki, Hideshi Ishii. Continuous trifluridine treatment in colorectal cancer cell lines- investigating its potential [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5266.
Benefits and Risks of Bariatric Surgery in Adults
Authors: David E. Arterburn, Dana A. Telem, Robert F. Kushner, Anita P. Courcoulas
Journal: JAMA (2020)

<h3>Importance</h3> Severe obesity and its related diseases, such as type 2 diabetes, hypertension, dyslipidemia, and sleep apnea, are very common in the United States, but currently very few patients with these conditions choose to undergo bariatric surgery. Summaries of the expanding evidence for both the benefits and risks of bariatric surgery are needed to better guide shared decision-making conversations. <h3>Observations</h3> There are approximately 252 000 bariatric procedures (per 2018 numbers) performed each year in the US, of which an estimated 15% are revisions. The 1991 National Institutes of Health guidelines recommended consideration of bariatric surgery in patients with a body mass index (calculated as weight in kilograms divided by height in meters squared) of 40 or higher or 35 or higher with serious obesity-related comorbidities. These guidelines are still widely used; however, there is increasing evidence that bariatric procedures should also be considered for patients with type 2 diabetes and a body mass index of 30 to 35 if hyperglycemia is inadequately controlled despite optimal medical treatment for type 2 diabetes. Substantial evidence indicates that surgery results in greater improvements in weight loss and type 2 diabetes outcomes, compared with nonsurgical interventions, regardless of the type of procedures used. The 2 most common procedures used currently, the sleeve gastrectomy and gastric bypass, have similar effects on weight loss and diabetes outcomes and similar safety through at least 5-year follow-up. However, emerging evidence suggests that the sleeve procedure is associated with fewer reoperations, and the bypass procedure may lead to more durable weight loss and glycemic control. Although safety is a concern, current data indicate that the perioperative mortality rates range from 0.03% to 0.2%, which has substantially improved since early 2000s. More long-term randomized studies are needed to assess the effect of bariatric procedures on cardiovascular disease, cancer, and other health outcomes and to evaluate emerging newer procedures. <h3>Conclusions and Relevance</h3> Modern bariatric procedures have strong evidence of efficacy and safety. All patients with severe obesity—and especially those with type 2 diabetes—should be engaged in a shared decision-making conversation about the risks and benefits of surgery compared with continuing usual medical and lifestyle treatment, and the decision about surgery should be driven primarily by informed patient preferences.
Long-Term Risks of Parkinson’s Disease, Surgery, and Colorectal Cancer in Patients With Slow-Transit Constipation
Authors: Eun Mi Song, Hyo Jeong Lee, Kee Wook Jung, Mi Jung Kim, Sung Wook Hwang, Sang Hyoung Park, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Jaewon Choe, Suk-Kyun Yang, Satish S.C. Rao, Seung-Jae Myung
Journal: Clinical Gastroenterology and Hepatology (2020)
Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression
Authors: Sabine Brandt, Tobias M. Ballhause, Anja Bernhardt, Annika Becker, Delia Salaru, Hien Minh Le-Deffge, Alexander Fehr, Yan Fu, Lars Philipsen, Sonja Djudjaj, Andreas J. Müller, Rafael Kramann, Mahmoud Ibrahim, Robert Geffers, Chris Siebel, Berend Isermann, Florian H. Heidel, Jonathan A. Lindquist, Peter R. Mertens
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement In patients with CKD, receptor Notch3 is strongly upregulated. Conversely, in experimental kidney disease models, Notch3 deficiency protects from organ damage. To determine whether Notch3 on immune cells or tissue-resident cells participates in the inflammatory response, animals with bone marrow chimerism were generated. These animal strains do not exhibit phenotypic differences in the absence of disease. However, after unilateral ureteral obstruction, distinct alterations in the immune response and organ fibrosis become apparent. Notch3 receptors expressed by immune cells are of relevance for transmigration into tissue; the receptors expressed by resident kidney cells orchestrate organ fibrosis. These events seem to be separable and distinct. Background Kidney injuries that result in chronic inflammation initiate crosstalk between stressed resident cells and infiltrating immune cells. In animal models, whole-body receptor Notch3 deficiency protects from leukocyte infiltration and organ fibrosis. However, the relative contribution of Notch3 expression in tissue versus infiltrating immune cells is unknown. Methods Chimeric mice deficient for Notch3 in hematopoietic cells and/or resident tissue cells were generated, and kidney fibrosis and inflammation after unilateral ureteral obstruction (UUO) were analyzed. Adoptive transfer of labeled bone marrow–derived cells validated the results in a murine Leishmania ear infection model. In vitro adhesion assays, integrin activation, and extracellular matrix production were analyzed. Results Fibrosis follows UUO, but inflammatory cell infiltration mostly depends upon Notch3 expression in hematopoietic cells, which coincides with an enhanced proinflammatory milieu ( e.g ., CCL2 and CCL5 upregulation). Notch3 expression on CD45 + leukocytes plays a prominent role in efficient cell transmigration. Functionally, leukocyte adhesion and integrin activation are abrogated in the absence of receptor Notch3. Chimeric animal models also reveal that tubulointerstitial fibrosis develops, even in the absence of prominent leukocyte infiltrates after ureteral obstruction. Deleting Notch3 receptors on resident cells blunts kidney fibrosis, ablates NF- κ B signaling, and lessens matrix deposition. Conclusions Cell-specific receptor Notch3 signaling independently orchestrates leukocyte infiltration and organ fibrosis. Interference with Notch3 signaling may present a novel therapeutic approach in inflammatory as well as fibrotic diseases.
Survival and quality of life after early discharge in low-risk pulmonary embolism
Authors: Stefano Barco, Irene Schmidtmann, Walter Ageno, Toni Anušić, Rupert M. Bauersachs, Cecilia Becattini, Enrico Bernardi, Jan Beyer-Westendorf, Luca Bonacchini, Johannes Brachmann, Michael Christ, Michael Czihal, Daniel Duerschmied, Klaus Empen, Christine Espinola-Klein, Joachim H. Ficker, Cândida Fonseca, Sabine Genth-Zotz, David Jiménez, Veli-Pekka Harjola, Matthias Held, Lorenzo Iogna Prat, Tobias J. Lange, Mareike Lankeit, Athanasios Manolis, Andreas Meyer, Thomas Münzel, Pirjo Mustonen, Ursula Rauch-Kroehnert, Pedro Ruiz-Artacho, Sebastian Schellong, Martin Schwaiblmair, Raoul Stahrenberg, Luca Valerio, Peter E. Westerweel, Philipp S. Wild, Stavros V. Konstantinides
Journal: European Respiratory Journal (2020)

Introduction Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. Methods The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. Results The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean± sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of −9.1% (p&lt;0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p&lt;0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p&lt;0.0001). Conclusions Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.
DOCA/salt-induced hypertension plus high-cholesterol/high-lipid diet : A large animal model of concentric LV hypertrophy with increased LV stiffness
Authors: M. Schwarzl, S. Seiler, P. Steendijk, S. Huber, H. Maechler, M. Truschnig-Wilders, B. Pieske, H. Post
Journal: Cardiovascular Research (2012)
Immune correlates of SARS-CoV-2 protection
Authors: Matthew Brown
Journal: Nature reviews. Immunology (2020)

Inhaled nanobodies against COVID-19Nanobodies (Nbs) are naturally occurring single-domain antibody fragments from camelid heavy-chain antibodies.They have unique biophysical properties, including small size and thermostability, that allow aerosolized administration.In this preprint, Gai et al. describe Nb phage display libraries from camels immunized with the SARS-CoV-2 spike receptorbinding domain (RBD).Out of 381 Nbs identified, 7 blocked the interaction between the virus entry receptor ACE2 and 8 RBD variants.Nb11-59, a candidate with the highest neutralizing activity, was further selected to validate its interaction with the RBD by structure prediction analysis.Production of Nb11-59 in a yeast expression system followed by its nebulization showed potential for rapid and high-quality manufacturing.
Abstract 180: Systematic genomic analysis of matched PDX, PDX-derived organoids (PDXO), and PDX-derived cell lines (PDXC)
Authors: Xiaoxi Xu, Wubin Qian, Sheng Guo, Henry Q. Li
Journal: Cancer Research (2020)

Abstract INTRODUCTION Patient-derived xenografts (PDX) are considered predictive in vivo models for assessing cancer therapeutics due to their close genomic and histopathological resemblance to primary patient tumors. PDX can also be used to derive in vitro organoids (PDXO) and cell lines (PDXC), as we recently proposed and demonstrated, essentially creating matched pairs of in vitro and in vivo models. Cell lines serve as a conventional solution for fast and affordable evaluation of chemo- and targeted therapies, but they suffer from reduced clinical translatability. Organoids maintain organ structures and relevant functions in 3D culture, and are considered to be more physiologically relevant cancer models1. It is possible that the three experimental models have different genomic profiles, caused by different growing conditions, and that this will affect therapeutic evaluation, yet a systematic analysis is so far lacking. METHODS We developed a set of PDX-PDXO-PDXC model trios. Models were characterized for morphology, histopathology, genomics, and response to anticancer drugs, followed by a comparative analysis with an emphasis on genomic profiles. RESULTS We found that PDXO and PDXC have varied model establishment rates from PDX depending on cancer type. PDXO and PDXC show characteristic morphology. Like PDX, they exhibit model-specific growth kinetics and drug response. A high concordance of drug response was observed between PDX and matched PDXO. Genome-level mutation analysis showed good conservation of both somatic and driver mutations among the trios, indicating largely identical tumorigenesis mechanisms. However, significant transcriptomic differences were observed in pairwise comparisons between PDX-PDXO, PDX-PDXC, and PDXO-PDXC. We performed an in-depth analysis of differentially expressed genes, pathways, and gene networks to understand the underlying molecular mechanisms and their potential impact on drug evaluation. CONCLUSIONS Our study is the first large-scale comparative study to help understand the relatedness and uniqueness of PDX, PDXO, and PDXC on genomics. REFERENCES [1] Tuveson, D. &amp; Clevers, H. Cancer modeling meets human organoid technology. Science 364, 952-955 (2019). Citation Format: Xiaoxi Xu, Wubin Qian, Sheng Guo, Henry Q. Li. Systematic genomic analysis of matched PDX, PDX-derived organoids (PDXO), and PDX-derived cell lines (PDXC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 180.
Abstract 18410: Effect of Intensified Diuretic Therapy on Biomarkers of Congestion, Inflammation, Oxidative Stress and Endothelial Activation in Outpatients With Acute Decompensated Heart Failure
Authors: Hannah Rosenblum, Rosa Aponte Medina, Pauline Trinh, Ryan T Demmer, Jai Radhakrishnan, Justin Fried, Veli Topkara, Rachel Bijou, Melana Yuzefpolskaya, Arthur R Garan, Paolo C Colombo, Amirali Masoumi
Journal: Circulation (2017)

Introduction: Symptomatic heart failure (HF) is associated with an elevation of biomarkers of venous congestion (proBNP and CD146), inflammation (endothelin-1 (ET-1), interleukin-6 (IL-6), tumor ne...