tbuckley/cabot-search huggingface dataset:
Abstract B14: Epigenetic remodeling of cancer metabolisms in cisplatin-resistant bladder cancer
Authors: Austin Yeon, Sungyong You, Minhyung Kim, Amit Gupta, Myung Hee Park, Daniel Weisenberger, Gangning Liang, Jayoung Kim
Journal: Clinical Cancer Research (2020)

Abstract Introduction and Objective: Alterations in DNA methylation are important epigenetic markers in bladder cancer (BC). These epigenome modifications drive the mechanisms of aggressive chemoresistant BC. Clinicopathologic biomarkers that indicate chemotherapeutic resistance are critical for better assessing treatment strategies for individual patients. Thus, in this study, we aimed to determine whether DNA methylation of certain metabolic enzymes is significantly altered in cisplatin-resistant BC cells. Methods: To characterize CpG methylation and nucleosome accessibility in cisplatin-resistant BC cells, the Illumina Infinium HM450 DNA methylation assay was performed. Perturbed gene expression was found to be associated with cisplatin resistance, and the biologic roles of spermidine/spermine N1-acetyltransferase (SAT1) and argininosuccinate synthase 1 (ASS1) were further studied using qRT-PCR analysis and various cell biology assays, including Western blot. Results: ASS1 and SAT1, genes for amino acid and polyamine metabolism catalysts, respectively, were found to be vastly hypermethylated, resulting in greatly downregulated expression. ASS1 expression is of particular interest because prior studies have demonstrated its potential association with BC stage and recurrence. In regard to chemoresistance, we found that aberrant expression or induced stimulation of SAT1 restored cisplatin sensitivity in the cell culture system. We also found that the addition of exogenous arginine deiminase through administration of ADI-PEG 20 (pegylated arginine deiminase) increased ASS1 expression and enhanced cisplatin's apoptotic effects. Conclusions: Our study demonstrates a novel mechanistic link between the epigenetic perturbation of SAT1 and ASS1 and cancer metabolism in cisplatin-resistant bladder cancer cells. These findings suggest potential utility of SAT1 and ASS1 as predictive biomarkers in resensitizing bladder cancer to chemotherapy and personalizing therapy. Citation Format: Austin Yeon, Sungyong You, Minhyung Kim, Amit Gupta, Myung Hee Park, Daniel Weisenberger, Gangning Liang, Jayoung Kim. Epigenetic remodeling of cancer metabolisms in cisplatin-resistant bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B14.
Pioglitazone Reduces Mortality and Adverse Events in Patients With Type 2 Diabetes and With Advanced Chronic Kidney Disease: National Cohort Study
Authors: Chieh-Li Yen, Chao-Yi Wu, Lai-Chu See, Yi-Jung Li, Min-Hua Tseng, Wei-Sheng Peng, Jia-Rou Liu, Yung-Chang Chen, Tzung-Hai Yen, Ya-Chung Tian, Chih-Wei Yang, Gerard F. Anderson, Huang-Yu Yang
Journal: Diabetes Care (2020)

Several oral hypoglycemic agents (OHA) are not recommended for patients with advanced chronic kidney disease (CKD). Early use of supplemental insulin, which can potentially increase the risk of hypoglycemia and cardiovascular events, was noted among patients with limited choices. Pioglitazone is a thiazolidinedione, which can be safely used in patients with CKD and patients with end-stage renal disease (ESRD) without dose adjustment. Previous research has indicated that pioglitazone can improve peripheral insulin sensitivity and potentially reduce cardiovascular risks (1). However, the benefit of pioglitazone in patients with type 2 diabetes (T2D) with advanced CKD has been overlooked. Using Taiwan’s National Health Insurance Research Database (NHIRD), which covers ∼99.8% of Taiwan’s population (nearly 23.37 million) and provides comprehensive health care information, we compared the incidence of major cardiac and cerebrovascular events (MACCE) and new-onset ESRD requiring dialysis and the rate of mortality in T2D patients with advanced CKD treated with pioglitazone and the most popular OHA, dipeptidyl peptidase 4 (DPP-4) inhibitors, in this population. DPP-4 inhibitors were known for their low risk of hypoglycemia and near-neutral effect on cardiovascular outcomes (2).

In this study, a total of 90,193 T2D …
No Evidence for Erythro-Myeloid Progenitor-Derived Vascular Endothelial Cells in Multiple Organs
Authors: Teng Feng, Zibei Gao, Shan Kou, Xinyan Huang, Zhen Jiang, Zhengkai Lu, Jufeng Meng, Chao-Po Lin, Hui Zhang
Journal: Circulation Research (2020)

Rationale: Endothelial cells are thought to emerge de novo from the mesoderm to form the entire circulatory system. Recently, erythro-myeloid progenitors (EMPs) have been proposed to be another remarkable developmental origin for blood vessels in multiple organs, including the hindbrain, liver, lung, and heart, as demonstrated by lineage tracing studies using different genetic tools. These observations challenge the current consensus that intraembryonic vessels are thought to expand solely by the proliferation of preexisting endothelial cells. Resolution of this controversy over the developmental origin of endothelial cells is crucial for developing future therapeutics for vessel-dependent organ repair and regeneration. Objective: To examine the contribution of EMPs to intraembryonic endothelial cells. Methods and Results: We first used a transgenic mouse expressing a tamoxifen-inducible Mer-iCre fusion protein driven by the Csf1r (colony stimulating factor 1 receptor) promoter. Genetic lineage tracing based on Csf1r-Mer-iCre-Mer showed no contribution of EMPs to brain endothelial cells identified by several markers. We also generated a knock-in mouse line by inserting an internal ribosome entry site-iCre cassette into the 3′ untranslated region of Csf1r gene to further investigate the cellular fates of EMPs. Similarly, we did not find any Csf1r-ires-iCre traced endothelial cells in brain, liver, lung, or heart in development either. Additionally, we found that Kit (KIT proto-oncogene receptor tyrosine kinase) was expressed not only in EMPs but also in embryonic hindbrain endothelial cells. Therefore, Kit promoter–driven recombinase, such as Kit-CreER, is a flawed tool for lineage tracing when examining the contribution of EMPs to hindbrain endothelial cells. We also traced CD45 (protein tyrosine phosphatase receptor type C; Ptprc) + circulating EMPs and did not find any CD45 lineage-derived endothelial cells during development. Conclusions: Our study suggested that EMPs are not the origin of intraembryonic endothelial cells.
MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity
Authors: Eros Di Giorgio, Liqing Wang, Yan Xiong, Tatiana Akimova, Lanette M. Christensen, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Tricia R. Bhatti, Ulf H. Beier, Wayne W. Hancock
Journal: Journal of Clinical Investigation (2020)

The transcription factor MEF2D is important in the regulation of differentiation and adaptive responses in many cell types. We found that among T cells, MEF2D gained new functions in Foxp3+ T regulatory (Treg) cells due to its interactions with the transcription factor Foxp3 and its release from canonical partners, like histone/protein deacetylases. Though not necessary for the generation and maintenance of Tregs, MEF2D was required for the expression of IL-10, CTLA4, and Icos, and for the acquisition of an effector Treg phenotype. At these loci, MEF2D acted both synergistically and additively to Foxp3, and downstream of Blimp1. Mice with the conditional deletion in Tregs of the gene encoding MEF2D were unable to maintain long-term allograft survival despite costimulation blockade, had enhanced antitumor immunity in syngeneic models, but displayed only minor evidence of autoimmunity when maintained under normal conditions. The role played by MEF2D in sustaining effector Foxp3+ Treg functions without abrogating their basal actions suggests its suitability for drug discovery efforts in cancer therapy.
SAT0045 Spondylodiscitis in ankylosing spondylitis
Authors: P Borman, U Seckin, H Gunduz, N Barca, L Damgaci
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Spondylodiscitis is a rare but well-known complication of ankylosing spondylitis (AS). <h3>Objectives</h3> The aim of this study was to evaluate the incidence of spondylodiscitis and to determine the clinical and radiological appearance in a group of patients with AS. <h3>Methods</h3> Thirty-two patients with a mean age of 36.4 ± 11.4 years were recruited to the study. Demographical, clinical and radiological characteristics of the patients were recorded. Bone scintigraphic evaluation and computerised tomography (CT) of the suspected lesions were determined. <h3>Results</h3> Five (15.6%) patients had radiographic abnormalities including irregular narrowed disc space borders and sclerosis of the adjent vertebral bodies in the thoracic and lumbar regions. All these patients had low back pain the clinical activity parameters were higher in 3 (9.3%) of 5 patients. No fracture or pseudoarthrosis were observed. Technetium scan showed increased uptake in the vertebral disc space and vertebral end plates (L4–5, T12-L1) in 2 (6.2%) of 5 patients and only 1 (3.1%) of them had typical CT findings including widening, irregularity and sclerosis at the L4–5 intervertebral space. <h3>Conclusion</h3> Spondylodiscitis may have variable clinical or radiological manifestations and imaging techniques are needed to identify this uncommon complication in patients with AS.
THU0020 Role of fcgammarii and fcgammariii in inflammation and cartilage damage during murine experimental antigen-induced arthritis
Authors: PL Van Lent, KC Nabbe, AB Blom, AE Holthuysen, LB Van de Putte, S Verbeek, WB Van den Berg
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> IgG-containing immune complexes, which are found in most RA joints, communicate with haematopoietic cells using three classes of Fc receptors (FcγRI, II, III). In a previous study we found that if an experimental arthritis was elicited in knee joints of FcR γ-chain deficient mice which lack functional FcγRI and III, joint inflammation was lower and severe cartilage destruction was absent. <h3>Objectives</h3> To examine the role of FcγRII and III in inflammation and functional cartilage damage in knee joints with chronic experimental antigen-induced arthritis (AIA) using FcγRIII and FcγRII deficient mice. <h3>Methods</h3> FcγRII and FcγRIII -/- mice and their controls were immunised with methylated BSA in complete adjuvant followed by induction of arthritis by local injection of mBSA into the right knee joint. The course of inflammation was studied by 99mTc uptake. Chronic inflammation and cartilage damage (depletion of proteoglycans, chondrocyte death and matrix erosion) was studied histologically in total knee joints sections stained with haematoxylin or safranin-O. Aggrecan breakdown in cartilage caused by metalloproteinases (MMP) was studied by immunolocalisation (VDIPEN neoepitopes) and image analysis. <h3>Results</h3> Three weeks after immunisation both humoral (total IgG, IgG1, IgG2a and IgG2b levels) and cellular (T cell responses as measured by lymphocyte proliferation) immunity raised against mBSA was comparable in all groups examined. IgG2a levels were comparable in FcγRIII-/- but higher in FcγRII-/- if compared to controls. Joint swelling at day 1, 3 and 7 was similar in FcγRIII -/- mice and significantly (103%) higher in FcγRII-/- on day 1 but not on later time-points. Histologically, at day 7 after AIA induction, exudate and infiltrate in the knee joint was similar in FcγRIII -/- and significantly higher (100% and 388%) in FcγRII-/- mice if compared to controls. MMP-induced neoepitopes determined in various cartilage layers (tibia and femur) were comparable in FcγRIII-/- and higher (respectively 155–360% and 67–75%) in FcγRII-/-. Initial depletion of proteoglycans was similar (40–70%) in all groups. In the chronic phase, chondrocyte and cartilage matrix erosion in tibia and femur stage was significantly elevated in FcγRII -/- but not in FcγRIII-/- mice. <h3>Conclusion</h3> FcγRIII is redundant or not involved in the presence of FcγRI whereas FcγRII is a crucial inhibiting factor in acute and chronic inflammation and cartilage erosion during antigen-induced arthritis. <h3>Reference</h3> Van Lent, <i>et al</i>. Arthritis Rheum. 2000;43(4):740–52
Improvement of Severe Fatigue Following Nuclease Therapy in Patients With Primary Sjögren’s Syndrome: A Randomized Clinical Trial
Authors: James Posada, Saba Valadkhan, Daniel Burge, Kristen Davies, Jessica Tarn, John Casement, Kerry Jobling, Peter Gallagher, Douglas Wilson, Francesca Barone, Benjamin A. Fisher, Wan‐Fai Ng
Journal: Arthritis & Rheumatology (2020)

To assess the safety and efficacy of RSLV-132, an RNase Fc fusion protein, in a phase II randomized, double-blind, placebo-controlled clinical trial in patients with primary Sjögren's syndrome (SS).
Association Between Fat Mass in Early Life and Later Fat Mass Trajectories
Authors: Kirsten S. de Fluiter, Inge A. L. P. van Beijsterveldt, Laura M. Breij, Dennis Acton, Anita C. S. Hokken-Koelega
Journal: JAMA Pediatrics (2020)

A rapid increase in weight in early life is associated with an increased risk for adiposity and cardiovascular diseases at age 21 years and beyond. However, data on associations of early change in measured fat mass percentage (FM%) with adiposity development are lacking.To investigate whether a rapid increase in FM% in the first months of life is associated with higher trajectories of body fat mass during the first 2 years of life.A birth cohort consisting of 401 healthy, term-born infants of the Sophia Pluto Cohort Study was analyzed. Participants were born between January 7, 2013, and October 13, 2017. Data were analyzed from February 1, 2020, to May 20, 2020.Longitudinal measurements of FM% by air-displacement plethysmography and dual-energy x-ray absorptiometry, and abdominal subcutaneous and visceral fat mass (FM) by ultrasonography in infants at ages 1, 3, 6, 9, 12, 18, and 24 months. A rapid increase in FM% was defined as a change in FM% of greater than 0.67 standard deviation scores (SDS).Associations between change in FM% SDS in the first and second 6-month period of life with body composition at age 2 years and whether a rapid increase in FM% SDS during the first 6 months leads to higher body FM and abdominal FM trajectories during the first 2 years of life.Of the 401 participants, 228 infants (57%) were male. Change in FM% SDS from age 1 to 6 months was positively associated with FM% (β, 0.044; 95% CI, 0.017-0.068), FMI (β, 0.061; 95% CI, 0.032-0.091), and abdominal subcutaneous FM (β, 0.064; 95% CI, 0.036-0.092) at age 2 years, but not with visceral FM. In contrast, no associations were found within the 6- to 12-month period. Infants with a rapid increase in FM% of greater than 0.67 SDS in the first 6 months of life had higher trajectories of FM%, FM index, and subcutaneous FM during the first 2 years of life (all P≤.001), but visceral FM index was not significantly different compared with infants without a rapid increase (P = .12).In this study, only the change in FM% in the first 6 months of life was associated with more adiposity at age 2 years. Infants with a rapid increase in FM% had higher trajectories of FM% and FM index during the first 2 years of life. These findings appear to support a critical window for adiposity programming in early life.
Intramyocardial Bone Marrow Cell Injection in Patients with Chronic Myocardial Ischemia : Results Long Term Follow-Up
Authors: S. Rodrigo, J. van Ramshorst, S.L. Beeres, P. Dibbets-Schneider, M. Stokkel, W.E. Fibbe, J.J. Zwaginga, E.E. van der Wall, M.J. Schalij, J.J. Bax, D.E. Atsma
Journal: Circulation (2011)
NIR-II emissive multifunctional AIEgen with single laser-activated synergistic photodynamic/photothermal therapy of cancers and pathogens
Authors: Yuling Xu, Yi Zhang, Jun Li, Jusung An, Chonglu Li, Suya Bai, Amit Sharma, Ganzhen Deng, Jong Seung Kim, Yao Sun
Journal: Biomaterials (2020)
Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion
Authors: Hong Luo, Jingwen Su, Ruixin Sun, Yansha Sun, Yi Wang, Yiwei Dong, Bizhi Shi, Hua Jiang, Zonghai Li
Journal: Clinical Cancer Research (2020)

Abstract Purpose: T-cell recruitment, survival, and proliferation are the important limitations to chimeric antigen receptor (CAR) T cells therapy in the treatment of solid tumors. In this study, we engineered CAR-T cells to coexpress cytokines IL7 and CCL21 (7 × 21 CAR-T), a cytokine combination in order to improve proliferation and chemotaxis of CAR-T cells. Experimental Design: CLDN18.2-specific second-generation CAR-T cells coexpressing cytokines were prepared using retroviral vector transduction. The proliferation and migration of genetically engineered CAR-T cells were evaluated in vitro. The antitumor activities of genetically engineered CAR-T cells were evaluated against multiple solid tumors in C57BL/6 mice in vivo. Results: In vitro, the proliferation and chemotaxis of 7 × 21 CAR-T cells are significantly improved when compared with those of the conventional CAR-T cells. In vivo, 7 × 21 CAR-T cells revealed superior therapeutic effects to either conventional CAR-T cells or 7 × 19 CAR-T cells which coexpress IL7 and CCL19 as previously reported in three different solid tumors without cyclophosphamide precondition. Interestingly, 7 × 21 CAR-T cells could also suppress the tumor growth with heterogeneous antigen expression and even induce tumor complete remission. Mechanistically, IL7 and CCL21 significantly improved survival and infiltration of CAR-T cells and dendritic cells in tumor. In addition, CCL21 also inhibited the tumor angiogenesis as proved by IHC. Conclusions: Coexpression of IL7 and CCL21 could boost CAR-T cells' antitumor activity, and 7 × 21 CAR-T cells may be served as a promising therapy strategy for solid tumors.
Abstract 13212: A New Non-Vascular System to Treat Resistant Hypertension
Authors: Richard R Heuser, Terry J Buelna, Winton L Berci, Brad S Hubbard
Journal: Circulation (2013)

INTRODUCTION: In the Western world, 30% to 40% of adults suffer from hypertension. Resistant hypertension (RH) prevalence has increased to over 25% of patients. To date, renal denervation to treat ...
Abstract CT401: The experience of treating patients with cancer during the COVID-19 pandemic in China
Authors: Li Zhang, F Zhu, L Xie, C Wang, J Wang, R Chen, P Jia, H Q. Guan, L Peng, P Peng, P Zhang, Q Chu, Q Shen, Y Wang, S Y. Xu, J P. Zhao, M Zhou, Y Chen
Journal: Cancer Research (2020)

Abstract Background: Cancer patients are regarded as highly vulnerable group in the current SARS-CoV-2/COVID-19 pandemic. Up to date, the clinical characteristics of cancer patients with COVID-19 are largely unknown. Patients and methods: In this retrospective cohort study, we collected and analyzed data of the cancer patients with y confirmed COVID-19 infection from three designated hospitals in Wuhan, China from Jan 13, 2020, to Feb 26, 2020. Univariate and multivariate analyses were performed to assess the risk factors associated with severe events defined as a condition that admission to an intensive care unit, the use of mechanical ventilation, or death. We also followed 124 cancer patients with immune checkpoint inhibitors (ICI) and their families for their infection rate and clinical outcome. Results: Twenty-eight COVID-19 infected cancer patients were included with median age of 65.0 years (IQR:56.0-70.0) and male gender of 60.7% (17/28). Amount of these 28 patients, 7 (25%) had lung cancer, and 8 (28.6%) were considered to be infected via hospital-associated transmission. Fifteen (53.6%) patients had severe events with the mortality rate of 28.6%. The last anti-tumor treatment within 14 days from the diagnoses of COVID significant increased risk of developing severe events (HR=4.079, 95%CI 1.086-15.322, P=0.037). The common chest CT findings were ground-glass opacity (21, 75.0%) and patchy consolidation (13, 46.3%). The patchy consolidation on CT had a higher risk for developing severe events (HR=5.438, 95%CI 1.498-19.748, P=0.010). There was only one patient (1/124, 0.8%) who have been on ICI treatment for his metastatic HCC confirmed with COVID infection, and with mild clinic presentation and a short hospital course. Conclusions: Cancer patients showed aggressive presentation and poor outcomes with the COVID-19 infection. It is recommended that vigorous screening for COVID-19 infection should be performed for cancer patients with anti-tumor. From our limited data, there is no evidence to suggest difference in cancer patients on ICI treatment. Citation Format: Li Zhang, F Zhu, L Xie, C Wang, J Wang, R Chen, P Jia, H Q. Guan, L Peng, P Peng, P Zhang, Q Chu, Q Shen, Y Wang, S Y. Xu, J P. Zhao, M Zhou, Y Chen. The experience of treating patients with cancer during the COVID-19 pandemic in China [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 CT401.
Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes
Authors: Sarah F Adams, Alizée J Grimm, Cheryl L-L Chiang, Ananda Mookerjee, Dallas Flies, Stephanie Jean, Georgia A McCann, Justine Michaux, HuiSong Pak, Florian Huber, Christopher Neal, Denarda Dangaj, Michal Bassani-Sternberg, Sylvie Rusakiewicz, Andrea Facciabene, George Coukos, Phyllis A Gimotty, Lana E Kandalaft
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Novel therapeutic strategies in ovarian cancer (OC) are needed as the survival rate remains dismally low. Although dendritic cell-based cancer vaccines are effective in eliciting therapeutic responses, their complex and costly manufacturing process hampers their full clinical utility outside specialized clinics. Here, we describe a novel approach of generating a rapid and effective cancer vaccine using ascites-derived monocytes for treating OC. Methods Using the ID8 mouse ovarian tumor model and OC patient samples, we isolated ascites monocytes and evaluated them with flow cytometry, Luminex cytokine and chemokine array analysis, ex vivo cocultures with T cells, in vivo tumor challenge and T cell transfer experiments, RNA-sequencing and mass spectrometry. Results We demonstrated the feasibility of isolating ascites monocytes and restoring their ability to function as bona fide antigen-presenting cells (APCs) with Toll-like receptor (TLR) 4 lipopolysaccharide and TLR9 CpG-oligonucleotides, and a blocking antibody to interleukin-10 receptor (IL-10R Ab) in the ID8 model. The ascites monocytes were laden with tumor antigens at a steady state in vivo. After a short 48 hours activation, they upregulated maturation markers (CD80, CD86 and MHC class I) and demonstrated strong ex vivo T cell stimulatory potential and effectively suppressed tumor and malignant ascites in vivo. They also induced protective long-term T cell memory responses. To evaluate the translational potential of this approach, we isolated ascites monocytes from stage III/IV chemotherapy-naïve OC patients. Similarly, the human ascites monocytes presented tumor-associated antigens (TAAs), including MUC1, ERBB2, mesothelin, MAGE, PRAME, GPC3, PMEL and TP53 at a steady state. After a 48-hour treatment with TLR4 and IL-10R Ab, they efficiently stimulated oligoclonal tumor-associated lymphocytes (TALs) with strong reactivity against TAAs. Importantly, the activated ascites monocytes retained their ability to activate TALs in the presence of ascitic fluid. Conclusions Ascites monocytes are naturally loaded with tumor antigen and can perform as potent APCs following short ex vivo activation. This novel ascites APC vaccine can be rapidly prepared in 48 hours with a straightforward and affordable manufacturing process, and would be an attractive therapeutic vaccine for OC.