tbuckley/cabot-search huggingface dataset:
THU0055 TPL2 INHIBITION SUPPRESSES MEK-ERK INFLAMMATORY SIGNALING AND PROINFLAMMATORY CYTOKINE PRODUCTION IN PRIMARY HUMAN MONOCYTES
Authors: Matthew R. Warr, Angie Hammond, Grace Park, Nathan Wright, James Taylor
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Tumor progression locus 2 (TPL2, also known as MAP3K8) is a mitogen-activated protein kinase kinase kinase and the primary regulator of ERK-mediated gene transcription downstream of multiple proinflammatory stimuli including bacterial products (eg, LPS and bacterial peptidoglycans), damage-associated molecular patterns (DAMPs), TNFα, and IL-1β.<sup>1</sup> Dysregulated signaling downstream of these inflammatory signals can drive uncontrolled immune cell activation and inflammation, which is associated with multiple chronic inflammatory and autoimmune diseases. As such, TPL2 inhibition represents a strategy to modulate inflammation in a variety of disease settings. <h3>Objectives</h3> We evaluated the effect of a highly selective TPL2 inhibitor on inflammatory signaling and cytokine production in LPS and TNFα-stimulated primary human monocytes. <h3>Methods</h3> Monocytes were precultured with a TPL2 inhibitor and stimulated with LPS or TNFα, and phosphosignaling and cytokine production were then evaluated at 30 minutes and 4 hours poststimulation. A431 cells (human epidermoid carcinoma cell line) were stimulated with TNFα or EGF and phospho–ERK was evaluated after 30 minutes. <h3>Results</h3> TPL2 inhibition selectively inhibited LPS and TNFα-stimulated phosphorylation of TPL2, MEK, and ERK, with little to no inhibition of phosphorylated p38, JNK, or p65 observed. TPL2 inhibition similarly inhibited both the RNA production and secretion of TNFα, IL-1β, IL-6, and IL-8 following LPS stimulation in primary human monocytes. To confirm TPL2 requirement for inflammatory, but not Ras-mediated (growth factor stimulated) ERK signaling, A431 cells were stimulated with either TNFα or EGF. Although TPL2 inhibition reduced TNFα-stimulated pERK, no effect on ERK activation downstream of EGF was observed. <h3>Conclusion</h3> This work demonstrates the selective effects of TPL2 inhibition on ERK-mediated signaling and proinflammatory cytokine gene transcription in primary human monocytes and highlights the potential for TPL2 inhibition to treat diseases associated with dysregulated inflammatory signaling and chronic inflammation. <h3>Reference</h3> [1] Gantke T,&nbsp;Sriskantharajah S,&nbsp;Ley S.&nbsp;Cell Res.&nbsp;2011;21:131-145. <h3>Disclosure of Interests</h3> Matthew R. Warr Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Angie Hammond Grant/research support from: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Grace Park Grant/research support from: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Nathan Wright Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., James Taylor Grant/research support from: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc.
Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer
Authors: Song Liu, Junko Matsuzaki, Lei Wei, Takemasa Tsuji, Sebastiano Battaglia, Qiang Hu, Eduardo Cortes, Laiping Wong, Li Yan, Mark Long, Anthony Miliotto, Nicholas W. Bateman, Shashikant B. Lele, Thinle Chodon, Richard C. Koya, Song Yao, Qianqian Zhu, Thomas P. Conrads, Jianmin Wang, George L. Maxwell, Amit A. Lugade, Kunle Odunsi
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Efficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates, with a validation rate of 0.5–2%. <h3>Methods</h3> Whole-exome and transcriptome sequencing analysis of treatment-naive EOC patients were performed to identify neoantigen candidates, and the immunogenicity of prioritized neoantigens was evaluated by analyzing spontaneous neoantigen-specfic CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses in the tumor and/or peripheral blood. The biological relevance of neoantigen-specific T-cell lines and clones were analyzed by evaluating the capacity of autologous ovarian tumor recognition. Genetic transfer of T-cell receptor (TCR) from these neoantigen-specific T-cell clones into peripheral blood T-cells was conducted to generate neoepitope-specific T-cells. The molecular signature associated with positive neoantigen T-cell responses was investigated, and the impacts of expression level and lymphocyte source on neoantigen identification were explored. <h3>Results</h3> Using a small subset of prioritized neoantigen candidates, we were able to detect spontaneous CD4<sup>+</sup> and/or CD8<sup>+</sup> T-cell responses against neoepitopes from autologous lymphocytes in half of treatment-naïve EOC patients, with a significantly improved validation rate of 19%. Tumors from patients exhibiting neoantigen-specific T-cell responses exhibited a signature of upregulated antigen processing and presentation machinery, which was also associated with favorable patient survival in the TCGA ovarian cohort. T-cells specific against two mutated cancer-associated genes, <i>NUP214</i> and <i>JAK1</i>, recognized autologous tumors<i>.</i> Gene-engineering with TCR from these neoantigen-specific T-cell clones conferred neoantigen-reactivity to peripheral T-cells. <h3>Conclusions</h3> Our study demonstrated the feasibility of efficiently identifying both CD4<sup>+</sup> and CD8<sup>+</sup> neoantigen-specific T-cells in EOC. Autologous lymphocytes genetically engineered with tumor antigen-specific TCR can be used to generate cells for use in the personalized adoptive T-cell transfer immunotherapy.
Declining FT4 concentrations following cranial irradiation: Indications for early development of mild central hypothyroidism?
Authors: L Van Lersel, S C Clement, A Y N Schouten-Van Meeteren, A M Boot, H L Claahsen-Van Der Grinten, B Granzen, K S Han, G O Janssens, E M Michiels, A S P Van Trotsenburg, W P Vandertop, D G Van Vuurden, H N Caron, L C M Kremer, H M Van Santen
Journal: Endocrine Reviews (2017)

Background:After exposure to cranial radiotherapy (cRT), hypothalamic-pituitary (HP) disorders are frequently observed in childhood brain tumor survivors (CBTS). It has been reported that the time to develop HP disorders varies, with a short lag time for GH deficiency (GHD) especially when compared to central hypothyroidism (CeH). (1, 2) In clinical practice, however, a decline in FT4 concentration in CBTS is frequently observed prior to or shortly after the diagnosis GHD. Declining FT4 concentrations with (inadequate) normallow TSH concentrations in CBTS may indicate radiation damage to TSH secreting cells. Hypothesis: The decline in FT4 concentration, often observed prior to or shortly after the diagnosis of GHD in CBTS who received cRT, can be validated in a large nationwide cohort. Methods: Inclusion criteria for the nationwide cohort study were: patients with a brain tumor diagnosed between 2002 and 2012, surviving >2 years after diagnosis and treated with cRT. All CBTS who developed GHD were included and CBTS with primary hypothyroidism were excluded. GHD was defined as an abnormal peak value of GH in one or two GH stimulation tests. The paired sample T-test was used to compare median FT4 concentrations at start of tumor treatment versus the median FT4 concentrations at diagnosis of GHD versus the median first FT4 concentrations after starting GH treatment. Results:Seventy-three CBTS had been diagnosed with GHD and were included for this study. Twenty-one CBTS (28.8%) were diagnosed with CeH prior to the diagnosis of GHD and therefore received treatment with thyroxine (T4). In 52 of the 73 CBTS (71.2%) FT4 concentrations were longitudinally analysed. GHD was diagnosed after a median follow-up time of 2.4yr after tumor diagnosis. The total median dose of cRT was 54Gy (range 15-72Gy). Median FT4 concentrations declined from 15.4 pmol/l after the start of tumor treatment to 14.0 pmol/l (P
Abstract 14708: Variation in Implementation and Outcomes Across Sites Participating in the Pediatric Heart Network (PHN) Collaborative Learning Study
Authors: Katherine E Bates, William T Mahle, Lauren B Retzloff, Janet E Donohue, Michael G Gaies, Susan C Nicolson, Lara S Shekerdemian, Madolin K Witte, Michael J Wolf, Judy A Shea, Donald S Likosky, Sara K Pasquali
Journal: Circulation (2017)

Introduction: The PHN Collaborative Learning Study increased early extubation after Tetralogy of Fallot (TOF) and coarctation repair through implementing a clinical practice guideline (CPG) at part...
A phase II study of dasatanib (BMS 354825) in recurrent or metastatic <i>ckit</i>-expressing adenoid cystic (ACC) and non-ACC malignant salivary glands tumors (MSGT).
Authors: Stuart J. Wong, Ezra E.W. Cohen, Theodore Karrison, David N. Hayes, Merrill S. Kies, Kevin J. Cullen, Tawee Tanvetyanon, Athanassios Argiris, Naoko Takebe, Dean Lim, Nabil F. Saba, Francis P. Worden, Jill Gilbert, Heinz-Josef Lenz, Albiruni R.A. Razak, John D. Roberts, Everett E. Vokes
Journal: Journal of Clinical Oncology (2013)

6022 Background: ACC is a rare disease, accounting for 1/3 rd of MSGT, in which 90% of cases express the protein product of the ckit proto-oncogene. Dasatinib is a potent and selective inhibitor of five oncogenic PTKs/kinase families including ckit. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. Methods: In a two-stage design, adult patients (pts) with recent radiographic progressive, recurrent or metastatic ACC, + cKIT, were treated with dasatinib 70 mg PO BID. Pts with non-ACC MSGT of other histologic types, were treated as a separate cohort. Response was assessed every 8 wks by imaging using RECIST criteria. The study design stipulated enrollment of n=40 ACC patients (20 in stage I and 20 in stage II) and 25 non-ACC patients (14 in stage I and 11 in stage II). Results: Fifty-four pts were enrolled, 40 ACC and 14 non-ACC. One additional pt was a screen failure. Baseline data on 54 pts are: M:F = 28:26, median age 56.6 yrs (range 20-82), PS 0:1:2 = 24:28:2, prior radiation:chemotherapy = 44:21. The most frequent adverse events experienced (as % of pts, worst grade 2 or higher and at least possibly related to study drug) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (11%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), and non-cardiac chest pain (6%). No grade 4 adverse events occurred and only 15 pts experienced a grade 3 adverse event (at least possibly attributed to study drug), primarily dyspnea (4 patients) and fatigue (3 patients). Significant cardiac toxicity was observed in one pt (grade 3 prolonged QT corrected interval). Among ACC pts, best response to dasatinib: 0 pts (0%) had PR, 21 pts (52%) had SD (range 2.8-13.8 months), 12 pts (30%) had PD, and 2 died prior to cycle 2. Median PFS was 4.8 mos. For 14 evaluable non-ACC pts, none had an objective response, triggering early stopping. 7 had SD (range 1.4-6.6 months), and 4 PD. Conclusions: Although there were no objective responses, dasatinib is well tolerated, with tumor stabilization achieved by 52% of ACC pts. Dasatinib demonstrated no activity in non-ACC MSGT. Clinical trial information: NCT00859937.
Abstract 16225: Angiotensin II Type 1 Receptor Autoantibody Induce Left Ventricular Remodeling in Offspring of Preeclamptic Mice
Authors: Lina Bai, Suli Zhang, Pengli Wang, Xiaochen Yin, Yulin Gong, Jingwei Bian, Huirong Liu
Journal: Circulation (2017)

Introduction: The aetiology of congenital heart defects (CHD) is mostly unknown, for which maternal factors have been identified as predisposing factors. Currently, the elevated prevalence of CHD a...
S910 A NEW MEMBRANE‐BOUND IL‐21/4–1BBL‐EXPANDED NK PRODUCT EXHIBITS ACTIVITY AGAINST ACUTE MYELOID LEUKEMIA ACTIVITY IN VIVO
Authors: X.‐Y. Zhao, Q. Jiang, H. Jiang, L.‐J. Hu, T. Zhao, X.‐X. Yu, X.‐J. Huang
Journal: HemaSphere (2019)

Background: Adoptive NK cells infusion is a promising immunotherapy for acute myeloid leukemia (AML) patients. Aims: The aim of this study was to explore that two weeks of clinical grade expansion could provide sufficient numbers and purity of NK cells for clinical application with an enhanced ant‐leukemia response in vitro. Methods: NK cells were expanded in the large‐scale expansion platform based on membrane‐bound interleukin‐21/4–1BBL K562 feeder cells (mbIL21/4‐1BBL). The phenotype as well as responsitveness of NKcells were evaluated before and post NK cells expansion. NCG mouse model were used to assess the in vivo persistence and in vivo anti‐leukemia effect of NK products. Finally, 20 minimal residual disease persistent or relapse (MRD+) AML were enrolled to evaluate the safety of adoptive expanded NK products infusion. Results: In this study, using the large‐scale expansion platform, we first demonstrated that 2 weeks of expansion could satisfy clinical use in number (∼4.1 × 10 9 NK cell) and purity (median 81%) from 2 × 10 7 peripheral blood mononuclear cells based on membrane‐bound interleukin‐21/4‐1BBL K562 feeder cells (mbIL21/4‐1BBL), with expansion folds of 1318 and 2876 at 2 and 3 weeks, respectively. The CD107α production as well as TNF‐α secretion capacity of NK products against AML cell lines, or primary AML blasts, were comparable between 2 weeks and 3 weeks expanded NK products, both of which were higher than those resting NK cells before expansion. The MbIL21/4‐1BBL expanded NK product xenografted into immunodeficient leukemia mice could be found in bone marrow, spleen, liver, lung and peripheral blood, persisting for at least 2 weeks and reducing the AML burden in vivo. NK cells infusions once, or three times every other days exhibited similar tumor control. Compared with the case‐paired 20 minimal residual disease persistent or relapse (MRD + ) AML patients with regular consolidation therapy, 20 AML MRD + patients who accepted the expanded NK treatment showed better leukemia‐free survival and overall survival. Summary/Conclusion: In conclusion, this study demonstrated that mbIL‐21/4‐1BBL expanded NK cells exhibited anti‐leukemia activity against AML in vitro and in a mouse model, and the infusion of expanded NK product was potentially efficacious for AML patient without adverse effects.
Rod-shape MSN@MoS<sub>2</sub> Nanoplatform for FL/MSOT/CT Imaging-Guided Photothermal and Photodynamic Therapy
Authors: Lifang Yang, Jinping Wang, Shan Yang, Qianglan Lu, Peishan Li, Nan Li
Journal: Theranostics (2019)

Rod-shape nanoplatform have received tremendous attention owing to their enhanced ability for cell internalization and high capacity for drug loading. MoS2, widely used in electronic devices, electrocatalysis, sensor and energy-storage, has been studied as photothermal agents over the years. However, the efficacy of rod-shape MoS2 based photothermal agents for photothermal therapy has not been studied before. Here, a near-infrared (NIR) light-absorbing MoS2 nanosheets coated mesoporous silica nanorods with human serum albumin (HSA) modifying and Ce6 loading (MSNR@MoS2-HSA/Ce6) were constructed for combined photothermal and photodynamic therapy. Methods: The near-infrared (NIR) light was used to trigger the synergistic anti-tumor therapy. In addition, breast cancer cell line was applied to evaluate the in vitro anti-tumor activity. The multi-modal imaging capacity and tumor-killing efficiency of the designed nanocomposites in vivo was also demonstrated with the 4T1 tumor-bearing mouse model. Results: These nanocomposites could not only perform NIR light triggered photodynamic therapy (PDT) and photothermal therapy (PTT), but also achieve in vivo fluorescence (FL) /multispectral optical tomography (MSOT)/X-ray computed tomography (CT) triple-model bioimaging. What's more, the rod-shape nanoplatform could be endowed with better anti-tumor ability based on the EPR effect and HSA-mediated active tumor targeting. At the same time, the hyperthermia generated by MoS2 could synergistically improve the PDT effect with the acceleration of the blood flow, leading to the increase of the oxygen level in tumor tissue. Conclusion: MSNR@MoS2-HSA/Ce6 proves to be a promising multi-functional nanoplatform for effective treatment of tumor.
Non-classical estrogen signaling in ovarian cancer improves chemo-sensitivity and patients outcome
Authors: Dapeng Hao, Jingjing Li, Jianlin Wang, Yuan Meng, Zhiqiang Zhao, Chao Zhang, Kai Miao, Chuxia Deng, Benjamin K. Tsang, Li Wang, Li-jun Di
Journal: Theranostics (2019)

Deficiency in homologous recombination repair (HRR) is frequently associated with hormone-responsive cancers, especially the epithelial ovarian cancer (EOC) which shows defects of HRR in up to half of cases.However, whether there are molecular connections between estrogen signaling and HRR deficiency in EOC remains unknown.Methods: We analyzed the estrogen receptor α (ERα) binding profile in EOC cell lines and investigated its association with genome instability, HRR deficiency and sensitivity to chemotherapy using extensive public datasets and in vitro/in vivo experiments.Results: We found an inverse correlation between estrogen signaling and HRR activity in EOC, and the genome-wide collaboration between ERα and the co-repressor CtBP.Though the non-classical AP-1-mediated ERα signaling, their targets were highly enriched by HRR genes.We found that depleting ERα in EOC cells up-regulates HRR activity and HRR gene expression.Consequently, estrogen signaling enhances the sensitivity of ovarian cancer cells to chemotherapy agents in vitro and in vivo.Large-scale analyses further indicate that estrogen replacement and ESR1 expression are associated with chemo-sensitivity and the favorable survival of EOC patients.Conclusion: These findings characterize a novel role of ERα in mediating the molecular connection between hormone and HRR in EOC and encourage hormone replacement therapy for EOC patients.
FRI0293 FACTORS ASSOCIATED WITH FIRST-YEAR AND OVERALL MORTALITY IN ANCA ASSOCIATED VASCULITIS; PATIENTS WITH RENAL LIMITED VASCULITIS MAKES NO BETTER THAN MICROSCOPIC POLYANGIITIS
Authors: Onay Gercik, Zeki Soypacaci, Fulya Çakalağaoğlu, Gokhan Kabadayi, Idil Kurut, Dilek Solmaz, Servet Akar
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Overall mortality in ANCA-associated vasculitis (AAV) over the last two decades has been reported to be decreasing with the use of immunosuppressive therapies. However, mortality rates remain high and most of the deaths occur in the first year after diagnosis despite treatment. <h3>Objectives</h3> In this study, we aimed to determine the prevalence of mortality in our AAV patients and to investigate the factors that may be associated with first-year and overall mortality. <h3>Methods</h3> Patients followed up in one center with the diagnosis of AAV were included in the study. Diagnostic subgroups were; granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and renal-limited vasculitis (RLV). The clinical and demographic characteristics of the patients were collected retrospectively. Factors predictive of mortality were evaluated by Kaplan-Meier method and the Cox proportional hazard model. <h3>Results</h3> In total 104 (45 [43%] female and mean age 54.9 ± 15.4 years) AAV patients (51 GPA; 25 MPA; 27 RLV and 1 EGPA) were included in the analysis. ANCA positivity was detected in 81 (77.9%) patients with IIF and/or ELISA. ESRD had developed in 31 (32.3%) of AAV patients and in 37.8% of patients with renal involvement. Mortality rate was 14.4% in the first year after diagnosis and 27.9% during a median follow-up period of 1289 (5-5804) days. The age at diagnosis was the only significant predictor of first-year mortality (p=0.006). Univariate analysis revealed that overall mortality was associated with AAV subgroups (p = 0.035), renal (p = 0.046) (figure) and, ENT (ear-throat) involvement (p = 0.025), ESRD (p = 0.025) and hemodialysis at the time of diagnosis (p = 0.040). However Cox regression analysis showed age at diagnosis as the only significant predictor also of the overall mortality (<i>P</i>=0,001). <h3>Conclusion</h3> Our findings suggest that there could be some survival differences between AAV subgroups and patients with or without renal and ENT involvement. However, <b>t</b>he age at diagnosis seems to be the only significant predictor of first-year and overall mortality in our AAV patients. *AAV: ANCA-Associated Vasculitis; GPA: Granulomatosis with PolyAngiitis; MPA: Microscopic PolyAngiitis; RLV: Renal Limited Vasculitis <h3>Disclosure of Interests</h3> Onay Gercik: None declared, Zeki Soypacaci: None declared, Fulya Çakalağaoğlu: None declared, Gokhan Kabadayi: None declared, Idil Kurut: None declared, Dilek Solmaz: None declared, Servet Akar Grant/research support from: MSD, Abbvie, Roche, UCB, Novartis, Pfizer, Amgen, Consultant for: MSD, Abbvie, Roche, UCB, Novartis, Pfizer, Amgen, Speakers bureau: Pfizer
Prioritizing putative influential genes in cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization
Authors: Kurt Taylor, George Davey Smith, Caroline L. Relton, Tom R. Gaunt, Tom G. Richardson
Journal: Genome Medicine (2019)

The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization (MR) was then applied using findings from genome-wide association studies (GWAS) to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently used Bayesian multiple-trait colocalization to further interrogate the findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility. Finally, we applied our analysis pipeline genome-wide using summary statistics from large-scale GWAS. Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol, respectively, were particularly insightful. Multiple-trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also affect cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses uncovered evidence of tissue specificity between gene expression in liver tissue and cholesterol levels. Applying our pipeline genome-wide using summary statistics from GWAS uncovered 233 association signals at loci which represent promising candidates for further evaluation. Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease.