tbuckley/cabot-search huggingface dataset:
Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer
Authors: Amelia U. Schirmer, Lucy M. Driver, Megan T. Zhao, Carrow I. Wells, Julie E. Pickett, Sean N. O’Bryne, Benjamin J. Eduful, Xuan Yang, Lauren Howard, Sungyong You, Gayathri R. Devi, John DiGiovanni, Stephen J. Freedland, Jen-Tsan Chi, David H. Drewry, Everardo Macias
Journal: Molecular Therapy (2021)

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.
NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma
Authors: Alejandra Leivas, Antonio Valeri, Laura Córdoba, Almudena García-Ortiz, Alejandra Ortiz, Laura Sánchez-Vega, Osvaldo Graña-Castro, Lucía Fernández, Gonzalo Carreño-Tarragona, Manuel Pérez, Diego Megías, María Liz Paciello, Jose Sánchez-Pina, Antonio Pérez-Martínez, Dean A. Lee, Daniel J. Powell, Paula Río, Joaquín Martínez-López
Journal: Blood Cancer Journal (2021)

Abstract CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA − T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM.
Annals Graphic Medicine - Dr. Mom: My Favorite Thing to Say on Rounds
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2021)

Web ExclusivesSeptember 2021Annals Graphic Medicine - Dr. Mom: My Favorite Thing to Say on RoundsFREEGrace E. Farris, MDGrace E. Farris, MDUniversity of Texas, Austin, Texas (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0053 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of Texas, Austin, Texas (G.E.F.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0024.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Dell Medical School at the University of Texas in Austin, Texas. You can view her work at her website: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org.This article was published at Annals.org on 24 August 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics September 2021Volume 174, Issue 9Page: W81-W82 ePublished: 24 August 2021 Issue Published: September 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Prognostic Value of Stress Cardiac Magnetic Resonance in Patients With Known Coronary Artery Disease
Authors: Panagiotis Antiochos, Yin Ge, Bobak Heydari, Kevin Steel, Scott Bingham, Shuaib M. Abdullah, J. Ronald Mikolich, Andrew E. Arai, W. Patricia Bandettini, Amit R. Patel, Afshin Farzaneh-Far, John F. Heitner, Chetan Shenoy, Steve W. Leung, Jorge A. Gonzalez, Dipan J. Shah, Subha V. Raman, Victor A. Ferrari, Jeanette Schulz-Menger, Matthias Stuber, Orlando P. Simonetti, Raymond Y. Kwong
Journal: JACC. Cardiovascular imaging (2021)
28095 Long-term safety of guselkumab: Results from the VOYAGE 1 and VOYAGE 2 trials with up to 5 years of treatment
Authors: Andrew Blauvelt, Kenneth B. Gordon, Christopher E.M. Griffiths, Kim A. Papp, Peter Foley, Michael Song, Megan Miller, Yaung-Kaung Shen, Yin You, Paraneedharan Ramachandran, Kristian Reich
Journal: Journal of the American Academy of Dermatology (2021)
Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF
Authors: Zhenzhen Chen, Tiankun Lu, Lan Huang, Zhiwei Wang, Zhongyi Yan, Yubo Guan, Wenjing Hu, Zusen Fan, Pingping Zhu
Journal: Journal of Clinical Investigation (2021)

Liver tumor-initiating cells (TICs) are involved in liver tumorigenesis, metastasis, drug resistance, and relapse, but the regulatory mechanisms of liver TICs are largely unknown. Here, we have identified a functional circular RNA, termed circRNA activating MAFF (cia-MAF), that is robustly expressed in liver cancer and liver TICs. cia-MAF-KO primary cells and cia-maf-KO liver tumors harbor decreased ratios of TICs, and display impaired liver tumorigenesis, self-renewal, and metastatic capacities. In contrast, cia-MAF overexpression drives liver TIC propagation, self-renewal, and metastasis. Mechanistically, cia-MAF binds to the MAFF promoter, recruits the TIP60 complex to the MAFF promoter, and finally promotes MAFF expression. Loss of cia-MAF function attenuates the combination between the TIP60 complex and the MAFF promoter. MAFF is highly expressed in liver tumors and liver TICs, and its antisense oligo (ASO) has therapeutic potential in treating liver cancer without MAFA/MAFG gene copy number alterations (CNAs). This study reveals an additional layer for liver TIC regulation as well as circRNA function, and provides an additional target for eliminating liver TICs, especially for liver tumors without MAFA/MAFG gene CNAs.
Dietary Fats High in Linoleic Acids Impair Antitumor T-cell Responses by Inducing E-FABP–Mediated Mitochondrial Dysfunction
Authors: Rong Jin, Jiaqing Hao, Yanmei Yi, Di Yin, Yuan Hua, Xiaohong Li, Hanmei Bao, Xianlin Han, Nejat K. Egilmez, Edward R. Sauter, Bing Li
Journal: Cancer Research (2021)

Abstract The most recent American Dietary Guidelines (2020–2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear. Here we demonstrated that high-fat diets (HFD) rich either in OA or LA induced a similar degree of murine obesity, but the LA-rich HFD specifically promoted mammary tumor growth. LA impaired antitumor T-cell responses by promoting naïve T-cell apoptosis and inhibiting TNFα production. While exogenous OA and LA were taken up by T cells with similar efficacy, only LA induced significant mitochondrial reactive oxygen species production and lipid peroxidation. Importantly, naïve T cells predominantly expressed epidermal fatty acid binding protein (E-FABP), which is central in facilitating LA mitochondrial transport and cardiolipin incorporation. Genetic depletion of E-FABP rescued LA-impaired T-cell responses and suppressed LA-rich HFD-associated mammary tumor growth. Collectively, these data suggest that dietary oils high in LA promote mammary tumors by inducing E-FABP–mediated T-cell dysfunction. Significance: These findings suggest that modulation of dietary oil composition and inhibition of E-FABP activity may represent novel strategies to enhance T-cell function in the prevention and treatment of obesity-associated cancers.
Osteopontin promotes osteosarcoma metastasis to the lung through interaction with integrin αvβ3
Authors: Wolf Hassenpflug, Mihaela Lorger, Jane Forsyth, Bruce Torbett, Brunhilde Felding-Habermann
Journal: Cancer Research (2008)

1960  Metastatic spreading to the lung is the key limiting factor to treatment of osteosarcoma, a highly aggressive bone cancer. Eighty percent of osteosarcoma patients have hematogenous lung metastases at the time of initial diagnosis. Less than half of them can be cured despite aggressive treatment regimens.  In order to identify mechanisms supporting osteosarcoma colonization of lung tissue we developed a novel orthotopic mouse model reproducing the metastatic features of human osteosarcoma. After orthotopic injection of SJSA1 osteosarcoma cells into the left tibia of 5 to 7 weeks old male C.B-17/lcrTac SCID mice, these animals developed primary tumors in the tibia that spontaneously metastasized to the lungs. We derived highly metastatic variants of SJSA1 from primary tumors and lung lesions. The lung derived variant of SJSA1 was 789-times more efficient in establishing hematogenous lung metastases than the parental cells.  Previously we showed that the metastatic behavior of osteosarcoma cells correlates with the expression of osteopontin, which is highly overexpressed in the more aggressive tumor cell variants.  We now show that the main function of osteopontin overexpression is to mediate an early survival advantage of the metastatic cells after their arrival in the lung. This effect is demonstrated in experimental metastasis assays in vivo using non-invasive bioluminescent imaging and can be modeled in vitro in cell proliferation assays in a 3D collagen matrix. Both endogenous and exogenous osteopontin promote growth of SJSA1 tumor cells in 3D collagen. Stable knockdown of osteopontin expression in SJSA1 variants by shRNA reduced osteosarcoma cell survival in 3D collagen, and markedly reduced in vivo lung colonization in our mouse model. We show that on osteosarcoma cells integrin αvb3 is the major receptor for osteopontin and mediates tumor cell survival and proliferation in response to the binding event. The integrin αvβ3 and osteopontin supported autocrine pathway depends on the activation state of the integrin, with the more aggressive cells displaying constitutively activated integrin αvβ3 receptors.  Our data show that osteopontin and integrin αvβ3 promote early tumor cell survival during metastatic target organ colonization from the blood stream. We are currently investigating the molecular pathways which drive tumor cell survival through interaction of osteopontin and integrin αvβ3. Our initial findings suggest that the integrin αvβ3 and osteopontin axis maybe a potential therapeutic target for treatment of metastatic osteosarcoma.
Theratyping cystic fibrosis<i>in vitro</i>in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells
Authors: Giovanni Sette, Stefania Lo Cicero, Giovanna Blaconà, Silvia Pierandrei, Sabina Maria Bruno, Valentina Salvati, Germana Castelli, Mario Falchi, Benedetta Fabrizzi, Giuseppe Cimino, Ruggero De Maria, Mauro Biffoni, Adriana Eramo, Marco Lucarelli
Journal: European Respiratory Journal (2021)

Question Cystic fibrosis (CF) is due to pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recent improvements have enabled pharmacological therapy aiming at restoring mutated CFTR expression and function. CFTR “modulators” have revolutionised the CF therapeutic landscape, particularly the last approved, Trikafta. This drug combination is indicated by the United States Food and Drug Administration and very recently by the European Medicines Agency for genotypes carrying at least one copy of CFTR with the F508del pathogenic variant. However, several genotypes are not yet eligible for Trikafta treatment. Materials/patients and methods We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients. This approach, coupled to the development of AESC-derived personalised disease models, as organoids and air–liquid interface (ALI) cultures, revealed highly suitable for CFTR pharmacological testing. Results and answer to the question We fully validated the experimental models and implemented the CFTR functional assays and biochemical CFTR protein characterisation, which allowed the evaluation of the efficacy of clinically available modulators in restoring CFTR maturation and function of each patient-derived “avatar” (theratyping). F508del homozygous genotypes, used as controls, confirmed the higher clinical activity of Trikafta in comparison with older modulators. In addition, Trikafta showed its efficacy on three rare genotypes previously not eligible for treatment with modulators, opening the way to clinical translation. Finally, encouraging results for innovative drug combinations were obtained.
N6-methyladenosine-modified circIGF2BP3 inhibits CD8+ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer
Authors: Zhenchuan Liu, Tingting Wang, Yunlang She, Kaiqing Wu, Shaorui Gu, Lei Li, Chenglai Dong, Chang Chen, Yongxin Zhou
Journal: Molecular Cancer (2021)

Abstract Background An in-depth understanding of immune evasion mechanisms in tumors is crucial to overcome resistance and enable innovative advances in immunotherapy. Circular RNAs (circRNAs) have been implicated in cancer progression. However, much remains unknown regarding whether circRNAs impact immune escape in non-small-cell lung carcinoma (NSCLC). Methods We performed bioinformatics analysis to profile and identify the circRNAs mediating immune evasion in NSCLC. A luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pulldown assays and fluorescence in situ hybridization were performed to identify the interactions among circIGF2BP3, miR-328-3p, miR-3173-5p and plakophilin 3 (PKP3). In vitro T cell-mediated killing assays and in vivo syngeneic mouse models were used to investigate the functional roles of circIGF2BP3 and its downstream target PKP3 in antitumor immunity in NSCLC. The molecular mechanism of PKP3-induced PD-L1 upregulation was explored by immunoprecipitation, RIP, and ubiquitination assays. Results We demonstrated that circIGF2BP3 (hsa_circ_0079587) expression was increased in NSCLC and negatively correlated with CD8 + T cell infiltration. Functionally, elevated circIGF2BP3 inactivated cocultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model, and this effect was dependent on CD8 + T cells. Mechanistically, METTL3 mediates the N 6 -methyladenosine (m 6 A) modification of circIGF2BP3 and promotes its circularization in a manner dependent on the m 6 A reader protein YTHDC1. circIGF2BP3 competitively upregulates PKP3 expression by sponging miR-328-3p and miR-3173-5p to compromise the cancer immune response. Furthermore, PKP3 engages with the RNA-binding protein FXR1 to stabilize OTUB1 mRNA, and OTUB1 elevates PD-L1 abundance by facilitating its deubiquitination. Tumor PD-L1 deletion completely blocked the impact of the circIGF2BP3/PKP3 axis on the CD8 + T cell response. The inhibition of circIGF2BP3/PKP3 enhanced the treatment efficacy of anti-PD-1 therapy in a Lewis lung carcinoma mouse model. Collectively, the PKP3/PD-L1 signature and the infiltrating CD8 + T cell status stratified NSCLC patients into different risk groups. Conclusion Our results reveal the function of circIGF2BP3 in causing immune escape from CD8 + T cell-mediated killing through a decrease in PD-L1 ubiquitination and subsequent proteasomal degradation by stabilizing OTUB1 mRNA in a PKP3-dependent manner. This work sheds light on a novel mechanism of PD-L1 regulation in NSCLC and provides a rationale to enhance the efficacy of anti-PD-1 treatment in NSCLC.
Circulating Protein Disulfide Isomerase Is Associated with Increased Risk of Thrombosis in <i>JAK2</i>-Mutated Myeloproliferative Neoplasms
Authors: Anish V. Sharda, Thomas Bogue, Alexandra Barr, Lourdes M. Mendez, Robert Flaumenhaft, Jeffrey I. Zwicker
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Thromboembolic events (TE) are the most common complications of myeloproliferative neoplasms (MPN). Clinical parameters, including patient age and mutation status, are used to risk-stratify patients with MPN, but a true biomarker of TE risk is lacking. Protein disulfide isomerase (PDI), an endoplasmic reticulum protein vital for protein folding, also possesses essential extracellular functions, including regulation of thrombus formation. Pharmacologic PDI inhibition prevents thrombus formation, but whether pathologic increases in PDI increase TE risk remains unknown. Experimental Design: We evaluated the association of plasma PDI levels and risk of TE in a cohort of patients with MPN with established diagnosis of polycythemia vera (PV) or essential thrombocythemia (ET), compared with healthy controls. Plasma PDI was measured at enrollment and subjects followed prospectively for development of TE. Results: A subset of patients, primarily those with JAK2-mutated MPN, had significantly elevated plasma PDI levels as compared with controls. Plasma PDI was functionally active. There was no association between PDI levels and clinical parameters typically used to risk-stratify patients with MPN. The risk of TE was 8-fold greater in those with PDI levels above 2.5 ng/mL. Circulating endothelial cells from JAK2-mutated MPN patients, but not platelets, demonstrated augmented PDI release, suggesting endothelial activation as a source of increased plasma PDI in MPN. Conclusions: The observed association between plasma PDI levels and increased risk of TE in patients with JAK2-mutated MPN has both prognostic and therapeutic implications.
Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary Cholangitis
Authors: Bo Li, Jun Zhang, Yong Chen, Qixia Wang, Li Yan, Rui Wang, Yiran Wei, Zhengrui You, Yikang Li, Qi Miao, Xiao Xiao, Min Lian, Weihua Chen, Dekai Qiu, Jingyuan Fang, M. Eric Gershwin, Ruqi Tang, Xiong Ma
Journal: Gut Microbes (2021)

Background: Increasing data suggests an interaction between bile acids and intestinal microbiota in the pathogenesis of primary biliary cholangitis (PBC). Bile acid sequestrants are widely used to bind bile acids in the intestinal lumen and are therefore posited to impact gut bacteria. Herein we aimed to investigate the effects of cholestyramine on the bile acid profile and gut microbiome in a cohort of icteric PBC patients.Results: Thirty-three PBC patients were treated with cholestyramine, serum and stool samples were collected at baseline, 4 and 16 weeks. Shotgun metagenomic sequencing and targeted metabolomic profiling were performed. Following cholestyramine administration, patients exhibited a high interpersonal variability in remission of cholestasis, and were therefore dichotomized according to the decrease of total bilirubin. Gut microbial co-abundance networks showed distinct taxa interactions between subjects with superior remission (SR) and those with inferior remission (IR) at baseline. After treatment, compositional shifts of the microbiome in the SR group were characterized with enrichment of two Lachnospiraceae species, typically producing short-chain fatty acids (SCFAs). In contrast, Klebsiella pneumonia, a commensal pathobiont, was only increased in the IR group. Correspondingly, metabolome analysis demonstrated that patients with SR, but not IR, were marked by elevations of SCFAs including valeric acid and caproic acid. Finally, integrative analysis identified robust associations between the variations of microbiota, metabolites, and inflammatory cytokines in SR group, indicating potential mechanistic links.Conclusions: Beneficial responses caused by cholestyramine were closely related with compositional and functional alterations in gut commensal, highlighting the possibility of exploring bile acid-microbiota interactions for treating PBC.
Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro
Authors: Aneta Ledererova, Lenka Dostalova, Veronika Kozlova, Helena Peschelova, Adriana Ladungova, Martin Culen, Tomas Loja, Jan Verner, Sarka Pospisilova, Michal Smida, Veronika Mancikova
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Anti-CD19 chimeric antigen receptor T cells (CART-19) frequently induce remissions in hemato-oncological patients with recurred and/or refractory B-cell tumors. However, malignant cells sometimes escape the immunotherapeutic targeting by CD19 gene mutations, alternative splicing or lineage switch, commonly causing lack of CD19 expression on the surface of neoplastic cells. We assumed that, in addition to the known mechanisms, other means could act on CD19 to drive antigen-negative relapse. Methods Herein, we studied the mechanism of antigen loss in an in vivo CD19-negative recurrence model of chronic lymphocytic leukemia (CLL) to CART-19, established using NOD- scid IL2Rg null mice and HG3 cell line. We validated our findings in vitro in immortalized B-cell lines and primary CLL cells. Results In our in vivo CLL recurrence model, up to 70% of CART-19-treated mice eventually recurred with CD19-negative disease weeks after initial positive response. We found that the lack of CD19 expression was caused by promoter DNA hypermethylation. Importantly, the expression loss was partially reversible by treatment with a demethylating agent. Moreover, this escape mechanism was common for 3 B-cell immortalized lines as well as primary CLL cells, as assessed by in vitro coculture experiments. Conclusions Epigenetically driven antigen escape could represent a novel, yet at least partially reversible, means of CD19 loss to CART-19 in B-cell tumors.
Ratiometric Raman nanotags enable intraoperative detection of metastatic sentinel lymph node
Authors: Zhouzhou Bao, Binge Deng, Yuqing Zhang, Xiaowei Li, Ziyang Tan, Zhuowei Gu, Bobo Gu, Zhifeng Shao, Wen Di, Jian Ye
Journal: Biomaterials (2021)