bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new risk factor indicator for papillary thyroid cancer based on immune infiltration
Authors: Yang Zhou , Wei Xiyi , Pan Yitong , Xu Jingyuan , Si Yan , Min Zhijun , Yu Bo 
Published: January 2021

AbstractIncreasing evidence has indicated a close association between immune infiltration in cancer and clinical outcomes. However, related research in thyroid cancer is still deficient. Our research comprehensively investigated the immune infiltration of thyroid cancer. Data derived from TCGA and GEO databases were analyzed by the CIBERSORT, ESTIMATE, and EPIC algorithms. The CIBERSORT algorithm calculates the proportions of 22 types of immune cells. ESTIMATE algorithm calculates a stromal score to represent all stromal cells in cancer. The EPIC algorithm calculates the proportions of cancer-associated fibroblasts (CAFs) and endothelial cells (ECs), which are the main components of stromal cells. We analyzed the correlation of immune infiltration with clinical characteristics and outcomes of patients. We determined that the infiltration of CD8+ T cells improved the survival of thyroid cancer patients. Overexpression of immune checkpoints was closely related to the development of thyroid cancer. In general, stromal cells were associated with the progression of thyroid cancer. Interestingly, CAFs and ECs had opposite roles in this process. In addition, the BRAFV600E mutation was related to the upregulation of immune checkpoints and CAFs and the downregulation of CD8+ T cells and ECs. Finally, we constructed an immune risk score model to predict the prognosis and development of thyroid cancer. Our research demonstrated a comprehensive panorama of immune infiltration in thyroid cancer, which may provide potential value for immunotherapy.
Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein
Authors: Meng Wen , Gao Shou-Jiang 
Published: January 2021

AbstractNucleocytoplasmic transport of signaling modulators is essential for regulating cellular responses to extracellular stimulation and stress, as well as pathogen infection. Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), mediates nuclear export of proteins, rRNAs, snRNAs, and some mRNAs. In this study, we have identified an essential role of XPO1 in regulating Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication during primary infection of primary human umbilical vein endothelial cells. Treatment with an XPO1 inhibitor KPT-8602 and short hairpin RNA (shRNA)-mediated knockdown of XPO1 reduced KSHV lytic replication but had no effect on KSHV entry and trafficking. XPO1 inhibition induced retention of autophagy adaptor protein p62 (SQSTM1) in the nucleus, which enhanced activation of TBK1 and IRF3. As a result, nuclear accumulation of p62 increased expression of innate immune-related genes including IRF7, ISG15, IFIT1, IFIT2, and IFIT3, leading to a reduction of KSHV lytic replication. These results illustrate a novel mechanism by which XPO1 mediates innate immune response and KSHV replication, and identify XPO1 as a potential therapeutic target and KPT-8602 as a promising therapeutic agent for KSHV infection.
STIM1 promotes angiogenesis by reducing exosomal miR-145 in breast cancer MDA-MB-231 cells
Authors: Pan Shunli , Zhao Xiaoxia , Shao Chen , Fu Bingjie , Huang Yingying , Zhang Ning , Dou Xiaojing , Zhang Zhe , Qiu Yuling , Wang Ran , Jin Meihua , Kong Dexin 
Published: January 2021

AbstractCancer cells secrete abundant exosomes, and the secretion can be promoted by an increase of intracellular Ca2+. Stromal interaction molecule 1 (STIM1) plays a key role in shaping Ca2+ signals. MicroRNAs (miRNAs) have been reported to be potential therapeutic targets for many diseases, including breast cancer. Recently, we investigated the effect of exosomes from STIM1-knockout breast cancer MDA-MB-231 cells (Exo-STIM1-KO), and from SKF96365-treated MDA-MB-231 cells (Exo-SKF) on angiogenesis in human umbilical vein endothelial cells (HUVECs) and nude mice. The exosomes Exo-STIM1-KO and Exo-SKF inhibited tube formation by HUVECs remarkably. The miR-145 was increased in SKF96365 treated or STIM1-knockout MDA-MB-231 cells, Exo-SKF and Exo-STIM1-KO, and HUVECs treated with Exo-SKF or Exo-STIM1-KO. Moreover, the expressions of insulin receptor substrate 1 (IRS1), which is the target of miR-145, and the downstream proteins such as Akt/mammalian target of rapamycin (mTOR), Raf/extracellular signal regulated-protein kinase (ERK), and p38 were markedly inhibited in HUVECs treated with Exo-SKF or Exo-STIM1-KO. Matrigel plug assay in vivo showed that tumor angiogenesis was suppressed in Exo-STIM1-KO, but promoted when miR-145 antagomir was added. Taken together, our findings suggest that STIM1 promotes angiogenesis by reducing exosomal miR-145 in breast cancer MDA-MB-231 cells.
Neuronal extracellular vesicle derived miR-98 prevents salvageable neurons from microglial phagocytosis in acute ischemic stroke
Authors: Yang Jin , Cao Lu-Lu , Wang Xi-Peng , Guo Wei , Guo Ruo-Bing , Sun Yu-Qin , Xue Teng-Fei , Cai Zhen-Yu , Ji Juan , Cheng Hong , Sun Xiu-Lan 
Published: January 2021

AbstractExtracellular vesicles (EVs), as a novel intercellular communication carrier transferring cargo microRNAs (miRNAs), could play important roles in the brain remodeling process after ischemic stroke. However, the detailed mechanisms involved in EVs derived miRNAs-mediated cellular interactions in the brain remain unclear. Several studies indicated that microRNA-98 (miR-98) might participate in the pathogenesis of ischemic stroke. Here, we showed that expression of miR-98 in penumbra field kept up on the first day but dropped sharply on the 3rd day after ischemic stroke in rats, indicating that miR-98 could function as an endogenous protective factor post-ischemia. Overexpression of miR-98 targeted inhibiting platelet activating factor receptor-mediated microglial phagocytosis to attenuate neuronal death. Furthermore, we showed that neurons transferred miR-98 to microglia via EVs secretion after ischemic stroke, to prevent the stress-but-viable neurons from microglial phagocytosis. Therefore, we reveal that EVs derived miR-98 act as an intercellular signal mediating neurons and microglia communication during the brain remodeling after ischemic stroke. The present work provides a novel insight into the roles of EVs in the stroke pathogenesis and a new EVs-miRNAs-based therapeutic strategy for stroke.
Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer
Authors: Long Zhi , Deng Liang , Li Chao , He Qiangrong , He Yao , Hu Xiheng , Cai Yi , Gan Yu 
Published: January 2021

AbstractThe rising of a highly aggressive subtype of castration-resistant prostate cancer (CRPC) named treatment-induced neuroendocrine prostate cancer (t-NEPC) after androgen deprivation therapy (ADT) is well known for its features of the neuroendocrine differentiation (NED) and androgen receptor (AR) independence. However, t-NEPC is still largely unknown. Here, we found that EHF is notably depressed in t-NEPC tumors, patient-derived xenografts, transgenic mice, and cell models. Results from cell lines uncovered that ADT represses EHF expression, which is required for the ADT-induced NED. Mechanism dissection revealed that ADT decreases the EHF transcription via relieving the AR binding to different androgen-responsive elements, which then promotes the expression and enzymatic activity of enhancer of zeste homolog 2 (EZH2), consequently catalyzing tri-methylation lysine 27 of histone H3 for transcriptional repression of its downstream genes to promote the NED. Furthermore, preclinical studies from cell and mice models proved that recovery of EHF expression or using EZH2 inhibitor can attenuate aggressive properties of CRPC cells, hinder the progression of t-NEPC, and promote the response of CPRC cells to enzalutamide. Together, we elucidate that the ADT/AR/EHF/EZH2 signaling is required for the ADT-enhanced NED and plays a critical role in the progression of t-NEPC.
Human primary epidermal organoids enable modeling of dermatophyte infections
Authors: Wang Xuan , Wang Shuyong , Guo Baolin , Su Yuxin , Tan Zuolong , Chang Mingyang , Diao Jinmei , Zhao Yi , Wang Yunfang 
Published: January 2021

AbstractTechnology of generating human epidermal derivatives with physiological relevance to in vivo epidermis is continuously investigated for improving their effects on modeling of human natural dermatological status in basic and clinical studies. Here, we report a method of robust establishment and expansion of human primary epidermal organoids (hPEOs) under a chemically defined condition. hPEOs reconstruct morphological, molecular, and functional features of human epidermis and can expand for 6 weeks. Remarkably, hPEOs are permissive for dermatophyte infections caused by Trichophyton Rubrum (T. rubrum). The T. rubrum infections on hPEOs reflect many aspects of known clinical pathological reactions and reveal that the repression on IL-1 signaling may contribute to chronic and recurrent infections with the slight inflammation caused by T. rubrum in human skin. Thus, our present study provides a new insight into the pathogenesis of T. rubrum infections and indicates that hPEOs are a potential ex vivo model for both basic studies of skin diseases and clinical studies of testing potential antifungal drugs.
SARS-CoV-2 infection is associated with a pro-thrombotic platelet phenotype
Authors: Bongiovanni Dario , Klug Melissa , Lazareva Olga , Weidlich Simon , Biasi Marina , Ursu Simona , Warth Sarah , Buske Christian , Lukas Marina , Spinner Christoph D. , Scheidt Moritz von , Condorelli Gianluigi , Baumbach Jan , Laugwitz Karl-Ludwig , List Markus , Bernlochner Isabell 
Published: January 2021

AbstractNovel coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, characterized by abnormal coagulation parameters and by increased incidence of cardiovascular complications. With this study, we aimed to investigate the activation state and the expression of transmembrane proteins in platelets of hospitalized COVID-19 patients. We investigated transmembrane proteins expression with a customized mass cytometry panel of 21 antibodies. Platelets of 8 hospitalized COVID-19 patients not requiring intensive care support and without pre-existing conditions were compared to platelets of healthy controls (11 donors) with and without in vitro stimulation with thrombin receptor-activating peptide (TRAP). Mass cytometry of non-stimulated platelets detected an increased surface expression of activation markers P-Selectin (0.67 vs. 1.87 median signal intensity for controls vs. patients,p = 0.0015) and LAMP-3 (CD63, 0.37 vs. 0.81,p = 0.0004), the GPIIb/IIIa complex (4.58 vs. 5.03,p < 0.0001) and other adhesion molecules involved in platelet activation and platelet–leukocyte interactions. Upon TRAP stimulation, mass cytometry detected a higher expression of P-selectin in COVID-19 samples compared to controls (p < 0.0001). However, we observed a significantly reduced capacity of COVID-19 platelets to increase the expression of activation markers LAMP-3 and P-Selectin upon stimulation with TRAP. We detected a hyperactivated phenotype in platelets during SARS-CoV-2 infection, consisting of highly expressed platelet activation markers, which might contribute to the hypercoagulopathy observed in COVID-19. In addition, several transmembrane proteins were more highly expressed compared to healthy controls. These findings support research projects investigating antithrombotic and antiplatelet treatment regimes in COVID-19 patients, and provide new insights on the phenotypical platelet expression during SARS-CoV-2 infection.
eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects
Authors: Caviedes Ariel , Maturana Barbara , Corvalán Katherina , Engler Alexander , Gordillo Felipe , Varas-Godoy Manuel , Smalla Karl-Heinz , Batiz Luis Federico , Lafourcade Carlos , Kaehne Thilo , Wyneken Ursula 
Published: January 2021

AbstractCell death by glutamate excitotoxicity, mediated by N-methyl-d-aspartate (NMDA) receptors, negatively impacts brain function, including but not limited to hippocampal neurons. The NF-κB transcription factor (composed mainly of p65/p50 subunits) contributes to neuronal death in excitotoxicity, while its inhibition should improve cell survival. Using the biotin switch method, subcellular fractionation, immunofluorescence, and luciferase reporter assays, we found that NMDA-stimulated NF-κB activity selectively in hippocampal neurons, while endothelial nitric oxide synthase (eNOS), an enzyme expressed in neurons, is involved in the S-nitrosylation of p65 and consequent NF-κB inhibition in cerebrocortical, i.e., resistant neurons. The S-nitro proteomes of cortical and hippocampal neurons revealed that different biological processes are regulated by S-nitrosylation in susceptible and resistant neurons, bringing to light that protein S-nitrosylation is a ubiquitous post-translational modification, able to influence a variety of biological processes including the homeostatic inhibition of the NF-κB transcriptional activity in cortical neurons exposed to NMDA receptor overstimulation.
KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer
Authors: Cao Zhi , Shi Xiaolei , Tian Feng , Fang Yu , Wu Jason Boyang , Mrdenovic Stefan , Nian Xinwen , Ji Jin , Xu Huan , Kong Chen , Xu Yalong , Chen Xi , Huang Yuhua , Wei Xuedong , Yu Yongwei , Yang Bo , Chung Leland W. K. , Wang Fubo 
Published: January 2021

AbstractLysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.
Global optical coherence tomography measures for detecting the progression of glaucoma have fundamental flaws
Authors: Sun Ashley , Tsamis Emmanouil , Eguia Melvi D. , Liebmann Jeffrey M. , Blumberg Dana M. , Al-Aswad Lama A. , Cioffi George A. , Gustavo De Moraes C. , Hood Donald C. 
Published: January 2021

Abstract
Objective
To understand the problems involved in using global OCT measures for detecting progression in early glaucoma.

Subjects/Methods
Eyes from 76 patients and 28 healthy controls (HC) had a least two OCT scans at least 1 year apart. To determine the 95% confidence intervals (CI), 151 eyes (49 HC and 102 patients) had at least two scans within 6 months. All eyes had 24-2 mean deviation ≥-6dB. The average (global) thicknesses of the circumpapillary retinal nerve fibre layer (cRNFL), GONH, and of the retinal ganglion cell layer plus inner plexiform layer (RGCLP), Gmac, were calculated. Using quantile regression, the 95% CI intervals were determined. Eyes outside the CIs were classified as “progressors.” For a reference standard (RS), four experts evaluated OCT and VF information.

Results
Compared to the RS, 31 of the 76 (40.8%) patient eyes were identified as progressors (RS-P), and 45 patient, and all 28 HC, eyes as nonprogressors (RS-NP). The metrics missed (false negative, FN) 15 (48%) (GONH) and 9 (29%) (Gmac) of the 31 RS-P. Further, GONH and/or Gmac falsely identified (false positive, FP) 10 (22.2%) of 45 patient RS-NP eyes and 7 (25%) of the 28 HC eyes as progressing. Post-hoc analysis identified three reasons (segmentation, centring, and local damage) for these errors.

Conclusions
Global metrics lead to FPs and FNs because of problems inherent in OCT scanning (segmentation and centring), and to FNs because they can miss local damage. These problems are difficult, if not impossible, to correct, and raise concerns about the advisability of using GONH and Gmac for detecting progression.
Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts
Authors:   PDXNET Consortium, Woo Xing Yi ,   EurOPDX Consortium, Giordano Jessica , Srivastava Anuj , Zhao Zi-Ming , Lloyd Michael W. , de Bruijn Roebi , Suh Yun-Suhk , Patidar Rajesh , Chen Li , Scherer Sandra , Bailey Matthew H. , Yang Chieh-Hsiang , Cortes-Sanchez Emilio , Xi Yuanxin , Wang Jing , Wickramasinghe Jayamanna , Kossenkov Andrew V. , Rebecca Vito W. , Sun Hua , Mashl R. Jay , Davies Sherri R. , Jeon Ryan , Frech Christian , Randjelovic Jelena , Rosains Jacqueline , Galimi Francesco , Bertotti Andrea , Lafferty Adam , O’Farrell Alice C. , Modave Elodie , Lambrechts Diether , ter Brugge Petra , Serra Violeta , Marangoni Elisabetta , El Botty Rania , Kim Hyunsoo , Kim Jong-Il , Yang Han-Kwang , Lee Charles , Dean Dennis A. , Davis-Dusenbery Brandi , Evrard Yvonne A. , Doroshow James H. , Welm Alana L. , Welm Bryan E. , Lewis Michael T. , Fang Bingliang , Roth Jack A. , Meric-Bernstam Funda , Herlyn Meenhard , Davies Michael A. , Ding Li , Li Shunqiang , Govindan Ramaswamy , Isella Claudio , Moscow Jeffrey A. , Trusolino Livio , Byrne Annette T. , Jonkers Jos , Bult Carol J. , Medico Enzo , Chuang Jeffrey H. 
Published: January 2021

AbstractPatient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.
Local sea level trends, accelerations and uncertainties over 1993–2019
Authors: Prandi Pierre , Meyssignac Benoit , Ablain Michaël , Spada Giorgio , Ribes Aurélien , Benveniste Jérôme 
Published: January 2021

AbstractSatellite altimetry missions provide a quasi-global synoptic view of sea level variations over more than 25 years and provide regional sea level (SL) indicators such as trends and accelerations. Estimating realistic uncertainties on these quantities is crucial to address current climate science questions. While uncertainty estimates are available for the global mean sea level (GMSL), information is not available at local scales so far. We estimate a local satellite altimetry error budget and use it to derive local error variance-covariance matrices, and estimate confidence intervals on trends and accelerations at the 90% confidence level. Over 1993–2019, we find that the average local sea level trend uncertainty is 0.83 mm.yr−1 with values ranging from 0.78 to 1.22 mm.yr−1. For accelerations, uncertainties range from 0.057 to 0.12 mm.yr−1, with a mean value of 0.062. We also perform a sensitivity study to investigate a range of plausible error budgets. Local error levels, error variance-covariance matrices, SL trends and accelerations, along with corresponding uncertainties are provided.
Plasma Hsp90 levels in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study
Authors: Štorkánová Hana , Oreská Sabína , Špiritović Maja , Heřmánková Barbora , Bubová Kristýna , Komarc Martin , Pavelka Karel , Vencovský Jiří , Distler Jörg H. W. , Šenolt Ladislav , Bečvář Radim , Tomčík Michal 
Published: January 2021

AbstractOur previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.