bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex
Authors: Weir Scott J. , Dandawate Prasad , Standing David , Bhattacharyya Sangita , Ramamoorthy Prabhu , Rangarajan Parthasarathy , Wood Robyn , Brinker Amanda E. , Woolbright Benjamin L. , Tanol Mehmet , Ham Tammy , McCulloch William , Dalton Michael , Reed Gregory A. , Baltezor Michael J. , Jensen Roy A. , Taylor John A. , Anant Shrikant 
Published: May 2021

AbstractCiclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).
HDAC6 regulates primordial follicle activation through mTOR signaling pathway
Authors: Zhang Tuo , He Meina , Zhao Lihua , Qin Shaogang , Zhu Zijian , Du Xinhua , Zhou Bo , Yang Yi , Liu Xinfeng , Xia Guoliang , Chen Tengxiang , Wang Yuanxi , Zhang Hua , Wang Chao 
Published: May 2021

AbstractPrimordial follicle pool established perinatally is a non-renewable resource which determines the female fecundity in mammals. While the majority of primordial follicles in the primordial follicle pool maintain dormant state, only a few of them are activated into growing follicles in adults in each cycle. Excessive activation of the primordial follicles accelerates follicle pool consumption and leads to premature ovarian failure. Although previous studies including ours have emphasized the importance of keeping the balance between primordial follicle activation and dormancy via molecules within the primordial follicles, such as TGF-β, E-Cadherin, mTOR, and AKT through different mechanisms, the homeostasis regulatory mechanisms of primordial follicle activation remain unclear. Here, we reported that HDAC6 acts as a key negative regulator of mTOR in dormant primordial follicles. In the cytoplasm of both oocytes and granulosa cells of primordial follicles, HDAC6 expressed strong, however in those activated primordial follicles, its expression level is relatively weaker. Inhibition or knockdown of HDAC6 significantly promoted the activation of limited primordial follicles while the size of follicle pool was not affected profoundly in vitro. Importantly, the expression level of mTOR in the follicle and the activity of PI3K in the oocyte of the follicle were simultaneously up-regulated after inhibiting of HDAC6. The up-regulated mTOR leads to not only the growth and differentiation of primordial follicles granulosa cells (pfGCs) into granulosa cells (GCs), but the increased secretion of KITL in these somatic cells. As a result, inhibition of HDAC6 awaked the dormant primordial follicles of mice in vitro. In conclusion, HDAC6 may play an indispensable role in balancing the maintenance and activation of primordial follicles through mTOR signaling in mice. These findings shed new lights on uncovering the epigenetic factors involved physiology of sustaining female reproduction.
Epithelial PBLD attenuates intestinal inflammatory response and improves intestinal barrier function by inhibiting NF-κB signaling
Authors: Chen Shengbo , Liu Hongbin , Li Zhijun , Tang Jingyi , Huang Bing , Zhi Fachao , Zhao Xinmei 
Published: May 2021

AbstractIntestinal barrier function defects and dysregulation of intestinal immune responses are two key contributory factors in the pathogenesis of ulcerative colitis (UC). Phenazine biosynthesis-like domain-containing protein (PBLD) was recently identified as a tumor suppressor in gastric cancer, hepatocellular carcinoma, and breast cancer; however, its role in UC remains unclear. Therefore, we analyzed colonic tissue samples from patients with UC and constructed specific intestinal epithelial PBLD-deficient (PBLDIEC−/−) mice to investigate the role of this protein in UC pathogenesis. We found that epithelial PBLD was decreased in patients with UC and was correlated with levels of tight junction (TJ) and inflammatory proteins. PBLDIEC−/− mice were more susceptible to dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis compared with wild-type (WT) mice. In DSS-induced colitis, PBLDIEC−/− mice had impaired intestinal barrier function and greater immune cell infiltration in colonic tissue than WT mice. Furthermore, TJ proteins were markedly reduced in PBLDIEC−/− mice compared with WT mice with colitis. Nuclear factor (NF)-κB activation was markedly elevated and resulted in higher expression levels of downstream effectors (C–C motif chemokine ligand 20, interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in colonic epithelial cells isolated from PBLDIEC−/− mice than WT mice with colitis. PBLD overexpression in intestinal epithelial cells (IECs) consistently inhibited TNF-α/interferon-γ-induced intestinal barrier disruption and TNF-α-induced inflammatory responses via the suppression of NF-κB. In addition, IKK inhibition (IKK-16) rescued excessive inflammatory responses induced by TNF-α in PBLD knockdown FHC cells. Co-immunoprecipitation assays showed that PBLD may interact with IKKα and IKKβ, thus inhibiting NF-κB signaling, decreasing inflammatory mediator production, attenuating colonic inflammation, and improving intestinal barrier function. Modulating PBLD expression may provide a novel approach for treatment in patients with UC.
ETV4 promotes breast cancer cell stemness by activating glycolysis and CXCR4-mediated sonic Hedgehog signaling
Authors: Zhu Tao , Zheng Juyan , Zhuo Wei , Pan Pinhua , Li Min , Zhang Wei , Zhou Honghao , Gao Yang , Li Xi , Liu Zhaoqian 
Published: May 2021

AbstractCancer stem cells (CSCs) are a major cause of tumor treatment resistance, relapse and metastasis. Cancer cells exhibit reprogrammed metabolism characterized by aerobic glycolysis, which is also critical for sustaining cancer stemness. However, regulation of cancer cell metabolism rewiring and stemness is not completely understood. Here, we report that ETV4 is a key transcription factor in regulating glycolytic gene expression. ETV4 loss significantly inhibits the expression of HK2, LDHA as well as other glycolytic enzymes, reduces glucose uptake and lactate release in breast cancer cells. In human breast cancer and hepatocellular carcinoma tissues, ETV4 expression is positively correlated with glycolytic signaling. Moreover, we confirm that breast CSCs (BCSCs) are glycolysis-dependent and show that ETV4 is required for BCSC maintenance. ETV4 is enriched in BCSCs, its knockdown and overexpression suppresses and promotes breast cancer cell stem-like traits, respectively. Mechanistically, on the one hand, we find that ETV4 may enhance glycolysis activity to facilitate breast cancer stemness; on the other, ETV4 activates Sonic Hedgehog signaling by transcriptionally promoting CXCR4 expression. A xenograft assay validates the tumor growth-impeding effect and inhibition of CXCR4/SHH/GLI1 signaling cascade after ETV4 depletion. Together, our study highlights the potential roles of ETV4 in promoting cancer cell glycolytic shift and BCSC maintenance and reveals the molecular basis.
Imaging-based spectrometer-less optofluidic biosensors based on dielectric metasurfaces for detecting extracellular vesicles
Authors: Jahani Yasaman , Arvelo Eduardo R. , Yesilkoy Filiz , Koshelev Kirill , Cianciaruso Chiara , De Palma Michele , Kivshar Yuri , Altug Hatice 
Published: May 2021

AbstractBiosensors are indispensable tools for public, global, and personalized healthcare as they provide tests that can be used from early disease detection and treatment monitoring to preventing pandemics. We introduce single-wavelength imaging biosensors capable of reconstructing spectral shift information induced by biomarkers dynamically using an advanced data processing technique based on an optimal linear estimator. Our method achieves superior sensitivity without wavelength scanning or spectroscopy instruments. We engineered diatomic dielectric metasurfaces supporting bound states in the continuum that allows high-quality resonances with accessible near-fields by in-plane symmetry breaking. The large-area metasurface chips are configured as microarrays and integrated with microfluidics on an imaging platform for real-time detection of breast cancer extracellular vesicles encompassing exosomes. The optofluidic system has high sensing performance with nearly 70 1/RIU figure-of-merit enabling detection of on average 0.41 nanoparticle/µm2 and real-time measurements of extracellular vesicles binding from down to 204 femtomolar solutions. Our biosensors provide the robustness of spectrometric approaches while substituting complex instrumentation with a single-wavelength light source and a complementary-metal-oxide-semiconductor camera, paving the way toward miniaturized devices for point-of-care diagnostics.
Development of selective bispecific Wnt mimetics for bone loss and repair
Authors: Fowler Tristan W. , Mitchell Troy L. , Janda Claudia Y. , Xie Liqin , Tu Shengjiang , Chen Hui , Zhang Haili , Ye Jingjing , Ouyang Brian , Yuan Tom Z. , Lee Sung-Jin , Newman Maureen , Tripuraneni Nikita , Rego Erica S. , Mutha Devin , Dilip Archana , Vuppalapaty Meghah , Baribault Helene , Yeh Wen-Chen , Li Yang 
Published: May 2021

AbstractThe Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis.
Impact of COVID-19 outbreaks and interventions on influenza in China and the United States
Authors: Feng Luzhao , Zhang Ting , Wang Qing , Xie Yiran , Peng Zhibin , Zheng Jiandong , Qin Ying , Zhang Muli , Lai Shengjie , Wang Dayan , Feng Zijian , Li Zhongjie , Gao George F. 
Published: May 2021

AbstractCoronavirus disease 2019 (COVID-19) was detected in China during the 2019–2020 seasonal influenza epidemic. Non-pharmaceutical interventions (NPIs) and behavioral changes to mitigate COVID-19 could have affected transmission dynamics of influenza and other respiratory diseases. By comparing 2019–2020 seasonal influenza activity through March 29, 2020 with the 2011–2019 seasons, we found that COVID-19 outbreaks and related NPIs may have reduced influenza in Southern and Northern China and the United States by 79.2% (lower and upper bounds: 48.8%–87.2%), 79.4% (44.9%–87.4%) and 67.2% (11.5%–80.5%). Decreases in influenza virus infection were also associated with the timing of NPIs. Without COVID-19 NPIs, influenza activity in China and the United States would likely have remained high during the 2019–2020 season. Our findings provide evidence that NPIs can partially mitigate seasonal and, potentially, pandemic influenza.
Barrier-free reverse-intersystem crossing in organic molecules by strong light-matter coupling
Authors: Yu Yi , Mallick Suman , Wang Mao , Börjesson Karl 
Published: May 2021

AbstractStrong light-matter coupling provides the means to challenge the traditional rules of chemistry. In particular, an energy inversion of singlet and triplet excited states would be fundamentally remarkable since it would violate the classical Hund’s rule. An organic chromophore possessing a lower singlet excited state can effectively harvest the dark triplet states, thus enabling 100% internal quantum efficiency in electrically pumped light-emitting diodes and lasers. Here we demonstrate unambiguously an inversion of singlet and triplet excited states of a prototype molecule by strong coupling to an optical cavity. The inversion not only implies that the polaritonic state lies at a lower energy, but also a direct energy pathway between the triplet and polaritonic states is opened. The intrinsic photophysics of reversed-intersystem crossing are thereby completely overturned from an endothermic process to an exothermic one. By doing so, we show that it is possible to break the limit of Hund’s rule and manipulate the energy flow in molecular systems by strong light-matter coupling. Our results will directly promote the development of organic light-emitting diodes based on reversed-intersystem crossing. Moreover, we anticipate that it provides the pathway to the creation of electrically pumped polaritonic lasers in organic systems.
Identification of clinical and radiographic predictors of central nervous system injury in genetic skeletal disorders
Authors: Cunha Antônio L , Champs Ana P S , Mello Carla M. , Navarro Mônica M. M. , Godinho Frederico J. C. , Carvalho Cássia M. B. , Ferrari Teresa C. A. 
Published: May 2021

AbstractSome studies report neurological lesions in patients with genetic skeletal disorders (GSDs). However, none of them describe the frequency of neurological lesions in a large sample of patients or investigate the associations between clinical and/or radiological central nervous system (CNS) injury and clinical, anthropometric and imaging parameters. The project was approved by the institution’s ethics committee (CAAE 49433215.5.0000.0022). In this cross-sectional observational analysis study, 272 patients aged four or more years with clinically and radiologically confirmed GSDs were prospectively included. Genetic testing confirmed the diagnosis in the FGFR3 chondrodysplasias group. All patients underwent blinded and independent clinical, anthropometric and neuroaxis imaging evaluations. Information on the presence of headache, neuropsychomotor development (NPMD), low back pain, joint deformity, ligament laxity and lower limb discrepancy was collected. Imaging abnormalities of the axial skeleton and CNS were investigated by whole spine digital radiography, craniocervical junction CT and brain and spine MRI. The diagnostic criteria for CNS injury were abnormal clinical and/or radiographic examination of the CNS. Brain injury included malacia, encephalopathies and malformation. Spinal cord injury included malacia, hydrosyringomyelia and spinal cord injury without radiographic abnormalities. CNS injury was diagnosed in more than 25% of GSD patients. Spinal cord injury was found in 21.7% of patients, and brain injury was found in 5.9%. The presence of low back pain, os odontoideum and abnormal NPMD remained independently associated with CNS injury in the multivariable analysis. Early identification of these abnormalities may have some role in preventing compressive CNS injury, which is a priority in GSD patients.
Association of killer cell immunoglobulin-like receptors with endemic Burkitt lymphoma in Kenyan children
Authors: Muriuki Beatrice M. , Forconi Catherine S. , Oluoch Peter O. , Bailey Jeffrey A. , Ghansah Anita , Moormann Ann M. , Ong’echa John M. 
Published: May 2021

AbstractEndemic Burkitt lymphoma (eBL) is an aggressive pediatric B cell lymphoma, common in Equatorial Africa. Co-infections with Epstein-Barr virus (EBV) and Plasmodium falciparum, coupled with c-myc translocation are involved in eBL etiology. Infection-induced immune evasion mechanisms to avoid T cell cytotoxicity may increase the role of Natural killer (NK) cells in anti-tumor immunosurveillance. Killer immunoglobulin-like receptor (KIR) genes on NK cells exhibit genotypic and allelic variations and are associated with susceptibility to diseases and malignancies. However, their role in eBL pathogenesis remains undefined. This retrospective study genotyped sixteen KIR genes and compared their frequencies in eBL patients (n = 104) and healthy geographically-matched children (n = 104) using sequence-specific primers polymerase chain reaction (SSP-PCR) technique. The relationship between KIR polymorphisms with EBV loads and eBL pathogenesis was investigated. Possession of ≥ 4 activating KIRs predisposed individuals to eBL (OR = 3.340; 95% CI 1.530–7.825; p = 0.004). High EBV levels were observed in Bx haplogroup (p = 0.016) and AB genotypes (p = 0.042) relative to AA haplogroup and AA genotype respectively, in eBL patients but not in healthy controls. Our results suggest that KIR-mediated NK cell stimulation could mute EBV control, contributing to eBL pathogenesis.
Optimization of OPEFB lignocellulose transformation process through ionic liquid [TEA][HSO4] based pretreatment
Authors: Nurdin Muhammad , Abimanyu Haznan , Putriani Hadijah , Setiawan L. O. M. Idal , Maulidiyah Maulidiyah , Wibowo Dwiprayogo , Ansharullah Ansharullah , Natsir Muh. , Salim La Ode Agus , Arham Zul , Mustapa Faizal 
Published: May 2021

AbstractResearch on the transformation of Oil Palm Empty Fruit Bunches (OPEFB) through pretreatment process using ionic liquid triethylammonium hydrogen sulphate (IL [TEA][HSO4]) was completed. The stages of the transformation process carried out were the synthesis of IL with the one-spot method, optimization of IL composition and pretreatment temperature, and IL recovery. The success of the IL synthesis stage was analyzed by FTIR, H-NMR and TGA. Based on the results obtained, it showed that IL [TEA][HSO4] was successfully synthesized. This was indicated by the presence of IR absorption at 1/λ = 2814.97 cm−1, 1401.07 cm−1, 1233.30 cm−1 and 847.92 cm−1 which were functional groups for NH, CH3, CN and SO2, respectively. These results were supported by H-NMR data at δ (ppm) = 1.217–1.236 (N–CH2–CH3), 3.005–3.023 (–H), 3.427–3.445 (N–H+) and 3.867 (N+H3). The TGA results showed that the melting point and decomposition temperature of the IL were 49 °C and 274.3 °C, respectively. Based on pretreatment optimization, it showed that the best IL composition for cellulose production was 85 wt%. Meanwhile, temperature optimization showed that the best temperature was 120 °C. In these two optimum conditions, the cellulose content was obtained at 45.84 wt%. Testing of IL [TEA][HSO4] recovery performance for reuse has shown promising results. During the pretreatment process, IL [TEA][HSO4] recovery effectively increased the cellulose content of OPEFB to 29.13 wt% and decreased the lignin content to 32.57%. The success of the recovery process is indicated by the increasing density properties of IL [TEA][HSO4]. This increase occurs when using a temperature of 80–100 °C. The overall conditions obtained from this work suggest that IL [TEA][HSO4] was effective during the transformation process of OPEFB into cellulose. This shows the potential of IL [TEA][HSO4] in the future in the renewable energy sector.
Flexible, high‐strength titanium nanowire for scaffold biomimetic periodontal membrane
Authors: Li Jin , Hua Licheng , Wang Weiyuan , Gu Chenjie , Du Jianke , Hu Conghu 
Published: May 2021

AbstractA layer of micro‐sized periodontal membrane can buffer most chewing forces to protect the interface between the natural tooth root and alveolar bone. Artificial dental implants usually direct contact onto the alveolar bone without a buffer layer, which increases the risk of surface damage. The main purpose of this work was the bionic design of a flexible layer of nanowire scaffold on a titanium implant surface according to the function of the periodontal membrane. Millions of nanowires were woven into a superhydrophilic layer of porous scaffold. The evolution of mechanical properties displayed that the biomimetic nanowire scaffold could absorb a maximum of about 1.59 KJ energy per square centimeter by low‐speed impact. The minimum tensile strength of one nanowire was 2 GPa. A biomimetic flexible periodontal membrane connection functioning between the natural tooth root and alveolar bone has great potential value for developing advanced artificial dental implants for dental restorations.
Resonance propagation analysis for inverter‐dominated multi‐AC‐bus systems
Authors: Liang Beihua , He Jinwei , Wang Chengshan 
Published: May 2021

AbstractHarmonic resonance in a system with multiple inverters connecting to a single AC bus has been well studied in previous literature. However, in reality, a large number of distributed inverters are often classified into several groups using a few matching transformers. Due to the impact of matching transformers’ leakage impedance, the entire system presents a multi‐AC‐bus grid‐tied system with more complicated resonance interactions. In this work, a completed analytical method is developed. It reveals that there are different resonance types in such a system, and the determining factors of these resonance types are analysed. Moreover, the simplified calculation formulas for each resonance frequency are derived. For parallel resonance problems, under normal circumstances, the harmonic source tends to cause resonance with its neighbouring converters, but it has little effect on remote converters with long electrical distances. However, under special circumstances, the harmonic source has almost no effect on neighbouring converters, but causes resonance with the remote converters. In this situation, the resonance path passes through the transformer and multiple AC buses. Verification results are provided to validate the correctness of theoretical analysis.