Search

Drug-induced liver injury (DILI) is a challenging clinical problem with respect to both diagnosis and management. As a newly emerging biomarker of liver injury, miR122 shows great potential in early and sensitive in situ detection of DILI. Glycyrrhetinic acid (GA) possesses desirable therapeutic effect on DILI, but its certain dose-dependent side effects after long-term and/or high-dose administration limit its clinical application. In this study, in order to improve the precise diagnosis and effective treatment of DILI, GA loaded all-in-one theranostic nanoplatform was designed by assembling of upconversion nanoparticles and gold nanocages. As a proof of concept, we demonstrated the applicability of this single-wavelength laser-triggered theranostic nanoplatform for the spatiotemporally controllable in situ imaging of DILI and miR122-controlled on-demand drug release in vitro and in vivo. This novel nanoplatform opens a promising avenue for the clinical diagnosis and treatment of DILI.

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

C2H2 zinc finger protein (C2H2-ZFP) plays an important role in regulating plant growth, development, and response to abiotic stress. To date, there have been no analyses of the C2H2-ZFP family in desiccation-tolerant moss. In this study, we identified 57 BaZFP transcripts across the Bryum argenteum (B. argenteum) transcriptome. The BaZFP proteins were phylogenetically divided into four groups (I–IV). Additionally, we studied the BaZFP1 gene, which is a nuclear C2H2-ZFP and acts as a positive regulator of growth and development in both moss and Arabidopsis thaliana. The complete coding sequence of the BaZFP1 gene was isolated from B. argenteum cDNA, which showed a high expression level in a dehydration–rehydration treatment process. The overexpression of the BaZFP1 gene in the Physcomitrium patens and B. argenteum promoted differentiation and growth of gametophytes. Heterologous expression in Arabidopsis regulated the whole growth and development cycle. In addition, we quantitatively analyzed the genes related to growth and development in transgenic moss and Arabidopsis, including HLS1, HY5, ANT, LFY, FT, EIN3, MUS, APB4, SEC6, and STM1, and found that their expression levels changed significantly. This study may pave the way for substantial insights into the role of C2H2-ZFPs in plants as well as suggest appropriate candidate genes for crop breeding.

Glycogen synthase kinase 3β (GSK3β) has a vital role in the regulation of many cellular processes. However, the role of GSK3β in muscle cell differentiation in sheep remains unknown. In this study, we investigated the function of GSK3β in skeletal muscle satellite cells (SMSCs) of sheep. An overexpression of GSK3β significantly inhibited myotube formation as well as the mRNA levels of myogenic genes (MyoD, MyoG, MyHC1, and MyHC2a) in sheep SMSCs. SB216763 treatment had a time-course effect on the phosphorylation levels of sheep GSK3β. In addition, reducing the activity of GSK3β lead to the promotion of sheep SMSCs differentiation as well as the mRNA levels of myogenic genes (MyoD, MyoG, MyHC1, and MyHC2a). This study illustrated the function of GSK3β to inhibit myogenesis in sheep SMSCs, which provided evidence for studying the mechanisms involved in the regulation of sheep SMSCs differentiation by GSK3β.

Manifestations of infantile nephropathic cystinosis (INC) often include cachexia and deficiency of circulating vitamin D metabolites. We examined the impact of 25(OH)D3 versus 1,25(OH)2D3 repletion in Ctns null mice, a mouse model of INC. Six weeks of intraperitoneal administration of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) resulted in Ctns−/− mice corrected low circulating 25(OH)D3 or 1,25(OH)2D3 concentrations. While 25(OH)D3 administration in Ctns−/− mice normalized several metabolic parameters characteristic of cachexia as well as muscle function in vivo, 1,25(OH)2D3 did not. Administration of 25(OH)D3 in Ctns−/− mice increased muscle fiber size and decreased fat infiltration of skeletal muscle, which was accompanied by a reduction of abnormal muscle signaling pathways. 1,25(OH)2D3 administration was not as effective. In conclusion, 25(OH)D3 supplementation exerts metabolic advantages over 1,25(OH)2D3 supplementation by amelioration of muscle atrophy and fat browning in Ctns−/− mice.

The ubiquitous environmental endocrine disruptor bisphenol A (BPA) can induce prostatic dysfunction. However, to date, studies have focused little on the perturbations of prostate health initiated by the BPA derivative bisphenol AF (BPAF) and co-exposure to bisphenol compounds. An in vivo study orally administrated male rats with BPA (10, 90 μg/kg), BPAF (10, 90 μg/kg) and the inhibitor of nuclear transcription factor-κB (NF-κB), pyrrolidinedithiocarbamate (PDTC, 100 mg/kg). Based on the anatomical analysis, pathological observations and PCNA over-expression, we considered that low-dose BPA and BPAF facilitated ventral prostatic hyperplasia in rats. The results of IHC and ELISA mirrored the regulation of NF-κB p65, COX-2, TNF-α and EGFR in BPA- and BPAF-induced prostatic toxicity. An in vitro study found that the additive effect of combined exposure to BPA (10 nM) and BPAF (10 nM) could cause an elevation in the proliferation of and a reduction in the apoptosis level of human prostate stromal cells (WPMY−1) and fibroblasts (HPrF). Meanwhile, the underlying biomarkers of the NF-κB signaling pathway also involved the abnormal proliferative progression of prostate cells. The findings recapitulated the induction of BPAF exposure and co-treatment with BPA and BPAF on prostatic hyperplasia and emphasized the modulation of the NF-κB signaling pathway.

In condensed matter, scattering processes determine the transport of charge carriers. In case of heterostructures, interfaces determine many dynamic properties such as charge transfer and transport, and spin current dynamics. Here, we discuss optically excited electron dynamics and their propagation across a lattice-matched, metal-metal interface of single crystal quality. Using femtosecond time-resolved linear photoelectron spectroscopy upon optically pumping different constituents of the heterostructure, we establish a technique that probes the electron propagation and its energy relaxation simultaneously. In our approach, a near-infrared pump pulse excites electrons directly either in the Au layer or in the Fe layer of epitaxial Au/Fe/MgO(001) heterostructures while the transient photoemission spectrum is measured by an ultraviolet probe pulse on the Au surface. Upon femtosecond laser excitation, we analyze the relative changes in the electron distribution close to the Fermi energy and assign characteristic features of the time-dependent electron distribution to transport of hot and nonthermalized electrons from the Fe layer to the Au surface and vice versa. From the measured transient electron distribution, we determine the excess energy, which we compare with a calculation based on the two-temperature model that takes diffusive electron transport into account. On this basis, we identify a transition with increasing Au layer thickness from a superdiffusive to a diffusive transport regime at 20–30 nm.

Diacylglycerol O-acyltransferase 1 (DGAT1) is a microsomal enzyme that plays a key role in the synthesis of triglycerides. Its gene (DGAT1) is regarded as a candidate gene for variation in milk and meat traits in cattle. The objective of this study was to use a PCR single-strand conformation polymorphism approach to explore sequence variation in two regions of ovine DGAT1 and to assess its effect on meat traits in New Zealand Southdown sheep. Three variant nucleotide sequences were identified in each region, with two single nucleotide polymorphisms (SNPs) and one nucleotide deletion being detected in intron 1 and two SNPs being found in exon 17. The effect of the exon 17 variation was not investigated due to one variant being predominant and the other two variants occurring at low frequencies. In intron 1, one variant (B1) was found to be associated with increase loin meat yield, suggesting that this may have value as a gene marker for improving meat traits.

A reasonable tundish flow behavior could improve liquid steel cleanliness by promoting floating and removal of the inclusions. The flow behaviors of the tundish could be obtained by water model experiments and numerical simulations, respectively. However, the difference in density between the tracer and water in the experiment can contribute to notable errors. A new type of tracer, which is a mixture of potassium chloride (KCl) and ethanol, was proposed in this study to reduce the errors. The numerical simulation model was validated by the experimental data and its error was below 2%. By comparing the flow behaviors in seven tundishes with different inner structures obtained by simulation, it is found that the C1 can significantly reduce the dead volume ratio and C4 can improve the uniformity of liquid steel charged though each outlet. The structural strength of the baffle in C1 scheme was not considered, resulting in a crack of the baffle in the industrial trial. Industrial trials of the molten steel flow in the C4-based tundish were conducted and reported a reduction of 43.81% in the inclusions over the prototype.

Ground surface roughness is difficult to predict through a physical model due to its complex influencing factors. BP neural networks (BPNNs), a promising method, have been widely applied in the prediction of surface roughness. This paper uses the concept of BPNN to predict ground surface roughness considering the state of the grinding wheel. However, as the number of input parameters increases, the local optimum solution of the model that arises is more serious. Therefore, “identify factors” are designed to judge the iterative state of the model, whilst “memory factors” are designed to store the best weights during network training. The iterative termination conditions of the model are improved, and the learning rate and update rules of the weights are adjusted to avoid the local optimal solution. The results show that the prediction accuracy of the presented model is higher and more stable than the traditional model. Under three types of iteration steps, the average prediction accuracy is improved from 0.071, 0.065, 0.066 to 0.049, 0.042, 0.039 and the standard deviation of prediction decreased from 0.0017, 0.0166, 0.0175 to 0.0017, 0.0070, 0.0076, respectively. Therefore, the proposed method provides guidance for improving the global optimization ability of BPNNs and developing more accurate models for predicting surface roughness.

Aerosols modify cloud properties and influence the regional climate. The impacts of aerosols on clouds differ for various cloud types, but their long-term relationships have not been fully characterized on a cloud regime basis. In this study, we quantified the cloud regime-dependent relationship between aerosol optical depth (AOD) and cloud properties over China using Moderate-Resolution Imaging Spectroradiometer (MODIS) data from 2002 to 2019. Daily clouds in each 1° by 1° grid were categorized into seven cloud regimes based on the “k-means” clustering algorithm. Overall, the cloud height increased, the cloud thickness and liquid water path increased, and the total cloud cover decreased for all cloud regimes during the study period. Linear correlations between AOD and cloud properties were found within stratocumulus, deep convective, and high cloud regimes, showing consistency with the classic aerosol–cloud interaction paradigms. Using stepwise multivariable linear regression, we found that the meteorological factors dominated the variation of cloud top pressure, while AOD dominated the variation of total cloud cover for most cloud regimes. There are regional differences in the main meteorological factors affecting the cloud properties.

Landslide susceptibility evaluation is critical for landslide prevention and risk management. Based on the slope unit, this study uses the information value method- random forest (IV-RF) model to evaluate the landslide susceptibility in the deep valley area. First, based on the historical landslide data, a landslide inventory was developed by using remote sensing technology (InSAR and optical remote sensing) and field investigation methods. Twelve factors were then selected as the input data for a landslide susceptibility model. Second, slope units with different scales were obtained by the r.slopeunits method and the information value method- random forest (IV-RF) model is used to evaluate the landslide susceptibility. Finally, the spatial distribution characteristics of landslide susceptibility grade under the optimal scale are analyzed. The results showed that under the slope unit obtained when c = 0.1 and a = 3 × 105 m2, the internal homogeneity/external heterogeneity of 8425 slope units extracted by the r.slopeunits method is the best, with an AUC of 0.905 and an F1 of 0.908. In this case, the accuracy of landslide susceptibility evaluation is the highest as well; it is shown that the finer slope units would not always lead to the higher accuracy of landslide susceptibility evaluation results; it is necessary to comprehensively consider the internal homogeneity and external heterogeneity of the slope units. Under the optimal slope unit scale, the number of landslides in the highly and extremely highly susceptible areas in the landslide susceptibility map accounted for 82.60% of the total number of landslides, which was consistent with the actual distribution of landslides; this study shows that the method, combining the slope unit and the information value method- random forest (IV-RF) model, for landslide susceptibility evaluation can obtain high accuracy.

IntroductionThis study aimed to establish a support vector machine (SVM) model to predict the dose for organs at risk (OARs) in intracavitary brachytherapy planning for cervical cancer with tandem and ovoid treatments.MethodsFifty patients with loco-regionally advanced cervical cancer treated with 200 CT-based tandem and ovoid brachytherapy plans were included. The brachytherapy plans were randomly divided into the training (N = 160) and verification groups (N = 40). The bladder, rectum, sigmoid colon, and small intestine were divided into sub-OARs. The SVM model was established using MATLAB software based on the sub-OAR volume to predict the bladder, rectum, sigmoid colon, and small intestine D2cm3. Model performance was quantified by mean squared error (MSE) and δ (δ=|D2cm3/Dprescription(actual)−D2cm3/Dprescription(predicted)|). The goodness of fit of the model was quantified by the coefficient of determination (R2). The accuracy and validity of the SVM model were verified using the validation group.ResultsThe D2cm3 value of the bladder, rectum, sigmoid colon, and small intestine correlated with the volume of the corresponding sub-OARs in the training group. The mean squared error (MSE) in the SVM model training group was 0.9. There was no significant difference between the D2cm3 -predicted and actual values in the validation group (all P > 0.05): bladder δ = 0.024 ± 0.022, rectum δ = 0.026 ± 0.014, sigmoid colon δ = 0.035 ± 0.023, and small intestine δ = 0.032 ± 0.025.ConclusionThe SVM model established in this study can effectively predict the D2cm3 for the bladder, rectum, sigmoid colon, and small intestine in cervical cancer brachytherapy.

IntroductionPulmonary adenofibroma (PAF), characterized by biphasic differentiation composed of gland-like space lined by respiratory epithelium and stromal spindle cells, is a rare benign tumor of the lung. PAF was reported infrequently and inconsistently with diagnostic criteria and withstood higher risk of misdiagnosis as solitary fibrous tumors (SFTs) due to their morphological resemblance. In this study, we report seven cases of PAF with gene sequencing results and summarize the data of previous literature.Materials and MethodsSeven cases of PAF with surgically resection samples were collected from Pathology department of West China Hospital, Sichuan University between 2009 to 2020. Immunohistochemical studies were performed in all cases and 3 cases underwent a 425-gene panel next-generation sequencing (NGS).ResultsFive female and two male patients were included in this study, with an average age of 51 years. All the patients were asymptomatic, and the lesion was identified on routine chest radiography. The tumor size measured by computed tomography (CT) ranged from 0.5 to 2.7 cm. Gland-like structures were mostly positive for glandular epithelium markers. The spindle cells in stroma expressed Desmin, SMA, ER and PR in 3 of 7 cases. No well-recognized molecular abnormalities can be identified by NGS in the 3 cases. To date, all the patients are alive, with no evidence of recurrence and metastasis.ConclusionPAF is a unique benign pulmonary tumor with low incidence. Biphasic morphology, IHC stains along with molecular detection is of great significance to make a clear diagnosis.

Alzheimer’s disease (AD) is the most frequent type of dementia. Acteoside (ACT) is a compound isolated from Cistanche tubulosa, which possesses excellent neuroprotective properties. However, the underlying mechanism of ACT in regulating microglia polarization remains ill-defined. Therefore, a computational network model was established to identify the driving targets of ACT and predict its mechanism by integrating multiple available databases. The AlCl3-induced AD model in zebrafish larvae was successfully constituted to demonstrate the therapeutic efficacy of ACT. Subsequently, LPS-induced BV-2 cells uncovered the positive role of ACT in M1/M2 polarization. The NF-κB and AMPK pathways were further confirmed by transcriptomic analysis, metabolomics analysis, molecular biology techniques, and molecular docking. The research provided an infusive mechanism of ACT and revealed the connection between metabolism and microglia polarization from the perspective of mitochondrial function. More importantly, it provided a systematic and comprehensive approach for the discovery of drug targets, including the changes in genes, metabolites, and proteins.

Primary ciliary dyskinesia (PCD) is a clinically and genetically heterogeneous ciliopathy affecting the cilia and sperm flagella. Mutations in genes related to the structural and functional defects of respiratory ciliary axoneme have been reported to be the predominant cause of this symptom; however, evidence regarding male infertility and genotype–phenotype associations between some of these genes and flagellar axoneme remains unclear. Here, we reported a male patient from a non-consanguineous Chinese family who exhibited left/right body asymmetry and oligoasthenoterazoospermia factor infertility. Novel compound heterozygous mutations in ARMC4 (NM:018076: c.2095C>T: p. Gln699*; c.1679C>T: p. Ala560Val) were identified in this patient, and his parents were a heterozygous carrier for the mutations. Morphological and ultrastructural analysis of the spermatozoa from the man showed aberrant sperm flagella with axonemal disorganization and outer dynein arm (ODA) loss. In addition, immunofluorescence analysis of the spermatozoa from the proband and a control man revealed a significant lower expression of ARMC4 protein due to pathogenic mutations. Therefore, our findings help to expand the spectrum of ARMC4 pathogenic mutations and linked biallelic ARMC4 mutations to male infertility for the first time.

Preimplantation embryonic lethality is a rare cause of primary female infertility. It has been reported that variants in the transducin-like enhancer of split 6 (TLE6) gene can lead to preimplantation embryonic lethality. However, the incidence of TLE6 variants in patients with preimplantation embryonic lethality is not fully understood. In this study, we identified four patients carrying novel biallelic TLE6 variants in a cohort of 28 patients with preimplantation embryonic lethality by whole-exome sequencing and bioinformatics analysis, accounting for 14.29% (4/28) of the cohort. Immunofluorescence showed that the TLE6 levels in oocytes from patients were much lower than in normal control oocytes, suggesting that the variants result in the lower expression of the TLE6 protein in oocytes. In addition, a retrospective analysis showed that the four patients underwent a total of nine failures of in vitro fertilization and intracytoplasmic sperm injection attempts, and one of them became pregnant on the first attempt using donated oocytes. Our study extends the genetic spectrum of female infertility caused by variants in TLE6 and further confirms previously reported findings that TLE6 plays an essential role in early embryonic development. In such case, oocyte donation may be the preferred treatment.

Introduction Approximately 7.2% of children in the world suffer from attention-deficit/hyperactivity disorder (ADHD). Due to the availability of the osmotic-release oral-system methylphenidate, ADHD currently has a remission rate of up to 30.72%. Nevertheless, it has been reported that patients with ADHD tend to exhibit vitamin A and vitamin D deficiency, which may aggravate the symptoms of ADHD. This study aims to determine the effect of vitamin A and vitamin D supplementation as adjunctive therapy to methylphenidate on the symptoms of ADHD.Methods and analysis This is a parallel, prospective, interventional multicentric study. Patients will be enrolled from the southern, central and northern parts of China. A target of 504 patients will be followed for 8 weeks. They will be allocated into three groups (vitamin AD, vitamin D and placebo) and administered the interventions accordingly. Data on changes in the symptoms of ADHD as well as changes in the serum concentrations of vitamin A and vitamin D will be recorded. Both responders and nonresponders based on the sociodemographic and clinical data will also be described to mitigate selection bias.Ethics and dissemination This study is performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Children’s Hospital of Chongqing Medical University, China (approval number: (2019) IRB (STUDY) number 262). The results of the trial will be reported in peer-reviewed scientific journals and academic conferences regardless of the outcomes.Trial registration number NCT04284059.

BackgroundAlthough C-ros oncogene 1 (ROS1) targeted therapies have demonstrated remarkable efficacy in ROS1-rearranged non-small cell lung cancer (NSCLC), patients inevitably develop resistance to ROS1-tyrosine kinase inhibitors (TKIs). Commonly acquired resistance mechanisms include a second mutation of the ROS1 kinase domain and activation of bypass signaling pathways. However, MMNG HOS Transforming gene (MET) amplification has not been reported as a novel mechanism of ROS1-TKIs resistance.Case PresentationWe report a case of a 62-year-old man diagnosed with ROS1-rearranged metastatic lung adenocarcinoma, who received first-line treatment with crizotinib for 19 months. During the course of disease, the primary lung tumor was under control while the brain metastasis progressed despite the treatment with lorlatinib. The biopsy and genetic tests of the metastatic brain tumor showed a high level of MET amplification (32 copies). However, fluorescence in situ hybridization of the primary cancer showed no MET amplification, suggesting that MET amplification may be associated with an acquired resistance to ROS1-TKIs.SummaryThis case suggested that MET amplification could be explored as a potential mechanism for developing ROS1-TKIs resistance. Combination treatment with highly potent and selective MET-TKIs warrants further investigations.

Targeting androgen receptor (AR) has been shown to be promising in treating glioblastoma (GBM) in cell culture and flank implant models but the mechanisms remain unclear. AR antagonists including enzalutamide are available for treating prostate cancer patients in clinic and can pass the blood–brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Although confocal microscopy demonstrated that AR is expressed but not specifically in glioma cancer stem cells (CSCs) (CD133+), enzalutamide treatment significantly decreased CSC population in cultured monolayer cells and spheroids, suppressed tumor sphere-forming capacity of GBM cells, and downregulated CSC gene expression at mRNA and protein levels in a dose- and time-dependent manner. We have, for the first time, demonstrated that enzalutamide treatment decreased the density of CSCs in vivo and improved survival in an orthotopic GBM mouse model. We conclude that AR antagonists potently target glioma CSCs in addition to suppressing the overall proliferation of GBM cells as a mechanism supporting their repurposing for clinical applications treating GBM.

Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disorder affecting motile cilia structure and function, which leads to respiratory diseases and infertility. Here, an induced pluripotent stem cell (iPSC) line of PCD was generated from peripheral blood mononuclear cells of a female patient carrying biallelic mutations in Cyclin O (CCNO) gene. Reprogramming was performed with the non-integrated episomal vectors. The obtained transgene-free iPSCs had normal karyotypes, expressed pluripotency genes, and differentiated into three germ layers. This iPSC line could be a useful guide for studying the pathogenic mechanism, establishing a disease model of PCD, and screening potential therapeutic targets.

PurposeTo investigate the influence of human papillomavirus (HPV) status on survival outcomes and treatment decisions for patients with de novo stage IV head and neck squamous cell cancers (HNSCC).MethodsPatients initially diagnosed with de novo stage IVC HNSCC between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results database. Cox multivariable analyses were performed to determine prognostic factors associated with head and neck cancers specific survival (HNCSS) and overall survival (OS).ResultsWe identified 303 patients who received chemotherapy in this study, including 52.5% of them had HPV-positive disease. HPV-positive HNSCC had better HNCSS (P < 0.001) and OS (P < 0.001) compared to those with HPV-negative disease. The results of Cox multivariable analyses showed that HPV-negative status (P = 0.007), N3 stage (P = 0.004), bone metastases (P < 0.001), and lung metastases (P = 0.003) were associated with worse HNCSS. Similar results were found regarding the OS. The sensitivity analyses indicated that HPV-positive HNSCC patients who were treated with radiotherapy had better survival outcomes. However, no survival benefits were found in those with HPV-positive disease receiving surgery. For HPV-negative patients, no survival benefit was observed among those treated with radiotherapy or surgery.ConclusionsApproximately half of the stage IVC HNSCC patients are HPV-related. The presence of HPV infection appears to be strongly associated with the survival outcome in patients with de novo stage IV HNSCC. Determination of HPV status may help guide clinicians in prognostic assessment and treatment decision-making in this population.

Currently, stem cell nanotechnology is one of the novel and exciting fields. Certain experimental studies conducted on the interaction of stem cells with nanostructures or nanomaterials have made significant progress. The significance of nanostructures, nanotechnology, and nanomaterials in the development of stem cell-based therapies for degenerative diseases and injuries has been well established. Specifically, the structure and properties of nanomaterials affecting the propagation and differentiation of stem cells have become a new interdisciplinary frontier in material science and regeneration medicines. In the current review, we highlight the recent major progress in this field, explore the application prospects, and discuss the issues, approaches, and challenges, to improve the applications of nanotechnology in the research and development of stem cells.

The long-term degradation of epoxy as the matrix and adhesive serviced in harsh environments plays a key role in engineering applications. Understanding how to improve the toughness and durability of epoxy through reasonable material replacement and design is significant to prolong the service life of engineering structures. In the present paper, thermoplastic polypropylene and thermosetting epoxy were exposed in a coupling environment of elevated temperature, water immersion and sustained bending loading. The evolutions of mechanical and thermal properties were further analyzed and compared. Long-term life prediction was conducted to evaluate the corrosive resistances of polypropylene and epoxy. It can be found that polypropylene has better hydrophobic behavior compared to epoxy. At 80 °C, the ratios of the diffusion coefficient and saturated water uptake between the two matrices were 114.4 and 2.94. At the longest immersion time of 90 days, the degradation percentages of tensile strength were 4.7% (40 °C), 7.5% (60 °C) and 8.8% (80 °C), respectively, which had the higher strength retention (>90%). The maximum strength increase in the multiples of polypropylene/epoxy and polypropylene/polyurethane was 1.95 and 1.75, respectively. The bending loading led to a maximum increase in tensile strength (~1.47%) owing to the oxygen isolation effect. The degradation mechanism was attributed to the active functional groups from the production process reacting with oxygen, resulting in the fracture of the local chain segment. By comparison, water molecules reacted with the hydroxyl groups or interrupted the intermolecular Van der Waals force/hydrogen bond of the epoxy, resulting in irreversible hydrolysis and property degradation. Through the comparison, it can be found that polypropylene and its composites have outstanding properties compared to epoxy, which can make them achieve great application prospects in engineering applications when considering a complex service environment.

The impact of climate change on glaciers and the hydrological processes in the easternmost end of the eastern Tianshan Mountains has yet to be understood. This study investigated the glacier change (area, surface elevation and volume change) and analyzed the variation of the observed runoff series over the past four decades in the Yushugou Basin, Eastern Tianshan Mountains. The hydrological processes were also simulated through the HBV-light model to quantify the impact of climate change on the glacier and runoff. The results showed that the glacier area has decreased by 13% and the total volume has decreased by 0.018 km3 over the past four decades. A significant increasing trend (p < 0.01) was detected for the annual runoff and monthly runoff (May to September; p < 0.01). The simulation results revealed that the Yushugou River was highly recharged by glacial runoff and a negative tendency was found for the glacier mass balance on the basin scale over the past 38 years. As a region with an extremely dry climate and the lowest precipitation in the Tianshan Mountains, the observation and simulation of glaciers is critical to the security assessment of local water resources.

Background: Obsessive-compulsive disorder (OCD) is a psychiatric disorder with high clinical heterogeneity manifested by the presence of obsessions and/or compulsions. The classification of the symptom dimensional subtypes is helpful for further exploration of the pathophysiological mechanisms underlying the clinical heterogeneity of OCD. Washing and checking symptoms are the two major symptom subtypes in OCD, but the neural mechanisms of the different types of symptoms are not yet clearly understood. The purpose of this study was to compare regional and network functional alterations between washing and checking OCD based on resting-state functional magnetic resonance imaging (rs-fMRI). Methods: In total, 90 subjects were included, including 15 patients in the washing group, 30 patients in the checking group, and 45 healthy controls (HCs). Regional homogeneity (ReHo) was used to compare the differences in regional spontaneous neural activity among the three groups, and local indicators were analyzed by receiver operating characteristic (ROC) curves as imaging markers for the prediction of the clinical subtypes of OCD. Furthermore, differently activated local brain areas, as regions of interest (ROIs), were used to explore differences in altered brain functioning between washing and checking OCD symptoms based on a functional connectivity (FC) analysis. Results: Extensive abnormalities in spontaneous brain activity involving frontal, temporal, and occipital regions were observed in the patients compared to the HCs. The differences in local brain functioning between checking and washing OCD were mainly concentrated in the bilateral middle frontal gyrus, right supramarginal gyrus, right angular gyrus, and right inferior occipital gyrus. The ROC curve analysis revealed that the hyperactivation right middle frontal gyrus had a better discriminatory value for checking and washing OCD. Furthermore, the seed-based FC analysis revealed higher FC between the left medial superior frontal gyrus and right caudate nucleus compared to that in the healthy controls. Conclusions: These findings suggest that extensive local differences exist in intrinsic spontaneous activity among the checking group, washing group, and HCs. The neural basis of checking OCD may be related to dysfunction in the frontal–striatal network, which distinguishes OCD from washing OCD.

Understanding the influence mechanism of abrasive/tool wear on machining is the key to realize high-efficiency ultra-precision machining of fused silica. To explore the effect of abrasive/tool wear on ductile machining, the smoothed particle hydrodynamics (SPH) cutting models with different edge radii are established. Through the analysis of equivalent rake angle, hydrostatic pressure, cutting force and maximum principal stress with the Flamant’s formula, the influence of edge radii on ductile-brittle transition (DBT) is discussed for the first time. The simulation results show that when the edge radius increases from less to larger than the cutting depth, the equivalent rake angle changes from positive to negative, and the maximum hydrostatic pressure gradually increases, which is beneficial to promote the ductile processing. Meanwhile, with the rise of edge radius (i.e., abrasive/tool wear), both the cutting force and crack initiation angle increase, while the friction coefficient and normalized maximum principal decrease. When the value of normalized maximum principal stress exceeds 2.702, the crack in the workpiece begins to initiate, and its initiation angle calculated by the Flamant’s formula is in good agreement with the simulation results as well as less than 50°. Finally, the nano-scratch experiment was carried out, and the material removal mechanism and friction coefficient f similar to the simulation were obtained, which further proved the accuracy of SPH model. This study is meaningful for understanding the effect of abrasive/tool wear on the removal mechanism of brittle materials and improving the quality and efficiency of cutting and grinding.

The choice of a manufacturing process, raw materials, and process parameters affects the quality of produced pre-consolidated tapes used in thermoplastic pultrusion. In this study, we used two types of pre-consolidated GF/PP tapes—commercially available (ApATeCh-Tape Company, Moscow, Russia) and inhouse-made tapes produced from commingled yarns (Jushi Holdings Inc., Boca Raton, FL, USA)—to produce pultruded thermoplastic Ø 6 mm bars and 75 mm × 3.5 mm flat laminates. Flat laminates produced from inhouse-made pre-consolidated tapes demonstrated higher flexural, tensile, and apparent interlaminar shear strength compared to laminates produced from commercial pre-consolidated tapes by as much as 106%, 6.4%, and 27.6%, respectively. Differences in pre-consolidated tape manufacturing methods determine the differences in glass fiber impregnation and, thus, differences in the mechanical properties of corresponding pultruded composites. The use of commingled yarns (consisting of matrix and glass fibers properly intermingled over the whole length of prepreg material) makes it possible to achieve a more uniform impregnation of inhouse-made pre-consolidated tapes and to prevent formation of un-impregnated regions and matrix cracks within the center portion of the fiber bundles, which were observed in the case of commercial pre-consolidated tapes. The proposed method of producing pre-consolidated tapes made it possible to obtain pultruded composite laminates with larger cross sections than their counterparts described in the literature, featuring better mechanical properties compared to those produced from commercial pre-consolidated tapes.

Intestinal microbiota has its role as an important component of human physiology. It produces metabolites that module key functions to establish a symbiotic crosstalk with their host. Among them, short chain fatty acids (SCFAs), produced by intestinal bacteria during the fermentation of partially and non-digestible polysaccharides, play key roles in regulating colon physiology and changing intestinal environment. Recent research has found that SCFAs not only influence the signal transduction pathway in the gut, but they also reach tissues and organs outside of the gut, through their circulation in the blood. Growing evidence highlights the importance of SCFAs level in influencing health maintenance and disease development. SCFAs are probably involved in the management of host health in a complicated (positive or negative) way. Here, we review the current understanding of SCFAs effects on host physiology and discuss the potential prevention and therapeutics of SCFAs in a variety of disorders. It provides a systematic theoretical basis for the study of mechanisms and precise intake level of SCFAs to promote human health.

RationaleThe thyroid is a rare site for distant metastases from breast carcinoma. The incidence of thyroid metastases in fine needle aspiration biopsy (FNAB) was less than 0.2%.Patient concernsWe report a case of 54-year-old woman with a history of breast carcinoma presented with diffuse scattered microcalcifications in thyroid and enlarged bilateral cervical lymph nodes detected on ultrasound (US). Physical examination of the patient revealed firm and enlarged thyroid lobes.DiagnosesFNAB and immunohistochemistry (IHC) of the thyroid lesion confirmed the thyroid metastases from breast cancer.Interventions and OutcomesDue to the comorbidities of breast carcinoma metastases to the right axillary, cervical lymph nodes and left chest wall, the patient received chemotherapy. After a follow-up of 19 months, the patient was alive without any new distant metastases.LessonsOur case highlights that thyroid metastases should be considered in a patient combined with thyroid lesions and a history of breast carcinoma. IHC played an important role in differentiating thyroid metastases from primary thyroid cancer.

Background: The factors associated with sleep disturbances in cancer patients remains unclear. This study aimed to explore the prevalence of sleep disorders and predictors associated with sleep disturbance in cancer patients from a radiotherapy department.Methods: Patients with cancers were recruited before the start of radiotherapy from our institution between January 2019 and February 2020. Pittsburgh Sleep Quality Index (PSQI) scale was used to assess sleep quality. Descriptive statistics, Chi-square test, and multivariate logistic regression analysis were used to conduct statistical analysis.Results: A total of 330 eligible patients were included. Of them, 38.3% (n = 127) had the globe PSQI score >7, indicating that they suffered from sleep disorders. Patients with lung cancer (45.2%) were more likely to suffer from sleep disturbance, followed by cervical cancer (43.8%), nasopharyngeal carcinoma (41.7%), esophageal cancer (41.5%), breast cancer (37.7%), and colorectal cancer (30%). With regard to the PSQI components, the mean sleep duration was 8 h, 20.3% (n = 67) of them reported poor subjective sleep quality, 6.1% (n = 20) needed medication to improve sleep, and 53.6% (n = 177) suffered daytime dysfunction. Multivariate logistic regression models showed body mass index (BMI) ≥ 20 kg/m2 [odds ratio (OR) 0.599, 95% confidence interval (CI) 0.329–0.948, P = 0.031] and the receipt of surgery (OR 0.507, 95% CI 0.258–0.996, P = 0.048) were the significant favorable predictors for sleep disturbance, while age, gender, marital status, education level, comorbidity, metastasis status, diagnostic status, and cancer type were not significantly associated with sleep disturbance.Conclusions: Approximately 40% of the cancer patients suffer from sleep disturbance before the start of radiotherapy. Patients with BMI ≥ 20 kg/m2 and receiving surgery are less likely to develop sleep disturbance in comparison with others.

BackgroundObservational studies have indicated an association between polycystic ovary syndrome (PCOS) and periodontitis, but it is unclear whether the association is cofounded or causal. We conducted a two-sample Mendelian randomization (MR) study to investigate the bidirectional relationship between genetically predicted PCOS and periodontitis.MethodsFrom two genome-wide association studies we selected 13 and 7 single nucleotide polymorphisms associated with PCOS and periodontitis, respectively, as instrumental variables. We utilized publicly shared summary-level statistics from European-ancestry cohorts. To explore the causal effect of PCOS on periodontitis, 12,289 cases of periodontitis and 22,326 controls were incorporated, while 4,890 cases of PCOS and 20,405 controls in the reverse MR. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented.ResultsGenetically determined PCOS was not causally associated with risk of periodontitis (odds ratio 0.97; 95% confidence interval 0.88–1.06; P = 0.50) per one-unit increase in the log-odds ratio of periodontitis. Similarly, no causal effect of periodontitis on PCOS was shown with the odds ratio for PCOS was 1.17 (95% confidence interval 0.91–1.49; P = 0.21) per one-unit increase in the log-odds ratio of periodontitis. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity.ConclusionThe bidirectional MR study couldn’t provide convincing evidence for the causal relationship between genetic liability to PCOS and periodontitis in the Europeans. Triangulating evidence across further observational and genetic-epidemiological studies is necessary.

Abstract The ripening of papaya is a physiological and metabolic process associated with accumulation of carotenoids, alternation of flesh color and flavor, which depending on genotype and external factors such as light and hormone. Transcription factors regulating carotenoid biosynthesis have not been analyzed during papaya fruit ripening. RNA-Seq experiments were implemented using different ripening stages of papaya fruit from two papaya varieties. Cis-elements in lycopene β-cyclase genes (CpCYC-B and CpLCY-B) were identified, and followed by genome-wide analysis to identify transcription factors binding to these cis-elements, resulting in the identification of CpbHLH1 and CpbHLH2, two bHLH genes. The expressions of CpbHLH1/2 were changed during fruit development, coupled with transcript increase of carotenoid biosynthesis-related genes including CpCYC-B, CpLCY-B, CpPDS2, CpZDS, CpLCY-E, and CpCHY-B. Yeast one-hybrid (Y1H) and transient expression assay revealed that CpbHLH1/2 could bind to the promoters of CpCYC-B and CpLCY-B, and regulate their transcriptions. In response to strong light, the results of elevated expression of carotenoid biosynthesis-related genes and the changed expression of CpbHLH1/2 indicated that CpbHLH1/2 were involved in light-mediated mechanisms of regulating critical genes in the carotenoid biosynthesis pathway. Collectively, our findings demonstrated several TF family members participating in the regulation of carotenoid genes and proved that CpbHLH1 and CpbHLH2 individually regulated the transcription of lycopene β-cyclase genes (CpCYC-B and CpLCY-B). This study yielded novel findings on regulatory mechanism of carotenoid biosynthesis during papaya fruit ripening.

Abstract Background High density surface electromyography (EMG) can be used to estimate muscle innervation zones (IZ). The objective of this study was to compare the differences in the distribution of the biceps brachii (BB) IZ derived from voluntary contractions (VC) and electrical stimulation (ES) of the musculocutaneous nerve. Methods Surface EMG signals were recorded from the medial and lateral BB with two 64-channel high density electrode matrices in eight healthy men. The surface EMG was recorded at different percentages of the maximal voluntary contraction (MVC) force (20–100% MVC) and at different percentages of the current needed to elicit a maximal M-wave (20–100% Imax). The IZs of the medial and lateral BB were identified from the EMG signals and expressed as a row number within a given medial-lateral column. Results ES current intensity had no significant effect on the group mean IZ location (p > 0.05). However, The IZ during VC was located more proximally with increasing force (p 0.05), but was more proximal in the latter than the former during 60–100% MVC (p

Recent studies have revealed that neurons can promote glioma growth through activity‐dependent secretion of neurotrophins, especially neuroligin‐3. It has therefore been suggested that blocking neuron‐derived neurotrophins may serve as a therapeutic intervention for gliomas. Carbonic anhydrase‐related proteins 11 and 10 (CA11 and CA10) are secreted synaptic proteins which function as neurexin ligands, and the gene‐encoding CA11 is part of a gene signature associated with radiotherapy and prognosis in gliomas. We therefore hypothesized that CA11/CA10 might participate in the neuronal activity‐dependent regulation of glioma growth. In this study, we report that CA11 secreted by depolarized cultured neurons within conditioned medium (CM) inhibited the growth of glioma cell lines. CM from depolarized neurons inhibited CA11 expression in glioma cell lines via the Akt signaling pathway. Consistently, CA11 expression was also reduced in clinical glioma samples and negatively associated with high histological grade. Low CA11 expression of gliomas was associated with short survival in four independent datasets [repository of brain neoplasia data (REMBRANDT), The Cancer Genome Atlas (TCGA) lower grade glioma (LGG), GSE4271, and GSE42669]. CA11 knockdown promoted cell growth, clone formation, and migration; inhibited apoptosis; and increased tumor size in xenografted nude mice. Similarly, CA10 and CA10 secreted by depolarized cultured neurons also inhibited the growth of glioma cell lines. Low CA10 expression was associated with short survival in REMBRANDT, TCGA LGG, and GEO GSE4271 datasets. Our results suggest that CA11 and CA10 negatively regulate neuronal activity‐dependent glioma growth and inhibit glioma aggression. Thus, CA11/CA10 may represent a potential therapeutic target for the treatment of gliomas.

ABSTRACTIn the last few decades, Ebola virus (EBOV) has emerged periodically and infected people in Africa, resulting in an extremely high mortality rate. With no available prophylaxis or cure so far, a highly effective Ebola vaccine is urgently needed. In this study, we developed a novel chimpanzee adenovirus-based prime-boost vaccine by exploiting two recombinant replication-deficient chimpanzee adenoviral vectors, AdC7 and AdC68, which express glycoproteins (GP) of the EBOV strain identified in the 2014 outbreak. Our results indicated that a single immunization using AdC7 or AdC68 could stimulate potent EBOV-specific antibody responses, whereas the AdC7 prime-AdC68 boost regimen induced much stronger and sustained humoral and cellular immune responses in both mice and rhesus monkeys, compared with AdC7 or AdC68 single vaccination or the AdC68 prime-AdC7 boost regimen. This prime-boost vaccine could also protect mice from the simulated infection with EBOV-like particle (EBOVLP) in biosafety level 2 (BSL-2) laboratories, and antibodies from the prime-boost immunized rhesus macaques could passively provide protection against EBOVLP infection. Altogether, our results show that the AdC7 prime-AdC68 boost vaccine is a promising candidate for further development to combat EBOV infections.

Objective: To compare the immediate effect of acupuncture at the contralateral versus ipsilateral Tiaokou (ST38) in patients with Chronic shoulder pain (CSP). Method: Altogether, 38 patients with unilateral CSP were randomly assigned to a contralateral ST38 group (Contra group) or ipsilateral ST38 group (Ipsi group). Each underwent 20 min of manual acupuncture: Contra group at the contralateral ST38, Ipsi group at the ipsilateral ST38. Primary outcome measure was the visual analog scale (VAS) score. Secondary outcome measure for assessing shoulder mobility was the Constant-Murley (CM) score, which included pain level, activities of daily living (ADL), and shoulder range of motion (ROM). These factors were assessed before and immediately after acupuncture. A value of P

Background: Cardiac hypertrophy is a key pathological process in the context of diabetic cardiomyopathy. Naringenin exhibits multiple pharmacological activities, but the effect of naringenin on cardiomyocyte hypertrophy under diabetic conditions is still far from clear. Methods: Cardiomyocyte hypertrophy was induced by high glucose (HG, glucose at 25.5 mmol/L) in H9c2 cells, which was determined by cell surface area, protein content and atrial natriuretic factor (ANF) mRNA expression. The effect of naringenin on cardiomyocyte hypertrophy was observed and its mechanisms were investigated by administration with various inhibitors on epoxyeicosatrienoic acids (EETs)/peroxisome proliferator-activated receptors (PPARs). The level of 14,15-EET was measured by ELISA. The mRNA and protein expressions were detected by qRT-PCR or Western blot, respectively. Results: Naringenin (0.1, 1, 10 μmol/L) inhibited cardiomyocyte hypertrophy in a concentration-dependent manner (P

Abstract Background Cardiotoxicity remains an important concern in drug discovery and clinical medication. Meanwhile, Sophora tonkinensis Gapnep. (S. tonkinensis) held great value in the clinical application of traditional Chinese medicine, but cardiotoxic effects were reported, with matrine, oxymatrine, cytisine, and sophocarpine being the primary toxic components. Methods In this study, impedance and extracellular field potential (EFP) of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were recorded using the cardio non-labeled cell function analysis and culture system (Cardio-NLCS). The effects of matrine, oxymatrine, cytisine, and sophocarpine (2, 10, 50 μM) on cell viability; level of lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), and cardiac troponin I (CTn-I); antioxidant activities; production of reactive oxygen species (ROS) and malondialdehyde (MDA); and disruption of intracellular calcium homeostasis were also added into the integrated assessment. Results The results showed that matrine and sophocarpine dose-dependently affected both impedance and EFP, while oxymatrine and cytisine altered impedance significantly. Our study also indicated that cardiotoxicity of matrine, oxymatrine, cytisine, and sophocarpine was related to the disruption of calcium homeostasis and oxidative stress. Four alkaloids of S. tonkinensis showed significant cardiotoxicity with dose dependence and structural cardiotoxicity synchronized with functional changes of cardiomyocytes. Conclusions This finding may provide guidance for clinical meditation management. Furthermore, this study introduced an efficient and reliable approach, which offers alternative options for evaluating the cardiotoxicity of the listed drugs and novel drug candidates.

Abstract Background Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the Factor VIII (FVIII) gene leading to deficient blood coagulation. As a monogenic disorder, HA is an ideal target for cell-based gene therapy, but successful treatment has been hampered by insufficient engraftment of potential therapeutic cells. Methods In this study, we sought to determine whether co-transplantation of endothelial colony-forming cells (ECFCs) and placenta-derived mesenchymal stromal cells (PMSCs) can achieve long-term engraftment and FVIII expression. ECFCs and PMSCs were transduced with a B domain deleted factor VIII (BDD-FVIII) expressing lentiviral vector and luciferase, green fluorescent protein or Td-Tomato containing lentiviral tracking vectors. They were transplanted intramuscularly into neonatal or adult immunodeficient mice. Results In vivo bioluminescence imaging showed that the ECFC only and the co-transplantation groups but not the PMSCs only group achieved long-term engraftment for at least 26 weeks, and the co-transplantation group showed a higher engraftment than the ECFC only group at 16 and 20 weeks post-transplantation. In addition, cell transplantation at the neonatal age achieved higher engraftment than at the adult age. Immunohistochemical analyses further showed that the engrafted ECFCs expressed FVIII, maintained endothelial phenotype, and generated functional vasculature. Next, co-transplantation of ECFCs and PMSCs into F8 knock-out HA mice reduced the blood loss volume from 562.13 ± 19.84 μl to 155.78 ± 44.93 μl in a tail-clip assay. Conclusions This work demonstrated that co-transplantation of ECFCs with PMSCs at the neonatal age is a potential strategy to achieve stable, long-term engraftment, and thus holds great promise for cell-based treatment of HA.

Background: Oxidized low-density lipoprotein (ox-LDL) causes vascular endothelial cell inflammatory response and apoptosis and plays an important role in the development and progression of atherosclerosis. Ginsenoside compound K (CK), a metabolite produced by the hydrolysis of ginsenoside Rb1, possesses strong anti-inflammatory effects. However, whether or not CK protects ox-LDL-damaged endothelial cells and the potential mechanisms have not been elucidated. Methods: In our study, cell viability was tested using a 3-(4, 5-dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide (MTT) assay. Expression levels of interleukin-6, monocyte chemoattractant protein-1, tumor necrosis factor-α, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 were determined by enzyme-linked immunosorbent assay and Western blotting. Mitochondrial membrane potential (ΔΨm) was detected using JC-1. The cell apoptotic percentage was measured by the Annexin V/ propidium iodide (PI) assay, lactate dehydrogenase, and caspase-3 expression. Apoptosis-related proteins, nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK) signaling pathways protein expression were quantified by Western blotting. Results: Our results demonstrated that CK could ameliorate ox-LDL-induced human umbilical vein endothelial cells (HUVECs) inflammation and apoptosis, NF-κB nuclear translocation, and the phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Moreover, anisomycin, an activator of p38 and JNK, significantly abolished the anti-apoptotic effects of CK. Conclusion: These results demonstrate that CK prevents ox-LDL-induced HUVECs inflammation and apoptosis through inhibiting the NF-κB, p38, and JNK MAPK signaling pathways. Thus, CK is a candidate drug for atherosclerosis treatment. Keywords: apoptosis, ginsenoside compound K, human umbilical vein endothelial cells, inflammation, oxidized low-density lipoprotein

Abstract Background Cystic lung lesions involving both lungs include a variety of diseases, such as pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis and pulmonary metastasis. Primary pulmonary meningioma accompanied with intrapulmonary metastasis was extremely rare and we were not aware of previous studies reporting with cystic radiological manifestation. Case presentation A 64-year-old female patient was admitted to our department for a mass located in right posterior mediastinum with multiple cystic pulmonary lesions. A thoracoscopic lung biopsy was performed and the diagnosis was confirmed as bilateral pulmonary metastasis from primary pulmonary meningioma. Conclusions Intrapulmonary metastasis from a primary pulmonary meningioma may manifest as multiple thin-walled cystic lesions on computed tomography. Differential diagnosis of cystic pulmonary disease should include this situation. Our case shows the new CT manifestation of metastatic primary pulmonary meningioma and the importance of immunomolecular analysis.

Background: Anlotinib, a multi-target tyrosine kinase inhibitor, has significant anti-cancer effects on breast cancer (BC), lung cancer, colon cancer and ovarian cancer, but its mechanism has not been investigated in BC. Methods: The cell viability and growth of human non-triple negative BC cell line MCF-7 and triple negative BC cell line MDA-MB-231 with the treatment of anlotinib were tested by Cell Counting Kit-8 (CCK-8) assay and Ki67 staining. The alteration of genes related to apoptosis and autophagy were investigated by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), western blots and immunocytochemistry (ICC). Cell apoptosis was valued by TUNEL staining and flow cytometry. Further, mouse breast tumour cell lines AT-3 cells were subcutaneously injected into C57BL/6 mice, and the effect of anlotinib intragastrically on tumour growth in vivo was examined. Results: We found that anlotinib suppressed the cell viability and depressed Ki67 staining in MCF-7 and MDA-MB-231 cell lines. Besides, the drug also enhanced cell autophagy and apoptosis of MCF-7 and MDA-MB-231 cell lines, which could be rescued by autophagy inhibitors wortmannin (wort) and 3-methyladenine (3-MA), and BECN1 knockdown. Furthermore, Akt/GSK-3α pathway was inactivated by anlotinib treatment, while rescued by wort, 3-MA and silencing of BECN1 in the MCF-7 or MDA-MB-231 cells. We also found that anlotinib inhibited implanted tumour growth of BC in syngeneic mice. Conclusions: Our study demonstrated that anlotinib inhibited breast cancer cell growth in vitro and in vivo. Anlotinib promoted cell apoptosis and inactivated Akt/GSK-3α pathway of BC cells by inducing cell autophagy. It indicated that anlotinib may be an effective new drug for BC treatment.

The crack distribution characteristics in grinding damage have a significant impact on subsequent polishing efficiency and part strength. Grinding tests were carried out on fused quartz using grinding wheels with different wear states. The results showed that the cracks produced by sharp abrasive grits were mainly near chevron cracks and had no preferred direction. However, the blunt abrasive grits produced near partial cone cracks had a preferred direction. At a depth of 96.7 μm from the surface, the amount of cracks in the range of 50°~90° with an inclination angle between the crack and the cutting direction could reach 88.9%. The statistical results showed that the depth and total length of cracks produced by sharp grits were larger than those produced by blunt grits (the maximum crack depth difference was about 40 μm). Therefore, it was concluded that sharp abrasive grits were not conducive to damage control. The findings of this research enhance our understanding of the formation mechanism of grinding damage.

The prevention of postprandial hyperglycemia and diabetic complications is crucial for diabetes management. Inhibition of α-glucosidase to slow carbohydrate metabolism is a strategy to alleviate postprandial hyperglycemia. In addition, suppression of non-enzymatic glycation can diminish the advanced glycation end products and reduce the oxidative stress and inflammation, thereby preventing the diabetic complications. In this study, an anti-oxidative proteoglycan (named FYGL) extracted from Ganoderma lucidum was investigated in vitro for its inhibitory effect on α-glucosidase and non-enzymatic glycation using molecular kinetics, intrinsic fluorescence assay, and bovine serum albumin glycation models. The molecular kinetics and fluorescence assay revealed that FYGL decreases α-glucosidase activity by forming a FYGL–α-glucosidase complex. To evaluate the anti-glycation effect, fructose-glycated and methylglyoxal-glycated BSA models were analyzed by spectroscopic and SDS-PAGE methods. Results showed that FYGL inhibited the glycation at every stage and suppressed glycoxidation, possibly due to its anti-oxidative capacity and FYGL–BSA complex formation. Furthermore, we demonstrated in vivo that FYGL could alleviate postprandial hyperglycemia in db/db mice as well as AGE accumulation and vascular injury in diabetic rats. Overall, FYGL possesses anti-postprandial hyperglycemia and anti-glycation functions and would be potentially used in clinic for diabetes and related complication management.

Photodynamic therapy is usually ineffective against deeply seated metastatic tumors due to poor penetration of the excitation light. Here, the authors design a biomimetic nanoreactor which can convert nutriment glucose into toxic singlet oxygen via chemiluminescence resonance energy transfer with no light excitation and demonstrate its high efficacy in a mouse lung metastatic model.

Haxilegen Glacier No.51 (43.731°N, 84.391°E; CN5Y741C0051) is located in the Kuytun river basin, Erenharbirga range, eastern Tien Shan. This study presents the annual mass balance of Haxilegen Glacier No.51 for 7 hydrological years and uses a temperature-index and an accumulation model to reconstruct the annual mass balance from 1999 to 2015. The model is calibrated against annual altitudinal mass-balance measurements and then applied to the period with no measurements. We find an accumulated mass balance of −6.06 ± 0.88 m w.e.a−1 over the period of 16 hydrological years, with an average annual value of −0.32 ± 0.22 m w.e.a−1. The mean glacier-wide annual, summer and winter balances for 1999 to 2015 are −0.37, −0.54 and 0.16 ± 0.22 m w.e.a−1, respectively, with a high correlation coefficient (r = 0.95, p < 0.001) between annual balance and summer balance. The calculated mass-balance sensitivity of the glacier to temperature is −0.51 m w.e.a−1 °C−1 and to precipitation is 0.08 m w.e.a−1 for a 10% increase. The sensitivity of seasonal mass balance indicates that temperature during the melt season (May–August) and annual precipitation are the major contributors to mass-balance fluctuation.

Abstract Background The monoclonal antibody daratumumab, approved for treating myeloma, targets CD38, a protein on myeloma and also on CD34+ hematopoietic progenitor cells. Because mobilized CD34+ cells are critical for stem cell transplant, we investigated the in vitro activity of daratumumab on mobilized CD34+ cells from myeloma patients with no prior exposure to daratumumab. Methods We determined the number of CD38 molecules per CD34+ cell, and whether daratumumab bound to CD34+ cells, whether C1q bound to daratumumab-coated CD34+ cells and whether daratumumab-related complement-dependent cytotoxicity (CDC) occurred. We also examined CD34+ cell progenitor cell colony capacity in assays with pre-plating incubation of CD34+ cells with daratumumab alone or with daratumumab and the CD59 inhibitory antibody BRIC229, and also assessed CD34+ cell responses to increasing doses of daratumumab in caspase 3/7 activity assays. Results Although 75% of mobilized CD34+ cells co-express CD38, CD38 was minimally present on CD34+ cells compared to Daudi and KG-1 controls, C1q did not bind to daratumumab-coated CD34+ cells, and CDC did not occur. CD34+ cells incubated in complement-rich human serum with daratumumab alone or with daratumumab and BRIC229, and then plated in progenitor cell assays, produced similar numbers of colonies as controls. In progenitor cell assays with cryopreserved or fresh unselected or CD34-selected cells, daratumumab did not affect progenitor cell capacity, and in caspase 3/7 activity assays CD34+ cells were not affected by increasing doses of daratumumab. Conclusion In vitro, daratumumab is not toxic to mobilized CD34+ progenitor cells from myeloma patients.

While reactive ductules (RDs) have been observed in viral hepatitis, biliary atresia, nonalcoholic fatty liver disease, and adult hepatocellular carcinoma (HCC), RDs in pediatric liver cancer remain uncharacterized. This study investigated the relationship of RDs with angiogenic paracrine factors, the extent of angiogenesis, and tumor cell proliferation in pediatric hepatoblastoma (HBL)/HCC livers. We quantified the extent of RDs and their expression of paracrine factors that include vascular endothelial growth factor (VEGF), vascular endothelial growth factor D (VEGFD), platelet‐derived growth factor C, and angiopoietin 1 (ANGPT1). In addition, we performed immunohistochemical detection of the endothelial marker clusters of differentiation (CD)34 and the proliferation marker Ki67 followed by correlation analyses. In HBL, we found the percentage of RDs with Ki67 expression (% Ki67+ RDs) significantly correlated with intratumoral Ki67+ areas (r = 0.5138, P = 0.0349) and % ANGPT1+ RDs positively correlated with % Ki67+ RDs (r = 0.5851, P = 0.0136). In HCC, the high ANGPT1+ RDs group (i.e., cases with % ANGPT1+ RDs ≥50) exhibited high intratumoral Ki67+ areas compared to the low ANGPT1+ RDs group. In the combined HBL and HCC liver tumor group, there was a positive association between % platelet‐derived growth factor C+ RDs and intratumoral Ki67+ areas (r = 0.4712, P = 0.0099) and the high VEGFD+ RDs group (≥50%) exhibited a high number of peritumoral CD34+ vessels compared to the low VEGFD+ RDs group. Conclusion: Paracrine factor‐expressing RDs are associated with angiogenesis and proliferation of pediatric liver tumors.

Background/Aims: The TLR/MyD88/NF-κB signaling pathway has been successfully used to treat renal interstitial fibrosis (RIF). However, the exact therapeutic mechanism is still unknown. Here, we assessed the therapeutic efficacy of TJ-M2010-2, a small molecular compound that inhibits MyD88 homodimerization, in RIF induced by ischemia reperfusion injury (IRI). Methods: In vivo, RIF was induced in mice by IRI, and the mice were prophylactically treated with TJ-M2010-2. In vitro, HK-2 cells were incubated with TGF-β1 to induce EMT, and the cells were pretreated with TJ-M2010-2. Results: We found that, compared with the IRI group, the TJ-M2010-2 group showed marked attenuation of RIF and renal function injury; decreased expression of TGF-β1, α-SMA, vimentin, MMP2 and MMP9; and increased E-cadherin expression. Furthermore, TGF-β1-induced EMT was blocked by TJ-M2010-2 in HK-2 cells, as evidenced by blocked morphologic transformation, restored E-cadherin expression and inhibited α-SMA expression. In addition, compared to the TGF-β1 group, the TJ-M2010-2 group showed profound inhibition of the expression of TRAF6, p65 and Snail and upregulation of the expression of IκBα. Conclusion: This MyD88 inhibitor may be a potential therapeutic agent to ameliorate RIF.