Search

STUDY OBJECTIVES This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN Prospective pharmacokinetics study. SETTING The intensive care unit in a tertiary-care medical center. PATIENTS A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Sex differences in behaviour partly arise from the sexual dimorphism of brain anatomy between males and females. However, the sexual dimorphism of the tree shrew brain is unclear. In the present study, we examined the detailed distribution of vasoactive intestinal polypeptide-immunoreactive (VIP-ir) neurons and fibres in the suprachiasmatic nucleus (SCN) and VIP-ir fibres in the bed nucleus of the stria terminalis (BST) of male and female tree shrews. The overall volume of the SCN in male tree shrews was comparable with that in females. However, males showed a significantly higher density of VIP-ir cells and fibres in the SCN than females. The shape of the VIP-stained area in coronal sections was arched, elongated or oval in the lateral division (STL) and the anterior part of the medial division (STMA) of the BST and oval or round in the posterior part of the medial division of the BST (STMP). The volume of the VIP-stained BST in male tree shrews was similar to that in females. The overall distribution of VIP-ir fibres was similar between the sexes throughout the BST except within the STMA, where darkly stained fibres were observed in males, whereas lightly stained fibres were observed in females. Furthermore, male tree shrews showed a significantly higher intensity of Nissl staining in the medial preoptic area (MPA) and the ventral part of the medial division of the BST than females. These findings are the first to reveal sexual dimorphism in the SCN, BST and MPA of the tree shrew brain, providing neuroanatomical evidence of sexual dimorphism in these regions related to their roles in sex differences in physiology and behaviour.

Yes-associated protein (YAP), as a co-activator of transcription factors, is a downstream protein in the Hippo signaling pathway with important functions in cell proliferation, apoptosis, invasion and migration. YAP also plays a key role in the development of CCl4-induced liver fibrosis. However, the mechanism of YAP during hepatic fibrosis progression and reversion is still unclear. Mild liver fibrosis was developed after 4 months of high-fat diet (HFD) stimulation, and we found that the YAP signaling pathway was activated. Here, we aim to reveal whether specific knockout of Yap gene in the liver can improve liver fibrosis induced by insulin resistance (IR) stimulated by HFD, and further explain its specific mechanism. We found that liver-specific Yap gene knockout improved IR-induced liver fibrosis and liver dysfunction, and this mechanism is related to the inhibition of the insulin signal pathway at the FoxO1 level. These findings provide a new insight, and Yap is expected to be a new target to reverse the early stage of liver fibrosis induced by IR.

Escherichia coli and Salmonella are common pathogenic bacteria in human intestine, which can infect epithelial cells and cause diseases. Adhesion to intestinal tissue is the first step of pathogen infection. This work was to investigate the protective function of surface layer protein (SLP) from Lactobacillus casei fb05 against the harmful effects of E. coli and Salmonella on intestinal tissue (collagen and HT-29 cells). The SLP of L. casei fb05 was identified by transmission electron microscopy and SDS-PAGE. The purified SLP could reduce the adhesion of E. coli and Salmonella to collagen and HT-29 cells as observed by light microscope. The flow cytometry results showed that the L. casei fb05 SLP decreased the two pathogens-induced apoptosis of HT-29 cells by about 45%–49%. In addition, the activation of caspase-9 and caspase-3 caused by the two pathogens was significantly declined by the interference of the L. casei fb05 SLP. All the findings demonstrated that the L. casei fb05 SLP could decrease the deleterious effects of E. coli and Salmonella on intestinal tract in two ways: reducing pathogen adhesion and inhibiting pathogen-induced apoptosis. The potential of L. casei fb05 SLP in the treatment of intestinal diseases might be explored in this work.

A new high-precision two-dimensional (2D) micro-accelerometer is proposed in this study to measure low-frequency vibration. A flexure hinge with low crosstalk and high axial stiffness is used as a spring, and a 2D optical angular displacement sensor is used to detect the motion of the inertial mass. The accelerometer is calibrated using a homemade one-dimensional horizontal micro-vibration calibration system. Furthermore, the accelerometer is dynamically identified through the adaptive least-square method. The resonance frequencies of the accelerometer in X- and Y-axes are identified as 43.16 and 40.31 Hz, respectively. The working frequency ranges of the accelerometer, which are approximately 20% of their resonant frequency, are obtained according to the calibration experimental results. The sensitivities of the accelerometer in the X- and Y-axes are 25.17 and 25.55 V/g, respectively. The resolutions of the accelerometer in the X- and Y-axes are 0.07 and 0.06 mg, respectively. These findings are consistent with the theoretical analysis results. The effectiveness of the accelerometer is verified by measuring low-frequency and low-amplitude dynamic responses.

Peripheral blood mononuclear cells are widely used as source material for anticancer immunotherapies. The conventional cryopreservation method for peripheral blood mononuclear cells is time-consuming and expansive, which involves controlled rate freezing followed by storage in liquid nitrogen. Instead, the convenient uncontrolled rate freezing cryopreservation method had been reported successfully in peripheral blood hematopoietic stem cells and peripheral blood progenitor cells. Therefore, we hypothesized that uncontrolled rate freezing cooling method maybe also applied to peripheral blood mononuclear cells cryopreservation. In this study, we evaluated the performance of uncontrolled rate freezing and controlled rate freezing cooling methods through cell recovery rate, viability, differentiation potential into cytokine-induced killer cells and the cellular properties of the cultured cytokine-induced killer cells. The results showed similar post-thaw viability and recovery rate in both controlled rate freezing and uncontrolled rate freezing cryopreserved peripheral blood mononuclear cells. Importantly, the uncontrolled rate freezing cryopreserved peripheral blood mononuclear cells exhibited higher growth ratio and earlier cell clustering during ex-vivo cytokine-induced killer cell culture than the controlled rate freezing ones. These two groups of expanded cytokine-induced killer cells also exhibited similar effector cell subset ratio and tumoricidal activity. In general, the performance of cryopreserved peripheral blood mononuclear cells using uncontrolled rate freezing cooling method, with the commercial cryoprotective agent CellBanker 2, was equal or better than the controlled rate freezing method. Our study implied that the combined use of cryoprotective agent CellBanker 2 and uncontrolled rate freezing could be a convenient cryopreservation method for peripheral blood mononuclear cells.

Preferable treatments for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with brain metastasis are elusive. The study intended to estimate the relative efficacy and safety of systemic therapies. Clinical trials about therapies for EGFR-mutant, brain-metastatic NSCLC were identified. Progression-free survival (PFS) and overall survival (OS) were analysed using random effects Bayesian network meta-analyses (NMAs) on the hazard ratio (HR)-scale. Nomogram and Kaplan-Meier plots based on clinical or individual factors are displayed using data obtained from the Surveillance Epidemiology and End Results (SEER) database. Third-generation EGFR- tyrosine kinase inhibitors (EGFR-TKI) (osimertinib), EGFR-TKIs + stereotactic radiosurgery (SRS)/whole brain radiotherapy (WBRT) (gefitinib/erlotinib + SRS/WBRT), and EGFR-TKIs (erlotinib) + anti-vascular endothelial growth factor receptor (anti-VEGFR) (bevacizumab) achieved superior PFS (HR: 0.30 (0.15-0.59); HR: 0.47 (0.31-0.72); HR: 0.50 (0.21-1.21) vs. deferring SRS/WBRT) and acceptability; EGFR-TKIs + SRS/WBRT was top ranking (vs. others) for OS followed by third-generation EGFR-TKI. In the dataset cohort of 1173 brain-metastatic NSCLC patients, the 6-month, 1-year, and 3-year survival rates were 59.8%, 41.3%, and 5.6%, respectively. Race and origin, and year of diagnosis were independent predictors of OS. Survival curves showed that the OS of patients varied significantly by histology and race. Third-generation EGFR-TKI and EGFR-TKIs + SRS/WBRT are more effective and potentially acceptable for EGFR-mutant NSCLC with brain metastases balancing OS and PFS. Surgeries without adjuvant therapies cannot significantly improve the OS of brain-metastatic NSCLC patients. The study highlights importance of osimertinib in these patients and provide a reference for clinical treatments.

Gliomas are infiltrative neoplasms with a highly invasive nature. Due to its distinct genomic, genetic and epigenetic features, the immune prognostic signature (IPS) and immune microenvironment of glioblastoma (GBM) merit further research. We aimed to explore prognosis-related immune genes and develop an IPS model for predicting prognosis in GBM. RNA-sequencing data, as well as clinical information, from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) public cohorts were analyzed. To develop the IPS, least absolute shrinkage and selection operator (LASSO) Cox analysis was performed for immune-related genes that were differentially expressed between GBM and normal tissues. Then, interaction effects of the IPS on the immune microenvironment were systematically analyzed; the precise prognostic model was developed based on the IPS and clinical data and was then further validated. A total of 21 immune prognostic genes were identified based on GBM microenvironment status. An 8-gene IPS was established, and the GBM patients were effectively stratified into low- and high-risk groups in the TCGA cohort as a training set. Univariate and multivariate Cox analyses revealed that IPS was an independent prognostic factor, and the prognostic performance of individual IPS genes was systematically illustrated. In addition, a comprehensive and novel nomogram model was initially established to estimate overall survival in TCGA-GBM patients, and high-risk patients had higher levels of dendritic cell and neutrophil infiltration. Furthermore, the nomogram model was developed and validated in the CGGA validation set. The low-risk IPS was linked to a stronger response to anti-PD-L1 immunotherapy and clinical advantages in the IMvigor210 cohort. This novel IPS with promising biomarkers classifies GBM patients into subgroups with distinct clinical outcomes and immunophenotypes. Our findings and this resource may help to characterize the immune microenvironment, inform cancer immunotherapy and facilitate the development of precision immuno-oncology.

Objective The current study aims to explore the establishment of the patient-derived tumor xenograft (PDTX) model. Materials and methods Twenty patients with gastric cancer, 10 males and 10 females, were enrolled in the current study. Firstly, the volume, invasion and metastasis of the xenografts were observed. Subsequently, the correlation between tumor tissues of the PDTX mouse model and the patients' primary tumor tissues was evaluated by pathological H&E staining and immunohistochemistry. Results The results showed that the PDTX models corresponding to 15 of the 20 patients were successfully established, and the success rate of PDTX model establishment was 75%. Furthermore, the PDTX models maintained the differentiation degree, morphological characteristics and structural characteristics of tumor cells. Conclusion A PDTX model can be used as a substitute for cancer patients in clinical practice and may be suitable for clinical pharmacodynamic screening and new drug development.

The tree shrew (Tupaia belangeri chinensis) is the closest living relative of primates. Yet, little is known about the anatomical distribution of tyrosine hydroxylase (TH)-immunoreactive (ir) structures in the hypothalamus of the tree shrew. Here, we provide the first detailed description of the distribution of TH-ir neurons in the hypothalamus of tree shrews via immunohistochemical techniques. TH-ir neurons were widely distributed throughout the hypothalamus of tree shrew. The majority of hypothalamic TH-ir neurons were found in the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON), as was also observed in the human hypothalamus. In contrast, rare TH-ir neurons were localized in the PVN and SON of rats. Vasopressin (AVP) colocalized with TH-ir neurons in the PVN and SON in a large number of neurons, but oxytocin and corticotropin-releasing hormone did not colocalize with TH. In addition, colocalization of TH with AVP was also observed in the other hypothalamic regions. Moreover, TH-ir neurons in the PVN and SON of tree shrews expressed other dopaminergic markers (aromatic l-amino acid decarboxylase and vesicular monoamine transporter, Type 2), further supporting that TH-ir neurons in the PVN and SON were catecholaminergic. These findings provide a detailed description of TH-ir neurons in the hypothalamus of tree shrews and demonstrate species differences in the distribution of this enzyme, providing a neurobiological basis for the participation of TH-ir neurons in the regulation of various hypothalamic functions.

Background It is very difficult to predict the early response to NAC only on the basis of change in tumor size. ADC value derived from DWI promises to be a valuable parameter for evaluating the early response to treatment. This study aims to establish the optimal time window of predicting the early response to neoadjuvant chemotherapy (NAC) for different subtypes of locally advanced breast carcinoma using diffusion-weighted imaging (DWI). Methods We conducted an institutional review board-approved prospective clinical study of 142 patients with locally advanced breast carcinoma. All patients underwent conventional MR and DW examinations prior to treatment and after first, second, third, fourth, sixth and eighth cycle of NAC. The response to NAC was classified into a pathologic complete response (pCR) and a non-pCR group. DWI parameters were compared between two groups, and the optimal time window for predicting tumor response was established for each chemotherapy regimen. Results For all the genomic subtypes, there were significant differences in baseline ADC value between pCR and non-pCR group (p

ObjectiveTo establish a radiomics signature and a nomogram model based on enhanced CT images to predict the Ki-67 index of lung cancer.MethodsFrom January 2014 to December 2018, 282 patients with lung cancer who had undergone enhanced CT scans and Ki-67 examination within 2 weeks were retrospectively enrolled and analyzed. The clinical data of the patients were collected, such as age, sex, smoking history, maximum tumor diameter and serum tumor markers. Our primary cohort was randomly divided into a training group (n=197) and a validation group (n=85) at a 7:3 ratio. A Ki-67 index ≤ 40% indicated low expression, and a Ki-67 index > 40% indicated high expression. In total, 396 radiomics features were extracted using AK software. Feature reduction and selection were performed using the lasso regression model. Logistic regression analysis was used to establish a multivariate predictive model to identify high and low Ki-67 expression in lung cancer. A nomogram integrating the radiomics score was established based on multiple logistic regression analysis. Area under the curve (AUC) was used to evaluate the prediction efficiency of the radiomics signature and nomogram.ResultsThe AUC,sensitivity, specificity and accuracy of the radiomics signature in the training and validation groups were 0.88 (95% CI: 0.82~0.93),79.2%,84.3%,81.2% and 0.86 (95% CI: 0.78~0.94),74.6%,88.1%,79.8%, respectively. A nomogram combining radiomics features and clinical risk factors (smoking history and NSE) was developed. The AUC, sensitivity, specificity and accuracy were 0.87 (95% CI: 0.80~0.95), 75.0%, 90.2% and 83.5% in the validation group, respectively.ConclusionThe radiomics signature and nomogram based on enhanced CT images provide a way to predict the Ki-67 expression level in lung cancer.

Chemotherapy resistance is an important problem for clinical therapy of osteosarcoma (OS). The potential effects of histone deacetylases (HDACs) on OS chemoresistance are studied. The expression of HDACs in OS cells resistance to doxorubicin (Dox) and cisplatin (CDDP) is checked. Among 11 members of HDACs, levels of HDAC6 are significantly upregulated in OS cells resistance to Dox and CDDP. Inhibition of HDAC6 via its specific inhibitor ACY1215 restores chemosensitivity of OS-resistant cells. Further, HDAC6 directly binds with estrogen-related receptors alpha (ERRα) to regulate its acetylation and protein stability. Inhibition of ERRα further strengthens ACY1215-increased chemosensitivity of OS-resistant cells. Mechanistically, K129 acetylation is the key residue for HDAC6-regulated protein levels of ERRα. Collectively, we find that ERRα contributes to HDAC6-induced chemoresistance of OS cells. Inhibition of HDAC6/ERRα axis might be a potential approach to overcome chemoresistance and improve therapy efficiency for OS treatment. 1. HDAC6 was significantly upregulated in Dox and CDDP resistant OS cells; 2. Inhibition of HDAC6 can restore chemosensitivity of OS cells; 3. HDAC6 binds with ERRα at K129 to decrease its acetylation and increase protein stability; 4. ERRα contributes to HDAC6-induced chemoresistance of OS cells.

BackgroundChronic rejection characterized by chronic allograft vasculopathy (CAV) remains a major obstacle to long-term graft survival. Due to multiple complicated mechanisms involved, a novel therapy for CAV remains exploration. Although mesenchymal stromal cells (MSCs) have been ubiquitously applied to various refractory immune-related diseases, rare research makes a thorough inquiry in CAV. Meanwhile, melatonin (MT), a wide spectrum of immunomodulator, plays a non-negligible role in transplantation immunity. Here, we have investigated the synergistic effects of MT in combination with MSCs in attenuation of CAV.MethodsC57BL/6 (B6) mouse recipients receiving BALB/c mouse donor aorta transplantation have been treated with MT and/or adipose-derived MSCs. Graft pathological changes, intragraft immunocyte infiltration, splenic immune cell populations, circulating donor-specific antibodies levels, cytokine profiles were detected on post-operative day 40. The proliferation capacity of CD4+ and CD8+ T cells, populations of Th1, Th17, and Tregs were also assessed in vitro.ResultsGrafts in untreated recipients developed a typical pathological feature of CAV characterized by intimal thickening 40 days after transplantation. Compared to untreated and monotherapy groups, MT in combination with MSCs effectively ameliorated pathological changes of aorta grafts indicated by markedly decreased levels of intimal hyperplasia and the infiltration of CD4+ cells, CD8+ cells, and macrophages, but elevated infiltration of Foxp3+ cells. MT either alone or in combination with MSCs effectively inhibited the proliferation of T cells, decreased populations of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. MT synergized with MSCs displayed much fewer splenic populations of CD4+ and CD8+ T cells, Th1 cells, Th17 cells, CD4+ central memory T cells (Tcm), as well as effector memory T cells (Tem) in aorta transplant recipients. In addition, the percentage of splenic Tregs was substantially increased in the combination therapy group. Furthermore, MT combined with MSCs markedly reduced serum levels of circulating allospecific IgG and IgM, as well as decreased the levels of pro-inflammatory IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, and MCP-1, but increased the level of IL-10 in the recipients.ConclusionsThese data suggest that MT has synergy with MSCs to markedly attenuate CAV and provide a novel therapeutic strategy to improve the long-term allograft acceptance in transplant recipients.

Background. Circulating tumor cells (CTCs) have been regarded as an independent prognostic marker for metastatic castration-resistant prostate cancer (mCRPC). Its prognostic value, however, in nonmetastatic prostate cancer (NMPC) is still unclear. Purpose. To elucidate whether CTCs can predict the biochemical recurrence (BCR) in NMPC patients following radical prostatectomy (RP) or radiotherapy (RT). Methods. PubMed, Cochrane Database, and Embase and the references in relevant studies were systematically searched. Studies that investigated the correlation of CTCs and BCR in NMPC patients after RP or RT were identified and reviewed. Overall odds ratio (OR) of BCR in such patients with/without CTCs was pooled. We also calculated and pooled overall prevalence of BCR in such CTC-positive patients. Results. In total, 12 studies comprising 1917 participants were eligible for the meta-analysis and showed that the presence of secondary circulating tumor cells (SCTCs) is associated with a higher BCR rate of 59% (95% CI: 22%-88%) in patients with NMPC after RP or RT ( OR = 6.12 ; 95% CI: 2.22-16.85; P < 0.001 ). However, regardless of the presence of primary circulating tumor cells (PCTCs), it has not been shown to be associated with higher BCR. Conclusions. Our research demonstrated that SCTC-positive patients are associated with higher BCR compared to SCTC-negative patients in NMPC. Therefore, it is recommended that NMPC patients undergo CTC surveillance intensively after RP or RT.

The existing micro-motion stage based on flexure hinge can hardly meet the requirements of a high-precision stage with large stroke and variable operating conditions (especially variable frequency operation). In this paper, a flexible hinge micro-motion stage with adjustable stiffness is presented. A wide range of stiffness and frequency adjustments are realized by changing the length of the flexure hinge through the movement of the support. However, the change on the stiffness of the flexure hinge is non-linear when is in large deformation. It is difficult to use the traditional PID algorithm to control such nonlinear system without the complete mathematical model, and much more complicated control strategies are required to deal with the condition of large deformation of the flexure hinge. In this paper, the active disturbance rejection control (ADRC) strategy is adopted to solve the above non-linear control problem without relying on the complete system model. A novel model-compensated ADRC based on the dynamic characteristics is proposed to further improve the performance of the micro-motion stage. Experiments show that the ADRC with model compensation (MADRC) can achieve high positioning and tracking precision faster than the conventional ADRC. The presented micro-motion stage based on stiffness-adjustable flexure hinges and MADRC design is capable to meet the industrial application requirements of large stroke or variable working conditions.

Circular FOXM1 (circFOXM1) has been demonstrated to participate in the initiation and development of cancers, including prostate cancer (PCa). However, there is no relevant information on the regulation of PCa by circFOXM1. The RNA level of circFOXM1 was detected by qRT-PCR in PCa tissues and cells. The protein expression was performed by western blot and immunohistochemistry assay. Cell proliferation was examined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide, colony formation and flow cytometry assays. The abilities of cell migration and invasion were determined by transwell assay. The relationship between circFOXM1 and miR-515-5p or ADAM10 was predicted by starBaseV2.0 online database, and identified by dual-luciferase reporter assay or RNA pull-down assay. The effects of circFOXM1 silencing and ADAM10 knockdown on PCa growth in vivo were evaluated by in-vivo tumor formation assay. As a result, we found that circFOXM1 and ADAM10 expression were upregulated in PCa tissues and cells. Functional analysis showed that circFOXM1 silencing repressed proliferation, migration and invasion, and induced cell cycle arrest, whereas these effects were partly reversed by miR-515-5p inhibitor. Additionally, circFOXM1 directly sponged miR-515-5p, and miR-515-5p bound to ADAM10. ADAM10 absence also repressed PCa process. Furthermore, in-vivo tumor formation assay revealed that both circFOXM1 silencing and ADAM10 knockdown repressed tumor growth in vivo. Thus, we came a conclusion that circFOXM1 contributed to PCa progression via regulating miR-515-5p/ADAM10 axis. These results may provide a theoretical basis for further studying the progression of PCa.

BackgroundThere have been reports of increasing azole resistance in Candida tropicalis, especially in the Asia-Pacific region. Here we report on the epidemiology and antifungal susceptibility of C. tropicalis causing invasive candidiasis in China, from a 9-year surveillance study.MethodsFrom August 2009 to July 2018, C. tropicalis isolates (n = 3702) were collected from 87 hospitals across China. Species identification was carried out by mass spectrometry or rDNA sequencing. Antifungal susceptibility was determined by Clinical and Laboratory Standards Institute disk diffusion (CHIF-NET10–14, n = 1510) or Sensititre YeastOne (CHIF-NET15–18, n = 2192) methods.ResultsOverall, 22.2% (823/3702) of the isolates were resistant to fluconazole, with 90.4% (744/823) being cross-resistant to voriconazole. In addition, 16.9 (370/2192) and 71.7% (1572/2192) of the isolates were of non-wild-type phenotype to itraconazole and posaconazole, respectively. Over the 9 years of surveillance, the fluconazole resistance rate continued to increase, rising from 5.7 (7/122) to 31.8% (236/741), while that for voriconazole was almost the same, rising from 5.7 (7/122) to 29.1% (216/741), with no significant statistical differences across the geographic regions. However, significant difference in fluconazole resistance rate was noted between isolates cultured from blood (27.2%, 489/1799) and those from non-blood (17.6%, 334/1903) specimens (P-value < 0.05), and amongst isolates collected from medical wards (28.1%, 312/1110) versus intensive care units (19.6%, 214/1092) and surgical wards (17.9%, 194/1086) (Bonferroni adjusted P-value < 0.05). Although echinocandin resistance remained low (0.8%, 18/2192) during the surveillance period, it was observed in most administrative regions, and one-third (6/18) of these isolates were simultaneously resistant to fluconazole.ConclusionThe continual decrease in the rate of azole susceptibility among C. tropicalis strains has become a nationwide challenge in China, and the emergence of multi-drug resistance could pose further threats. These phenomena call for effective efforts in future interventions.

The suprachiasmatic nucleus (SCN) is essential for the neural control of mammalian circadian timing system. The circadian activity of the SCN is modulated by its afferent projections. In the present study, we examine neuroanatomical characteristics and afferent projections of the SCN in the tree shrew (Tupaia belangeri chinensis) using immunocytochemistry and retrograde tracer Fluoro-Gold (FG). Distribution of the vasoactive intestinal peptide was present in the SCN from rostral to caudal, especially concentrated in its ventral part. FG-labeled neurons were observed in the lateral septal nucleus, septofimbrial nucleus, paraventricular thalamic nucleus, posterior hypothalamic nucleus, posterior complex of the thalamus, ventral subiculum, rostral linear nucleus of the raphe, periaqueductal gray, mesencephalic reticular formation, dorsal raphe nucleus, pedunculopontine tegmental nucleus, medial parabrachial nucleus, locus coeruleus, parvicellular reticular nucleus, intermediate reticular nucleus, and ventrolateral reticular nucleus. In summary, the morphology of the SCN in tree shrews is described from rostral to caudal. In addition, our data demonstrate for the first time that the SCN in tree shrews receives inputs from numerous brain regions in the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. This comprehensive knowledge of the afferent projections of the SCN in tree shrews provides further insights into the neural organization and physiological processes of circadian rhythms.

A new design strategy through the synergy of Mo(VI)–Mo(V) intervalence charge transfer and π(radical)–π(radical/cation) interactions is proposed to obtain semiconductors with photoresponsive ranges covering the whole UV–SWIR (ultraviolet–shortwave near-infrared; ca. 250–3000 nm) region. With this strategy, a viologen-based molybdate semiconductor with a UV–SWIR photoresponsive range was obtained through UV/X-ray irradiation or thermal annealing. The thermally annealed semiconductor has the highest conversion and the best photocurrent response in the range of 355–2400 nm.

Rogressive deconstruction of filament actin (F-actin) in hippocampal neurons in the epileptic brain have been associated with epileptogenesis. Previous clinical studies suggest that glucocorticoids treatment plays beneficial roles in refractory epilepsy. Glucocorticoids treatment affects dendritic spine morphology by regulating local glucocorticoid receptors and F-actin cytoskeleton dynamics. However, how glucocorticoids regulate epileptogenesis by controlling F-actin cytoskeleton is not clear yet. Here we study the function of glucocorticoids in epileptogenesis by examining F-actin abundance, hippocampal neuron number, and synaptic markers in pilocarpine-induced epileptic mice in the presence or absence of dexamethasone (DEX) treatment. We found that spontaneous seizure duration was significantly reduced; F-actin damage in hippocampal subfields was remarkably attenuated; loss of pyramidal cells was dramatically decreased; more intact synaptic structures indicated by pre- and postsynaptic markers were preserved in multiple hippocampal regions after DEX treatment. However, the number of ZNT3 positive particles in the molecular layer in the hippocampus of pilocarpine epileptic mice was not altered after DEX treatment. Although not sufficient to cease epileptogenesis, our results suggest that dexamethasone treatment ameliorates the damage of epileptic brain by stabilizing F-actin cytoskeleton in the pilocarpine epileptic mice.

Background Kawasaki disease (KD) is an acute multisystem vasculitic syndrome that predominantly affects infants and young children. Neurological complications are rare in patients with KD and the diagnosis is challenging. We report a case of KD that manifested as bilateral facial nerve palsy and meningitis. Case report A 6-month-old boy presented with a 10-day history of fever. Four days before admission, the patient developed a rash, conjunctival injection, perioral and perianal excoriation, and bilateral facial nerve palsy. Brain magnetic resonance imaging was normal. Echocardiography showed dilated coronary arteries and coronary artery aneurysms. A cerebrospinal fluid examination showed an elevated leukocyte count. A diagnosis of KD was made, and the patient was treated with gamma globulin and aspirin. The patient’s fever subsided on the following day and the right-sided facial nerve palsy was relieved 1 month later. An 18-month follow-up showed that the left-sided facial nerve palsy persisted and the patient’s condition remained stable. Conclusion KD manifesting as bilateral facial nerve palsy and meningitis is extremely rare. Clinicians should be aware of this condition, and early diagnosis and appropriate treatment should be emphasized.

Compared with traditional composite panels, the modeling, analysis and design of variable-stiffness panels with curvilinear fibers are much more complicated. Although the design flexibility is greatly enhanced, the design of variable-stiffness structures must meet manufacturing constraints to ensure that the designed structures can be fabricated finally. In order to design variable-stiffness composite panels that is very challenging due to its nonlinearity and non-convexity, a novel multi-stage design method for variable-stiffness panels is developed based on lamination parameters. First, lamination parameters are taken as design variables, and the stiffness distribution is obtained efficiently by few iterations. Next, the lamination parameters are transformed into actual layups. Finally, the realistic fiber path is regenerated by considering manufacturing constraints. In addition, the isogeometric analysis, which is more suitable for variable-stiffness structure, is used instead of the traditional finite element analysis to improve the analysis accuracy. Illustrative example demonstrates the high computational efficiency and optimization capacity of proposed method, compared to gradient-based algorithm and evolutionary algorithm.

BACKGROUND The aim of this study was to assess the correlations of Twist expression with pathological and computed tomography (CT) characteristics and prognosis of non-small cell lung cancer (NSCLC). MATERIAL AND METHODS We enrolled 120 patients with lung cancer who underwent CT examination. The Twist protein expression level was detected in 120 cases of cancer tissues and a control group using immunohistochemical method. The survival curve was plotted using the Kaplan-Meier method and analyzed via log-rank test. RESULTS The Twist expression was associated with tumor stage, differentiation degree, and presence or absence of lymph node metastasis, but had no correlations with sex, age, or histological type. Grade-3 bronchial involvement, pleural indentation, and hilar and mediastinal lymph node enlargement occurred more frequently in the high-expression Twist group compared with the low-expression Twist group. The overall survival rate of patients with Twist overexpression was significantly lower than that of patients with normal Twist expression. The mean survival time was 69.8 months in Twist protein expression-negative patients and 45.8 months in Twist protein expression-positive patients. Finally, the positive expression of Twist protein was significantly correlated with the long-term survival and prognosis of patients. CONCLUSIONS The Twist gene might be involved in the occurrence and development of NSCLC, which is correlated with patient prognosis.

In this study, we compared three commercially available and two widely used CPAs for their ability of cryopreserving PBMCs. Similar survival (81.0%) and recovery rate (73.7%) were observed among cells using these five CPAs. However, all the cryopreserved PBMCs exhibited a significantly lower survival rate when compared with the fresh samples (94.3%). We further evaluated effector cell subpopulation and tumoricidal activity of PBMC-derived cytokine-induced killing (CIK) cells and natural killing (NK) cells. Similar and high survival (CIK: 88.6%; NK: 87.5%) and recovery (CIK: 99.5%; NK: 99.7%) rates were detected in CIK and NK cells prepared from cryopreserved PBMCs using the five CPAs. The CD3+CD56+ effector percentage (27.3%) of cryopreserved PBMC-derived CIK cells using the five different CPAs and their tumoricidal activities on melanoma CHL-1 cells (45.7%) and bladder cancer cell line T-24 (44.7%) were similar but significantly lower than those of the fresh PBMC-derived controls (effector: 30.7%; CHL-1: 84.2%; T-24: 82.2%). Cryopreserved PBMC-derived NK cells also exhibited similar tumoricidal activities (CHL-1: 73.8%; T-24: 71.9%) but was significantly lower than that of the fresh control group. We were not able to identify a specific CPA that performed superior than others in PBMC cryopreservation.

It was previously reported that a tube holding chitosan carriers loaded with neurotrophin-3 (NT-3), after insertion into a 5 mm long transection gap in the adult rat spinal cord, triggered de novo neural tissue generation and functional recovery. Here, we report an effort to validate these findings using stringent blinding methodologies, which are crucial for robustness in reproducing biomedical studies. Radio frequency identification (RFID) chips were utilized to label rats that were randomly assigned into three experimental groups: transection with chitosan-NT-3 implant (C-NT3), transection only (T-controls), and laminectomy only (S-controls), blinding the experimenters to the treatments. Three months after surgery, animals only known by their RFID were functionally, electrophysiologically, and anatomically assessed. The data were then collected into the proper groups and statistically analyzed. Neural tissue with nestin-, Tuj1-, and NeuN-positive cells was found bridging the transection gap in C-NT3 rats, but not in T-controls. Motor- and somatosensory-evoked potentials were detected in C-NT3 rats and S-controls, but not in T-controls. Hind limb movement was significantly better in C-NT3 rats compared with T-controls. Our validation study indicates that C-NT3 implants facilitate neural tissue generation, at least in part, by eliciting endogenous neurogenesis. Our data support the use of C-NT3 implants for tissue remodeling in the injured spinal cord.

Two Cu(II) complexes of the non-steroidal anti-inflammatory drug Naproxen were synthesized, characterized and evaluated for anti-inflammatory, analgesic, ulcerogenic and urease inhibition activities. The complex 1 [Cu(nap)2(H2O)3]·H2O was reported previously, and the crystal structure of complex 2 [Cu(nap)2(dap)(H2O)] (nap = Naproxen, dap = 1,3-diaminopropane) was confirmed by X-ray diffraction crystallography. The anti-inflammatory and ulcerogenic study showed that the compounds 1 and 2 were the promising anti-inflammatory agents and demonstrated significant gastric tolerance when compared with Naproxen, especially for complex 1 with the edema inhibition of 93.6% after 3 h, and ulcer index of 15 ± 2. Analgesic and urease inhibition assay showed that complex 2 was a potent urease inhibitor with the IC50 value of 1.69 ± 0.08 μM and pain inhibition value of 65%. As effective urease inhibitors, molecular docking study was performed to investigate the binding mode of the complexes with urease.

Throughout the life cycle of mammals, the subgranular area of the hippocampal dentate gyrus, the subventricular area of the lateral ventricle and the subcentral canal of the medullary crest produce new neurons continuously. The researchers used active biomaterial scaffolds to improve the local microenvironment in adult central nervous system, to activate endogenous neurogenesis, to reconstruct functional neural networks, and ultimately to improve limb dysfunction. This review focuses on the concept of the adult endogenous neurogenesis, the activation of endogenous neurogenesis to repair traumatic brain injury and spinal cord injury, and the formation of the endogenous incubation theory in adult mammals, the current controversy on the existence of human neurogenesis and analysis of the main reasons for such controversy. The challenges of eventual clinical transformation.

For composite panels with cutouts, curvilinear fiber path can adjust the in-plane stiffness distribution to increase the buckling resistance, but it results in huge computational cost for the buckling analysis when FEA is employed. In this study, variable-stiffness panels with cutouts are analyzed via isogeometric method, where cutouts are represented by the level set method . The method for suppressing artificial buckling modes is proposed to improve the prediction accuracy. Moreover, the analytical sensitivity is derived to facilitate fiber path optimization, and a new bi-level optimization framework considering manufacturing constraints is established. Finally, the proposed method is verified by variable-stiffness aircraft panel with multiple cutouts, which can not only provide an accurate prediction of buckling load, but also exhibit high convergence rate and low computational cost for fiber path optimization.

The repair of peripheral nerve injury is still a great challenge in clinic. Autologous nerve transplantation is the gold standard for the treatment of long-distance peripheral nerve defects, but this method remains associated with high morbidity of the donor site and lack of matching donor. In this study, a novel chitosan scaffold (CS) loaded with control-released basic fibroblast growth factor (bFGF) was used to repair 20 mm sciatic nerve defects in adult rat. The ultrastructure of bFGF-CS was observed by scanning electron microscope. The tensile tester and nano-indentation were used to evaluate its mechanical properties. Cholera toxin B-subunit (CTB) tracing, sciatic nerve function index, electromyography, immunofluorescence staining of regenerated nerve and motor endplate were used to evaluate the regeneration of sciatic nerve in rats. The results showed that the structure and mechanical properties of bFGF-CS was beneficial to the regeneration of sciatic nerve. At 12 weeks after operation, bFGF-CS facilitated sciatic nerve regeneration in rat. CTB successfully crossed the sciatic nerve defect area to reach the cell body of sciatic nerve. The motor endplate was reconstructed, thus promoting the behavioral recovery. These findings suggest that the bFGF-CS provides an effective means of repairing 20 mm sciatic nerve defects and shows great potential for clinical application.

The regenerative potential of endogenous neural stem cells (NSCs) in the adult mammalian brain is considered as a possible source of neural repair. However, adult neurogenesis after traumatic brain injury (TBI), especially in the sensorimotor cortex of the brain, is unknown. Here, we reported that a controlled release system, bFGF-sodium hyaluronate collagen scaffolds (bFGF-CRS), implanted into the injured area after traumatic brain injury, could effectively activate endogenous NSCs to proliferate and migrate to the injured area. Immunofluorescence results reveal that these actived NSCs differentiate into new naive neurons, mature neurons and reconstruct cortical layers I-VI. Neurocircuit tracing results show that newborn neurons reconstruct neural circuits with the contralateral cerebral cortex and ipsilateral thalamus VL in the injured area, partially restore CST neural circuits, and finally improve the function of sensorimotor behavior in the horizontal and vertical plane of the right forelimb. In addition, transplantation of bFGF-CRS promoted Nestin+ SVZ cells to proliferate and migrate to the injured area, and could differentiate into neurons, which were involved in repairing brain injury. Our study showed that bFGF-CRS broadened the strategy for treating neurological disorders such as traumatic brain injury by recruiting endogenous NSCs for neural repair.

Visceral organs are the participants and maintainers of various life activities of the body. Various injuries such as trauma, surgery, organ transplantation, inflammatory bowel disease, and other serious diseases will cause damage to internal organs. The main reason is the double impact of ischemia and reperfusion, which in turn causes the activation of complement-phagocytic-lymphocyte in the body, causing local and systemic inflammatory reactions, dysfunction of coagulation system, hypermetabolic status, etc., eventually leading to multiple organ dysfunction syndrome (MODS), and even multiple systemic organ failure (MSOF) also called multiple organ failure (MOF). Visceral organ damage, especially multiple organ function damage, is an important feature of the aggravation of traumatic injury and the occurrence of complications. For open wounds, damaged organs can be repaired and reconstructed by surgery. However, for closed injury such as ischemia-reperfusion injury to intestine, liver, kidney, and lung; ischemic injury of donors during organ transplantation; and multiple organ damage after traumatic (burn) injury, especially the occult shock of the intestinal tract, etc., the organ itself has ischemic damage that is difficult to distinguish with the naked eye; the pathogenesis of such damage is complex, wide, and concealed; there is a lack of effective prosthetic measures; and the repair after injury is often not easy to attract people’s attention, thus leading to the death of patients. According to experts’ statistics, more than half of all deaths are caused by visceral complications after severe burns; two-thirds of the injured in serious traffic accidents are accompanied by visceral injury, which is the primary cause of disability and death. MODS is also ranked first in the cause of death in the intensive care unit. In general, the death of the visceral injury after severe trauma is mainly divided into two stages: early death, which is closely related to shock or severe brain injury; and late death, which is mainly caused by MODS or multiple system organ failure (MSOF), and its occurrence is associated with systemic inflammatory response syndrome (SIRS), ischemia-reperfusion injury, and endotoxemia. Among them, organ ischemia-reperfusion injury and microcirculatory dysfunction (the second hit) are one of the central links of visceral complications after severe trauma. For visceral injury, previous studies focused on the pathogenesis of visceral injury and initially clarified the role of infection, uncontrolled inflammatory response, and oxygen-free radical activation in the occurrence of severe visceral injury. However, it is worth noting that previous studies have focused too much on the pathogenesis of organ damage, while there is a lack of in-depth discussion on the outcome of damaged organs. Therefore, it is essential to strengthen the prevention and treatment of visceral injuries and promote the early repair and reconstruction of damaged organs to guarantee life safety. How to accelerate and promote the repair of damaged internal organs has become the key to determine the success of serious trauma treatment, especially to prevent MODS and MSOF.

Stiffened plates are widely used in aerospace structures as load-bearing components. In order to obtain a novel design of stiffened structures with excellent performance, a generative design method of stiffened plates (GDMSP) based on the homogenization method is proposed in this paper, which optimizes the stiffener layout based on an equivalent model. Then, the detailed model can then be obtained by extracting the stiffener path from the discrete distribution of stiffener angles. Moreover, the optimized design can be obtained by size optimization based on the detailed model. Two examples are used to illustrate the proposed framework, including the stiffness maximization of a rectangle stiffener plate and the buckling load maximization of a square stiffener plate. The optimized stiffener configurations are characterized by streamlines and uniform lines, respectively. For the first example, the stiffness of the stiffener design has an improvement of 17%. For the second example, the optimized design improves the buckling load by 35%. Results indicate that the proposed method can effectively provide a novel generative design for stiffened plates. Moreover, the obtained results have a clear stiffener path and have a noticeable improvement in performance, which can be directly used to establish a detailed model.

BACKGROUND: To investigate the clinical characteristics and risk factors of human immunodeficiency virus (HIV)-negative patients with Talaromyces marneffei (T. marneffei) infection. METHODS: We retrospectively collected the clinical information of HIV-negative patients with T. marneffei infection from January 1, 2010 to June 30, 2019, and analyzed the related risk factors of poor prognosis. RESULTS: Twenty-five cases aging 22 to 79 years were included. Manifestations of T. marneffei infection included fever, cough, dyspnea, chest pain or distress, lymphadenopathy, ear, nose, and throat (ENT) and/or skin lesions, bone or joint pain, edema and pain in the lower extremities, digestive symptoms, icterus, malaise, and hoarseness. Two cases had no comorbidity, while 23 cases suffered from autoimmune disease, pulmonary disease, cancer, and other chronic diseases. Sixteen cases had a medication history of glucocorticoids, chemotherapy or immunosuppressors. Pulmonary lesions included interstitial infiltration, nodules, atelectasis, cavitary lesions, pleural effusion or hydropneumothorax, bronchiectasis, pulmonary fibrosis, pulmonary edema, and consolidation. The incidence of osteolytic lesions was 20%. Eight patients received antifungal monotherapy, and 11 patients received combined antifungal agents. Fifteen patients survived and ten patients were dead. The Cox regression analysis showed that reduced eosinophil counts, higher levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), myoglobin (Mb), procalcitonin (PCT), and galactomannan were related to poor prognosis (hazard ratio [HR]>1, P

Mesenchymal stem cells (MSC) are a popular candidate in cellular therapy for many diseases. MSCs are well known by their feature of self-renewal and their differentiation potential. NESTIN is a cytoskeletal protein expressed in MSC that functions directly in cell proliferation and differentiation. Here, we demonstrated that adding UltraGRO, a medium supplement, could maintain and partially recover the expression of NESTIN in human umbilical cord derived MSCs (UC-MSCs). Furthermore, the UC-MSCs cultured with UltraGRO showed a better immunomodulation ability in a colitis mouse model compared with those cultured in other types of media. This indicates that the use of novel culture medium benefits the maintenance of NESTIN expression and NESTIN may be one of the vital factors that regulates the performance of MSCs.

Progressive hemifacial atrophy (PHA) is mainly characterized by asymmetrical atrophy of craniofacial tissue; however, 10% to 30% of patients with PHA exhibit ocular manifestations. Here, we describe abnormal ocular findings in a Chinese patient with PHA. The patient was a 29-year-old Chinese man. Characteristic ocular findings in his affected eye included keratic precipitate, corneal endothelial degeneration, fundus tessellation, pupillary dilation, direct light reflex loss, and visual evoked potential alteration. Whole exosome sequencing revealed that the patient harbored a mutation in the CRB1 gene; this gene has been associated with various retinal dystrophies. During 10 years of follow-up, the patient’s ocular status remained stable. To the best of our knowledge, this is the first report of ocular manifestations of PHA in a Chinese patient, and the first report of a CRB1 mutation in a patient with PHA; these findings may inform future research regarding PHA.

Aims The beneficial effects of cannabinoid type 2 receptor (CB2R) activation have been verified in various tissue repair processes. Our recent study revealed CB2R activation promotes myogenesis partly through Nrf2 signaling in a mouse skeletal muscle ischemia-reperfusion (IR) injury model. Other relevant mechanisms need to be further elucidated. Macrophages orchestrate tissue regeneration mainly by changing their phenotype and function. The aim of this study was to investigate the role of CB2R in IR-induced skeletal muscle regeneration, focusing on its impact on macrophage polarization and the consequences on myogenesis. Main methods The effects of CB2R on skeletal muscle regeneration, and the macrophage infiltration and M1/M2 polarization were tested with the IR injury model in wild type (WT) and CB2R knockout (CB2R-KO) mice. The effect of CB2R on peritoneal macrophage polarization, and its impact on the myoblasts differentiation was evaluated by co-culture experiments in vitro. Key findings The present study revealed the myofiber regeneration was hindered in the CB2R-KO mice. The infiltration of M1 macrophages and relevant markers' protein expression were enhanced in the CB2R-KO mice, while that of M2 macrophages was decreased compared with the WT mice. The in vitro studies further demonstrated that the absence of CB2R promoted M1 polarization while inhibited M2 polarization. The promoted M1 polarization and retarded M2 polarization in CB2R-KO macrophages hindered myoblasts differentiation. Significance Overall, these results suggested CB2R plays a beneficial effect on skeletal muscle regeneration partly by regulating macrophage M1/M2 polarization after IR injury in mice.

Although autogenous nerve transplantation is the gold standard for treating peripheral nerve defects of considerable length, it still has some shortcomings, such as insufficient donors and secondary injury. Composite chitosan scaffolds loaded with controlled release of nerve growth factor can promote neuronal survival and axonal regeneration after short-segment sciatic nerve defects. However, the effects on extended nerve defects remain poorly understood. In this study, we used chitosan scaffolds loaded with nerve growth factor for 8 weeks to repair long-segment (20 mm) sciatic nerve defects in adult rats. The results showed that treatment markedly promoted the recovery of motor and sensory functions. The regenerated sciatic nerve not only reconnected with neurons but neural circuits with the central nervous system were also reconstructed. In addition, the regenerated sciatic nerve reconnected the motor endplate with the target muscle. Therefore, this novel biomimetic scaffold can promote the regeneration of extended sciatic nerve defects and reconstruct functional circuits. This provides a promising method for the clinical treatment of extended peripheral nerve injury. This study was approved by the Animal Ethics Committee of Capital Medical University, China (approval No. AEEI-2017-033) on March 21, 2017.

The concept of a curvilinearly stiffened panel is promising for aerospace and aircraft structures with cutouts, since the stiffness distribution and loading path can be flexibly tailored in terms o...