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It is increasingly appreciated that cancer cell heterogeneity and plasticity constitute major barriers to effective clinical treatments and long-term therapeutic efficacy. Research in the past two decades suggest that virtually all treatment-naive human cancers harbor subsets of cancer cells that possess many of the cardinal features of normal stem cells. Such stem-like cancer cells, operationally defined as cancer stem cells (CSCs), are frequently quiescent and dynamically change and evolve during tumor progression and therapeutic interventions. Intrinsic tumor cell heterogeneity is reflected in a different aspect in that tumors also harbor a population of slow-cycling cells (SCCs) that are not in the proliferative cell cycle and thus are intrinsically refractory to anti-mitotic drugs. In this Perspective, we focus our discussions on SCCs in cancer and on various methodologies that can be employed to enrich and purify SCCs, compare the similarities and differences between SCCs, CSCs and cancer cells undergoing EMT, and present evidence for the involvement of SCCs in surviving anti-neoplastic treatments, mediating tumor relapse, maintaining tumor dormancy and mediating metastatic dissemination. Our discussions make it clear that an in-depth understanding of the biological properties of SCCs in cancer will be instrumental to developing new therapeutic strategies to prevent tumor relapse and distant metastasis.

The development of plastic hinges in a steel frame structure with steel beam-to-column end-plate connection joints by strengthening the end-plate area is a widely used design concept. This study explores the realization of this design concept with a beam web opening and without end-plate stiffening. The factors that impact the mechanical properties and failure modes of these joints are the end-plate thickness, opening diameter, opening position, and opening type. These parameters are tested for monotonic loading of six beam-column joints, and 220 finite element models are parametrically analysed. Additionally, the development of plastic hinge of the beam based on the development trend of maximum strain of each component section is studied. The initial rotational stiffness, ductility, bearing capacity, deformation capacity, and failure mode are used as the evaluation criteria to assess the behaviour of this joint. The research indicates that a castellated steel beam-to-column end-plate connection can realize the occurrence of plastic hinge and exhibit good ductility and load-bearing performance. This study highlights the premise that the beam web opening and end-plate thickness parameters must be within a specific range to achieve accurate results; additionally, the division method of the interval of parameters is described. The influence of end-plate thickness on the working mechanism of the connection is clarified, and the mechanical properties and failure modes of connections under different parameter intervals are studied. This study proposes a method for calculating the initial rotational stiffness of the connection to achieve good accuracy by considering the participation of the components on the beam in the rotation of the connection.

Background Extended curettage has increasingly become the preferred treatment for giant cell tumour of bone (GCTB), but the high recurrence rate after curettage poses a major challenge for orthopaedic surgeons. Computed tomography (CT) is valuable in the evaluation of GCTB. Our aim was to identify specific features of GCTB around the knee in pre-operative CT images that might have prognostic value for local recurrence. Methods We retrospectively analyzed data from 124 patients with primary GCTB around the knee who underwent extended curettage from 2010 through 2019. We collected demographic, clinical, and therapeutic data along with several CT-derived tumour characteristics. CT-derived tumor characteristics included tumour size, the distance between the tumour edge and articular surface (DTA), and destruction of posterior cortical bone (DPC). Akaike information criterion (AIC) was used to select which variables to enter into multivariate logistic regression models and to determine significant factors affecting recurrence. Results The total recurrence rate was 21.0% (26/124), and the average follow-up time was 69.5 ± 31.2 months (24–127 months). Age, DTA ( Conclusion Identifying certain features of GCTB around the knee on CT has prognostic value for patients treated with extended curettage. A three-factor model predicts tumour recurrence well after extended curettage.

Background: Chromogranin A (CgA) levels have been reported to predict mortality in patients with heart failure. However, information on the prognostic value and clinical availability of CgA is limited. We compared the prognostic value of CgA to that of previously proven natriuretic peptide biomarkers in patients with acute heart failure.Methods: We retrospectively evaluated 272 patients (mean age, 68.5±15.6 years; 62.9% male) who underwent CgA test in the acute stage of heart failure hospitalization between June 2017 and June 2018. The median follow-up period was 348 days. Prognosis was assessed using the composite events of 1-year death and heart failure hospitalization.Results: In-hospital mortality rate during index admission was 7.0% (n=19). During the 1-year follow-up, a composite event rate was observed in 12.1% (n=33) of the patients. The areas under the receiver-operating characteristic curves for predicting 1-year adverse events were 0.737 and 0.697 for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and CgA, respectively. During follow-up, patients with high CgA levels (>158 pmol/L) had worse outcomes than those with low CgA levels (≤158 pmol/L) (85.2% vs. 58.6%, p

INTRODUCTION To improve compliance with voiding diaries in children with primary monosymptomatic nocturnal enuresis (PMNE), a new modified 3-day weekend frequency-volume chart (FVC) was designed, and the compliance and validity of this modified FVC was evaluated by comparing with the International Children's Continence Society (ICCS) recommended voiding diary. METHODS A total of 1200 patients with PMNE were enrolled in the study from 13 centers in China and were randomly assigned to record this modified FVC or the ICCS-recommended voiding diary. The primary outcome measure was the compliance, assessed by comparing the completing index and the quality score of diaries between two groups. The secondary outcome measure was the validity, evaluated by comparing the constituent of subtypes, micturition parameters and response rate to desmopressin. RESULTS Among the 1200 participants enrolled in the study, 447 patients completed the ICCS-recommended voiding diary and 469 completed the modified diary. The diurnal completing index and the quality score of the modified FVC group were better than those of the ICCS group. In addition, there was no significant difference between these two groups in the subtype classification, or in the response rate to desmopressin. CONCLUSIONS The modified FVC could be applied to obtain the voiding characteristics of children with PMNE as the ICCS-recommended voiding diary does and offers a reasonable and better choice for children with PMNE from the unselected population in the future.

BACKGROUND The development of peripheral T-cell lymphoma (PTCL) after chemotherapy for Hodgkin’s lymphoma (HL) is rare, and highly aggressive TCL/leukemia has not been reported to date. The relationship between HL and PTCL needs further exploration to understand the pathogenesis of metachronous lymphoma (ML) and find effective treatment options. We report a patient with ML, whose biopsy of a right cervical lymph node initially confirmed classical HL (CHL). CASE SUMMARY We report a patient with ML, whose biopsy of a right cervical lymph node initially confirmed CHL, with typical reed–sternberg cells expressing CD30 and PAX-5. T-cell leukemia/lymphoma occurred 3 years after treatment, and a lymph node biopsy at the onset confirmed PTCL, nonspecific type, expressing CD3, CD4 and CD8. The patient was treated with standard doses of chemotherapy, programmed cell death-ligand 1 monoclonal antibody, and chidamide, all of which failed to achieve complete remission. The patient was diagnosed with refractory state, and eventually died of leukocyte stasis. CONCLUSION The accuracy of the diagnosis needs to be confirmed when chemotherapeutic drugs are not effective.

Objective: Multiple brain metastases are a severe condition for cancer patients. To date, no general consensus exists regarding the optimal treatment procedure for multiple brain metastases. Radiotherapy is the most commonly used treatment option. The role of surgical resection for multiple brain metastases is unclear. The aim of this study was to compare the outcomes of patients with multiple brain metastases treated with either surgery or stereotactic radiosurgery (SRS). Methods: The medical records of 279 consecutive adult patients with multiple brain metastases treated with either surgery (26 patients) or SRS (253 patients) were retrospectively reviewed. Propensity score matching was conducted to correct for discrepancies in the baseline characteristics, and 78 patients (26 receiving surgery and 52 receiving SRS) were chosen for comparison of outcomes, such as overall survival, local tumor control rate, and symptom improvement. Results: The tumor size in the surgery group was significantly greater than that in the SRS group after propensity score matching. However, the neurological recovery rate, incidence of leptomeningeal metastasis after surgery, 1-year local tumor control rate, and overall survival were not significantly different between groups. Conclusions: Our data demonstrate that surgery and radiosurgery have identical overall survival and local tumor control rates in patients with 2 to 4 brain metastases. Although SRS remains the primary and standard option for patients with brain metastasis, surgery offers several distinct advantages, such as establishing a diagnosis or relieving mass effects, and may additionally be beneficial in carefully selected patients with 2–4 brain metastases.

Background Renal ischemia reperfusion injury (IRI) has become a growing concern in clinical practice with high morbidity and mortality rates. There is currently no effective prophylactic regimen available to prevent its occurrence and to improve its clinical prognosis. Dl-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Little is known about its role in preventing kidney injury. Methods The kidneys of male C57BL/6J mice were subjected to 33 min of ischemia followed by 24 h of reperfusion. NBP was administered by gavage prior to surgery. The reno-protective effect of NBP was evaluated by serum creatinine, kidney injury markers and renal pathological changes. Furthermore, the inflammation, oxidative stress, and apoptosis markers in kidney tissue were examined. In vitro, HK2 cells were treated prophylactically with NBP and then exposed to hypoxia/reoxygenation (H/R). Cell viability and apoptosis related protein were quantified to verify the protective effect of NBP. Pro-inflammation genes expression as well as ROS generation were further investigated also. Results NBP pretreatment significantly improved renal dysfunction and alleviated pathological injury, renal inflammation response, oxidative stress and cell apoptosis. Consistently, NBP attenuated H/R induced increases in ROS, pro-inflammatory genes expression, apoptosis and cleaved caspase-3 levels in HK2 cells. Conclusion Our promising results validated for the first time that NBP could ameliorate renal IRI via attenuating inflammation, oxidative stress, and apoptosis, which indicated that NBP might be a good candidate against AKI.

This letter investigates the problem of determining the static target in multistatic systems using bistatic range (BR) measurements, which can be obtained by some local sensor signal processing methods. The localization problem is first formulated as a semidefinite programming problem by using the semidefinite relaxation technique. Then, an initial position estimate is given by augmenting the unknown parameter space, which is required for solving the SDP problem. Specifically, this initialization is also a closed-form solution. Compared with existing algorithms, the proposed estimator has the advantage of not relying on the prior knowledge of BR measurement noise power. Simulation results validate the performance of the proposed estimator.

Objective: To investigate the effect of Astragalus polysaccharides (APS) on myocardial remodeling and expression of miR-21 after myocardial infarction. Methods: Sixty SPF grade healthy male rats were divided into the sham operation group, the model group, astragalus polysaccharide low, medium and high dose groups and atorvastatin group randomly with 10 rats in each group. The left anterior descending coronary artery (LAD) was ligated to establish myocardial infarction model in rats, and the corresponding drug intervention was given for 4 weeks. The changes of myocardial morphology and collagen were observed by HE and Masson staining. The levels of IL-1β, IL-6, TNF-α and IL-10 were detected by ELISA. The mRNA expressions of miR-21, MMP2, TIMP-2, Col-I, and Col-III was detected by RT-PCR. The protein expressions of TLR4, MyD88 and NF-κB p65 were detected by Western blot. Results: Compared with the model group, APS could improve the pathological morphology of myocardial tissue, increase the level of IL-10 in myocardial tissue, reduce the staining area of collagen and the contents of IL-1 β, IL-6 and TNF-α (P

Paclitaxel (PTX) is a first-line chemotherapeutic agent to treat prostate cancer (PCa), but a large number of patients acquired drug resistance after short-term treatment. To develop combinational therapeutics to overcome PTX-resistant PCa, we established PTX-resistant LNCaP (LNCaP/PTX) cells and found that the LNCaP/PTX cells exhibited epithelial-mesenchymal transition (EMT) and enhanced metastasis during the selection process. We revealed that β-tubulin III, androgen receptor, and CXCR4 expressions were significantly increased in LNCaP/PTX cells and directly contributed to PTX resistance and EMT. Therefore, we developed prostate-specific membrane antigen aptamer (Apt)-functionalized shell-core nanoparticles (PTX/siRNAs NPs-Apt); the hydrophobic DSPE encapsulating PTX formed the dense inner core and the hydrophilic Apt-PEG2K with calcium phosphate (CaP) absorbing siRNAs formed the outer shell to sequentially release siRNAs and PTX, where CaP could trigger lysosomal escape to ensure that pooled siRNAs efficiently released into the cytoplasm to reverse EMT and resensitize PTX, while the PTX located in the core was subsequently released to exert the killing effect of chemotherapy to achieve the best synergistic effect. PTX/siRNAs NPs-Apt showed an enhanced tumor-targeting ability and achieved superior efficacy in the subcutaneous and orthotopic PCa tumor model with minimal side effects.

Osteosarcoma has a poor prognosis, and the poor understanding of the genetic drivers of osteosarcoma hinders further improvement in therapeutic approaches. Transcription factor forkhead box P1 (FOXP1) is a crucial modulator in skeletal development and aging. Here, we determined the role and regulatory mechanisms of FOXP1 in osteosarcoma. Higher FOXP1 expression correlated with malignancy in both osteosarcoma cell lines and clinical biopsies. FOXP1 overexpression and knockdown in osteosarcoma cell lines revealed that FOXP1 promoted proliferation, tumor sphere formation, migration and invasion, and inhibited anoikis. Mechanistically, FOXP1 acted as a repressor of P21 and RB (retinoblastoma protein) transcription, and directly interacted with the tumor suppressor p53 to inhibit its activity. Extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/JNK) signaling and c-JUN/c-FOS transcription factors were found to be upstream activators of FOXP1. Moreover, FOXP1 silencing via lentivirus or adeno-associated virus (AAV)-mediated delivery of shRNA suppressed osteosarcoma development and progression in cell-derived and patient-derived xenograft animal models. Taken together, we demonstrate that FOXP1, which is transactivated by ERK/JNK-c-JUN/c-FOS, drives osteosarcoma development by regulating the p53-P21/RB signaling cascade, suggesting that FOXP1 is a potential target for osteosarcoma therapy.

Aspergillus fumigatus is one of the ubiquitous fungi with airborne conidia, which accounts for most aspergillosis cases. In immunocompetent hosts, the inhaled conidia are rapidly eliminated. However, immunocompromised or immunodeficient hosts are particularly vulnerable to most Aspergillus infections and invasive aspergillosis (IA), with mortality from 50% to 95%. Despite the improvement of antifungal drugs over the last few decades, the therapeutic effect for IA patients is still limited and does not provide significant survival benefits. The drawbacks of antifungal drugs such as side effects, antifungal drug resistance, and the high cost of antifungal drugs highlight the importance of finding novel therapeutic and preventive approaches to fight against IA. In this article, we systemically addressed the pathogenic mechanisms, defense mechanisms against A. fumigatus, the immune response, molecular aspects of host evasion, and vaccines’ current development against aspergillosis, particularly those based on AFMP4 protein, which might be a promising antigen for the development of anti-A. fumigatus vaccines.

Plasma membrane glutamate transporters move glutamate across the cell membrane in a process that is thought to involve elevator-like movement of the transport domain relative to the static trimerization domain. Conformational changes associated with this elevator-like movement have been blocked by covalent crosslinking of cysteine pairs inserted strategically in several positions in the transporter structure, resulting in inhibition of steady-state transport activity. However, it is not known how these crosslinking restraints affect other partial reactions of the transporter that were identified based on pre-steady-state kinetic analysis. Here, we re-examine two different introduced cysteine pairs in the rat glutamate transporter EAAC1 recombinantely expressed in HEK293 cells, W440C/K268C and K64C/V419C, with respect to the molecular mechanism of their impairment of transporter function. Pre-steady-state kinetic studies of glutamate-induced partial reactions were performed using laser photolysis of caged glutamate to achieve sub-millisecond time resolution. Crosslinking of both cysteine pairs abolished steady-state transport current, as well as the majority of pre-steady-state glutamate-induced charge movements, in both forward and reverse transport mode, suggesting that it is not only the elevator-like movement associated with translocation, but also other transporter partial reactions that are inhibited. In contrast, sodium binding to the empty transporter, and glutamate-induced anion conductance were still intact after the W440C/K268C crosslink. Our results add to the previous mechanistic view of how covalent restraints of the transporter affect function and structural changes linked to individual steps in the transport cycle.

Macrocybe gigantea (M. gigantea) is a macrofungus genus that contains a big number of fairly fleshy gilled mushrooms with white spores. This macrofungus produces diverse bioactive compounds, antioxidants, and water-soluble polysaccharides. However, the genomic resources of this species remain unknown. Here, we assembled the genome of M. gigantea (41.23 Mb) into 336 scaffolds with a N50 size of 374,455 bp and compared it with the genomes of eleven other macrofungi. Comparative genomics study confirmed that M. gigantea belonged to the Macrocybe genus, a stand-alone genus different from the Tricholoma genus. In addition, we found that glycosyl hydrolase family 28 (GH28) in M. gigantea shared conserved motifs that were significantly different from their counterparts in Tricholoma. The genomic resource uncovered by this study will enhance our understanding of fungi biology, especially the differences in their growth rates and energy metabolism.

Background Solanum nigrum L. decoction has been used as a folklore medicine in China to prevent the postoperative recurrence of bladder cancer (BC). However, there are no previous pharmacological studies on the protective mechanisms of this activity of the plant. Thus, this study aimed to perform a systematic analysis and to predict the potential action mechanisms underlying S. nigrum activity in BC based on network pharmacology. Methods Based on network pharmacology, the active ingredients of S. nigrum and the corresponding targets were identified using the Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform database, and BC-related genes were screened using GeneCards and the Online Mendelian Inheritance in Man database. In addition, ingredient-target (I–T) and protein–protein interaction (PPI) networks were constructed using STRING and Cytoscape, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, and then the pathways directly related to BC were integrated manually to reveal the pharmacological mechanism underlying S. nigrum-medicated therapeutic effects in BC. Results Seven active herbal ingredients from 39 components of S. nigrum were identified, which shared 77 common target genes related to BC. I-T network analysis revealed that quercetin was associated with all targets and that NCOA2 was targeted by four ingredients. Besides, interleukin 6 had the highest degree value in the PPI network, indicating a hub role. A subsequent gene enrichment analysis yielded 86 significant GO terms and 89 significant pathways, implying that S. nigrum had therapeutic benefits in BC through multi-pathway effects, including the HIF-1, TNF, P53, MAPK, PI3K/Akt, apoptosis and bladder cancer pathway. Conclusions S. nigrum may mediate pharmacological effects in BC through multi-target and various signaling pathways. Further validation is required experimentally. Network pharmacology approach provides a predicative novel strategy to reveal the holistic mechanism of action of herbs.

Purpose We aimed to study the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) risk model's prognostic value and relationship with left ventricular remodeling in dilated cardiomyopathy. Patients and Methods Dilated cardiomyopathy patients were prospectively recruited and underwent clinical assessments. MAGGIC risk score was calculated. Patients were followed up for adverse events and echocardiography. Primary endpoints were all-cause mortality and first rehospitalization due to heart failure. Secondary endpoint was left ventricular remodeling defined as a decline in left ventricular ejection fraction >10% or an increase in left ventricular end-diastolic diameter >10%. Survival status was examined using Cox regression analysis. The model's ability to discriminate adverse events and left ventricular remodeling was calculated using a receiver operating characteristics curve. Results In total, 114 patients were included (median follow-up time = 31 months). The risk score was independently related to adverse events (2-year all-cause mortality: hazard ratio [HR] = 1.122; 95% confidence interval [CI], 1.043-1.208; 1-year first rehospitalization due to heart failure: HR = 1.094; 95% CI, 1.032-1.158; 2-year first rehospitalization due to heart failure: HR = 1.088; 95% CI, 1.033-1.147, all P < 0.05). One-year change in left ventricular end-diastolic diameter was correlated with the risk score (r = 0.305, P = 0.002). The model demonstrated modest ability in discriminating adverse events and left ventricular remodeling (all areas under the curve were 0.6-0.7). Conclusion The MAGGIC risk score was related to adverse events and left ventricular remodeling in dilated cardiomyopathy.

Background Microfibril-associated protein 2 (MFAP2) is a protein coding gene that exerts important phenotypic effects on cell motility, and increasing research has indicated that MFAP2 was correlated with many cancers. However, the functional and potential clinical role of MFAP2 in papillary thyroid cancer (PTC) has not yet been verified. Materials and methods We performed whole transcriptome sequencing on 78 paired PTC tissues and corresponding adjacent normal tissues and found that MFAP2 was highly expressed in PTC tissues. Then, we analyzed the expression of MFAP2 and its relation with the clinicopathological features of PTC in The Cancer Genome Atlas (TCGA) PTC genomic dataset. We detected MFAP2 expression in 40 paired PTC tissues and corresponding adjacent normal tissues through RT-qPCR (real time-quantitative polymerase chain reaction) to validate the sequencing data and TCGA cohort. Cell functional assays were performed to elucidate the function of MFAP2 in PTC cells, Western blot assay was performed to explore the correlation between MFAP2 and EMT (epithelial-mesenchymal transition)-related proteins. Results Statistical analysis showed that MFAP2 was obviously upregulated in PTC tissues compared to matched normal tissues, and the expression levels of MFAP2 in PTC tissues were strongly related with lymph node metastasis (p=0.016). The results of RT-qPCR of our own tissue specimens showed the same conclusions as that in TCGA dataset. The results of functional assays in PTC cell lines showed that MFAP2 could promote proliferation, colony formation, migration and invasion abilities and decrease the apoptotic rate in PTC cells. Western Blot assay showed that MFAP2 could regulate the expression of EMT-related proteins. Conclusion MFAP2 increases the proliferation, motility and decreases the apoptosis of PTC cells, and might be a potential therapeutic target for papillary thyroid cancer.

This study investigated the impact of white matter hyperintensities (WMHs) on the progression from mild parkinsonian signs (MPS) to parkinsonism and Parkinson's disease (PD). Participants with MPS completed 5 years of follow-up. WMHs were divided into periventricular WMHs and deep WMHs according to magnetic resonance imaging scans. The diagnosis of MPS, parkinsonism, and PD was based on the motor portion of the Unified Parkinson's Disease Rating Scale. Cox proportional hazard models were used to identify the association between WMHs and MPS progression. Of the 636 participants, 166 (26.1%) with MPS developed parkinsonism and PD after follow-up. After adjusting for potential factors, severe WMHs were associated with an increased risk of MPS progression, moderate and severe periventricular WMHs and severe deep WMHs were associated with the risk of MPS progression, and severe WMHs were associated with the progression of gait/balance impairment, bradykinesia, and rigidity. Additionally, participants treated for vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia had a lower risk of MPS progression.

High-level wind power penetration has significantly changed the power system's static and dynamic characteristics, which tends to decrease the overall system transient instability. This study proposes a multi-objective preventive-emergency coordinated control method against transient instability in the presence of uncertain wind power generation. This method optimally coordinates preventive control (PC) and emergency control (EC) to simultaneously minimise the total control cost and the expected stability margin. PC includes synchronous generator dispatch and wind farm power curtailment to reduce the overall percentage of renewable power to a safe level. EC adopts an emergency demand response scheme, in which the demand is immediately reduced for stabilising post-contingency system and avoiding wide-spread blackout. Wind power uncertainty is modelled through Taguchi's testing scenarios. The proposed method was verified on both New England 39-bus system and Nordic-32 system using industry-grade dynamic models and simulation software. Simulation results verified that the proposed method can optimally balancing system control cost and system expected stability margin.

Ke Gong,1 Yang Dong,1 Liting Wang,1 Yi Duan,2 Jian Yu,1 Ying Sun,1 Min Bai,3 Yourong Duan1 1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, People’s Republic of China; 2Department of Clinical Medicine, North Sichuan Medical College, Sichuan 637100, People’s Republic of China; 3Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of ChinaCorrespondence: Yourong DuanState Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute, Renji Hospital School of Medicine, Shanghai Jiao Tong University, 2200/25 Xietu Road, Shanghai 200032, People’s Republic of ChinaTel/ Fax +86-021-64437139Email yrduan@shsci.orgMin BaiDepartment of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, People’s Republic of ChinaTel/ Fax +86-13917045725Email baimin101@126.comPurpose: Platinum/paclitaxel-based chemotherapy is the strategy for ovarian cancer, but chemoresistance, inherent or acquired, occurs and hinders therapy. Therefore, further understanding of the mechanisms of drug resistance and adoption of novel therapeutic strategies are urgently needed.Methods: In this study, we report that sphingosine-1-phosphate receptor-1 (S1PR1)-mediated chemoresistance for ovarian cancer. Then we developed nanoparticles with a hydrophilic PEG2000 chain and a hydrophobic DSPE and biodegradable CaP (calcium ions and phosphate ions) shell with pH sensitivity as a delivery system (CaP-NPs) to carry BAF312, a selective antagonist of S1PR1 (BAF312@CaP-NPs), to overcome the cisplatin (DDP) resistance of the ovarian cancer cell line SKOV3DR.Results: We found that S1PR1 affected acquired chemoresistance in ovarian cancer by increasing the phosphorylated-signal transduction and activators of transcription 3 (P-STAT3) level. The mean size and zeta potential of BAF312@CaP-NPs were 116 ± 4.341 nm and − 9.67 ± 0.935 mV, respectively. The incorporation efficiency for BAF312 in the CaP-NPs was 76.1%. The small size of the nanoparticles elevated their enrichment in the tumor, and the degradable CaP shell with smart pH sensitivity of the BAF312@CaP-NPs ensured the release of BAF312 in the acidic tumor niche. BAF312@CaP-NPs caused substantial cytotoxicity in DDP-resistant ovarian cancer cells by downregulating S1PR1 and P-STAT3 levels.Conclusion: We found that BAF312@CaP-NPs act as an effective and selective delivery system for overcoming S1PR1-mediated chemoresistance in ovarian carcinoma by inhibiting S1PR1 and P-STAT3.Keywords: cisplatin, chemotherapy, antagonist of S1PR1, pH sensitivity, nanoparticles

Multiple ANRIL transcriptional isoforms, such as lncANRIL and circANRIL have been identified. We sought to explore their diagnostic value in patients with coronary artery disease (CAD). First, we selected six target ANRIL isoforms and measured their expression in CAD patients and controls in the peripheral blood. Their diagnostic values were evaluated. circANRIL(exon14-4) was identified as the best potential biomarker. Afterwards, we validated its diagnostic value and evaluated its prognostic value in a larger clinical cohort. Among six tested ANRILs, lncANRIL(exon1) and lncANRIL(exon4-6) in the CAD patients were significantly increased, while circANRIL(exon14-4) was downregulated. circANRIL(exon14-4) had the highest diagnostic value among the three isoforms. The combination of circANRIL(exon14-4) and other factors resulted in a more accurate differentiation of CAD patients. Moreover, lower expression of circANRIL(exon14-4) was associated with higher incidence of MACE. circANRIL(exon14-4) is closely associated with CAD risk and severity, which provides a promising circulating biomarker for CAD diagnosis and prognosis.

In mainland China, dialysis for children with end-stage renal disease (ESRD) was not introduced until the 1980s. To describe the development of pediatric dialysis in different regions of China, a national pediatric dialysis network, namely, International Pediatric Dialysis Network-China (IPDN-China) ( www.pedpd.org.cn ), was launched in 2012. Original and updated information from the renal centers registered with the IPDN-China was collected between 2012 and 2016 from two sources, namely, the registry and the survey, and demographic features were analyzed. Due to promotion by the IPDN-China, the number of registered renal centers increased from 12 to 39 between 2012 and 2016, with a significant increase in the coverage of the Chinese administrative divisions (from 26.5 to 67.6%) (p < 0.01); and the coverage of the pediatric (0~14 years old) population increased to nearly 90% in 2016. The distribution of renal centers indicated that East China had the highest average number of registered centers per million population (pmp) 0~14-year-old age group. Seventeen relatively large dialysis centers were distributed across 14 divisions. Various modalities of renal replacement therapy (RRT) were available in most centers. The IPDN-China has promoted collaborations between dieticians, psychologists, and social workers on dialysis teams to provide better service to children with ESRD and their families. The proportion of centers with all three types of paramedic support (i.e., dieticians, psychologists, and social workers) as well as the proportion of centers with a partial paramedic team significantly increased between 2012 (25.0%) and 2016 (69.2%) (p < 0.05). In terms of the point prevalent cases of patients (aged < 18 years), data from the survey of 39 registered centers revealed that the number of children with ESRD who were on RRT was 578 (49% received a kidney transplant) at the end of 2016, which was more than that reported in previous surveys. Data from the registry showed that 349 dialysis patients had been enrolled as of the end of 2016. The median age at RRT start was 9.5 years, and the leading cause of ESRD was congenital abnormalities of the kidney and urinary tract (CAKUT). The IPDN-China has helped to promote the development of pediatric dialysis for ESRD in China by improving the organization of care for dialysis patients and increasing the availability and the quality of RRT for patients who need it. To improve knowledge about the epidemiology and outcomes of pediatric RRT around the country, a sustained effort needs to be made by the IPDN-China to increase the enrollment of dialysis patients and increase the number of registered centers in the future.

This study analyzed the characteristics of BRAFV600E mutation in papillary thyroid carcinoma (PTC) in Chinese coastal areas. We intended to identify noninvasive methods to determine BRAFV600E status in thyroid nodules prior to surgery. BRAFV600E mutation and the sonographic characteristics of thyroid nodules were investigated in 670 PTC patients in our hospital. We aimed to determine the relationship between BRAFV600E mutation and the clinicopathological and sonographic imaging characteristics of PTC. The mutation rate of the BRAFV600E was 78.2%. BRAFV600E mutation was significantly associated with central node (univariate analyses, P = .005; multivariate analyses, P < .001, odds ratio [OR] = 10.255) and lateral node metastases (univariate analyses, P = .001; multivariate analyses, P < .001, OR = 22). It was less frequent in PTC coexisting with Hashimoto’s thyroiditis (univariate analyses, P = .016; multivariate analyses, P < .001, OR = .034). Nodules without blood flow had a significantly higher mutation rate of BRAFV600E in PTC patients (univariate analyses, P = .026). BRAFV600E mutation was significantly associated with high suspicion in the Thyroid Imaging Reporting and Data System 5 (univariate analyses, P = .004; multivariate analyses, P = .014, OR = 6.456). Our results strongly suggest that BRAFV600E mutation plays a potential role in lymph node metastasis (central node metastasis, OR = 10.225; lateral node metastasis, OR = 22). Some sonographic imaging features might be helpful in estimating the status of BRAFV600E preoperatively.

Objective To find novel potential gene mutations other than EXT1 and EXT2 mutations, to expand the mutational spectrum of EXT and to explore the correlation between clinical outcome and genotype in patients with hereditary multiple exostoses (HME). Methods The study recruited seven families diagnosed with multiple osteochondromas (MO). Family histories and clinical information were collected in detail through comprehensive physical and image examination. Patients with deformities and functional limitations were classified as "severe" and the remaining without functional limitations were classified as "mild," in accordance with previous study. Whole-exome sequencing (WES) was performed on a total of 13 affected individuals, 1 available unaffected relative, and 10 healthy unrelated individuals. Sanger sequencing was used to validate the screened mutations. Finally, the structural change in protein caused by pathogenic mutations was analyzed using information from the relevant database online and we attempted to correlate clinical phenotype with genotype in patients with HME. Results Other than EXT1 and EXT2, no novel potential gene mutations were found through WES. We identified nine heterozygous mutations in EXT1 or EXT2. Of these mutations, four have not been reported previously. These are c.996delT in exon 2 of EXT1 (family 1), c.544C > T in exon 3 of EXT2 (family 2), c.1171C > T in exon 7 of EXT2 (family 5), and c.823- 824delAA in exon 5 of EXT1 (family 7). The other five mutations have already been reported in previous works. It was surprising that we found two mutation sites, in exon 2 and exon 5, respectively, of EXT1 in 1 patient diagnosed with MO, when his father had two mutation sites, in exon 6 and exon 5, respectively, of EXT1 and EXT2 (family 4). In addition, 1 patient showed degeneration, while his father only exhibited slight symptoms (family 7). In our study, among 51 affected patients in seven families, the sex ratio (male vs female) was 58.9% (n = 30) vs 41.2% (n = 21). Male patients seemed to show more severe symptoms compared to females, but because the sample was small, we did not obtain statistically significance results. Conclusion Whole-exome sequencing to screen pathogenic gene mutations was applied successfully. Although no third-gene mutation associated with HME was found, a total of nine mutations across EXT1 and EXT2 were identified, four of which are novel. Our results expand the mutational spectrum of EXT and can be used in genetic counseling and prenatal diagnosis for patients with MO.

Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemic agents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). However, their underlying mechanism remains unclear. In this study, DPP4 upregulation, mitochondrial fragmentation, and altered mitochondrial dynamics-associated protein expression were observed in the tubules of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin-stimulated tubular cells. The inhibition of DPP4 by sitagliptin (Sita) ameliorated these mitochondrial perturbations both in vivo and in vitro, whereas DPP4 overexpression aggravated mitochondrial fusion-fission disorder and tubular cell injury in albumin-treated HK-2 cells. Downstream of DPP4, the SDF-1α/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sita treatment, this signaling pathway was restored, and the mitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found in the mitochondria of tubular cells, and this effect was weakened by overloading albumin and by CXCR4 siRNA treatment, suggesting a possible link between DPP4-mediated SDF-1α/CXCR4/STAT3 signaling and mitochondrial dysfunction in diabetic tubular cells. The results suggest that a novel mechanism links the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF-1α/CXCR4/STAT3 signaling pathway could become a potential target for managing DKD.

We systematically observed the structure and distribution of vascular bundles of castor ( Ricinus communis ) testa, endosperm and embryo with germination, separation, paraffin sectioning technique, and microscopic observation techniques, stained with safranine and fast green, along with schiff’s reagent, respectively. (1) Micropyle at the dorsal base of the seed was not covered by the caruncle. (2) The testa consisted of three parts: episperm, endopleura and the caruncle, in which the episperm was composed of the long columnar epidermal layer, sponge parenchma and palisade parenchma from outside to inside, while the endopleura was composed of Malpighian layer, sponge parenchma and the inner integument layer, with an air chamber surrounded by the inner layer and outer layer of endopleura at the end of the caruncle, similar to that of eggs. (3) Both the episperm and endopleura were distributed with vascular bundles, and the large ones of the episperm only distributed in the spongy parenchma of the ventral raphe of the seed, which extended from the hilum to the opposite end of the caruncle; while those of endopleura were also distributed in the spongy parenchtma, and they branched step by step through the bundle band, ending at the edge of the air chamber at the end of the caruncle; those of both the episperm and endopleura were continuous through the junction point of the chalazal end to form the vascular system of the testa. (4) The caruncle was composed of epidermis and parenchyma, in which parenchyma consisted of small parenchyma cells on the outside and large parenchyma cells on the inside. In the middle and ventral part of the caruncle, there were only two vascular bundles, which constituted the vascular system of the caruncle independently. In the caruncle, caruncle channel was also found, with the inner end opening in the air chamber of the endopleura and the outer end being blind. (5) No vascular bundles were found in the endosperm, which consisted of parenchymal cells containing a large number of aleurone grains. In the embryo, the vascular bundles were collateral, which differentiated in the hypocotyle and entered the main vein of two cotyledons from both sides of the top of the hypocotyle respectively, gradually reduced from 4 to 1 in the main veins, and the branches became thinner in the cotyledon, forming the vascular system of embryo. The cotyledon epidermis and mesophyll cells contained aleurone grains, but no aleurone grains were found in the plumule, hypocotyle and radicle. Two cotyledons separated from each other on the adaxial surface, while their abaxial surfaces were connected with the endosperm through the mucilaginous layers. The hypocotyle and radicle were spatially separated from the endosperm. These results provide an anatomical basis for comprehensively understanding the structure of the seeds and studying the seed development and germination and their material transportation.

The SNAT enzyme participates in the biosynthesis of melatonin, which is reported to regulate thermotolerance in many plants. However, the mechanistic basis of this regulation remains unclear. In this study, we identified the SlSNAT gene, which is responsible for melatonin biosynthesis in tomato. SlSNAT expression levels were 3- and 5-fold higher in SlSNAT overexpression lines OX-2 and OX-6, respectively. The melatonin levels were 3- and 4-fold higher than those in wild type. The melatonin levels decreased by 50% when the expression of SlSNAT was downregulated to 40%. Overexpression of SlSNAT in tomato plants provided significantly enhanced thermotolerance with better growth performance in Photosystem II (PSII) maximum photochemical quantum yield (Fv/Fm) and alleviated heat injury. Both exogenous melatonin treatment and endogenous melatonin manipulation by SlSNAT overexpression decreased the levels of reactive oxygen species�accumulation and Fv/Fm. The SlSNAT overexpression line showed protected ribulose bisphosphate carboxylase oxygenase proteins and upregulated response of heat transcription factors and heat shock proteins under heat stress. HSP40, a DnaJ-type chaperone, was found to interact with SlSNAT in the chloroplast. Downregulation of HSP40 showed lower melatonin synthesis under heat stress. HSP40 functions as a chaperone to protect the SNAT enzyme during melatonin synthesis under heat stress. HSP40 interacted with SlSNAT and together participated in melatonin-related thermotolerance regulation in tomato.

Background Since the trauma knowledge of trauma providers correlates with the outcomes of injured patients, this study aims to assess the socio-demographic characteristics and levels of trauma knowledge of trainees in the China trauma care training (CTCT) program in addition to their post-course test results to provide support for the development of trauma care training programs and trauma systems in China. Methods A cross-sectional study was conducted by collecting demographic information, hospital-related information and trauma knowledge of the trainees from 19 regions in China. All participants were assessed by questionnaires collecting the socio-demographic data, the trauma care knowledge levels and the information of the hospitals. Results There were 955 males (78.9%) and 256 females (21.1%) enrolled. Among them, 854 were physicians (70.5%), 357 were registered nurses (29.5%). In addition, 64 of them also played an administrative role in the hospitals (5.3%). The score of the trainees who were members of the emergency department staff (72.59 ± 14.13) was the highest among the scores of all the personnel surveyed, followed by those of the trainees from the intensive care unit (ICU) (71.17 ± 12.72), trauma surgery department (67.26 ± 13.81), orthopedics department (70.36 ± 14.48), general surgery department (69.91 ± 14.79) and other departments (69.93 ± 16.91), P = 0.031. The score of the professors (73.09 ± 15.05) was higher than those of the associate professors (72.40 ± 14.71), lecturers (70.07 ± 14.25) and teaching assistants (67.58 ± 15.16), P P = 0.001. The mean scores before and after the training were 71.02 ± 14.82 and 84.24 ± 13.77, respectively, P < 0.001. The mean score of trauma knowledge after the training of trainees from different provinces and with different educational backgrounds was higher than that before the training, with a statistically significant difference (P Conclusions The level of trauma knowledge of trauma care providers was associated with their department, professional position and previous participation in related academic conferences. Trauma care experience and participation in academic lectures and training program including CTCT may effectively improve individuals’ level of trauma knowledge.

Shell model calculations have been carried out for 90Nb nucleus with the model space in which the valence protons occupy the f5/2, p3/2, p1/2, and g9/2 orbitals and the valence neutrons occupy the p1/2, g9/2, d5/2, and g7/2 orbitals. According to the calculated results, the negative parity is from the contribution of the proton of the f5/2, p3/2, and p1/2 orbits. The moderate spin states of 90Nb are mainly due to the excitation of protons from the f5/2 and p3/2 orbits to the p1/2 and g9/2 orbits across the Z = 38 subshell closure, and the high spin states arise from the excitation of a single neutron from the g9/2 orbit into the d5/2 orbit across the N = 50 shell closure.

Background To explore the changes of inflammatory and oxidative stress responses in Henoch-Schönlein purpura (HSP) children, and further analyzed the therapeutic effects and mechanisms of hemoperfusion (HP) on HSP with severe gastrointestinal (GI) involvement. Methods There were 200 children with HSP were divided into three groups according to their clinical manifestations: 60 in HSP without GI and renal involvement group, 60 in HSP with GI involvement group, and 80 in HSPN group. The HSP with GI involvement group was subdivided into conventional treatment (n = 30) and HP (n = 30) groups. Thirty children who visited the department of children healthcare for healthy physical examinations from January to December 2017 were set as healthy control group. The IL-6 and TNF-α levels were detected by chemoluminescence method. The MDA, SOD and T-AOC levels were determined by thiobarbituric acid colorimetric method, hydroxylamine method and chemical colorimetry. Results Compared with healthy group, IL-6, TNF-α and MDA levels in HSP were increased in each group, while SOD and T-AOC were decreased (P = 0.000). IL-6, TNF-α and MDA levels in the HSPN group were the highest, SOD and T-AOC levels were the lowest (P = 0.000). Compared with those before treatment, IL-6, TNF-α and MDA levels in the conventional and HP groups were decreased and SOD and T-AOC levels were increased (P = 0.000). The changes in HP group were more significant than those in conventional group (P P = 0.000, 0.004). Conclusions Inflammatory and oxidative stress may be involved in the acute phase of HSP children. The intensity of inflammatory and oxidative stress responses were related to the degree of renal involvement. HP can reduce glucocorticoid dosage and the rate of renal involvement in children with severe HSP with GI involvement. The mechanism may be related to the fact that HP can effectively remove IL-6, TNF-α, MDA in HSP children.

Aim: To analyze the m6A methylome of osteosarcoma stem cells (OSCs). Materials & methods: Chemoresistant OSCs were enriched by doxorubicin treatment. Expression of m6A-related enzymes was detected by quantitative real-time-PCR and western blot. MeRIP-seq and RNA-seq were performed to identify differences in m6A methylation and gene expression. Data analysis was conducted to explore the modified genes and their clinical significance. Results: Three m6A-related enzymes were altered in OSCs. Differentially methylated genes were enriched in some pathways regulating pluripotency of stem cells. The expression of several candidate genes were found consistent with that in GSE33458 dataset, and associated with poor prognosis in osteosarcoma patients. Conclusion: m6A may play a role in the emergence and maintaining of OSCs and affect the prognosis.