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The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance. Significance: These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.

Tumor-associated macrophages (TAMs) are known to participate in osteosarcoma (OS) progression. As demonstrated in our previous research, miR-363 played a tumor inhibitory effect in OS cells via lowering the PDZ domain containing 2 (PDZD2) expression. The regulatory roles of TAMs on miR-363/PDZD2 and the internal mechanism relating to long noncoding RNA p53 upregulated regulator of P53 levels (lncRNA PURPL) are examined in this study. TAM-like macrophages were formed by inducing CD14+ peripheral blood mononuclear cells (PBMCs). The TAMs migration was detected after MG-63 cells transfected with miR-363 mimics or inhibitors. We then analyzed the regulatory activity of PURPL on miR-363 expression. We also tested the influences of PURPL overexpression/knockdown on MG-63 cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), as well as TAMs migration. Silence in PDZD2 expression was used to confirm the effects of PURPL on MG-63 cells. We successfully induced TAM-like macrophages. MG-63 cells transfecting miR-363 mimics suppressed TAMs migration while transfecting a converse effect was seen in miR-363 inhibitor. TAMs raised PURPL expression in MG-63 cells, which was an upstream regulator of miR-363. Along with TAMs migration, PURPL overexpression promoted MG-63 cell proliferation, migration, invasion, and EMT. An opposite influence was seen due to the PURPL knockdown. The silence of PDZD2 weakened the influences of PURPL overexpression on MG-63 cells and TAMs migration. On modulating the PURPL/miR-363/PDZD2 axis, TAMs-promoted OS development might be achieved.

Previous studies reveal that hydrogen sulphide (H2 S) exerts neuroprotection against neurotoxin-induced Parkinson's disease (PD), but the underlying mechanism remains elusive. The present study was aimed to investigate whether H2 S inhibits neuronal apoptosis of substantia nigra with the involvement of autophagy via promoting leptin signalling in 6-hydroxydopamine (6-OHDA)-induced PD rats. In this study, neuronal apoptosis was analysed by TUNEL staining, the activity of caspase-3 was measured by Caspase-3 fluorometric assay kit, the expressions of Bax, Bcl-2, Beclin-1, LC3II, P62 and leptin were determined by Western blot analysis, and the numbers of autophagosomes and autolysosomes were assessed by transmission electron microscopy. Results showed that NaHS, a donor of exogenous H2 S, mitigates 6-OHDA-induced the increases in the numbers of TUNEL-positive cells, the activity of caspase-3 and the expression of Bax, and attenuates 6-OHDA-induced a decrease in the expression of Bcl-2 in substantia nigra of rats. In addition, 6-OHDA enhanced the expressions of Beclin-1, LC3-II and P62, increased the number of autophagosomes, and decreased the number of autolysosomes in the substantia nigra, which were also blocked by administration of NaHS. Furthermore, NaHS reversed 6-OHDA-induced the down-regulation of leptin expression in the substantia nigra, and treatment with leptin-OBR, a blocking antibody of leptin receptor, attenuated the inhibition of NaHS on neuronal apoptosis and the improvement of NaHS on the blocked autophagic flux in substantia nigra of 6-OHDA-treated rats. Taken together, these results demonstrated that H2 S attenuates neuronal apoptosis of substantia nigra depending on restoring impaired autophagic flux through up-regulating leptin signalling in PD.

We have previously demonstrated that hydrogen sulfide (H2S), the third endogenous gasotransmitter, ameliorates the depression- and anxiety-like behaviors in diabetic rats, but the underlying mechanism remains unclear. The present was aimed to investigate whether the hippocampal phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway mediates H2S-ameliorated depression- and anxiety-like behaviors in diabetic rats by improving the hippocampal neurogenesis. The depression-like behaviors were examined by Tail suspension test (TST), the anxiety-like behaviors were examined by Elevated plus maze test (EPM), and the locomotor activity was detected by Open Field Test (OFT). The expressions of doublecortin (DCX), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), p-AKT, and AKT in the hippocampus were determined by Western blot analysis. Results showed that NaHS, a donor of exogenous H2S, not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed streptozotocin (STZ)-disturbed hippocampal neurogenesis, as evidenced by the increases in the expressions of DCX and NeuN as well as the decrease in the expression of GFAP in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited PI3K/AKT pathway by LY294002 significantly abolished H2S-exerted the improvement of hippocampal neurogenesis and the antidepressant- and anxiolytic-like effects in the STZ-induced diabetic rats. Taken together, these results uncover that the activation of hippocampal PI3K/AKT pathway plays an important role to restore hippocampal neurogenesis and subsequently to mediate the antidepressant- and anxiolytic-like roles of H2S in STZ-induced diabetic rats and enhance our understanding of the robustness of H2S as a therapeutic strategy for treatment of depression in diabetes mellitus.

Transcription factors (TFs) play crucial regulatory roles in controlling the expression of the target genes in plants. APETALA2/Ethylene-responsive factors (AP2/ERF) are part of a large superfamily of plant-specific TFs whose members are involved in the control of plant metabolism, development and responses to various biotic and abiotic stresses. However, the AP2/ERF superfamily has not been identified systematically in Masson pine (Pinus massoniana), which is one of the most important conifer in southern China. Therefore, we performed systematic identification of the AP2/ERF superfamily using transcriptome sequencing data from Masson pine. In the current study, we obtained 88 members of the AP2/ERF superfamily. All PmAP2/ERF members could be classified into 3 main families, AP2 (7 members), RAV (7 members), ERF (73 members) families, and a soloist protein. Subcellular localization assays suggested that two members of PmAP2/ERF were nuclear proteins. Based on pine wood nematode (PWN) inoculated transcriptome and qPCR analysis, we found that many members of PmAP2/ERF could respond to PWN inoculation and PWN related treatment conditions in vitro. In general, members of the AP2/ERF superfamily play an important role in the response of Masson pine responds to PWN. Furthermore, the roles of the AP2/ERF superfamily in other physiological activities of Masson pine remain to be further studied.

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection.

PurposeUniversal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management.MethodsWe prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes.ResultsThe prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years.ConclusionUniversal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks.Trial registration numberNCT03365986.

Purpose This paper aims to present a new design for removable partial dentures (RPDs) for partially edentulous patients to improve the efficiency and quality of RPD manufacturing. Additive and subtractive manufacturing technologies and zirconium silicate micro-ceramic bonding in the aesthetic zone are used herein. Design/methodology/approach A case was presented. First, RPD digital definitive casts were acquired, and then digital frameworks with crown retainers and digital crowns were obtained by computer-aided design (CAD). The titanium alloy frameworks and resin crowns were fabricated by three-dimensional (3D) printing and computer-aided manufacturing (CAM) processes, respectively. The crowns adhered to the crown retainers. Ceramage bonding was used to reform the gingival anatomy in the aesthetic zone during the fabrication of the RPDs. The finished RPDs were assessed by a clinician and delivered to the patient. Findings The RPDs were conventionally assessed by a clinician, were deemed to be accurate and satisfied both the patient and clinician. Originality/value This novel method provides a way to fabricate RPDs with a combination of additive and subtractive manufacturing technologies. The design of the framework was different from that of a conventional framework because it contained the crown retainers, and the traditional base retainer no longer existed. Ceramage bonding was used to replicate the gingival anatomy in the aesthetic zone. The new RPDs provided accuracy and were less time-consuming to produce than those produced with the traditional method. The new method enables the digital manufacturing of nearly the entire RPDs.

Objective The aim of the present study was to evaluate the effect of quercetin on the acid resistance of human dentin through both laboratory and clinical studies. Methods Two hundred and twelve dentin blocks (2 mm × 2 mm × 2 mm) were prepared and used. For the laboratory study, dentin specimens were randomly divided into 8 groups (n = 12): deionized water, ethanol, 1.23 × 104 μg/ml sodium fluoride (NaF), 120 μg/ml chlorhexidine, 183.2 μg/ml epigallocatechin gallate (EGCG), and 75 μg/ml, 150 μg/ml, and 300 μg/ml quercetin (Q75, Q150, and Q300). The specimens were treated with the respective solutions for 2 min and then subjected to in vitro erosion (4 cycles/d for 7 d). The surface microhardness loss (%SMHl), erosive dentin wear, and surface morphology were evaluated and compared. For the impact on MMP inhibition, the release of crosslinked carboxyterminal telopeptide of type I collagen (ICTP) and the thickness of the demineralized organic matrix (DOM) were measured using additional dentin specimens. For the clinical study, the specimens were treated with NaF or Q300 for 2 min and then subjected to in vivo erosion (4 cycles/d for 7 d). The %SMHl and erosive dentin wear of the specimens were measured to determine whether quercetin similarly inhibits erosion in situ. Results The quercetin-treated group had a significantly lower %SMHl and erosive dentin wear than any other group, and the effect was concentration-dependent in vitro (P Significance The application of quercetin was shown, for the first time, to increase the acid resistance of human dentin, possibly through MMP inhibition and DOM preservation.

Background:Medical test orders can display the physiological functions of patients by using medical means. The medical staff determines the patient's condition through medical test orders and completes the treatment. However, for most patients and their families, there are so many terminologies in the medical test list and they are inconvenient to understand and query, which would affect the patients’ cognition and treatment effect. Therefore, it is especially necessary to develop a consulting system that can provide related analysis after getting medical test data.Objective :This paper starts with information acquisition and speech recognition. It proposes a natural scene information acquisition and analysis model based on deep learning, focusing on improving the recognition rate of routine test list and achieving targeted smart search to allow users to get more accurate personalized health advice.Methods :Based on medical characteristics, considering the needs of patients, this paper constructs an APP-based conventional medical test consultation system, using artificial intelligence and voice recognition technology to collect user input; analyzing user needs with the help of conventional medical information knowledge database.Results:This model combines speech recognition and data mining methods to obtain routine test list data and is suitable for accurate analysis of problems in routine check-up procedure. The app provides effective explanations and guidance for the treatment and rehabilitation of patients.Conclusion:It organically links the Internet with personalized medicine, which can effectively improve the popularity of medical knowledge and provide a reference for the application of medical services on the Internet. Meanwhile, this app can contribute to the improvement of medical standards and provide new models for modern medical management.

The histone demethylase KDM4B functions as a key co-activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti-androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next-generation anti-androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide-resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c-Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA, which regulates the sensitivity to next-generation AR-targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c-Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti-androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR-dependent c-Myc expression and overcome resistance to AR-targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Purpose To develop a predictive model with pre-treatment magnetic resonance imaging (MRI) findings of the structured report template and clinical parameters for poor responses prediction after neoadjuvant chemoradiotherapy (neoCRT) in locally advanced rectal cancers (LARC) patients. Method Patients with clinicopathologically confirmed LARC (training and validation datasets, n = 100 and 71, respectively) were enrolled. Patients’ clinical data were retrospectively collected. MRI findings of the structured report template were analysed. The tumour regression grade (TRG) system as proposed by Mandard et al was used. Poor response was defined as TRG 3–5. Univariate logistic regression analysis and a lasso regression model were performed to select the significant predictive features from the training set. A nomogram was constructed based on a multivariable logistic regression analysis. Calibration, discrimination, and clinical usefulness of the nomogram were assessed. The calibrative and discriminative ability of our model were compared with those of models including the tumour-node-metastasis (TNM) stage and clinical factors. Results The MRI-reported T4b stage, MRI-reported extramural venous invasion (EMVI) positivity, MRI-detected number of positive mesorectal lymph nodes (LNs) > 0, and preoperative oxaliplatin and capecitabine (CAPOX) chemotherapy regimen were incorporated into our nomogram. The nomogram showed good discrimination, with areas under the receiver operating characteristic (ROC) curves of 0·823 and 0·820 in the training and test sets, respectively, and good calibration in both datasets. The decision curve analysis confirmed that the nomogram was clinically useful. The calibrative and discriminative ability of our model were better than those models including the TNM stage and clinical factors. Conclusion A nomogram based on pre-treatment MRI features of the structured report template and clinical risk factors has potential for use as a non-invasive tool to preoperatively predict poor responses in LARC patients after neoCRT.

Background Addition of oxaliplatin to capecitabine remains controversial for locally advanced rectal cancer (LARC). And cumulative oxaliplatin dose (COD) varied among clinical trials showing different therapeutic effects of this regimen. The objective of this study was to explore how COD affected tumor metastasis and patient survival. Methods Totally 388 patients diagnosed with stage cII-III rectal cancer and treated with neoadjuvant chemoradiotherapy followed by radical surgery plus adjuvant chemotherapy were consecutively enrolled into this study and retrospectively reviewed. After grouping by total chemotherapy cycle (TCC), influences of COD on adverse effects and patients’ survivals were analyzed in each group. Univariate and multivariate survival analyses were performed through Kaplan-Meier approach and COX proportional hazards model, respectively. Age, gender, anemia, differentiation, carcinoembryonic antigen, carbohydrate antigen 19–9, pretreatment clinical stage and postsurgical pathologic stage were used as covariates. Results COD 2 emerged as an independent predictor of poorer overall, metastasis-free and disease-free survivals, in patients treated with TCC ≤ 7. The hazard ratios were 1.972, 1.763 and 1.637 (P values were 0.021, 0.028 and 0.041), respectively. But it was note-worthy that COD ≥460 mg/m2 increased incidence of acute toxicities from 38.4 to 70.8% (P Conclusions For LARC patients treated with insufficient TCC (≤ 7), oxaliplatin of ≥460 mg/m2 might be needed to improve survival, though it might resulted in more acute toxicities.

Sufficient bone mass plays a vital role in dental implant fixation and durability. However, bone deficiency is common clinically, and peri-implant infection causes alveolar bone to further resorb. ...

In vivo regeneration of lost or dysfunctional islet β cells can fulfill the promise of improved therapy for diabetic patients. To achieve this, many mitogenic factors have been attempted, including gamma-aminobutyric acid (GABA). GABA remarkably affects pancreatic islet cells' (α cells and β cells) function through paracrine and/or autocrine binding to its membrane receptors on these cells. GABA has also been studied for promoting the transformation of α cells to β cells. Nonetheless, the gimmickry of GABA-induced α-cell transformation to β cells has two different perspectives. On the one hand, GABA was found to induce α-cell transformation to β cells in vivo and insulin-secreting β-like cells in vitro. On the other hand, GABA treatment showed that it has no α- to β-cell transformation response. Here, we will summarize the physiological effects of GABA on pancreatic islet β cells with an emphasis on its regenerative effects for transdifferentiation of islet α cells to β cells. We will also critically discuss the controversial results about GABA-mediated transdifferentiation of α cells to β cells.

Objectives:To improve the prenatal diagnosis for anomalous origin of pulmonary artery branches by comparing and analyzing different types of fetal echocardiography features.Methods:Between June 2012 and December 2018, fetal echocardiographic features were analyzed retrospectively from fetuses with a prenatal diagnosis of anomalous origin of pulmonary artery branch. The main points of identification were summarized.Results:A total of 12 fetuses were diagnosed, including anomalous origin of a pulmonary artery branch from the innominate artery and six cases with unilateral absence of pulmonary artery. The shared characteristic sonographic finding was the lack of confluence at the bifurcation of the main pulmonary artery. The differences between the two conditions are highlighted by the origin of the anomalous vessel. In fetuses with anomalous origin of one pulmonary artery branch, the affected pulmonary artery arose from the posterior wall of the ascending aorta as noted on three vessels and trachea view as well as the long axis of the left ventricular outflow tract. This is in contrast to fetuses with unilateral absence of pulmonary artery, where the origin of affected pulmonary artery arises from the base of the innominate artery via the ipsilateral patent arterial duct as evident on the three vessels and trachea view and the coronal view of innominate (brachiocephalic) artery.Conclusion:(1) The main similarity is an absence of a confluence at the bifurcation of the main pulmonary artery. (2) The main distinguishing feature is the origin of the anomalous vessel from either the subclavian or directly from the aorta.

Background It was reported that tumor-expressed dickkopf-related (DKK) proteins affect micro-environment. However, the influence of DKK1 on colorectal cancer (CRC) liver oligometastases (CRCLOM) remains unclear. Methods CRC cases after resection of liver oligometastases were enrolled in Sun Yat-Sen University Cancer Center with intact clinical data. Serum DKK1 was detected by ELISA assay. Immunofluorescent staining examination for CD3 and CD8 in slices were also conducted. Results Among 65 patients included, the recurrence-free survival (RFS) and overall survival (OS) were significantly better in the low serum DKK1 group (RFS: P = 0.021; OS: P = 0.043). DKK1 was overexpressed in stage IV CRC patients in TCGA data. The number of CD8+ tumor-infiltrating lymphocytes (TILs) in invasive margin of CRC liver oligometastases was significantly higher in low serum DKK1 group (P = 0.042). Conclusion Elevated serum DKK1 level was associated with poorer RFS and OS, and less CD8+ TILs in invasive margin in CRC liver oligometastases. DKK1 might serve as a supplementalprognostic factor for clinical risk score and a potential target for immunotherapy.

Inflammatory conditions are common complications in colorectal cancer (CRC) and play significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICIs) remains unclear. We included a high microsatellite instability (MSI-H) CRC patient whose primary tumor progressed and liver metastasis regressed after Pembrolizumab treatment. An organoid-T cell coculture model demonstrated an inhibited local immune response instead of systemic immunosuppression. Single-cell RNA sequencing suggested that neutrophils suppress the immune microenvironment, mostly through CTLA-4-associated pathways. A cohort of 73 patients with MSI-H CRC who received ICIs were enrolled, among whom inflammatory conditions were correlated with a poor tumor response. We demonstrated that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil-associated immunosuppression. Additional CTLA-4 blockade may improve the sensitivity to PD-1 blockade. Clinically, inflammatory conditions could predict a poor response to ICIs in MSI-H CRCs.

Osteoporotic fracture healing is a complex clinical issue. The present study was conducted to investigate the repair properties of 11R‑VIVIT on osteoporotic fractures and to examine the potential effects of 11R‑VIVIT on osteoporotic bone marrow‑derived mesenchymal stem cells (BMSCs), A rat model of osteoporotic femoral fracture was established, and the effects of the daily local injection of 11R‑VIVIT or saline on fracture repairing were evaluated by micro‑CT scans and H&E staining. Moreover, BMSCs from osteoporotic rats were treated with 11R‑VIVIT, and the osteogenic and adipogenic differentiation of BMSCs was evaluated. The results revealed that 11R‑VIVIT promoted bone formation and increased fracture healing. In addition, 11R‑VIVIT promoted the differentiation of osteoporotic BMSCs into osteoblasts rather than adipocytes. Furthermore, mechanistic analysis revealed that 11R‑VIVIT promoted autophagy by blocking the protein kinase B (AKT)/nuclear factor of activated T‑cells (NFATc1) signaling pathway. Consistently, the activation and inhibition of autophagy using rapamycin and LY294002 confirmed the regulatory effects of 11R‑VIVIT on autophagy. On the whole, the findings of the present study demonstrate that 11R‑VIVIT promotes fracture healing in osteoporotic rats and enhances the osteogenic differentiation of osteoporotic BMSCs by dysregulating the AKT/NFATc1 signaling pathway.

The effectiveness and safety of electroacupuncture (EA) for depression have been identified by abundant clinical trials and experimental findings. The c-Jun-NH(2)-terminal kinase (JNK) signaling pathway is considered to be involved in the antidepressant mechanism of EA. However, the antidepressant effect of EA via modulating the expression of c-Fos/activator protein-1 (AP-1) under the condition of JNK inhibition remains unexplored. In this study, we investigated the antidepressant effect and possible mechanism of EA in regulating the expression of c-Fos/AP-1 under the condition of JNK inhibition by SP600125 in rats exposed to chronic unpredictable mild stress (CUMS). The depression-like behaviors were evaluated by the body weight, sucrose preference test (SPT), and open field test (OFT). The expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum of CUMS induced rat model of depression were detected by ELISA. The results indicated that treatment with EA and fluoxetine can reverse the CUMS-induced depression-like behaviors in rats and can up-regulate the expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum. Of note, the data demonstrated that SP600125, the inhibitor of JNK signaling pathway, can exert synergistic effect with EA in regulating CUMS-induced abnormal activation of the JNK signaling pathway. The antidepressant effect of EA might be mediated by modulating the expression of c-Fos/AP-1.摘要:目前电针抗抑郁的有效性和安全性得到大量临床研究和实验结果的证实，JNK信号通路被认为是参与了电针抗抑郁的机制过程。然而，电针通过在阻断JNK信号通路条件下调节c-Fos/AP-1表达的抗抑郁机制尚未阐明。在本研究中，我们主要探究电针通过SP600125抑制JNK信号通路条件下调节慢性温和不可预知性应激(CUMS)抑郁模型c-Fos/AP-1表达的抗抑郁效应机制。通过体重监测、糖水偏好实验和旷场实验评价抑郁样行为；采用酶联免疫吸附剂测定技术(ELISA)检测下丘脑c-Jun、垂体c-Fos及血清c-Fos、AP-1水平。结果显示，电针及氟西汀干预显著改善了CUMS诱导的大鼠抑郁样行为，并逆转了CUMS诱导的下丘脑水平c-Jun、垂体c-Fos及血清c-Fos、AP-1上调表达。值得注意的是，研究数据表明JNK信号通路特异性阻断剂SP600125同电针一起在调节CUMS诱导的JNK信号通路异常激活上起到协同作用，电针抗抑郁效应可能是通过调节应激诱导的c-Fos/AP-1表达介导的。.

This meta-analysis studied toric intraocular lens (IOL) alignment accuracy using image-guided and manual marking methods by comparing the axis misalignment of toric IOLs, percentage of eyes with toric IOL axis misalignment within ±5 degrees, postoperative astigmatism, difference vector, and postoperative uncorrected distance visual acuity. The methodological quality was assessed using the modified Quality Assessment of Diagnostic Accuracy Studies-2 tool. Continuous variables were analyzed using weighted mean differences, and dichotomous variables were compared using the odds ratio. Five studies comprising a total of 257 eyes were analyzed. For heterogeneity, neither sensitivity analysis nor the Egger test detected statistical findings. The image-guided marking group had smaller toric IOL axis misalignment (P .00001), less postoperative astigmatism (P = .003), and a smaller difference vector (P .00001) than the manual marking group. The overall evidence from the studies indicates that image-guided marking is better than manual marking, resulting in less axis misalignment, a smaller difference vector, and less postoperative astigmatism.

Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48‐linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.

Biogas, e.g., biomethane, is produced by fermentation of organic matter and can be used as an alternative fuel or as a raw material for the production of hydrogen and syngas. However, biogas includes hydrogen sulfide (H2S) as a byproduct of fermentation. Hydrogen sulfide is toxic, has a foul odor, corrodes equipments, and deactivates catalysts. Thus, hydrogen sulfide has to be removed before biogas combustion or conversion. Compared with classical wet desulfurization, low-temperature dry desulfurization is of interest due to higher desulfurization, simpler operation, less pollution, and less energy consumption. Here, we review solid sorbents for low-temperature biogas desulfurization, such as activated carbon, metal-exchanged zeolites, single metal oxides, composite metal oxides, ordered mesoporous silica, and metal–organic frameworks.

Acupuncture is one of the most useful tools in complimentary medicine, and has demonstrated potential value for treating chronic renal failure (CRF). However, the underlying mechanisms for its therapeutic effect remain unknown. In the present study, the effects of acupuncture on renal interstitial fibrosis (RIF) were explored in a rabbit model of CRF. Rabbits were assigned to the following five groups: sham, model, losartan potassium (Posi), acupuncture (Acup) and acupuncture+inhibitor (Acup+Inhib) groups. The CRF rabbits were administered a drug or/and acupuncture on Shenshu, Mingmen and Pishu. The body weights, urine protein, serum creatinine (SCr) and blood urea nitrogen (BUN) levels of the rabbits were measured. Transforming growth factor β (TGF‑β), integrin‑linked kinase (ILK) and Smad3 expression were detected by qRT‑PCR. Tumor necrosis factor‑α (TNF‑α) and endothelial nitric oxide synthase (eNOS) expression were analyzed by western blot methods. The concentrations of TGF‑β, IL‑8, TNF‑α and IL‑1β in blood serum were detected using ELISA kits. In addition, pathological characteristics of the rabbit tissues were evaluated by H&E and Masson's trichrome staining methods, and TGF‑β expression was detected by immunohistochemistry (IHC) assays. Results showing decreased body weights and increased urine protein, SCr and BUN levels confirmed that the CRF model had been successfully constructed. It was also found that acupuncture significantly reduced the levels of TNF‑α, Smad3, ILK and TGF‑β expression, dramatically decreased the concentrations of TGF‑β, IL‑8, TNF‑α and IL‑1β in blood serum, and significantly increased eNOS expression in the CRF model rabbits by affecting the TGF‑β/Smad signaling pathway. In addition, it was demonstrated that acupuncture could relieve RIF by affecting the TGF‑β/Smad pathway. These observations indicate that acupuncture may be useful for treating CRF, and suggest the TGF‑β/Smad pathway as a target for CRF therapy.

Objective: As a member of the N-myc downregulated gene family, N-Myc downstream-regulated gene 2 (NDRG2) contributes to tumorigenesis of various types of cancer. The expression status of NDRG2 in colorectal cancer (CRC) and its prognostic value remain to be elucidated. The goal of this study was to determine the expression pattern of NDRG2 in human CRC and its association of NDRG2 expression with prognosis. Methods: Immunohistochemistry was used to determine the level of NDRG2 expressions in 316 CRC tissues. The medical records of consecutive CRC patients undergoing primary tumor resection from September 2000 to February 2015 were retrospectively selected. Then, we compared to specific clinicopathological features in patients with different level of NDRG2 expressions. The correlation of NDRG2 expression with 3-year survival rate was assessed by Kaplan-Meier method and Cox regression modeling. Results: NDRG2 was expressed in 94.6% (299/316) of CRC tissues. The median IHC score of NDRG2 expression was significantly lower in tumor tissues compared with that of tumor-adjacent normal tissues [4.50(range 0.00-12.00) vs. 10.00 (range 0.00-12.00), P < 0.001].Survival analysis indicated that patients with low NDRG2 expression had poorer 3-year OS than those with high NDRG2 expression (59.9% vs. 76.6%, P = 0.017). Low NDRG2 expression also presented a significantly poorer 3-year OS rate in patient with stage IV disease (29.4% vs. 56.5%, P = 0.002), liver metastasis(32.2% vs. 54.7%, P = 0.005) and those receiving liver resection(56.5% vs. 71.9% , P = 0.012). Multivariate analysis indicated that high NDRG2 expression was independently associated with poor OS (hazard ratio [HR]: 1.499; 95% confidence interval [CI]: 1.037-2.165; P = 0.031). Conclusions: Low expression of NDRG2 was associated with unfavorable prognosis in CRC patients with primary tumor resection. Detection of NDRG2 expression might be useful for providing valuable information of individualized therapy for CRC patients.

To identify the relationship between clinical pathological characteristics and the recurrence score (RS) on a 21-gene expression assay in patients with hormone receptor-positive, node-negative breast cancer, as well as the effect of RS on adjuvant decision-making.The retrospective study was conducted among luminal breast cancer patients admitted to Xijing Hospital between October 10, 2016, and September 14, 2018. Real-time PCR was used for 21-genome detection. Based on the calculated RS, participants were classified into low-risk, moderate-risk, and high-risk groups. Single-factor analysis and multiple logistic regression analysis were performed to explore independent predictors of high RS. Moreover, the effect of RS on adjuvant decision-making was studied.Two hundred twenty-two patients with luminal breast cancer, aged 48.3 ± 9.66, were enrolled. Among them, 33.8% had low (13 ± 3.34), 45.5% intermediate (23 ± 3.65), and 20.7% high (37 ± 3.44) RS. According to the single-factor analysis, age, tumor size, Ki-67, molecular subtype, CK5/6 expression, E-cadherin level, and histological grade were positively associated with high RS. Multiple logistic analyses showed that tumor size and histological grade were independent variables that might predict high RS in patients with hormone receptor-positive, node-negative breast cancer. For adjuvant decision-making, the proportion of adjuvant chemotherapy in the intermediate-/high-risk groups was higher than that in the low-risk group, P 0.001. Compared with the data worldwide, the changes of treatment selection in the present study were similar to those in Japan (23.0% vs. 26%) and America (23.0% vs. 23.0%). Considering the pathology types, 14.3% of patients with invasive breast cancer with lower RS changed treatment recommendations, predominantly from chemo-endocrine to endocrine treatment alone, whereas the percentage in intermediate/high RS groups was 8.1%.Tumor size and histological grade were independent variables, predicting high risk in patients with hormone receptor-positive, node-negative breast cancer; 21-gene RS assessment was potentially a critical tool in guiding adjuvant decision-making in China.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

Carbohydrate antigen 19-9 (CA19-9) is one of the most widely used tumor markers in gastrointestinal cancer. However, serum CA19-9 is not a recommended routine measurement in colon cancer. In this study, we evaluated the value of the preoperative serum CA19-9 level for the prediction of postoperative prognosis in stage III colon cancer. The medical records of 367 consecutive patients with stage III colon cancer who underwent curative resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and April 2015 were retrospectively reviewed. We determined the optimal cutoff value of CA19-9 for 3-year recurrence using the receiver operating characteristic (ROC) method. Differences in disease-free survival (DFS) and overall survival (OS) rates stratified by CA19-9 level were compared by using Kaplan-Meier and log-rank tests. A Cox proportional hazards model was used to identify prognostic variables for DFS and OS. The statistically determined best cutoff value for CA19-9 was 24 U/ml. High CA19-9 levels (> 24 U/ml) were significantly associated with poorly differentiated tumors, abnormal carcinoembryonic antigen (CEA) levels, and a high cumulative incidence of lung metastasis. Additionally, compared with low CA19-9 levels, high preoperative CA19-9 levels were associated with inferior 3-year DFS and OS rates, especially for high-risk patients (T4Nany or TanyN2). Multivariate analyses revealed that CA19-9 was an independent factor associated with both DFS (hazard ratio [HR], 2.248; 95% confidence interval [CI], 1.393-3.628; P = 0.001) and OS (HR: 2.081; 95% CI: 1.137-3.808; P = 0.017). The results of this study showed that high levels of preoperative serum CA19-9 indicated a worse prognostic outcome for stage III colon cancer patients. An early follow-up protocol to assess lung metastasis and a full course of adjuvant chemotherapy should be used for these patients.

Background The treatment of lumbar infectious spondylitis is controversial. In this study, we attempted to demonstrate that unilateral percutaneous endoscopic debridement with physiologic saline and negative pressure drainage postoperatively may achieve a satisfactory result in lumbar infectious spondylitis. Methods We retrospectively analyzed 17 patients with lumbar infectious spondylitis who underwent percutaneous endoscopic debridement and drainage (PEDD) through a posterolateral transforaminal approach. Each biopsy specimen was submitted without delay after surgery and examined for microorganisms and evaluated histopathologically. Patients were assessed by careful physical examination, MacNab criteria, Oswestry Disability Index (ODI), visual analog scale (VAS), regular serological tests, imaging studies for clinical function, and patient satisfaction. Results Of the 17 patients, 14 (82.4%) had satisfactory relief of their back pain according to MacNab criteria at 1 week after PEDD. Three patients (17.6%) who had advanced infections with multilevel involvement and paraspinal abscesses underwent anterior debridement and autograft interbody fusion with instrumentation within 2 weeks. However, there were no other severe surgery-related complications. Causative bacteria were identified in most cases, and Staphylococcus aureus was the most prevalent strain. Conclusions Unilateral PEDD with physiological saline or empirical antibiotics did not disrupt lumbar stability and avoided the important intraspinal structures such as the dural sac and nerve roots. It not only had a high rate of identification of the causative pathogen, but also provided effective infection control and pain relief. PEDD may be a useful technique for treatment of lumbar infectious spondylodiscitis patients who have no severe deformities and are unable to undergo the conventional anterior surgery due to poor health or advanced age.

ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Venous access

Background Shanghai had a local outbreak of COVID-19 from January 21 to 24. Timely and precise strategies were taken to prevent further spread of the disease. We discussed and shared the experience of COVID-19 containment in Shanghai. Process The first two patients worked at two hospitals but no staff from the two hospitals were infected. The suspected case and his two close contacts were confirmed to be infected within 12 h. The testing rate of individuals was low. The scope of screening was minimized to two related districts and the close contact tracing was completed within 12 h, which were precise and cost-effective. Conclusions Active monitoring, precise epidemiological investigation and timely nucleic acid testing help discover new cases, minimize the scope of screening, and interrupt the transmission. Graphic abstract

Su-ping Guo,1,2,* Chen Chen,1,2,* Zhi-fan Zeng,1,2 Qiao-xuan Wang,1,2 Wu Jiang,2,3 Yuan-hong Gao,1,2 Hui Chang1,2 1Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 3Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuan-hong Gao; Hui ChangDepartment of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of ChinaTel +86-13560182168; +86-13480295989Email gaoyh@sysucc.org.cn; changhui@sysucc.org.cnBackground: Serum lipids have been reported as prognosticators for malignancies, including rectal cancer (RC). Yet, their value in predicting the response of RC to neoadjuvant chemoradiotherapy (NACRT) remains unknown. This study aimed to assess the predictive abilities of serum lipids for a bad response, and to build a serum lipid-based prediction model.Methods: In total, 751 patients diagnosed with stage cII–III RC and treated with NACRT plus surgery from January 2007 to August 2018 were retrospectively reviewed and randomly divided into two data sets, in a ratio of 1:1. Receiver operating characteristics (ROC) analysis was conducted in the development set to select possible predictors of bad NACRT response from pathoclinical factors, including serum lipids. Multivariate logistic regression was conducted to further determine independent predictors, which were then used to develop a prediction index (PI). Finally, the PI was verified in the validation set, through ROC analysis and chi-squared test.Results: Five independent predictors were identified: tumor length ≥ 4 cm, cT4 stage, carcinoembryonic antigen ≥ 5.0 ng/mL, irradiation with three-dimensional conformal radiotherapy technique, and apolipoprotein A-I ≤ 1.20 g/L. Each of them was assigned a number of points. In the validation set, the area under the curve of PI appeared as 0.642 (95% confidence interval 0.586– 0.697). The sensitivity, specificity, positive and negative predictive values, and concordance were 72.3%, 52.3%, 63.8%, 61.9%, and 63.0%, respectively.Conclusion: Serum apolipoprotein A-I was found to correlate negatively with the RC response to NACRT. It could serve as a biomarker for guiding individualized treatment and a potential target for improving sensitivity to chemoradiation.Keywords: rectal cancer, radiotherapy, apolipoprotein A-I, tumor response, prediction model

18F-Alfatide II has been translated into clinical use and been proven to have good performance in identifying breast cancer. In this study, we investigated 18F-Alfatide II for evaluation of axillary lymph nodes (ALN) in breast cancer patients and compared the performances with 18F-FDG. Methods: A total of 44 female patients with clinically suspected breast cancer were enrolled and underwent 18F-Alfatide II and 18F-FDG PET/CT within a week. Tracer uptakes in ALN were evaluated by visual analysis, semiquantitative analysis with maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and SUVmax ratio of target/non-target (T/NT). Results: Among 44 patients, 37 patients were pathologically diagnosed with breast cancer with metastatic (17 cases) or non-metastatic (20 cases) ALN. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of visual analysis were 70.59%, 90.00%, 81.08%, 85.71% and 78.26% for 18F-Alfatide II, 64.71%, 90.00%, 78.38%, 84.62% and 75.00% for 18F-FDG, respectively. By combining 18F-Alfatide II and 18F-FDG, the sensitivity significantly increased to 82.35%, the specificity was 85.00%, the accuracy increased to 83.78%, the PPV was 82.35% and the NPV significantly increased to 85.00%. Three cases of luminal B subtype were false negative for both 18F-Alfatide II and 18F-FDG. The other 2 false negative cases of 18F-Alfatide II were triple-negative subtype and 3 false negative cases of 18F-FDG were luminal B subtype too. The AUCs of three semi-quantitative parameters (SUVmax, SUVmean, T/NT) for 18F-Alfatide II were between 0.8 and 0.9, whereas those for 18F-FDG were more than 0.9. 18F-Alfatide II T/NT had the highest Youden index (76.5%), specificity (100%), accuracy (89.19%) and PPV (100%) among these semi-quantitative parameters. 18F-Alfatide II uptake as well as 18F-FDG uptake in metastatic axillary lymph nodes (MALN) was significantly higher than that in benign axillary lymph nodes (BALN). Both 18F-Alfatide II and 18F-FDG did not show difference in primary tumor uptake irrespective of ALN status. Conclusion: 18F-Alfatide II can be used in breast cancer patients to detect metastatic ALN, however, like 18F-FDG, with high specificity but relatively low sensitivity. The combination of 18F-Alfatide II and 18F-FDG can significantly improve sensitivity and NPV. 18F-Alfatide II T/NT may serve as the most important semi-quantitative parameter to evaluate ALN.

Objective: To evaluate the associations between fetal α-thalassemia and risk of adverse pregnancy outcomes. Design: Case control study. Setting: Forty-two hospitals in Nanning, China. Participants: Pregnant women >20 weeks of gestation. Methods: Multivariate logistic regression analyses were performed to explore associations between fetal α-thalassemia and adverse pregnancy outcomes. Receiver operating characteristic curve analyses were used to assess the use of selected factors in predicting low Apgar scores. Main Outcome and Measure: Pregnancy outcomes of thalassemic women whose fetuses had non-thalassemia, α-thalassemia trait or HbH disease. Results: With thalassemic women whose fetuses were normal as the reference, fetuses in the HbH disease group showed a higher increase in the odds of Apgar scores being

This cross-sectional study investigates the prevalence of depression and anxiety and their associations with lifestyle changes among adolescents in Wuhan, China, during the coronavirus disease 2019 pandemic.