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Past studies have shown mixed results of postoperative radiation (PORT) for pN2 NSCLC patients. We hypothesize that PORT can improve overall survival (OS) in pN2 NSCLC patients with high lymph node ratio (LNR).The National Cancer Database was queried for non-metastatic pN2 NSCLC patients with R0 surgery and adjuvant chemotherapy from 2004 to 2016. Cox models were used to assess the impact of PORT and LNR on OS adjusted for patient characteristics and treatment information.Among 4,050 patients, 1,728 (42.7%) had PORT. There was increased use of IMRT in the more recent period (53.8% in 2010-2016 vs 24.0% in 2004-2009). PORT was associated with better OS in the overall cohort. For patients with inadequate lymph node dissection (LND), PORT marginally improved OS (HR = 0.91, p = 0.058). Among patients with adequate LND, PORT did not improve OS for patients with LNR15% (HR = 1.11, p = 0.21), or LNR 15-29% (HR = 1.03, p = 0.73), but it significantly improved OS for patients with LNR ≥30% (HR = 0.83, p = 0.006). In patients with LNR≥30%, IMRT significantly improved OS when compared to no PORT (HR = 0.75, p0.05) while 3D RT did not (HR = 0.89, p = 0.32).PORT was associated with better survival for pN2 NSCLC patients after R0 resection, adequate LND with high LNR, after accounting for multiple confounders. Among the whole cohort, most of the OS benefits of PORT were driven by patients with inadequate LND, high LNR or use of IMRT.

Recently, pharmaceuticals and personal care products in the water environment exhibited potential risks to both human and aquatic organisms. In order to improve the sensitivity and accuracy of pharmaceutical detection, the polyimidazolyl acetate ionic liquid was synthesized by Radziszewski reaction and coated on cellulose filter papers as a thin-film extraction phase for extraction of non-steroidal anti-inflammatory drugs from water. The attenuated total reflection-infrared spectrometry, thermogravimetric analysis, and scanning electron microscope analyses demonstrated that the polyimidazolyl acetate ionic liquid was successfully prepared and attached to the surface of the cellulose filter paper through chemical bonding. The adsorption capacity of the homemade thin-film extraction material for the four non-steroidal anti-inflammatory drugs was greater than 8898 ng/cm

The arteriovenous fistulas (AVF) continue to be the most prevalent type of vascular access for hemodialysis (HD). However, the appropriate locations of AVF are controversial. We conducted the meta-analysis to investigate the differences in patency between upper-arm and forearm AVF.PubMed, EMBASE, CENTRAL, and ISI Web of Science were searched to identify studies with differences in AVF patency at different locations. Reviewers searched the database, screened studies according to inclusion criteria, and conducted Meta-analysis.A total of 12 studies involving 3437 patients were selected. Pooled data showed that primary patency (PP) of AVF were higher in upper-arm than forearm at 1 and 2 years (odds ratio [OR] = 1.54, p = 0.0005; OR = 2.45, p = 0.001), but the differences in cumulative patency (CP) were not statistically significant at 1 and 2 years (OR = 2.10, p = 0.08; OR = 2.16, p = 0.1). The differences in PP and CP between upper-arm and forearm AVF in patients older than 65 years were not statistically significant at 1 (OR = 1.61, p = 0.05; OR = 2.05, p = 0.17) and 2 years (OR = 3.40, p = 0.13; OR = 1.38, p = 0.16). In Asian patients, the differences in PP and CP between upper-arm and forearm AVF were not statistically significant at 1 (OR = 1.17, p = 0.41; OR = 1.02, p = 0.94) and 2 years (OR = 2.95, p = 0.08; OR = 1.23, p = 0.41).In this study, the CP of upper-arm and forearm AVF was similar in overall population. There was no difference in PP and CP of AVF between upper-arm and forearm in Asian population or the elderly. The forearm AVF could be consider to be the first choice. for Asian patients or the elderly.

Objectives The aim of this study was to explore the diagnostic efficiency of serum exosomal miR-451a as a novel biomarker for pancreatic cancer. Methods Serum samples were collected prior to treatment. First, we analyzed microRNA (miRNA) profiles in serum exosomes from eight pancreatic cancer patients and eight healthy volunteers. We then validated the usefulness of the selected exosomal miRNAs as biomarkers in another 191 pancreatic cancer patients, 95 pancreatic benign disease (PB) patients, and 90 healthy controls. Results The expression of miR-451a in serum-derived exosomes from pancreatic cancer patients was significantly upregulated compared with those from PB patients and healthy individuals. Serum exosomal miR-451a showed excellent diagnostic power in identifying pancreatic cancer patients. In addition, exosomal miR-451a showed a significant association with clinical stage and distant metastasis in pancreatic cancer, and the expression level of serum exosomal miR-451a was sensitive to therapy and relapse. Conclusions Serum exosomal miR-451a might serve as a novel diagnostic marker for pancreatic cancer.

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The association of hepatitis B virus (HBV) infection with HCC is hitherto documented. Exosomal miRNAs contribute to cancer progression and chemoresistance. HBV X protein has been known to modulate miRNAs that facilitate cell proliferation and the process of hepatocarcinogenesis. However, there has been no report on hepatitis B core antigen (HBc) regulating exosomal miRNAs to induce drug resistance of HCC cells. AIM To elucidate the mechanism by which HBc promotes Doxorubicin hydrochloride (Dox) resistance in HCC. METHODS Exosomes were isolated by ultracentrifugation. The morphology and size of exosomes were evaluated by Dynamic Light Scattering (DLS) and transmission electron microscopy (TEM). The miRNAs differentially expressed in HCC were identified using The Cancer Genome Atlas (TCGA) database. The level of miR-135a-5p in patient tissue samples was detected by quantitative polymerase chain reaction. TargetScan and luciferase assay were used to predict and prove the target gene of miR-135a-5p. Finally, we identified the effects of miR-135a-5p on anti-apoptosis and the proliferation of HCC in the presence or absence of Dox using flow cytometry, Cell counting kit 8 (CCK-8) assay and western blot. RESULTS We found that HBc increased the expression of exosomal miR-135a-5p. Integrated analysis of bioinformatics and patient samples found that miR-135a-5p was increased in HCC tissues in comparison with paracancerous tissues. Bioinformatic analysis and in vitro validation identified vesicle-associated membrane protein 2 (VAMP2) as a novel target gene of miR-135a-5p. Functional assays showed that exosomal miR-135a-5p induced apoptosis protection, cell proliferation, and chemotherapy resistance in HCC. In addition, the rescue experiment demonstrated that VAMP2 reversed apoptosis protection, cell growth, and drug resistance by miR-135a-5p. Finally, HBc promoted HCC anti-apoptosis, proliferation, and drug resistance and prevented Dox-induced apoptosis via the miR-135a-5p/VAMP2 axis. CONCLUSION These data suggested that HBc upregulated the expression of exosomal miR-135a-5p and promoted anti-apoptosis, cell proliferation, and chemical resistance through miR-135a-5p/VAMP2. Thus, our work indicated an essential role of the miR-135a-5p/VAMP2 regulatory axis in chemotherapy resistance of HCC and a potential molecular therapeutic target for HCC.

Cytogenetic abnormalities have been proven to be the most valuable parameter for risk stratification of childhood acute lymphoblastic leukemia (ALL). However, studies on the prevalence of cytogenetic abnormalities and their correlation to clinical features in Chinese pediatric patients are limited, especially large-scale studies.We collected the cytogenetics and clinical data of 1541 children newly diagnosed with ALL between 2001 and 2014 in four Chinese hospitals, and retrospectively analyzed their clinical features, prognosis and risk factors associated with pediatric ALL.All of these patients had karyotyping results, and some of them were tested for fusion genes by fluorescence in situ hybridization or reverse-transcription polymerase chain reaction. Overall, 930 cases (60.4%) had abnormal cytogenetics in this study, mainly including high hyperdiploidy (HHD, n=276, 17.9%), hypodiploidy (n=74, 4.8%), t(12;21)/TEL-AML1 (n=260, 16.9%), t(1;19)/E2A-PBX1 (n=72, 4.7%), t(9;22)/BCR-ABL (n=64, 4.2%), and t(v;11q23)/MLL rearrangements (n=40, 2.6%). The distribution of each cytogenetic abnormality was correlated with gender, age, white blood cell count at diagnosis, and immunophenotype. In addition, multivariate analysis suggested that t(v;11q23)/MLL rearrangements (OR: 2.317, 95%CI: 1.219-3.748, P=0.008) and t(9;22)/BCR-ABL (OR: 2.519, 95%CI: 1.59-3.992, P0.001) were independent risk factors for a lower event-free survival (EFS) rate in children with ALL, while HHD (OR: 0.638, 95%CI: 0.455-0.894, P=0.009) and t(12;21)/TEL-AML1 (OR: 0.486, 95%CI: 0.333-0.707, P0.001) were independent factors of a favorable EFS.The cytogenetic characteristics presented in our study resembled other research groups, emphasizing the important role of cytogenetic and molecular genetic classification in ALL, especially in B-ALL.

Introduction: High platelet reactivity (HPR) caused by clopidogrel tolerance is an adverse reaction of acute coronary syndrome (ACS) patients who receive clopidogrel antiplatelet therapy after percutaneous coronary intervention (PCI) surgery. Platelet microRNA (miRNA) is related to platelet reactivity. This study explored the mechanism of platelet miRNA in regulating platelet reactivity. Methods: We recruited 50 ACS/PCI patients and divided them into the HPR group (P2Y12 reaction units [PRU] ≥300) and the LPR group (PRU < 170) according to the PRU through the VerifyNow P2Y12 assay. P2Y12-related miRNAs were screened by TargetScan, miRWalk, and Gene Expression Omnibus. The expressions of P2Y12 and miRNAs in the HPR group and the LPR group were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Pearson correlation analysis was used to determine the correlation between P2Y12 and miRNAs. The interactions between P2Y12 and miR-107 were predicted by TargetScan and verified by dual-luciferase reporter assay. The regulation of miR-107 mimic or inhibitor on P2Y12 expression was detected by qRT-PCR and Western blot. Results: There were 22 patients in the LPR group and 28 patients in the HPR group. PY212 was highly expressed in the HPR group compared with the LPR group. We screened the P2Y12-related miRNAs (miR-145-5p, miR-4701-3p, miR-107, and miR-15b-5p), but only miR-107 and miR-15b-5p expressions were downregulated in the HPR group and were negatively correlated with PY212 expression. P2Y12 was the target gene of miR-107. PY212 expression was inhibited by miR-107 overexpression but suppressed by miR-107 silencing. Conclusion: Platelet miR-107 participated in clopidogrel resistance in ACS/PCI patients by regulating P2Y12 expression.

OBJECTIVE: To investigate the distribution of body mass index (BMI) and risk factors for obesity in children with Diamond-Blackfan Anemia (DBA). METHODS: The children with DBA who attended National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, from January 2003 to December 2020 were enrolled as subjects. The related clinical data and treatment regimens were recorded. The height and weight data measured within 1 week before or after follow-up time points were collected to calculate BMI. The risk factors for obesity were determined by multivariate regression analysis in children with DBA. RESULTS: A total of 129 children with DBA were enrolled, among whom there were 80 boys (62.0%) and 49 girls (38.0%), with a median age of 49 months (range 3-189 months). The prevalence rate of obesity was 14.7% (19/129). The multivariate logistic regression analysis showed that the absence of ribosomal protein gene mutation was closely associated with obesity in children with DBA (adjusted OR=3.63, 95%CI: 1.16-11.38, adjusted P=0.027). In children with glucocorticoid-dependent DBA, obesity was not associated with age of initiation of glucocorticoid therapy, duration of glucocorticoid therapy, and maintenance dose of glucocorticoids (P>0.05). CONCLUSIONS: There is a high prevalence rate of obesity in children with DBA, and the absence of ribosomal protein gene mutation is closely associated with obesity in children with DBA.

Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites are released and among the most potent is adenosine triphosphate (ATP), which is released via ATP-permeable channels. In these hemichannels, connexin 43 (Cx43) is the most common member. However, its role in renal interstitial fibrosis (RIF) has not been fully examined. We analyzed renal samples from patients with obstructive nephropathy and mice with unilateral ureteral obstruction (UUO). Cx43-KSP mice were generated to deplete Cx43 in TECs. Through transcriptomics, metabolomics, and single-cell sequencing multi-omics analysis, the relationship among tubular Cx43, ATP, and macrophages in renal fibrosis was explored. The expression of Cx43 in TECs was upregulated in both patients and mice with obstructive nephropathy. Knockdown of Cx43 in TECs or using Cx43-specific inhibitors reduced UUO-induced inflammation and fibrosis in mice. Single-cell RNA sequencing showed that ATP specific receptors, including P2rx4 and P2rx7, were distributed mainly on macrophages. We found that P2rx4- or P2rx7-positive macrophages underwent pyroptosis after UUO, and in vitro ATP directly induced pyroptosis by macrophages. The administration of P2 receptor or P2X7 receptor blockers to UUO mice inhibited macrophage pyroptosis and demonstrated a similar degree of renoprotection as Cx43 genetic depletion. Further, we found that GAP 26 (a Cx43 hemichannel inhibitor) and A-839977 (an inhibitor of the pyroptosis receptor) alleviated UUO-induced fibrosis, while BzATP (the agonist of pyroptosis receptor) exacerbated fibrosis. Single-cell sequencing demonstrated that the pyroptotic macrophages upregulated the release of CXCL10, which activated intrarenal fibroblasts. Cx43 mediates the release of ATP from TECs during renal injury, inducing peritubular macrophage pyroptosis, which subsequently leads to the release of CXCL10 and activation of intrarenal fibroblasts and acceleration of renal fibrosis.

OBJECTIVE: To study the association between paroxysmal nocturnal hemoglobinuria (PNH) clone and immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA). METHODS: A retrospective analysis was performed on the medical data of 151 children with SAA who were admitted and received IST from January 2012 to May 2020. According to the status of PNH clone, these children were divided into a negative PNH clone group (n=135) and a positive PNH clone group (n=16). Propensity score matching was used to balance the confounding factors, and the impact of PNH clone on the therapeutic effect of IST was analyzed. RESULTS: The children with positive PNH clone accounted for 10.6% (16/151), and the median granulocyte clone size was 1.8%. The children with positive PNH clone had an older age and a higher reticulocyte count at diagnosis (P0.05). The positive PNH clone group had a significantly lower overall response rate than the negative PNH clone group at 6, 12, and 24 months after IST (P

Prospective cohort studies linking ultra-processed foods (UPF) and subclinical thyroid dysfunction (SCTD) are limited, especially in Chinese adults.

Rationale: Capillaries are composed of endothelial cells and the surrounding mural cells, pericytes. Microvascular repair after injury involves not only the proliferation of endothelial cells but also pericyte-based vessel stabilization. Exogenous bone marrow derived-putative endothelial progenitor cells (b-pEPCs) have the potential for vascular repair; however, their effect on vascular structure stabilization and pericyte-related pathobiological outcomes in the injured kidney has not been fully examined. Methods: We applied ischemia-reperfusion (IR) to induce renal vascular injury and renal fibrosis in mice. Platelet-derived growth factor receptor β (PDGFR-β)-DTR-positive mice were generated to deplete pericytes, and exogenous b-pEPCs and the PDGFR-β ligand, PDGF chain B (PDGF-BB), were employed to explore the relationship among b-pEPCs, pericytes, vascular repair, and early renal fibrosis. Results: Administration of b-pEPCs reduced IR-induced pericyte-endothelial detachment, pericyte proliferation, and myofibroblast transition via a paracrine mode, which preserved not only vascular stabilization but also ameliorated IR-initiated renal fibrosis. PDGF-BB upregulated the expression of PDGFR-β, exacerbated vascular abnormality, and pericyte-myofibroblast transition, which were ameliorated by b-pEPCs administration. The exogenous b-pEPCs and their culture medium (CM) induced vascular injury protection, and renal fibrosis was blocked by selective deletion of pericytes. Conclusion: Exogenous b-pEPCs directly protect against IR-induced vascular injury and prevent renal fibrosis by inhibiting the activation of PDGFR-β-positive pericytes.

Objectives The aim of this study was to determine the survival benefits by adjuvant radiation therapy (RT) in pancreatic cancer patients with different total lymph nodes examined (TNE), number of positive lymph nodes (NPN), and lymph nodes ratio (LNR). Methods National Cancer Database was queried for nonmetastatic pancreatic cancer patients from 2004 to 2015. Cox models were utilized. Interaction terms were applied to evaluate the effect of RT in different NPN, LNR, and margin strata. Multivariate analysis was performed. Results Of 19,759 patients identified, 10,910 patients qualified. Compared with TNE of 1 to 9, TNE of 10 to 14, 15 to 19, 20 to 24, and 25 or greater had progressive overall survival (OS) benefits. Adjuvant RT had similar OS benefits among them. In negative margin patients, adjuvant RT improved OS when NPN was 2 to 3 (hazards ratio [HR], 0.84; P = 0.01) or LNR was 0.15 to 0.25 (HR, 0.79; P = 0.002). In positive margin patients, adjuvant RT nonsignificantly improved OS when NPN was 1 to 3 (HR, 0.89; P = 0.36) or when NPN was 4 or greater (HR, 0.79; P = 0.07). Conclusions Higher TNE correlates with better survival. Adjuvant RT may not compensate for inadequate lymph node dissection. Adjuvant RT improves survival in negative-margin patients with 2 to 3 positive lymph nodes or LNR of 0.15 to 0.25.

OBJECTIVE: To study the efficacy and safety of early intratracheal administration of budesonide combined with pulmonary surfactant (PS) in preventing bronchopulmonary dysplasia (BPD). METHODS: A prospective randomized controlled trial was designed. A total of 122 infants with a high risk of BPD who were admitted to the neonatal intensive care unit of the Third Affiliated Hospital of Zhengzhou University from January to July 2021 were enrolled. The infants were randomly divided into a conventional treatment group with 62 infants (treated with PS alone at an initial dose of 200 mg/kg, followed by a dose of 100 mg/kg according to the condition of the infant) and an observation group with 60 infants (treated with PS at the same dose as the conventional treatment group, with the addition of budesonide 0.25 mg/kg for intratracheal instillation at each time of PS application). The two groups were compared in terms of the times of PS use, ventilator parameters at different time points, oxygen inhalation, incidence rate and severity of BPD, incidence rate of complications, and tidal breathing pulmonary function at the corrected gestational age of 40 weeks. RESULTS: Compared with the conventional treatment group, the observation group had a significantly lower proportion of infants using PS for two or three times (P0.05). CONCLUSIONS: Compared with PS use alone in preterm infants with a high risk of BPD, budesonide combined with PS can reduce repeated use of PS, lower ventilator parameters, shorten the duration of respiratory support, and reduce the incidence rate and severity of BPD, without increasing the incidence rate of glucocorticoid-related complications.

To analyze the clinical characteristics and factors affecting prognosis in children with severe aplastic anemia (SAA).Two hundred and five children with SAA treated in our department from January 2008 to April 2018 were selected, and the clinical characteristics and factors affecting prognosis were retrospectively analyzed.Among 205 SAA children, the effective rate (CR+PR) at 3, 6 and 12 months after immunosuppressive therapy (IST) treatment was 50.9%, 59.0% and 73.9%, respectively, and 5-year overall survival rate was 93.1%±2.0%. Univariate analysis showed that 5-year overall survival rate of SAA children of spontaneous delivery was higher than that of cesarean section (P=0.039), while multivariate analysis showed that birth way had no significant influence on 5-year overall survival rate (P0.05). The response rate at 3 months after IST of children with a recent history of decoration before SAA onset was higher than those without history of decoration (P0.05).Most of the SAA children can achieve high response rate and overall survival rate. Patients with recent history of home/school decoration may be the factor affecting hematological response after 3 months of IST, but have no influence on long-term overall survival.重型再生障碍性贫血患儿的临床特征及预后分析.分析重型再生障碍性贫血(SAA)患儿的基本临床特征及预后影响因素。.选择2008年1至2018年4月收治的SAA患儿205例，对其基本临床特征及预后影响因素进行回顾性分析。.205例SAA患儿中，免疫抑制治疗（IST）后3、6和12个月的有效率（CR+PR）分别为50.9%、59.0%和73.9%，患儿5年总生存（OS）率为93.1%±2.0%。单因素生存分析显示，顺产出生的SAA患儿较剖宫产出生者5年OS率高（P=0.039），多因素Cox回归模型分析显示，出生方式对SAA患儿5年OS率无显著影响（P0.05）。发病近期有装修材料接触史的SAA患儿IST后3个月反应率高于无装修材料接触史的SAA患儿（P0.05）。.SAA患儿经IST治疗后可获得较高的反应率和OS率，发病近期有家庭/学校装修材料接触史可能为SAA患儿IST后3个月反应率的影响因素，但对患儿长期生存未见显著影响。.

Background: The promotion of a healthy diet via health education is a component of the “Healthy China 2030” plan. However, few studies have reported whether health knowledge about nutrition and diet has gained public attention, and whether it is needed by the public.Methods: The numbers of views, shares, and reads of articles published by the official WeChat account of a hospital in China were accessed. The influence index was obtained via the entropy analysis of these three indices. A questionnaire survey was developed based on the purpose of the study and the conclusion of the content analysis, which conducted to analyze users' requirements for health knowledge and their influencing factors. Moreover, risk factors were explored by logistic regression models.Results: Of the 103 articles considered in this study, four articles in the Top 10 were related to nutrition and diet. The influence index of nutrition and diet knowledge was found to be the highest in the content analysis (p < 0.05). The higher degrees of humor (β = 0.224, p = 0.027), nutrition and diet articles (β = 0.776, p = 0.034), and cover articles (β = 0.312, p = 0.021) have significant influences on the influence index. In total, 581 questionnaires were obtained, and 78.1% of the respondents reported believing that the health knowledge of greatest concern was that related to nutrition and diet. Multivariate logistic regression analyses were conducted to explore the associations between the features of the articles and users reading nutrition and diet knowledge; it was found that gender (female, OR: 4.651, 95%Cl: 2.598, 8.325, and p < 0.001), age (young adult, OR: 0.358, 95%Cl: 0.266, 0.481, and p < 0.001), cancer precaution knowledge (OR: 4.333, 95%Cl: 2.262, 8.299, and p < 0.001), traditional Chinese medicine (OR: 2.121, 95%Cl: 1.064, 4.230, and p = 0.033), the knowledge acquisition approach [circle of friends (OR: 2.586, 95%Cl: 1.373, 4.868, and p = 0.003), social media (OR: 2.183, 95%Cl: 1.204, 3.960, and p = 0.010)), hospitals (OR: 3.194, 95%Cl: 1.793, 5.692, and p < 0.001), television media (OR: 4.348, 95%Cl: 2.341, 8.077, and p < 0.001)], and social media strategies [professionalism and authority (OR: 2.354, 95%Cl: 1.231, 4.505, and p = 0.006)] have statistically significant relationships with users reading nutrition and diet knowledge.Conclusion: Nutrition and diet knowledge could contribute to WeChat user engagement of health information dissemination. Nutrition professionals should improve the scientific popularization ability and effectively use social media for health promotion.

Alzheimer's disease (AD) is a neurodegenerative disease leading to irreversible and progressive brain damage. Close monitoring is essential for slowing down the progression of AD. Magnetic Resonance Imaging (MRI) has been widely used for AD diagnosis and disease monitoring. Previous studies usually focused on extracting features from whole image or specific slices separately, but ignore the characteristics of each slice from multiple perspectives and the complementarity between features at different scales. In this study, we proposed a novel classification method based on the fusion of multi-view 2D and 3D convolutions for MRI-based AD diagnosis. Specifically, we first use multiple sub-networks to extract the local slice-level feature of each slice in different dimensions. Then a 3D convolution network was used to extract the global subject-level information of MRI. Finally, local and global information were fused to acquire more discriminative features. Experiments conducted on the ADNI-1 and ADNI-2 dataset demonstrated the superiority of this proposed model over other state-of-the-art methods for their ability to discriminate AD and Normal Controls (NC). Our model achieves 90.2% and 85.2% of accuracy on ADNI-2 and ADNI-1 respectively, thus it can be effective in AD diagnosis. The source code of our model is freely available at https://github.com/fengduqianhe/ADMultiView.

Although triple-negative breast cancer (TNBC) accounts for only 15% of breast cancer cases, it is associated with a high relapse rate and poor outcome after standard treatment. Currently, the effective drugs and treatment strategies for TNBC remain limited, and thus, developing effective treatments for TNBC is pressing. Several studies have demonstrated that both chalcone and syringaldehyde have anticancer effect, but their potential anti-TNBC bioactivity are still unknown.The present study aimed to synthesize a chalcone-syringaldehyde hybrid (CSH1) and explore its potential anti-TNBC effects and the underlying molecular mechanism.Cell cytotoxicity was determined by 3-(4,5-dimethythiazol)-2,5-diphenyltetrazolium bromide (MTT). The activity of cell proliferation was measured by colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) staining assay. Cell cycle distribution and cell apoptosis were determined by fluorescence-activated cell sorter (FACS). The situation of DNA damage was observed using fluorescence microscopy. The ability of cell-matrix adhesion, migration and invasion was detected using cell adhesion assay and transwell assay. Transcriptome sequencing was performed to find out the changed genes. Levels of various signaling proteins were assessed by western blotting.CSH1 treatment triggered DNA damage and inhibited DNA replication, cell cycle arrest, and cell apoptosis via suppressing signal transducer and activator of transcription 3 (STAT3) phosphorylation. Whole genome RNA-seq analysis suggested that 4% of changed genes were correlated to DNA damage and repair, and nearly 18% of changed genes were functionally related to cell adhesion and migration. Experimental evidence indicated that CSH1 treatment significantly affected the distribution of focal adhesion kinase (FAK) and its phosphorylation, resulting in cell-matrix-adhesion reduction and migration inhibition of TNBC cells. Further mechanistic studies indicated that CSH1 inhibited TNBC cell proliferation, adhesion, and migration by inhibiting cytoskeleton-associated protein 2 (CKAP2)-mediated FAK and STAT3 phosphorylation signaling.These results suggest that CKAP2-mediated FAK and STAT3 phosphorylation signaling is a valuable target for TNBC treatment, and these findings also reveal the potential of CSH1 as a prospective TNBC drug.

Dasatinib, an orally administered Src-family kinase inhibitor, is combined with the standard chemotherapeutic regimen to enhance antineoplastic activity against core-binding factor acute myeloid leukemia (CBF-AML) in adults; however, limited data are available for use in children. In the present study, we studied the pharmacokinetics and safety of dasatinib in children.Dasatinib (60 or 80 mg/mTwenty pediatric patients (3.3-14.4 years of age) were included, and a total of 40 dasatinib concentrations were available for population pharmacokinetic analysis. The mean (standard deviation) of the estimated area under the concentration-time curve extrapolated to steady state (AUCThe population pharmacokinetics of orally administered dasatinib were evaluated in pediatric CBF-AML patients. The AUC

To retrospective analyze the reason of death in children with acute lymphoblastic leukemia (ALL) treated with CCLG-ALL 2008 protocol, and the experience was summarized in order to reduce the mortality.916 children diagnosed as ALL and accepted CCLG-ALL 2008 protocol from April 2008 to April 2015 in our hospital were enrolled, the dead cases in them were analyzed retrospectively.169 children died, including 111 (65.7%) males and 58 (34.3%) females. Recurrence was the main reason of death. 150 (88.7%) children died due to recurrence, among them, 86 (57.3%) cases gave up directly. The second reason of death was infection. The main clinical sites of infection were concentrated in respiratory system and digestive system. Bacterial infection was most common (Gram-negative was common).Enough finance and improving family compliance can decrease the mortality in children with ALL. Early rational use of antibiotics can reduce infection-related mortality in children with ALL.CCLG-ALL2008方案治疗儿童急性淋巴细胞白血病死亡病例分析.回顾性分析应用CCLG-ALL2008方案治疗儿童急性淋巴细胞白血病（ALL）患者的死亡原因，总结经验，以期降低患儿死亡率.2008年4月至2015年4月在本院诊断并接受CCLG-ALL2008方案治疗的儿童ALL患者共计916例，选取其中死亡的病例进行回顾性分析.死亡患者共169例，男性111例（65.7%），女性58例（34.3%）。复发为主要的死亡原因，由复发导致死亡的患者有150例（88.7%），其中86例（57.3%）复发后家属直接放弃治疗。第二死亡原因为感染，感染部位主要集中在呼吸系统和消化系统，以细菌感染为主（多见于革兰氏阴性杆菌）.加强经济支持、提高家属依从性可以降低儿童ALL的死亡率，早期合理地使用抗生素可以降低儿童ALL的感染相关死亡率.

Purpose: Hepatocellular carcinoma (HCC), one of the most common and deadliest malignancies worldwide, has a poor prognosis, owing to its high potential for vascular invasion and metastasis and the lack of biomarkers for early diagnosis. Thus, it must be a crucial factor for investigating therapeutic strategies for HCC to identify the functional molecular targets. Here, we reported a novel chemokine, CKLF1, that might act as a pivotal modulator in the invasion and metastasis of HCC and could serve as an attractive target for cancer therapy. Experimental Design: Bioinformatics analysis, PCR, Western blotting, and IHC were performed to detect the expression of CKLF1 in HCC. The function of CKLF1 was demonstrated by a series of in vitro and in vivo experiments. Pharmacologic treatment, flow cytometry, and Western blotting were carried out to demonstrate the potential mechanisms of CKLF1. Results: We proved that CKLF1 was overexpressed in HCC tissues and was related to tumor stage, vascular invasion, and patient survival. Then, functional assays showed that CKLF1 promoted hepatocellular carcinogenesis and metastatic potential. Finally, the IL6/STAT3 signaling pathway was involved in the mechanistic investigation. The results demonstrated that CKLF1 enhanced the progression of HCC and prevented doxorubicin-induced apoptosis through activating the IL6/STAT3 pathway. Conclusions: These data showed that CKLF1 inhibited apoptosis and promoted malignant transformation through the IL6/STAT3 pathway, and ultimately enhanced the development and metastasis of HCC. Thus, our work revealed that CKLF1 was a significant prognostic factor of HCC and might be a potential molecular therapeutic target for HCC.

Background Keto-analogues administration plays an important role in clinical chronic kidney disease (CKD) adjunctive therapy, however previous studies on their reno-protective effect mainly focused on kidney pathological changes induced by nephrectomy. This study was designed to explore the currently understudied alternative mechanisms by which compound α-ketoacid tablets (KA) influenced ischemia–reperfusion (IR) induced murine renal injury, and to probe the current status of KA administration on staving CKD progression in Chinese CKD patients at different stages. Methods In animal experiment, IR surgery was performed to mimic progressive chronic kidney injury, while KA was administrated orally. For clinical research, a retrospective cohort study was conducted to delineate the usage and effects of KA on attenuating CKD exacerbation. End-point CKD event was defined as 50% reduction of initial estimated glomerular filtration rate (eGFR). Kaplan–Meier analysis and COX proportional hazard regression model were adopted to calculate the cumulative probability to reach the end-point and hazard ratio of renal function deterioration. Results In animal study, KA presented a protective effect on IR induced renal injury and fibrosis by attenuating inflammatory infiltration and apoptosis via inhibition of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. In clinical research, after adjusting basic demographic factors, patients at stages 4 and 5 in KA group presented a much delayed and slower incidence of eGFR decrease compared to those in No-KA group (hazard ratio (HR) = 0.115, 95% confidence interval (CI) 0.021–0.639, p = 0.0134), demonstrating a positive effect of KA on staving CKD progression. Conclusion KA improved IR induced chronic renal injury and fibrosis, and seemed to be a prospective protective factor in end stage renal disease.

OBJECTIVE: To study the clinical features and prognosis of childhood acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). METHODS: A retrospective analysis was performed on the medical data of 14 children who were diagnosed with AML-MRC from June 2014 to March 2020, including clinical features, laboratory examination results, and prognosis. RESULTS: Among the 14 children with AML-MRC, there were 9 boys and 5 girls, with a median age of 11 years (range: 1-17 years), a median leukocyte count of 8.3×10(9)/L [range: (2.0-191.0)×10(9)/L], a median hemoglobin level of 73 g/L (range: 44-86 g/L), and a median platelet count of 75×10(9)/L [range: (4-213)×10(9)/L] at diagnosis. According to the FAB classification, the children with AML-M5 accounted for 71% (10/14). Among the 14 children, 4 had multi-lineage dysplasia (MLD), 2 had a history of myelodysplastic syndrome (MDS), 5 had MDS-related cytogenetic changes, 2 had MLD with MDS-related cytogenetic changes, and 1 had a history of MDS with MLD. The median follow-up time was 10.6 months (range: 0.4-54.4 months) for 14 children, among whom 2 gave up treatment immediately after diagnosis and 12 had an evaluable treatment outcome. The 2-year overall survival (OS) rate was 50%±15%, and the 2-year disease-free survival (DFS) rate was 33%±13%. Of the 12 children, 7 underwent haploidentical hematopoietic stem cell transplantation (HSCT), among whom 5 achieved DFS and 2 died, with a 2-year OS rate of 71%±17% and a 2-year DFS rate of 43%±19%; 5 children underwent chemotherapy alone, among whom 1 achieved DFS, 3 died, and 1 was lost to follow-up, with a 2-year OS rate of 40%±30% and a 2-year DFS rate of 30%±24%. There was no significant difference in the survival condition between the transplantation and chemotherapy groups (P > 0.05). CONCLUSIONS: Childhood AML-MRC is often observed in boys, and AML-M5 is the most common type based on FAB classification. Such children tend to have a poor prognosis. HSCT is expected to improve the poor prognosis of children with AML-MRC. However due to the small number of cases, it is necessary to increase the number of cases for further observation.

Purple-fleshed sweetpotato is a rich source of antioxidants such as polyphenols. Chinese steamed bread (CSB) is a popular food product for many people. The effect of CSB making process on the structure and phenolic profiles of CSB enriched with purple sweetpotato flour (PSPF) at different concentrations was investigated. The mixing process greatly reduced the gluten strength due to the incorporation of PSPF. The addition of PSPF induced extensive structural modification on CSB due to the starch-polyphenol and protein-polyphenol interactions. The total phenolic contents, in vitro antioxidant activity, and the contents of hydroxycinnamic acid derivatives were decreased by fermentation and proofing, but they were increased after steaming and storage. The anthocyanins were significantly degraded during the CSB making process. The textural and structural properties of CSB were significantly affected by the PSPF substitutions. The results of this study are useful to develop functional CSB with improved nutritional quality and phenolic profiles.

To analyze the outcomes of the children suffered from philadelphia chromosome positive acute lymphoblastic leukemia (Ph21 cases of firstly diagnosed PhAmong 21 patients, 17 were male and 4 were female with a median age of 8 years old (range, 4-12 years), the median follow-up time was 30 moths (range, 10-133 months). All the patients were treated with chemotherapy induced by the high-risk project of CCLG-ALL 2008. Among 14 patients treated with TKI plus chemotherapy, nine patients achieved complete remission. During 3 months after treatment, patients without complete molecular response or with the second complete remission and intensity desire of transplantation were treated with allo-HSCT, among 9 patients with allo-HSCT, six patients achieved long term survival.At TKI era, TKI combined with strong chemotherapy can make Ph21例Ph阳性急性淋巴细胞白血病儿童不同治疗疗效分析.分析Ph+急性淋巴细胞白血病（ALL）患儿TKI联合化疗和异基因造血干细胞移植（allo-HSCT）的疗效。.回顾性分析2008年1月至2015年4月在中国医学科学院血液病医院儿童血液病中心就诊应用CCLG-2008-ALL方案治疗的21例年龄12岁Ph21例患者中，男性17例，女性4例，中位年龄为8（4-12）岁，中位随访时间为58（10-133）个月。所有患儿均采用CCLG-2008-ALL高危组治疗方案诱导化疗，14例酪氨酸激酶抑制剂联合高危组巩固化疗的患者，至末次随访时间，9例患者获得长期生存； 治疗3个月时，对于未达到分子生物学缓解（5例）、复发重新获得缓解（2例）、有强烈移植愿望（2例）的患者行异基因造血干细胞移植，9例移植患者中6例患者获得长期生存。.在TKI时代，Ph

This study aimed to evaluate the value of real-time contrast-enhanced ultrasound (CEUS) combined with contrast-enhanced computed tomography (CECT) in the differential diagnosis of clear cell renal cell carcinoma (CCRCC), papillary renal cell carcinoma (PRCC), and chromophobe renal cell carcinoma (CRCC).In the present study, 82 patients with CCRCC, 24 patients with PRCC, and 19 patients with CRCC were confirmed by pathology of the resected tumor. All patients were evaluated by CEUS and CECT before the operation. In addition, the contrast enhancement mode of CEUS and CECT and the contrast parameters of the region of interest (ROI) time-intensity curve between the lesions and the surrounding normal renal parenchyma by CEUS were compared and analyzed.Compared with the pathological results, the diagnostic accuracy of ultrasound in the 3 groups was 87.8% (72/82), 83.3% (20/24) and 73.7% (14/19). There was no significant difference between CEUS and CECT in the diagnostic accuracy of all groups (P0.05). Meanwhile, compared with the surrounding renal parenchyma by CEUS, 82.5% (66/80) of CCRCC lesions showed "fast-forward and fast/slow-retrograde," while 83.3% (20/24) of PRCC, and 84.2% (16/19) showed "slow-forward and fast/slow-retrograde." Significant differences in the enhancement modes of CEUS were found among the CCRCC, PRCC, and CRCC lesions (P0.05). And the enhancement modes could be quantitatively analyzed by the ROI time-intensity curve of the lesion. Moreover, lesions enhanced by CECT and 74.4% (61/82) of CCRCC lesions showed "fast-forward and fast/slow-retrograde," while 66.7% (16/24) of PRCC and 84.2% (16/19) of CRCC showed "slow-forward and fast/slow-retrograde." The contrast modes and enhancement uniformity of CEUS and CECT showed no significant differences among the CCRCC, PRCC, and CRCC lesions (P0.05).CEUS and quantitative analysis of ROI time-intensity curve can be used for differential diagnosis of the 3 RCC subtypes. The combination of CEUS and CECT can help us differentiate RCC subtypes and is of great significance for clinical treatment strategies and prognostication.

OBJECTIVE: To study the clinical significance of minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (B-ALL) pediatric patients with different fusion gene backgrounds. METHODS: A retrospective analysis was performed on the medical data of 441 B-ALL children who were treated from January 2008 to April 2015. Among the 441 children, 336 had negative fusion gene, 79 had positive ETV6-RUNX1 fusion gene, and 26 had positive E2A-PBX1 fusion gene. Flow cytometry was used to detect MRD, and the influence of MRD on day 15 (TP1), day 33 (TP2), and week 12 (TP3) of induction therapy on prognosis was analyzed. RESULTS: In patients with negative fusion gene, the positive MRD group had significantly lower overall survival (OS) rate and event-free survival (EFS) rate (P < 0.05) and significantly higher recurrence rate and mortality rate at TP1, TP2, and TP3, compared with the negative MRD group (P < 0.05). In patients with positive ETV6-RUNX1, the positive MRD group had significantly lower OS and EFS rates (P < 0.05) and significantly higher recurrence rate and mortality rate (P < 0.05) than the negative MRD group only at TP1. In patients with positive E2A-PBX1, there were no significant differences in the OS rate, recurrence rate, and mortality rate between the positive and negative MRD groups at TP1, TP2, and TP3 (P > 0.05). CONCLUSIONS: MRD has the most definite prognostic significance in pediatric B-ALL patients with negative fusion gene, while it has unsatisfactory prognostic significance in those with positive ETV6-RUNX1 or positive E2A-PBX1.

To investigate the consistency between FCM and PCR on the detecting of MRD in TCF3-PBX155 cases of paediatric TCF3-PBX1Among the 55 children with TCF3-PBX1The detection result of MRD in TCF3-PBX1 detect by FCM and PCR shows better consistency. MRD positivity detected by FCM at the end of induction therapy (day 33) predicts a high risk of relapse in TCF3-PBX1 ALL patients.儿童TCF3-PBX1评价流式细胞仪（FCM）和逆转录-聚合酶链反应（PCR）2种方法检测TCF3-PBX1选取2008年4月到2015年4月本院收治的TCF3-PBX155例儿童TCF3-PBX1TCF3-PBX1

Pathogenic mutations in 3-keto-dihydrosphingosine reductase (KDSR) gene are associated with keratinization disorders and impaired platelet function. However, no case with both homozygotic mutation of

Background Anti-tumour necrosis factor (TNF)-α drugs are used by increasing numbers of reproductive-age women. Although the neonatal outcomes have been described, there are concerns regarding the risk of infection in offspring following exposure to anti-TNF-α. Methods A literature search was conducted using Pubmed, EMBASE, and the Cochrane Database, from inception through August 2020. We evaluated the risk of infection in autoimmune disease (AID) offspring unexposed to anti-TNF-α compared to AID offspring exposed to anti-TNF-α, as well as to unexposed non-AID offspring. Results Our primary analysis showed that both AID offspring unexposed to anti-TNF-α [risk ratio (RR) 1.09; 95% confidence interval (CI), 1.03–1.16; I2=0%] and AID offspring exposed to anti-TNF-α (RR 1.39; 95% CI, 1.2–1.61; I2=0%] was associated with an increased risk of infection during the first year of life compared with the unexposed non-AID offspring. However, our secondary analysis demonstrated that AID offspring exposed to anti-TNF-α was not associated with an increased risk of infection when compared with AID offspring unexposed to anti-TNF-α (RR=1.1; 95% CI, 0.86–1.4). Conclusion Our results suggest that in utero exposure to anti-TNF-α does not appear to increase the risk of infection during the first year of life in the offspring; however, AID itself was associated with a marked excess risk of infection in the children.

Chinese steamed breads (CSB) and noodles are staple foods for many people. The production of frozen steamed products and boiled noodles has kept increasing. This is due to the increasing demand of ready-to-eat frozen food products from the market. Frozen storage significantly increases the self-life of the products and reduces the production costs. On the other hand, the freezing and frozen storage lead to quality loss of the frozen products. This review summarizes effects of freezing and frozen storage on diverse quality attributes (e.g., structural and textural properties) of frozen northern-type steamed breads and boiled noodles. Food safety of the frozen products related to the COVID-19 pandemic is discussed. To counteract the quality loss of the frozen products, suitable processing methods, selection of basic ingredients and uses of various food additives can be done. Research gaps to improve the textural, cooking and nutritional quality of frozen CSB and noodles are suggested.

To study the long-term efficacy of CCLG-ALL2008 protocol used for treatment of childhood acute lymphoblastic leukemia (ALL).Nine hundred and forty children with newly diagnosed ALL from January 2008 to April 2015 were treated with CCLG-ALL2008 protocol. Overall survival (OS) and event-free survival (EFS) rates were estimated by the Kaplan-Meier method. Cox proportional hazards model was used for analyses of prognostic factors.Among the 940 newly diagnosed ALL patients, 570 patients were male, and 370 patients were female, the median age of onset was 5 years old (from 1 to 15 years old). The complete reaction rate (CR) was 96.7%. Survival analysis of 916 ALL patients with CR estimated by follow up [ (median follow up period 64 months (from 3 to 123 months) ] showed that, the expected 10 year OS rate was (78.6±1.5)% and the EFS rate was (66.0±1.8)%. The long-term OS rate of standard risk, intermediate risk and high risk patients was (93.0±1.5)%, (77.6±2.7)%, and (59.3±3.7)%, respectively, and the long-term EFS rate in standard risk, intermediate risk and high risk patients was (84.2±2.2)%. (67.8±2.9)%, and (42.1±3.9)% respectively. 10 year OS rate in B-ALL patients (79.8±1.6)% was significantly higher than that in T-ALL patients (53.5±6.3)% (P＜0.01). Among of all the patients, patients 201 (21.9%) relapsed, the median relapse time was 19 months (from 2 months to 81 months). The 10 year EFS rate was (81.7±3.7）% in the patients with MRD rate ＜0.01% after induction therapy, which was significantly higher than that in the patients with MRD rate＞0.01% (48.4±9.8)%.The therapeutic efficacy of the CCLG-ALL2008 protocol is closed to the level of supior study group in the world. Risk stratification can improve the outcome for childhood ALL. Immunophenotyping shows the outcome of B-ALL is better than that of T-ALL. MRD negative patients after induction therapy shows better prognosis compared with that of MRD positive patients.单中心应用CCLG-ALL2008方案治疗940例 儿童急性淋巴细胞白血病的长期疗效分析.分析应用CCLG-ALL2008方案治疗初诊急性淋巴细胞白血病（ALL）患儿的长期疗效.回顾性分析2008年1月至2015年4月期间，本院确诊为ALL的940例初诊患儿应用CCLG-ALL2008方案治疗的临床特征及疗效。采用Kaplan-Meier生存分析评估患儿总体生存（OS）率和无事件生存（EFS）率，运用COX回归比例风险模型分析影响预后的因素.940例初诊ALL患儿，男性570例，女性370例，中位年龄为5（1-15）岁。完全缓解（CR）率为96.7%。对获得完全缓解的916例患儿进行随访[中位随访时间为64（3-123）个月]的生存分析显示，预期10年OS率为（78.6±1.5）%，EFS率为（66.0±1.8）%。低危组10年OS率为（93.0±1.5）%，EFS率为（84.2±2.2）%；中危组10年OS率为（77.6±2.7）%，EFS率为（67.8±2.9）%；高危组10年OS率为（59.3±3.7）%，EFS率为（42.1±3.9）%。B-ALL的10年OS率（79.8±1.6）%、EFS率（67.7± 1.8）%，明显优于T-ALL的OS率为（63.6±5.6）%和EFS率为（53.5±6.3）%。复发201例（21.9%）中，复发中位时间为CR后19 （2-81） 个月。诱导缓解后微小残留病监测（MRD）≥0.01%者10年EFS为（48.4±9.8）%,明显低于＜0.01%患儿的EFS率（81.7±3.7）.CCLG-ALL2008方案对儿童初诊ALL疗效接近发达国家治疗的水平，危险分组是良好的个体化治疗指标。B-ALL预后优于T-ALL，诱导缓解后MRD阴性患者预后明显优于阳性患者.

Acute lymphoblastic leukemia (ALL) is a common pediatric cancer. The second malignant neoplasms (SMNs) in long-term survivors of pediatric ALL are relatively rare. Herein we report a 10-year-old girl who was diagnosed as primitive neuroectodermal tumor (PNET) 5 years after the initial diagnosis of ALL with radiotherapy-free treatment. PNET is an exceedingly rare neoplasm in SMNs of survivors of childhood ALL. It is predisposed to be misdiagnosed and the pathogenesis is unclear. The outcome is poor. Long-term follow-up is necessary for the survival children of ALL.

OBJECTIVE: To study the clinical features and prognosis of core binding factor acute myeloid leukemia (CBF-AML) in children. METHODS: A retrospective analysis was performed from the chart review data of children who were newly diagnosed with CBF-AML in the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, from August 2009 to November 2015. According to the type of fusion gene, the children were divided into CBFB-MYH11 and AML1-ETO groups. Clinical features and prognosis were analyzed and compared between the two groups. RESULTS: A total of 91 children with CBF-AML were enrolled in this study, among whom there were 74 (81%) in the AML1-ETO group and 17 (19%) in the CBFB-MYH11 group. Additional chromosomal abnormalities were observed in 38 children (42%), and deletion of sex chromosome was the most common abnormality and was observed in 28 children (31%). After the first course of induction treatment, the complete remission rate was 97% (88/91), the recurrence rate was 29% (26/91), the 5-year event-free survival (EFS) rate was 65%±6%, and the 5-year overall survival (OS) rate was 75%±5%. There were no significant differences between the AML1-ETO and CBFB-MYH11 groups in 5-year EFS rate (62%±7% vs 77%±11%, P > 0.05) or 5-year OS rate (72%±6% vs 88%±9%, P > 0.05). CONCLUSIONS: AML1-ETO is the main type of fusion gene in children with CBF-AML, and deletion of sex chromosome is the most common type of additional chromosomal abnormalities. Children with CBF-AML often have a good prognosis, and the children with AML1-ETO have a similar prognosis to those with CBFB-MYH11.

The Sul 1 cacao (Theobroma cacao) genotype has become more popular among cocoa producers due to its resistance toward vascular streak dieback, a devastating dieback disease in cacao plants. Sul 1 cocoa beans were subjected to prolonged fermentation of 10 days (240 h). Changes in the composition of methylxanthines, polyphenols, and volatiles and sensory profiles of the cocoa beans as affected by fermentation were analyzed. The first 48 h of fermentation significantly determined the composition of the methylxanthines and polyphenols in the cocoa beans. A prolonged fermentation (>96 h) period did not further reduce the contents of methylxanthines and polyphenols in the cocoa beans. Important volatiles characteristic of the cocoa/chocolate flavor were mostly developed after 48 h of fermentation. The fermentation for 72 h retained considerable amounts of methylxanthines and polyphenols in the beans while producing cocoa mass with good sensory profiles.

To study the effect of apoptotic drug Navitoclax (NTX) combined with chemotherapy drug Daunorubicin (DNR) on apoptosis of erythroleukemia cells.K562, HEL and TF-1 cells in logarithmic growth phase were treated with NTX, DNR and combination of the two drugs. CCK-8 test, Annexin V-DAPI double-staining flow cytometry, real-time RT-PCR were used to detect cell growth, cell apoptosis and expression of BAX, BAK, BCL-2, BCL-xl and BIM respectively. The effects of NTX, DNR and combination of the two drugs on apoptosis of K562, HEL and TF-1 cells were compared and analyzed.NTX combined with DNR could significantly inhibit the growth of K562, HEL and TF-1 cells; Apoptosis detection results showed that the apoptotic rate of K562, HEL and TF-1 cells in combination group was significantly higher than that in NTX and DNR single group; the expression level of apoptosis-related genes BAK and BAX in K562 cells in combination group was significantly higher than that in two single drug groups, and the expression level of anti-apoptotic protein genes BCL-2 and BCL-xl was significantly lower than that in two single drug groups (P＜0.05); the expression level of BAK in HEL cells treated with combined drugs for 24 hours was higher than that in DNR group (P ＜ 0.05); the expression level of BCL-2 in TF-1 cells treated with combined drugs for 24 hours was lower than that in two single drugs groups while the expression level of BAK in 48 hours was the highest in combined drugs group, and the expression level of BCL-2 and BCL-xl in combined drugs group was lower than that in NTX group (P＜0.05).NTX combined with DNR can significantly promote the apoptosis of erythroleukemia cell lines K562, HEL and TF-1, and induce the expression of apoptosis-related genes. This study provides a new scheme for the clinical treatment of erythroleukemia.Navitoclax联合柔红霉素促进红白血病细胞系K562、HEL和TF-1的凋亡.研究促凋亡药物Navitoclax（NTX）联合化疗药物柔红霉素（Daunorubicin，DNR）对红白血病细胞凋亡的影响.取对数生长期的K562、HEL和TF-1细胞，给予NTX、DNR以及2药联合，CCK-8检测细胞生长，Annexin V-DAPI双染流式细胞术检测细胞的凋亡，real-time RT-PCR检测凋亡相关基因BAX，BAK，BCL-2、BCL-xl、BIM的表达，对比分析NTX、DNR与2药联合对K562、HEL和TF-1细胞凋亡的影响.NTX联合DNR能明显抑制K562、HEL和TF-1细胞的生长；凋亡检测结果显示，联合用药组K562、HEL和TF-1细胞凋亡率明显高于NTX、DNR单用药组（P＜0.05）；凋亡相关基因检测结果显示，K562细胞前凋亡蛋白基因BAK、BAX的表达水平在联合用药组明显高于2个单药组,抗凋亡蛋白基因BCL-2、BCL-xl的表达水平明显低于2个单药组（P＜0.05）；HEL细胞联合用药24 h BAK的表达水平高于DNR单药组（P＜0.05）；TF-1细胞联合用药24 h BCL-2的表达低于2个单用药组，48 h BAK的表达联合用药组最高，BCL-2、BCL-xl的表达水平在联合用药组低于NTX单药组（P＜0.05）.NTX联合DNR能明显促进红白血病细胞系K562、HEL和TF-1细胞凋亡，诱导凋亡相关基因的表达。本研究期待为红白血病的临床治疗提供新方案.

OBJECTIVE: To study the clinical features and genetic mutations of children with Shwachman-Diamond syndrome (SDS) and malignant myeloid transformation. METHODS: Next-generation sequencing was used to analyze the gene mutations in 11 SDS children with malignant myeloid transformation, and their clinical features and genetic mutations were analyzed. RESULTS: Of the 11 children with SDS, 9 (82%) presented with refractory cytopenia of childhood (RCC), 1 (9%) had myelodysplastic syndrome with excess blasts (MDS-EB), and 1 (9%) had acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). The median age of onset of malignant myeloid transformation was 48 months (ranged 7 months to 14 years). Of the 11 children, 45% had abnormalities in the hematological system alone. Mutations of the SBDS gene were detected in all 11 children, among whom 5 (45%) had c.258+2T > C homozygous mutation and 3 (27%) had c.184A > T+c.258+2T > C compound heterozygous mutation. The new mutations of the SBDS gene, c.634_635insAACATACCTGT+c.637_638delGA and c.8T > C, were rated as "pathogenic" and "possibly pathogenic" respectively. The 3-year predicted overall survival rates of children transformed to RCC and MDS-EB/AML-MRC were 100% and 0% respectively (P=0.001). CONCLUSIONS: SDS children may have hematological system symptoms as the only manifestation, which needs to be taken seriously in clinical practice. The type of malignant transformation is associated with prognosis.

OBJECTIVE: To compare the efficacy of the CAMS-2005 and CAMS-2009 regimens in treating children with non-core binding factor acute myeloid leukemia (non-CBF AML) and to study the prognosis factors. METHODS: A total of 161 children who were initially diagnosed with non-CBF AML from April 2005 to December 2015 were enrolled as study subjects, and were divided into a CAMS-2005 regimen group (n=52) and a CAMS-2009 regimen group (n=109) according to the chemotherapy regimen provided. The efficacy was retrospectively compared between the two groups. RESULTS: The complete remission (CR) rate at the first course of treatment was higher in the CAMS-2009 regimen group than that in the CMAS-2005 regimen group (63.3% vs 46.2%; P < 0.05). There were no significant differences between the two groups in treatment-related mortality rate (11.9% vs 17.3%), recurrence rate (27.5% vs 28.8%), and three-year overall survival (OS) rate (44%±5% vs 28%±6%) (P > 0.05). Children who achieved CR at the first course of treatment had significantly higher OS and event-free survival rates than those who did not achieved CR (P < 0.01). CONCLUSIONS: The CAMS-2009 regimen is superior to the CAMS-2005 regimen in improving the CR rate in children with non-CBF AML after induction treatment. Whether CR is achieved at the first course of treatment can affect the OS rate of children with non-CBF AML.

Human endogenous retrovirus W family envelope protein (HERV-W env) is associated with several neurological and psychiatric disorders, including multiple sclerosis (MS) and schizophrenia. Clinical studies have demonstrated a common link between inflammatory abnormalities and HERV-W env in neuropsychiatric diseases. Nonetheless, the molecular mechanisms by which HERV-W env mediates neuroinflammation are still unclear. In this study, we found that HERV-W env significantly increased the mRNA and protein levels of TNF-α and IL-10 in U251 and A172 cells. HERV-W env also induced a notable increase in Toll-like receptor 4 (TLR4). Knockdown of TLR4 impaired the expressions of TNF-α and IL-10 induced by HERV-W env. Overexpression of HERV-W env led to the upregulation of MyD88 but caused a decrease in MyD88s. MyD88s overexpression suppressed the expressions of TNF-α and IL-10 induced by HERV-W env. These findings indicate that HERV-W env upregulates the expressions of IL-10 and TNF-α by inhibiting the production of MyD88s in glial cells. This work sheds light on the immune pathogenesis of HERV-W env in neuropsychiatric disorders.

To understand the epidemiological characteristics of childhood acute lymphoblastic leukemia (ALL) by analyzing the clinical data of 982 patients.A retrospective analysis was performed on 982 children with ALL who were admitted to our center from April 2008 to May 2015. The sex, age and season of onset, risk factors related with the disease, and molecular biological characteristics were analyzed.The ratio of male to female in ALL was 1.5∶1, the median age of onset was 5 years old, and the peak age of onset was 2 to 5 years old. The peak season of onset was spring. Analysis of birth and feeding history showed that the children born after normal period of gestation accounted for 98.0%. Among the born children 55.9% of children were born with natural lobour, and 44.1% of children were born by cesarean section. The breast feeding children accounted for 79.8%, while artificial/mixed feeding children accounted for 20.2%. The median birth weight was 3.5 kg (1.8-7.2 kg). There were 34 cases (3.5%) with abnormal birth history, including 10 cases with umbilical cord around the neck. 31.4% of the patients had a recent history of house decoration, and the median exposure time to decoration environment was 12 months (1-36 months). Among the first to third grade relatives of the children, 44 patients (4.5%) sufferd from blood system diseases, including 23 patients with leukemia, 53 (5.4%) had malignant tumors, and most of them were lung cancer, digestive system tumors and breast cancer. The immunophenotype showed that B-ALL accounted for 90.7% and T-ALL accounted for 9.3%. In molecular biological tests, TEL/AML1 positive patients accounted for 21.0%, E2A/PBX1 positive patients accounted for 5.2%, BCR-ABL positive patients accounted for 6.1%, and MLL positive patients accounted for 2.5%.The childhood ALL occurs in more boys, the peak age of onset is 2-5 years old, the peak season of onset is spring, the peak of birth season is autumn and winter, the proportion of cesarean section, high birth weight and non-breastfeeding after birth are higher than the average value of infants in most parts of the country during the same period. The proportion of childhood ALL patient's exposure to ionizing radiation and house decoration environment, and relatives with history of blood and malignant tumors are high.982例儿童急性淋巴细胞白血病流行病学研究.分析982例儿童急性淋巴细胞白血病（ALL）临床病例，了解儿童ALL流行病学特征.对本中心2008年4月至2015年5月收治的982例ALL患儿临床资料采用回顾性分析的方法，分析其性别、发病年龄、发病季节、发病相关危险因素及分子生物学特征等.ALL患儿男女比例为1.5∶1，中位发病年龄5岁，发病年龄高峰为2-5岁。发病高峰季节为春季。出生和喂养史分析显示，足月产患儿占98.0%；55.9%患儿是顺产，44.1%患儿是剖腹产。母乳喂养者占79.8%，人工混合喂养儿占20.2%。中位出生体重3.5 kg，其中巨大儿占18.3%。有出生异常史者34例（3.5%），其中脐带绕颈者10例。发病近期有家庭装修史者占31.4%，中位装修环境暴露时间12个月。患儿一至三级亲属中，有血液系统疾病者44例（4.5%），有恶性肿瘤者53例（5.4%）。免疫表型分析结果显示，B-ALL占90.7%，T-ALL占9.3%。分子生物学检测中，TEL/AML1阳性者占21.0%，E2A/PBX1阳性者占5.2%，BCR-ABL阳性者占6.1%，MLL阳性者占2.5.本研究中儿童急性淋巴细胞白血病男性患儿较多，发病年龄高峰为2-5岁，发病季节高峰为春季，出生季节高峰为秋冬季，剖宫产术分娩、出生时为巨大儿及出生后非母乳喂养比例高于同期全国大部分地区婴儿的均值，有电离辐射及家居环境暴露史与亲属血液病、恶性肿瘤病史者比例较高.

To analyze the therapeutic outcomes of acute lymphoblastic leukemia(ALL) patients with MLL gene rearrangement.Clinical outcomes of 28 ALL patients aged less than 12 years old with MLL gene rearrangement treated with Chinese Childhood Leukemia Group ALL 2008 (CCLG -ALL 2008) protocol from January 2008 to April 2015 were retrospectively analyzed.Among 28 patients, 14 were boys and 14 were girls, median age was 36(4-144) months and median follow-up period was 12.5 (ranged 2-106) months, and 10 were infants. All patients were given induction chemotherapy and the high-risk project of CCLG-ALL 2008. At the last time of follow-up, five patients gave up and were loss to follow-up. The 5 years OS and EFS were 52.2% and 47.8% respectively for the other 23 patients. The 5 years OS and EFS(28.6% and, 88.9%), (P=0.012), (28.6%, 77.8%), (P=0.048) rate of WBC≥50×10The 5 years OS is 52.2% and 5 years EFS is 47.8% for those ALL patients with MLL gene rearrangement. The WBC≥50×1028例MLL阳性急性淋巴细胞白血病患儿的治疗转归.分析MLL回顾性分析自2008年1月至2015年4月在中国医学科学院血液病医院儿童血液病中心就诊应用CCLG-2008-ALL方案治疗的28例年龄小于12岁MLL28例患者中男性14例，女性14例，中位年龄为36（4-144）个月，其中1岁以下患者共计10例。中位随访时间为12.5（2-106）个月。所有患儿均采用CCLG- 2008-ALL高危组治疗方案诱导及巩固化疗，直至末次随访日期（2019年6月1日），5例患者诱导治疗后早期放弃治疗，后期失访，剩余23例可分析的患者5年EFS和OS率分别为47.8%和52.2%。初诊时白细胞数≥50×10本研究中伴有MLL 阳性的急性淋巴细胞白血病患者5年OS率为52.2%，5年EFS率为47.8%。白细胞数≥50×10

Pain is common in Parkinson's disease, and there is no effective treatment. We conducted a clinical trial to determine whether high-frequency repetitive transcranial magnetic stimulation over the primary motor cortex alleviates musculoskeletal pain in patients with Parkinson's disease.In this single-center and double-blind trial, 52 patients with Parkinson's disease and musculoskeletal pain were randomly allocated to 26-member groups receiving 5 sessions of either 20-Hz repetitive transcranial magnetic stimulation or sham stimulation over the primary motor cortex. The participants underwent assessments in the "ON" medication state at baseline, after the fifth session, and at 2- and 4-week follow-up timepoints. The primary outcomes were pain scores on a numeric rating scale. The secondary outcomes were scores on clinical scales assessing motor symptoms, depression, anxiety, autonomic symptoms, sleep quality, and the overall severity of Parkinson's disease.Analyses revealed significant group × time interactions for numeric rating scale pain scores (p 0.001), motor symptom scores (p 0.001), depression scores (p = 0.009), anxiety scores (p = 0.013), and overall disease severity scores (p 0.001). Post hoc analyses confirmed that the repetitive transcranial magnetic stimulation group, but not the sham stimulation group, exhibited significant improvements in numeric rating scale pain scores, motor symptom scores, depression scores, anxiety scores, and overall disease severity scores.High-frequency repetitive transcranial magnetic stimulation over the primary motor cortex may be an effective adjunct therapy for alleviating musculoskeletal pain in patients with Parkinson's disease.

To analyze the clinical efficacy and side effects of reduced-dose of cyclophosphamide combined cyclosporine A for severe aplastic anemia(SAA) children.Ten pediatric patients with SAA from January 2008 to May 2012 were enrolled. All the patients were treated with reduced dose of cyclophosphamide combined cyclosporine A. The dose of cyclophosphamide was 30 mg/(kg·d)×4 d, the dose of cyclosporine A gradually increased15 mg/L accroding to the blood concentration.The median follow-up time of the 10 pediatric patients was 100 months (6-126 months). Among 10 children with SAA, 4 cases achieved complete response(CR), 3 cases obtained partial response (PR) and the overall response rate was 70%, the remaining 3 cases showed no response (NR). One refractory patient treated by cyclophosphamide was progressed to paroxysmal nocturnal hemoglobinuria(PNH) at 25 months and was dead at 42 months after therapy.The results show that reduced-dose cyclophosphamide (30 mg/kg·d for 4 consecutive days) combinated with CsA (initial dose 4 mg/kg·d, and drugvallery concentration150 ng/ml) can make 7 of 10 children with severe aplastic anemia achieve complete response or partial response, and this regimen may be the second line regimen selected for some SAA children.减低剂量环磷酰胺联合环孢菌素A治疗重型再生障碍性贫血患儿的疗效分析.观察减低剂量环磷酰胺联合环孢菌素A治疗重型再生障碍性贫血（以下简称重型再障）患儿的疗效及副反应.自2008年1月到2012年5月就诊的10例重型再障患儿均接受减低剂量的环磷酰胺联合环孢菌素A治疗，具体应用剂量为环磷酰胺30 mg/(kg·d)×4 d，环孢菌素A起始剂量为4 mg/(kg·d), 后根据血药浓度调整用药剂量，使环孢菌素A谷浓度在150 ng/ml以上.中位随访时间为 100 (6-126) 个月，10例患儿中有4例获得完全缓解，3例获得部分缓解，总有效率为70%，其余3例无效。1例难治的重型再障患儿在应用环磷酰胺治疗后25个月进展为阵发性血红蛋白尿，治疗后42个月死于脑梗.减低剂量的环磷酰胺联合环孢菌素A使本组10例儿童重型再生障碍性贫血患者中7例获得缓解或部分缓解，为儿童重型再障患者提供一个备选的二线治疗方案.

Background: Non-pharmacological treatments (education, exercise, and physical therapy) are remain basic approaches to long-term management of ankylosing spondylitis (AS) patients. As an important part of non-pharmacological treatments, Health Qigong is widely used for AS treatment. We will perform the systematic review to confirm the safety and efficacy of Health Qigong for AS. Methods: Systematical search of 6 electronic databases will be done, including English and Chinese, until December 2019. All randomized controlled trials (RCTs) involving Health Qigong in combination with conventional therapy for AS will be included. Study selection, data extraction, and validation were performed independently by 2 reviewers. RevMan (V.5.3) will be used for mata-analysis. Results: This systematic review will identify the safety and efficacy of Health Qigong in the treatment of AS and update evidence summaries of Health Qigong. At the end of the treatment, the primary outcome is Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) with a range of 0 to 10,and the secondary outcomes will include functional ability that measured by Bath Ankylosing Spondylitis Functional Index (BASFI), mobility measured by Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion, night spinal pain, adverse reactions, laboratory measures such as erythrocyte sedimentation rate (ESR) and C protein response (CRP). Conclusion: This study will provide evidence that whether Health Qigong can benefit patients with ankylosing spondylitis by reducing disease activity, alleviating pain to support the application of Health Qigong in the AS treatment. Registration number: CRD42019159126

An increasing number of studies have begun considering human endogenous retroviruses (HERVs) as potential pathogenic phenomena. Our previous research suggests that HERV-W Envelope (HERV-W ENV), a HERV-W family envelope protein, is elevated in schizophrenia patients and contributes to the pathophysiology of schizophrenia. The dopamine (DA) hypothesis is the cornerstone in research and clinical practice related to schizophrenia. Here, we found that the concentration of DA and the expression of DA receptor D2 (DRD2) were significantly higher in schizophrenia patients than in healthy individuals. Intriguingly, there was a positive correlation between HERV-W ENV and DA concentration. Depth analyses showed that there was a marked consistency between HERV-W ENV and DRD2 in schizophrenia. Studies in vitro indicated that HERV-W ENV could increase the DA concentration by regulating DA metabolism and induce the expression of DRD2. Co-IP assays and laser confocal scanning microscopy indicated cellular colocalization and a direct interaction between DRD2 and HERV-W ENV. Additionally, HERV-W ENV caused structural and functional abnormalities of DA neurons. Further studies showed that HERV-W ENV could trigger the PP2A/AKT1/GSK3 pathway via DRD2. A whole-cell patch-clamp analysis suggested that HERV-W ENV enhanced sodium influx through DRD2. In conclusion, we uncovered a relationship between HERV-W ENV and the dopaminergic system in the DA neurons. Considering that GNbAC1, a selective monoclonal antibody to the MSRV-specific epitope, has been promised as a therapy for treating type 1 diabetes and multiple sclerosis (MS) in clinical trials, understanding the precise function of HERV-W ENV in the dopaminergic system may provide new insights into the treatment of schizophrenia.

Purpose Simulation-based medical education (SBME) is gaining prominence as a tool to meet Accreditation Council for Graduate Medical Education–mandated competency-based assessment educational goals. SBME is used in radiation oncology, although the type and extent are not clear. This study reports a systematic literature review designed to clarify the type and extent of radiation oncology SBME. Methods and Materials The systematic review focused on radiation oncology SBME literature. The methods followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria were identified according to the PICOS (population, intervention, comparison, outcome, and setting) framework. The population included undergraduate, graduate, and continuing medical education learners. Studies were limited to English-language studies published on or after January 1, 1990, in peer-reviewed journals. PubMed, MedEdPORTAL, and in-press articles were searched. The PubMed search was conducted using predefined search terms. References and similar articles were examined. Medical Subject Headings terms in selected articles were reviewed to ensure relevant terms were included. Results Fifty-four SBME publications met the inclusion criteria. Only 9 of 54 studies (17%) self-identified as SBME. SBME types included screen-based simulators (56%), simulated environments (13%), virtual reality and haptic systems (13%), simulated patients (11%), part-task trainers (6%), and computer-based systems with mannequins (2%). A variety of radiation oncology skill sets were addressed, including contouring (54%), treatment planning (20%), clinical decision making (17%), anatomy and/or radiology (13%), radiation biology and/or physics (13%), communication skills and/or patient education (13%), brachytherapy (13%), and immobilization (11%). A target learning population was defined in 47 studies, including residents (53%), attending physicians (36%), medical students (21%), medical physicists (11%), radiation therapists (9%), nurses (6%), administrative staff (4%), and dosimetrists (4%). Learner feedback was reported in 32 studies. Conclusions Overall, this systematic literature review provides context and guidance for future radiation oncology SBME development. Appropriately framing SBME reports in the radiation oncology literature will facilitate development, implementation, and evaluation of SBME interventions. SBME resources should be centralized to facilitate dissemination and share resources.

Background Type 2 diabetes has an underlying pathology with thyroid dysfunction. However, few studies have investigated the association between thyroid hormones and diabetic peripheral neuropathy. Our aim was to evaluate the relationship between thyroid hormones and electrophysiological properties of peripheral nerves in type 2 diabetes. Patients and Methods The medical records of 308 patients with type 2 diabetes were enrolled in this study. Subjects stratified by sex were divided into subgroups based on the diagnosis of nerve conduction study. The nerve conduction parameters were separately described with the spectrum of thyroid hormones. Multivariate regression models to analyze the potential links between thyroid hormones and nerve conduction parameters. Results The serum free triiodine thyronine levels between normal and abnormal nerve conduction groups were statistically different in total (4.55±0.65 vs 4.37±0.63, P Conclusions Serum free triiodine thyronine level is associated with nerve conduction in diabetes. Low free triiodine thyronine may be a potential risk for diabetic peripheral neuropathy.