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Hypochlorous acid (HOCl) is an essential signal molecule in cancer cells. Activated GRP78 ATPase by a HOCl probe named ZBM-H inhibits lung cancer cell growth. However, the role and underlying mechanism of GRP78 ATPase in lung cancer cell migration have not been established. Here, we reported that activation of GRP78 ATPase by ZBM-H suppressed A549 cell migration and inhibited EMT process. Notably, ZBM-H time-dependently decreased the protein level of integrin β4 (ITGB4) in A549 cells. Combinatorial treatment of 3BDO (an autophagy inhibitor) and ZBM-H partially rescued the protein level of ITGB4. Consistently, 3BDO partially reversed ZBM-H-inhibited cell migration. Furthermore, ZBM-H promoted the interaction between ANXA7 and Hsc70, which participated in the regulation of selective autophagy and degradation of ITGB4.

Backgrounds:. Azithromycin mass drug administration (MDA) is a key part of the strategy for controlling trachoma. This systematic review aimed to comprehensively summarize the present studies of azithromycin MDA on trachoma; provide an overview of the impact of azithromycin MDA on trachoma in different districts; and explore the possible methods to enhance the effectiveness of azithromycin MDA in hyperendemic districts. Methods:. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov were searched up to February 2021 with no language restriction. Studies reporting the effect of azithromycin MDA on trachoma were included. Mathematical modeling studies, animal studies, case reports, and reviews were excluded. The trachomatous inflammation-follicular (TF) 30.0%), especially with baseline TF >50.0%, annual MDA was unable to achieve the TF 10.0% is not appropriate for all eligible districts.

The objective of this study was to predict hematoma expansion (HE) by radiomic models based on different machine learning methods and determine the best radiomic model through the comparison. A total of 108 patients with intracerebral hemorrhage were retrospectively evaluated. Images of baseline non-contrast computed tomography (NCCT) and follow-up NCCT scan within 24 h were retrospectively reviewed. An HE was defined as a volume increase of more than 33% or an increase greater than 12.5 mL from the volume of the baseline NCCT. Texture parameters of the baseline NCCT images were selected by the least absolute shrinkage and selection operator (LASSO) regression. We used support vector machine (SVM), decision tree (DT), conditional inference trees (CIT), random forest (RF), k‑nearest neighbors (KNN), back-propagation neural network (BPNet) and Bayes to build models. Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA) was performed and compared among models. Every model had a relatively high AUC (all > 0.75), SVM and KNN had the highest AUC of 0.91. There were significant differences between SVM and CIT (Z > 2.266, p = 0.02345), KNN and CIT (Z = 2.4834, p = 0.01301), RF and CIT (Z = 2.6956, p = 0.007027), KNN and BPNet (Z = 2.0122, p = 0.0442), RF and BPNet (Z = 1.9793, p = 0.04778). There was no significant difference among SVM, DT, RF, KNN and Bayes (p > 0.05). The SVM obtained the largest net benefit when the threshold probability was less than 0.33, while KNN obtained the largest net benefit when the threshold probability was greater than 0.33. Combined with ROC and DCA, SVM and KNN performed better in all the models for predicting HE. Radiomic models based on different machine learning methods can be used to predict HE and the models generated by SVM and KNN performed best.

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics., The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric Gs which offers insights into the molecular details of ago-allosterism.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of them are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric non-peptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryo-electron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3 and 7, one arm of both compounds inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8-D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts showing an interaction feature substantially similar to a previously known small molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by non-peptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine tuning of pharmacological efficacy in the development of future small molecule therapeutics targeting GLP-1R.SignificanceGLP-1R agonists are efficacious in the treatment of type 2 diabetes and obesity. While most clinically used agents require subcutaneous injection, Boc5, as the first orthosteric non-peptidic agonist of GLP-1R, suffers from poor oral bioavailability that hinders its therapeutic development. The cryo-electron microscopy structures of Boc5 and its closely related analog WB4-24 presented here reveal a previously unknown binding pocket located deeper in the transmembrane domain for non-peptidic GLP-1R agonists. Molecular interaction with this site may facilitate a broad spectrum of in vivo agonistic activities, in addition to that with the upper helical bundles presumably responsible for biased signaling. These findings deepen our understanding of peptidomimetic agonism at GLP-1R and may help design better drug leads against this important target.

Background Adding clomiphene citrate (CC) and/or letrozole (LE) to in vitro fertilization (IVF) cycles for mild ovarian stimulation is a general approach. Although lots of researches have demonstrated partial benefits of the strategy, all-around effects of oral medications remained deficient. This paper aims to assess whether an addition of oral medication will result in considerable outcomes on T-Gn (total dose of gonadotropin), Gn days, total retrieved ova, high quality embryos, blastocyst number, ovarian hyperstimulation syndrome (OHSS) rate, clinical pregnancy rate and cumulative pregnancy rate, even if it was not conventional mild/minimal stimulations. Results Participants were categorized to three diverse populations as high responders, normal responders and poor responders according to basal antral follicle count. T-Gn in patients treated with CC/LE distinctly decreased from 2496.96 IU/d to 1827.68 IU/d, from 2860.28 IU/d to 2119.99 IU/d, and from 3182.15 IU/d to 1802.84 IU/d, respectively. For high ovary responders and normal responders, the OHSS incidence rate also declined from 29.2 to 4.3% (P P = 0.090). Other, there was no statistical difference with respect to the T-retrieved ova (total retrieved ova), high quality embryos, cultured blastocyst and blastocyst number in high responders. For normal responders and poor ovary responders, T-Gn, Gn days, T-retrieved ova, high quality embryos, cultured blastocyst and blastocysts number in oral medications group all apparently decreased. Clinical pregnancy rate per fresh cycle of poor responders with prior oral medications was significantly decreased (25.7% vs. 50.8%, P = 0.005), and no significant differences in high responders and normal responders were expressed (52.5% vs. 44.2%, P = 0.310; 51.9% vs. 42.4%, P = 0.163) between two groups of participants. The numbers of cumulative pregnancy rates were lower in the conventional group compared to the add group for high (75.90% versus 81.03%, P = 0.279), normal (62.69% versus 71.36%, P = 0.016) and poor (39.74% versus 68.21%, P Conclusions The addition of CC/LE to the ovulation induction during IVF has certain efficacy in terms of low cost, low OHSS incidence. CC/LE deserves more recommendations as a responsible strategy in high responders due to advantageous pregnancy outcomes. For normal responders, the strategy needs to be considered with more comprehensive factors.

Adipose-derived stem cell (ADSC)-based therapeutic strategies are in fast-pace advancement in wound treatment due to their availability and the ability to self-renew, undergo multilineage differentiation and self-renewal. Existing studies have successfully explored ADSCs to facilitate scar-free healing of small wounds, but whether the healing of large-area wounds that exhibit over 50% of skin tissue loss in the entire body could be achieved remains controversial. This study sought to review the mechanism of physiological wound healing, and discuss the roles played by chemokines, biological factors and biomaterial scaffolds. The possibility of applying ADSC-conditioned medium or ADSC-released exosomes as ‘off-the-shelf’ tissue engineering products, integrated with biomaterial scaffolds to facilitate wound healing, was analyzed.

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.

Background Most Parkinson's patients suffered from sleep problems. There is increasing evidence that Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) has a positive effect on several sleep parameters, improving overall sleep quality in patients with PD. However, the results are controversial. Methods We performed a retrospective study and meta-analysis to assess the Parkinson's disease sleep scale (PDSS) in Parkinson's patients. Results We reviewed our data of patients who underwent STN-DBS, and then extracted five other trials to perform a meta-analysis. The pooled results showed an advantage on post-operative PDSS in both our medical center and pooled results (MD = 20.41, 95% CI = [13.03, 27.79], I2 = 61%, P Conclusion In the retrospective study and meta-analysis of 6 trials, we found that DBS can significantly increase sleep quality. Furthermore, motor function improved and Parkinsonian medication was significantly decreased postoperatively. The sample size was enough and no further investigations would change the conclusion.

The objective of this study was to investigate whether computed tomography texture analysis can be used to differentiate papillary renal cell carcinoma (PRCC) subtypes. Sixty-two PRCC tumors were retrospectively evaluated, with 30 type 1 tumors and 32 type 2 tumors. Texture parameters quantified from three-phase contrast-enhanced CT images were compared with least absolute shrinkage and selection operator (LASSO) regression. Receiver operating characteristic (ROC) analysis was performed, and the area under the ROC curve (AUC) was calculated for each parameter. The selected texture parameters of each phase were used to generate support vector machine (SVM) classifiers. Decision curve analysis (DCA) of the classification was performed. The two texture parameters with the top two AUC values were – 333–7 Correlation (AUC = 0.772) and 45–7 Entropy (AUC = 0.753) in the corticomedullary phase, 333–4 Correlation (AUC = 0.832) and 45–7 Entropy (AUC = 0.841) in the nephrographic phase, and 135–7 Entropy (AUC = 0.858) and – 333–1 InformationMeasureCorr2 (AUC = 0.849) in the excretory phase. Entropy and Correlation have a high correlation with the two types of PRCC and are increased in type 2 PRCC. A model incorporating the texture parameters with the top two AUC values in each phase produced an AUC of 0.922 with an accuracy of 84% (sensitivity = 89% and specificity = 80%). The nephrographic-phase model and the model combining the texture parameters of the three phases can differentiate the two types with the largest net benefit. Computed tomography texture analysis can be used to distinguish type 2 PRCC from type 1 with high accuracy, which may be clinically important.

Background As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization. Methods Here, we applied single-cell genomic amplification and RNA-Seq to a specimen of human prostate BCC (CK34βE12+ /P63+ /PAP- /PSA- ). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the transcriptomes of 69 single cells were also obtained. Results The five putative driver genes mutated in BCC are CASC5, NUTM1, PTPRC, KMT2C, and TBX3, and the top three nucleotide substitutions are C>T, T>C, and C>A, similar to common prostate cancer. The distribution of the variant allele frequency values indicated that these single cells are from the same tumor clone. The 69 single cells were clustered into tumor, stromal, and immune cells based on their global transcriptomic profiles. The tumor cells specifically express basal cell markers like KRT5, KRT14, and KRT23 and epithelial markers EPCAM, CDH1, and CD24. The transcription factor covariance network analysis showed that the BCC tumor cells have distinct regulatory networks. By comparison with current prostate cancer datasets, we found that some of the bulk samples exhibit basal cell signatures. Interestingly, at single-cell resolution the gene expression patterns of prostate BCC tumor cells show uniqueness compared with that of common prostate cancer-derived circulating tumor cells. Conclusions This study, for the first time, discloses the comprehensive mutational and transcriptomic landscapes of prostate BCC, which lays a foundation for the understanding of its tumorigenesis mechanism and provides new insights into prostate cancers in general.

Gastroesophageal reflux disease (GERD) is a disease that stomach contents continually refluxing into esophagus causes symptoms and/or complications. The study was working to find natural plant extracts with good effects and small side effects to treat reflux esophagitis (RE). The anti-inflammatory effects of hexane extract of Magnolia sieboldii (MsHE) were conducted on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The ameliorative effects of MsHE on esophageal damage in rats induced by gastric acid reflux was explored in vivo. The results showed that MsHE decreased the production of nitric oxide (NO) and expression levels of iNOS, COX-2 and TNF-α on LPS-stimulated RAW 264.7 cells and MsHE treatment ameliorated the rats' esophageal tissue damage induced by gastric acid and inhibited the increase of inflammatory mediators and pro-inflammatory cytokines by regulating NF-κB signaling pathway. In addition, MsHE protected the function of barrier of epithelial cells against inflammatory conditions through increasing the expression of tight junctions. Furthermore, liquid chromatography-mass spectrometry analysis was used for determine the active ingredients contained in MsHE. The results show that MsHE can alleviate experimental rat RE by regulating NF-κB signaling pathway. In summary, MsHE may be used as a source material of drug candidate for the treatment of RE.

Hypospadias, a malformation of male external genitalia, is characterized by an aberrant opening of the urethra on the ventral side of the penis. It is considered a complex disorder with both environmental and genetic factors involved in its pathogenesis. To identify the genetic abnormality involved in the pathogenesis of hypospadias, we performed whole exome sequencing (WES) analysis in 42 hypospadias patients with karyotype 46, XY in the Nanhai MeternityChild Health Hospital of Foshan. All the likely pathogenic variants were confirmed by Sanger sequencing and assessed by Sorting Intolerant from Tolerant (SIFT), PROVEAN, PolyPhen2, ClinPred, LRT, Mutation Assessor, FATHMM, and GERP software. We discovered 27 gene mutations in 20 patients, including eight cases of the SRD5A2 gene, 4 cases of the AR gene, 3 cases of the CYP17A1 gene, 1 case of the WT1 gene, 1 case of the ANOS1 gene, 1 case of the NR5A1 gene, 1 case of the FGFR1 gene, and one case of the DHX37 gene. Our study is the first to describe six novel missense mutations, AR(c.302G A, c.2593G T, and c.1705G T), CYP17A1(c.1298 T C), FGFR1 (c.995C T) and DHX37(c.923G A). In summary, genetic defect detection was useful for early diagnosis of severe hypospadias in the Han Chinese population. Nevertheless, most cases remain unexplained, and the exact pathogenesis of hypospadias still needs further study.

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation.

To assess the relationship between preconception body mass index (BMI) and cervical length (CL).Data was collected from a prospective cohort study conducted in Beijing, China. A total of 4843 qualified women participated in this study, whose health-related information was recorded at the very beginning and their cervical length was measured with transvaginal ultrasound examination during 22-24 gestational weeks. Logistic regression was used to evaluate the relationship between preconception BMI and cervical length, after adjusting for potential confounders.Of all the participants in the analysis, 580 (12.0%) women had a short cervical length (CL less than 30 mm). After adjusting for the age and parity status, the adjusted odds ratios of short CL for underweight: adjusted OR = 1.28 (95% CI: 1.02, 1.60); overweight: adjusted OR = 0.74 (95% CI: 0.55, 0.99); obesity: adjusted OR = 0.38 (95% CI: 0.17, 0.88) compared with normal weight. The mean CL in underweight, normal weight, overweight and obesity group demonstrated a significant linear increased trend (33.47, 34.16 and 34.96 mm, respectively) (This research revealed that low preconception BMI women were more likely to have a short CL.

Background and aims Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure-induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA-mediated genomic alterations that could be implicated in human cancers with AA-associated mutational signature. Approach and results We subjected mice, including phosphatase and tensin homolog (Pten)-deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4 . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose-dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4 -treated or Pten-deficient mice. AAI led to DNA damage and AAI-DNA adduct that could initiate liver cancers through characteristic adenine-to-thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA-associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI-DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA-implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA-affected human tumors. Conclusions This study provides evidence for AA-induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA-associated human cancers, especially liver cancers.

To investigate the efficacy of high-risk myelodysplastic syndrome (MDS) patients treated by different doses of decitabine (DAC) and its safety.Thirty patients with high-risk MDS were all treated by demethylation drug DAC. According to the doses of DAC, 30 patients were divided into 10-day regimen [6 mg/(mThe patients were followed up to May 2020, in the 10-day regimen group, 10 cases achieved complete remission (CR), 3 cases achieved partial remission (PR), and 2 cases were progressive disease (PD). Four cases died, including 1 case for heart failure, 2 cases for respiratory failure and 1 case for serious infection. In the 5-day regimen group, 11 cases achieved CR, 1 case achieved PR, 3 cases were PD. Five cases died, including 2 cases for heart failure and 3 for serious infection. The CR rate and ORR of the patients in the two groups were 66.67% vs 73.33%, 86.67% vs 80.00%, respectively, which showed no significant differences, and the efficacy also showed no significant difference. After treatment, the levels of WBC, NE, Hb and PLT of the patients in 10-day regimen group were higher than those in 5-day regimen. In the 10-day regimen group, there were 11 cases of pneumonia, 2 cases of bacteremia, 1 case of skin infection and 1 case of urinary tract infection. While in the 5-day regimen group, 13 cases of pneumonia, 5 cases bacteremia, 1 case of skin infection and 3 cases of urinary tract infection. There were 2 cases with mild gastrointestinal response in the 10-day regimen group, and 7 cases with obvious nausea and anorexia in the 5-day regimen group. The symptoms were relieved after the treatment of acid suppression, stomach protection and antiemetic. The liver, kidney and heart function were monitored. One case liver function damage and 2 cases cardiac insufficiency were observed in the 10-day regimen group. Seven cases regimen cardiac insufficiency and 4 cases regimen liver function damage were observed in the 5-day regimen group.10-day regimen and 5-day regimen are equally effective, but 10-day regimen is less myelosuppressive and more safer, which can be applied in clinical.不同剂量地西他滨治疗高危骨髓增生异常综合征患者疗效及安全性的回顾性分析.探讨不同剂量地西他滨治疗高危骨髓增生异常综合征（MDS）患者的临床疗效及安全性。.选取高危MDS患者30例，均使用去甲基化药物地西他滨治疗。根据患者使用地西他滨剂量不同，分为10 d [6 mg/（m随访至2020年5月，10 d方案组获完全缓解10例，部分缓解3例，疾病进展2例；完全缓解率为66.67%，总反应率为86.67%，死亡4例，其中1例死于心衰，2例死于呼吸衰竭，1例死于重症感染。5 d方案组获完全缓解11例，部分缓解1例，疾病进展3例，完全缓解率为73.33%，总反应率为80.00%，死亡5例，2例死于心衰，3例死于重症感染。两组疗效和生存率比较差异均无统计学意义（P0.05）。治疗后10 d方案组白细胞数、中性粒细胞数、血红蛋白及血小板数均值均高于5 d方案组。10 d方案组发生肺炎11例，菌血症2例，皮肤感染1例，泌尿系感染1例。5 d方案组肺炎13例，菌血症5例，皮肤感染1例，泌尿系感染3例。10 d方案组有2例患者出现轻微消化道反应， 5 d方案组有7例出现明显恶心、食欲减退，经抑酸护胃、止吐等对症处理后，症状缓解。监测肝肾功能及心功能，10 d方案组1例出现肝功能损伤，2例出现心功能不全；5 d方案组4例出现肝功能损伤，7例发生心功能不全。.10 d方案组和5 d方案组疗效相当，但10 d方案组骨髓抑制程度及不良反应发生率均较5 d方案组少，安全性更高，具有广泛的临床应用价值。.

Background: Prostate tumor overexpressed-1 (PTOV1) was firstly depicted as gene and protein overexpressed in prostate cancers and preneoplastic lesions of high-grad intraepithelial neoplasia. Recently, people have paid recent attention to the oncogenic PTOV1 protein as a regulator with various cellular functions and pathways that tend to enhance cell growth and self-renewal in numerous cancer cell types. Its prognostic role in cancers remains controversial. Methods: Eligible studies are identified by comprehensively searching literature in all available databases. The associations between PTOV1 expression and overall survival, disease-free survival, relapse-free survival, progression-free survival, and clinicopathological characteristics are estimated by employing hazard ratios and the confidence intervals of 95%. STATA 12.0 software was adopted to perform the meta-analysis. Results: This study will provide high-quality synthesis to evaluate the associations between PTOV1 expression and overall survival, disease-free survival /relapse-free survival , progression-free survival, and clinicopathological features. Conclusion: The study will provide updated evidence to assess whether the expression of PTOV1 is in association with poor prognosis in patients with cancers. PROSPERO registration number: CRD42020183853.

Central nervous system lymphoma (CNSL) is an aggressive lymphoma. Orelabrutinib, an oral Bruton tyrosine kinase inhibitor, is a new treatment strategy for CNSL. This study aims to evaluate the efficacy and safety of orelabrutinib-based regimens in the treatment of patients with CNSL.Twenty-three patients with CNSL were included in this retrospective study. All patients received the orelabrutinib-based regimen. Efficacy was evaluated based on investigators' assessment of overall response rate (ORR), complete response/unconfirmed complete response (CR/CRu), partial response (PR), stable disease (SD), progressive disease (PD), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The safety of orelabrutinib-based regimens has also been evaluated.A total of 17.39% of patients received orelabrutinib-based regimens for consolidation therapy, and 82.61% of patients for induction therapy (4 newly diagnosed CNSL, 15 relapsed/refractory CNSL). In the newly diagnosed CNSL group, the ORR was 100% (1 CR, 1 CRu, 2 PR). The 6-month DOR rate, 6-month PFS rate, and 6-month OS rate were 100%, 100%, and 100%, respectively. Of the 15 relapsed/refractory CNSL patients, five therapy regimens were applied (orelabrutinib, n = 3; orelabrutinib/immunotherapy, n = 3; orelabrutinib/chemotherapy, n = 2; orelabrutinib/immunochemotherapy, n = 6; orelabrutinib/radiotherapy, n = 1). The ORR was 60.00% (4 CR, 5 PR). The 6-month DOR rate, 6-month PFS rate, and 6-month OS rate were 92.30%, 67.70%, and 70.00%, respectively. Twenty-one patients reported adverse events (AEs), and 6 patients experienced grade ≥ 3 AEs.Orelabrutinib-based regimens were efficacious and well-tolerated in patients with CNSL. These combined therapies offer a new potential therapeutic strategy for patients with CNSL.

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 μM, 15 μM, and 30 μM. The IC50 of calycosin is 30.35 μM, which is lower than hydroquinone (37.35 μM), kojic acid (6.51 × 103 μM), and arbutin (3.67 × 104 μM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information.

Cadmium (Cd) and arsenic (As) contamination in paddy soils poses serious health risks to humans. The accumulation of Cd and As in rice (Oryza sativa L.) depends on their bioavailability, which is affected by soil physicochemical properties and soil microbial activities. However, little is known about the intricate interplay between rice plants and their rhizosphere microbes during the uptake of Cd and As. In this study, different bacterial communities were established by sterilizing paddy soils with γ-radiation. A pot experiment using two paddy soils with different levels of contamination was conducted to explore how the bacterial community composition affects Cd and As accumulation in rice plants. The results showed that the sterilization treatment substantially changed the bacterial composition in the rhizosphere, and significantly increased the grain yield (by 33.5–38.3%). The sterilization treatment resulted in significantly decreased concentrations of Cd (by 18.2–38.7%) and As (by 20.3–36.7%) in the grain, straw, and root of rice plants. The accumulation of Cd and As in rice plants was negatively correlated with the relative abundance of sulfate-reducing bacteria and iron-oxidizing bacteria in the rhizosphere. Other specific taxa associated with the accumulation of Cd and As in rice plants were also identified. Our results suggest that regulating the composition of the rhizosphere bacterial community could simultaneously reduce Cd and As accumulation in rice grain and increase the grain yield. These results would be useful for developing strategies to cultivate safe rice crops in areas contaminated with Cd and As.

Influenza A virus (H1N1), a swine-origin influenza A virus, causes seasonal epidemics that result in severe illnesses and deaths. Leonurine has been reported to function as an anti-inflammatory agent with protective effects on nervous, urinary and cardiovascular systems. However, the therapeutic effects of leonurine on the pneumonia caused by H1N1 infection remain unclear. Hematoxylin and eosin staining was performed to evaluate the lung injuries of mice infected by H1N1. The amount of immune cells was analyzed by flow cytometry. Enzyme-linked immunosorbent assay was used to evaluate the alteration of multiple cytokines in lung tissues. Real-time quantitative polymerase chain reaction assay was performed to investigate the ribonucleic acid (RNA) levels of certain genes. The protein levels in toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR4/NF-κB) signaling were estimated by western blot assay. Leonurine treatment significantly inhibited the mortality caused by H1N1 infection. Leonurine treatment (60 mg/kg) alleviated the lung injuries caused by virus infection. The inflammatory cell accumulation and cytokine expression were inhibited by the leonurine administration. Leonurine inhibited the mRNA expression of pro-inflammatory cytokines in the lung homogenates at day 5 postinfection. Leonurine regulated the TLR4/NF-κB signaling in the lung homogenates of H1N1-infected mice at day 5 postinfection. Leonurine protects against H1N1 infection-induced pneumonia in mice.

Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G(s) protein stimulated by the endogenous peptide ligand α-MSH, FDA-approved drugs afamelanotide (Scenesse™) and bremelanotide (Vyleesi™), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.

ObjectivesThe objective was to examine care willingness and demand of residents under 60 years of age after retirement.SettingThe staged cluster sampling method was used between August and October 2018 in Dujiangyan, Sichuan Province, China.Participants2282 participants under 60 years of age were surveyed in 2018 by the staged cluster sampling method in China.Primary and secondary outcome measuresThe results of care willingness and demand were assessed by multiple comparisons of χ2 test and multivariable logistic regression.ResultsThe respondents who preferred institution-based care, home-based care and community-based care accounted for 39.5%, 38.3% and 20.2% respectively, whereas only 2.1% preferred home-based self-care. The main reasons for the respondents to choose institution-based care included better medical care (31.9%), better daily care (27.0%), burden reduction for children (26.3%), better accommodation (22.8%), satisfied living environment (21.6%) and low consumption (12.3%). The factors that affected care willingness and demand included age, ethnicity, educational attainment, marital status, occupation and the current type of residence.ConclusionsThe results revealed the care willingness and demand of residents under 60 years of age after retirement and relevant decision factors. This study provides a certain theoretical and practical significance for the development of the care willingness mode and promotes the cognition of policy-makers and researchers, and also provides the basis for decision-making.

Emergence delirium is a common complication in preschool children after general anesthesia and may result in undesirable complications. This study aimed to determine whether breathing training after watching an informative video during the pre-operative visit could reduce the incidence of emergence delirium in preschool children after otorhinolaryngologic surgery under general anesthesia.A single-center, double-blinded, randomized controlled trial.Perioperative care.A total of 170 children undergoing otorhinolaryngologic surgery, aged 3-7 years, ASA physical status I or II were involved.Patients were randomized to receive breathing training during the pre-operative visit (Training group) or to receive pre-operative visit only (Control group) the day before surgery.Emergence delirium was measured by the Pediatric Anesthesia Emergence Delirium score during the anesthesia recovery time. Data regarding extubation time and post-anesthesia care unit stay time were collected.Children who received breathing training during the pre-operative visit had a significantly lower incidence of emergence delirium than those who only underwent the pre-operative visit (10.4% vs. 35.1%, P 0.001). The awakening time score and the maximum score in the post-anesthesia care unit were significantly lower in the training group compared with the control group [4.4 ± 3.4 vs. 6.9 ± 4.2, P 0.001 and 5.0 (5.0) vs 7.0 (7.0), P = 0.001, respectively]. We found no differences in the extubation time and post-anesthesia care unit stay time between groups.We concluded that breathing training based on video learning during the pre-operative visit in preschool children undergoing otorhinolaryngologic surgery could significantly decrease the incidence of emergence delirium.Chinese Clinical Trial Registry (Reference number: ChiCTR1900026162); registered on September 24, 2019.

DNA nanomaterials have attracted ever-increasing attention over the past decades due to their incomparable programmability and multifunctionality. In particular, DNA dendrimer nanostructures, as a major research focus, have been applied in the fields of biosensing, therapeutics, and protein engineering, benefiting from their highly branched configuration. With the aid of specific recognition probes and inherent signal amplification, DNA dendrimers can achieve ultrasensitive detection of nucleic acids, proteins, cells, and other substances, such as lipopolysaccharides (LPS), adenosine triphosphate (ATP), and exosomes. By virtue of their void-containing structures and biocompatibility, DNA dendrimers can deliver drugs or functional nucleic acids into target cells in chemotherapy, immunotherapy, and gene therapy. Furthermore, DNA dendrimers are being applied in protein engineering for efficient directed evolution of proteins. This review summarizes the main research progress of DNA dendrimers, concerning their assembly methods and biomedical applications as well as the emerging challenges and perspectives for future research.

BACKGROUND The aim of this study was to investigate predictive factors of occult mediastinal lymph node metastasis (MLNM) in preoperative 18 F-fluorodeoxy-glucose PET/CT node-negative lung adenocarcinoma patients. METHODS We reviewed the clinical data and PET/CT parameters of 360 consecutive pulmonary adenocarcinoma patients who were scheduled to undergo anatomical pulmonary resection and systemic mediastinal node dissection. The nodal metastasis was pathologically defined and all resected tumors were classified according to the 2011 IASLC/ATS/ERS classification. Univariate and multivariate analysis were conducted to evaluate the associations between clinicopathological variables and MLNM. RESULTS Of all 360 patients, 54 (15.0%) had pathological N2 diseases. The serum CEA level, nodule type, hilar nodal SUVmax, tumor SUVmax, size, location and histologic subtype were associated with MLNM significantly on univariate analysis. On multivariate analysis, CEA ≥ 5.0 ng/mL (P

Purpose To investigate the effect of cold and room temperature tumescence anesthesia solution (TAS) on the treatment of lower limb varicose veins via endovenous laser ablation. Design On the basis of the TAS temperature, patients were divided into two groups: group A (n = 26) received room temperature (24°C) TAS, and group B (n = 25) received cold (4°C) TAS. Methods A numerical rating scale was used to evaluate pain. Perioperative and intraoperative nursing care and clinical observations were performed following a generalized standard. Findings Percentages of patients who felt pain in groups A and B were 69.2% and 36.0%. Average numerical rating scale scores of patients in the two groups (A and B) on the day of surgery and on postoperative days 1, 2, and 3 were 4.3 versus 2.1, 3.5 versus 1.0, 3.0 versus 0.8, and 1.6 versus 0.3, respectively. Conclusions Cold TAS reduces intraoperative and postoperative pain more effectively than room temperature.