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Background Intellectual disability (ID) constitutes the most common group of neurodevelopmental disorders. Exome sequencing has enabled the discovery of genetic mutations responsible for a wide range of ID disorders. Case presentation In this study, we reported on two male siblings, aged 4 and 2 years, with motor and mental developmental delays and mild dysmorphic facial features. To identify the genetic causes of these symptoms, we employed trio-whole exome sequencing for the proband. We found a novel hemizygous missense variant in the PAK3 gene (c.1112G > A, p.Cys371Tyr), which encodes the p21-activated kinase 3, in the proband, which inherited from mother. The younger brother also has the hemizygous variant, which was confirmed by Sanger sequencing. The variant is located in the kinase domain and was regarded as a likely pathogenic variant in this family. Conclusion We diagnosed two male siblings with developmental delays as having a PAK3 likely pathogenic variant. This finding expands the list of PAK3 gene mutations associated with neurodevelopmental disorders and provides further details on its clinical features.

Noninvasive assessment of severity of liver fibrosis is crucial for understanding histology and making decisions on antiviral treatment for chronic HBV in view of the associated risks of biopsy. We aimed to develop a computer-assisted assessment system for the evaluation of liver disease severity by using machine leaning classifier based on physical-layer with serum markers. The retrospective data set, including 920 patients, was used to establish Decision Tree Classifier (DTC), Random Forest Classifier (RFC), Logistic Regression Classifier (LRC), and Support Vector Classifier (SVC) for liver fibrosis severity assessment. Training and testing samples account for 50% of the data set, respectively. The best indicator combinations were selected in random combinations of 24 indicators including 67 108 760 group indicators by four different machine learning classifiers. The resulting classifiers prospectively tested in 50% testing patients, and the sensitivity, specificity, overall accuracy, and receiver operating characteristics (ROC) were used to compare four classifiers to existed 19 models. Results show that the RFC-based classifier system, with 9 indicators, is feasible to assess severity for liver fibrosis with diagnostic accuracy (greater than 0.83) superior to existing 19 models. Additional studies based on a large data set with full serum markers and imaging information are necessary to enhance diagnostic accuracy and to expand clinical application.

PURPOSE/OBJECTIVE(S) To compare the prognostic value of neoadjuvant rectal (NAR) score and MRI-based nomogram model for locally advanced rectal cancer (LARC) treated with neoadjuvant therapy. MATERIALS/METHODS Retrospective analysis was performed for 233 patients with LARC (T3-4 and/or N1-2, M0), who were initially treated in our institution from Mar.2015 to Mar.2018. All patients had baseline MRI assessments and received neoadjuvant therapy and TME surgery. The neoadjuvant rectal (NAR) score was calculated according to the baseline MRI factor (cT) and pathological stage (pT, pN). NAR = [5pN-3(cT-pT)+12]2/9.61. The patients were sequentially allocated to two cohorts (training cohort and validation cohort) in a ratio of 4:3 based on the date of image examination. The nomogram model was constructed based on the results of univariate logistic regression analysis and multivariable cox regression analysis of the training cohort for disease-free survival (DFS). The nomogram and NAR score were evaluated by Harrell's concordance index (C-index), calibration plots, receiver operating characteristic curve (ROC) analysis, and decision curve analysis (DCA) in both training and validation cohort. RESULTS With a median follow-up of 43.2 months (13.3-61.3months) in the training cohort and 32.0 months (12.3-39.5 months) in the validation cohort. Multivariate cox regression analysis identified the MRI-detected extramural vascular invasion (mrEMV), pathological T stage (ypT) and perineural invasion (PNI) as independent predictors. According to previous studies, lymph vascular invasion (LVI) (which was founded to be significant after univariate regression analysis) and three other independent predictors are included in the nomogram model. The univariate survival analysis showed that the nomogram model and NAR score were correlated with 3-year DFS (P < 0.05). For comparison, the nomogram performed better over the NAR score (C-index 0.76 (95% CI 0.70-0.84) versus 0.66 (95% CI 0.60-0.71) for the training cohort, and 0.77 (95% CI 0.70-0.85) versus 0.69(0.60-0.78) for the validation cohort).The nomogram model achieved a better 3-year DFS predictive capacity (AUC = 0.84 in the training cohort; AUC = 0.77 in the validation cohort) than NAR score (AUC = 0.70 in the training cohort; AUC = 0.73 in the validation cohort). DCA revealed that the use of the nomogram model was associated with better benefit gains relative to the prediction of 3-year DFS compared to NAR score in training cohort (threshold probability range between 0.06 and 0.54) and validation cohort (threshold probability range between 0.08 and 0.50). CONCLUSION We developed and validated a novel nomogram model based on MRI factor and pathological factors for predicting DFS in LARC treated with neoadjuvant therapy. Compared with NAR score, nomogram model shows the better potential predictive value of prognosis, which could improve the risk stratification and individual treatment for LARC patients.

Purpose/Objective(s) In view of anti-tumor immunosuppression, lymphopenia during radiotherapy was shown to be related to adverse outcome of small-cell lung cancer patients (SCLC). However, the relationship between treatment related lymphopenia and efficacy of prophylactic cranial irradiation (PCI) for SCLC is not fully understood. We hypothesize that PCI related lymphopenia is associated with rapid brain metastasis and inferior survival. Materials/Methods Limited-stage small cell lung cancer (LS-SCLC) with PCI were included in this study, and clinicopathological variables, and the lowest lymphocyte counts during treatment were retrospectively collected in. Severe Lymphopenia was defined as the lowest absolute lymphocyte count Results A total of 153 LS-SCLC patients with PCI were enrolled in this study, and 34 (22.2%) of them experience severe lymphopenia. Logistic regression showed that none of age, gender, ECOG PS, RT techniques was associated with PCI-related lymphopenia. The median follow-up was 10.9 months. And patients experienced severe lymphopenia during treatment were found to have inferior PFSI (median PFSI: 22.6 vs.NR months, P = 0.012). And multivariate analysis found that severe lymphopenia was the only significant risk factor for intracranial progression. However, sever lymphopenia during PCI was not the prognostic factors for PFSO and PFSE of LS-SCLC patients receiving PCI (median PFSO: 14.4 vs. 15.8 months, P = 0.218; median PFSE: NR vs. 33.6 months, P = 0.532; respectively). Conclusion Severe lymphopenia during prophylactic cranial irradiation was the risk factor for intracranial progression in LS-SCLC patients receiving PCI, but not for PFSO and extracranial progression.

PURPOSE/OBJECTIVE(S) A reliable model is needed to estimate the risk of postoperative recurrence and the benefits of postoperative radiotherapy (PORT) in patients with thoracic esophageal squamous cell cancer (TESCC). MATERIALS/METHODS The study retrospectively reviewed 3652 TESCC patients in stage I-III after radical esophagectomy, with or without PORT. In one institution as the training cohort (n = 1620), independent risk factors associated with locoregional recurrence (LRR), identified by the competing risk regression, were used to establish a predicting nomogram, which was validated in an external cohort (n = 1048). Area under curve (AUC) values of receiver operating characteristic curves were calculated to evaluate discrimination. Risk stratification was conducted using a decision tree analysis based on the cumulative point score of the LRR nomogram, and the effect of PORT was evaluated in each risk group. RESULTS Sex, age, tumor location, tumor grade, and N category were identified as independent risk factors for LRR and added into the nomogram. The AUC values were 0.638 and 0.706 in the training and validation cohorts, respectively. Three risk groups were established. For patients in the intermediate- and high-risk groups, PORT significantly improved the 5-year overall survival by 8.8% and 11.1%, respectively (P < 0.05). Though PORT was significantly associated with reduced LRR in the low-risk group, overall survival was not improved. CONCLUSION The nomogram can effectively estimate the individual risk of LRR, and patients in the intermediate- and high-risk groups are highly recommended to undergo PORT.

BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

Two new furoquinoline alkaloids, named 1'-oxo-isoplatydesmine (1) and demethoxyacrophylline (2), as well as 11 known alkaloids (3-13) were isolated from the root bark of Dictamnus dasycarpus Turcz. The structures of 1 and 2 were established by detailed spectroscopic elucidation, such as 1 D & 2 D NMR and HRMS, etc. The unexpected autoracemization of 1 was discussed based on the stereochemistry of reported dihydrofuroquinolines. Compounds 3–5 exhibited moderate inhibitory activities against Bacillus subtilis, Candida albicans, and Pseudomonas aeruginosa with MICs 32–64 μg/ml, revealing the active principles of D. dasycarpus for treating skin diseases in its traditional usage.

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Objective To explore the genetic spectrum of cerebral palsy (CP) in a Chinese paediatric cohort. Study design This was a retrospective observational study of patients with CP from the Children’s Hospital of Fudan University between June 2015 and December 2019. Their clinical data and exome sequencing data were collected and analysed. Results A total of 217 patients with CP were enrolled, and genetic variants were identified in 78 subjects (35.9%): 65 patients with single-nucleotide variants (SNVs), 12 patients with copy number variants (CNVs) and one patient with both an SNV and a CNV. The genetic diagnosis rates were significantly higher in patients without clinical risk factors than in patients with clinical risk factors (χ 2 =21.705, P = .000) and were significantly higher in patients with a family history than in those without a family history (χ 2 =4.493, P=0.034). Variants in genes related to neurologic disorders were the most commonly detected variants, affecting 41 patients (62.1%, 41/66). Among the patients with SNVs detected, the top 12 genes were found to cover 62.1% (41/66) of cases, and 39.4% (26/66) of patients with SNVs had medically actionable genetic findings. Conclusions The overall genetic diagnostic rate in this study was 35.9%, and patients without any clinical risk factors or with a family history were more likely to have genetic risk factors. The top 12 genes detected in this study as well as genes related to neurologic disorders or other medically actionable disorders should be noted in the analysis of genetic testing results in patients with CP.

Acetaminophen (N‐acetyl‐para‐aminophenol [APAP]) overdose is the most common cause of drug‐induced liver injury in the Western world and has limited therapeutic options. As an important dietary component intake, fructose is mainly metabolized in liver, but its impact on APAP‐induced liver injury is not well established. We aimed to examine whether fructose supplementation could protect against APAP‐induced hepatotoxicity and to determine potential fructose‐sensitive intracellular mediators. We found that both high‐fructose diet feeding before APAP injection and fructose gavage after APAP injection reduced APAP‐induced liver injury with a concomitant induction of the hepatic carbohydrate‐response element‐binding protein α (ChREBPα)–fibroblast growth factor 21 (FGF21) pathway. In contrast, Chrebpα liver‐specific‐knockout (Chrebpα‐LKO) mice failed to respond to fructose following APAP overdose, suggesting that ChREBPα is the essential intracellular mediator of fructose‐induced hepatoprotective action. Primary mouse hepatocytes with deletion of Fgf21 also failed to show fructose protection against APAP hepatotoxicity. Furthermore, overexpression of FGF21 in the liver was sufficient to reverse liver toxicity in APAP‐injected Chrebpα‐LKO mice. Conclusion: Fructose protects against APAP‐induced hepatotoxicity likely through its ability to activate the hepatocyte ChREBPα–FGF21 axis.

Ethnopharmacological relevance Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors, seriously compromising patients’ quality of life. Previous studies showed that Zengshengping (ZSP), a popular traditional Chinese medicine, has certain inhibiting effects on both oral precancerous lesions and OSCC. However, few reports underlined ZSP side effects such as liver toxicity, which limit its long-term application. Aim of the study was to evaluate the chemopreventive effect of a modified ZSPs formula on oral cancer in a hamster model. Its effect on hamster liver was also assessed. Materials and Methods The original medicine (ZSP-1) and other two formulas slightly different and called ZSP-2 and ZSP-3 were prepared ahead of time. DMBA (0.5%) was topically applied for 6 weeks to induce a premalignant lesion on hamsters’ cheek pouch, then ZSP-1/2/3 were intragastrically administered for 8 weeks. Hamster treated with DMBA + each of the ZSPs represented the ZSP-1/2/3 groups, while those without ZSP-1/2/3 treatment represented the DMBA group. To assess the effect of ZSPs in the liver, intragastric administration of ZSP-1/2/3 was carried out to other groups of hamsters for 12 weeks and the blood was collected every two weeks to detect the hepatic function. Some of the hamsters were sacrificed at the end of 12 weeks, while the remaining animals were sacrificed after other 4 weeks to estimate the effect of ZSP-1/2/3 withdrawal on the liver. Results showed that tumor development in the ZSP-1/2/3 groups was less than that in DMBA group. BrdU, CD31 and COX-2 expression in the hyperplastic tissues was significantly lower in the ZSP-1/2/3 groups than that in the DMBA group. In addition, VEGF and COX-2 expression in ZSP-1/2/3 groups was lower while caspase-9 and p53 expression was higher than those in the DMBA group. Finally, PTEN expression in ZSP-1/2/3 groups was higher than that in the DMBA group. As regard the effect in the liver, ALP in the ZSP-1/2/3 groups was higher than that in the control group treated with an intragastric administration of ddH2O. After 4 weeks of withdrawal, the hamsters of the ZSP-3 group did not recover from the increase in ALP. Histopathology showed the presence of inflammatory lesions in each group after 12 weeks, especially in the ZSP-1/3 groups, and the number of apoptotic cells in the ZSP-3 group was higher than that in the other groups, without any recovery after withdrawal of the drug. At 12 weeks, the MDA in the ZSP-1 group was higher than that in the control group and the ZSP-2 group, but the difference disappeared after drug withdrawal because the MDA in the ZSP-1/3 groups decreased. Conclusions ZSP-2 possessed a chemopreventive effect against oral cancer by inhibiting inflammation, proliferation of tumor cells, generation of microvessels and by promoting tumor cell apoptosis. In addition, hepatotoxicity of ZSP-2, which might be related to oxidative stress injury, was reduced to some extent.

Nursing home residents are at a higher risk of suicidal ideation, and depressive symptoms and limitations on activities of daily living (ADL) are presumed to be contributory factors, whereas resilience may buffer the negative effects of risk factors. This study aimed to investigate the prevalence of suicidal ideation and the moderating effect of resilience on suicidal ideation to dilute the adverse contribution of ADL limitation and depressive symptoms. A stratified random sampling was used to recruit 538 residents from 37 nursing homes in China. Participants' suicidal ideation, resilience, depressive symptoms, and ADL limitation were measured and tested by structural equation modeling. Statistics show that 14.9% of participants had suicidal ideation and the model where resilience moderated the effects of ADL limitation and depressive symptoms on suicidal ideation had the best model fit index. This suggests that positive psychological interventions for resilience building might be effective in reducing suicidal ideation.

PURPOSE/OBJECTIVE(S) The high intracranial efficacy of target therapy agents challenges the sequence of local radiation therapy (RT) and systematic tyrosine kinase inhibitors (TKI) in brain metastases (BM) patients. Therefore, we conducted a single institutional retrospective cohort study to demonstrate the appropriate treatment strategy of upfront RT or upfront TKI in these patients, including an assessment of its feasibility and toxicity. MATERIALS/METHODS Patients with brain metastases who received hypofractionated stereotactic radiotherapy (HFSRT) with/without whole brain radiotherapy (WBRT) at our institution from October 2010 to October 2020 were included in this study. The primary endpoint was intracranial progression-free survival (IPFS). The secondary endpoints were overall survival (OS), brain metastases specific survival (BMSS) and toxicity. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank tests were used to evaluate and compare OS and BMSS. Multivariate analysis was performed using Cox logistic regression analysis. RESULTS Among 885 patients, 570 patients enrolled in the study. 130 patients received upfront TKI with RT, 193 patients received upfront RT with TKI, and 247 patients received RT alone. The median follow-up time was 56.4 months. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.51 (95% CI, 0. 40- 0.667) than upfront TKI group (median IPFS, 17.2 months vs. 8.5 months; P

PURPOSE/OBJECTIVE(S) To compare the prognostic predictive power of the 11th Japan Esophageal Society (JES) system with the 8th American Joint Committee on Cancer (AJCC) system in patients with thoracic esophageal squamous cell carcinoma (TESCC), and to estimate the survival benefits of postoperative radiotherapy (PORT) based on substage of the JES system. MATERIALS/METHODS Area under the curve (AUC) values of receiver operating characteristic curve were calculated to evaluate prognostic efficacy. Propensity score matching (PSM) analysis was conducted to balance the two groups (surgery only [S group] or surgery plus postoperative radiotherapy [S+RT group]) across substages of the 11th JES system according to independent prognostic factors for overall survival (OS) identified using the Cox proportional hazards regression. RESULTS A total of 2960 patients were eligible. The 5-year OS AUC for the 8th AJCC system was significantly higher than that for the 11th JES system (0.701 vs. 0.675, P < 0.001). Before PSM, PORT significantly improved 5-year OS rates for patients in stage III and IVA by 9.1% (P < 0.001) and 21.1% (P < 0.001), respectively. After PSM, the 5-year OS rates in stage II, III, and IVA of the S+RT group were significantly higher than those in the S group (70.9%, 39.7%, and 35.1% vs. 57.8%, 27.2%, and 10.3%, respectively; P < 0.001). CONCLUSION The 11th JES system was less capable of predicting prognosis than the 8th AJCC system and patients in stage III of the JES system were highly recommended to undergo PORT.

Purpose/Objective(s) To create a radiomics model of prognostic prediction for soft-tissue sarcoma (STS) of the extremities and trunk treated with neoadjuvant radiotherapy. Materials/Methods we used a dataset of 62 STS patients treated with neoadjuvant radiotherapy from our institution between January 2015 and December 2019 (n = 20) and the NCI's Cancer Imaging Archive between November 2004 and November 2011(TCIA, n = 42). After tumor segmentation and preprocessing, 851 radiomic features were extracted from pretreatment fat saturated T2-weighted MRI image. The Radiomics-score was to be constructed based on the least absolute shrinkage and selection operator (LASSO) regression results. Kaplan-Meier analysis (log-rank test) and Cox's proportional hazards regression model were used to evaluate the prognostic factor of the 2-years disease-free survival (DFS). The nomogram model was established based on log-rank test and Cox's proportional hazards regression model. The Harrell's concordance index (C-index), receiver operating characteristic curve (ROC) analysis and calibration curves were used to evaluate the nomogram models. Decision curve analysis (DCA) was performed to analyze the clinical usefulness of the model. Results The cohort included 62 patients (30 females (48.4%), mean age: 50.9 ± 19.1 years). The most frequent histotypes were liposarcoma (24.2%) and undifferentiated sarcoma (22.6%). Most of tumors were deep-seated (74.2%) and located in the extremity (88.5%). A total of 851 radiomic features were extracted from T2-FS images. After data dimension reduction with LASSO, 42 most valuable features remained and their coefficients were from lasso-cox regression. The radiomics-score calculation formula consisted of these features. The univariate survival analysis showed that tumor location (P = 0.032), clinical stage (P = 0.022), tumor size (P = 0.005) and radiomics-score were correlated with DFS (P Conclusion The radiomics-score based pretreatment MRI was an independent prognostic factor for DFS of the extremities and trunk STS patients. The combined clinical-radiomics model added accuracy to predict DFS and thus contributed to the individual selection of neoadjuvant therapy.

BackgroundDevelopmental disorders (DDs) are early onset disorders affecting 5%–10% of children worldwide. Chromosomal microarray analysis detecting CNVs is currently recommended as the first-tier test for DD diagnosis. However, this analysis omits a high percentage of disease-causing single nucleotide variations (SNVs) that warrant further sequencing. Currently, next-generation sequencing can be used in clinical scenarios detecting CNVs, and the use of exome sequencing in the DD cohort ahead of the microarray test has not been evaluated.MethodsClinical exome sequencing (CES) was performed on 1090 unrelated Chinese DD patients who were classified into five phenotype subgroups. CNVs and SNVs were both detected and analysed based on sequencing data.ResultsAn overall diagnostic rate of 41.38% was achieved with the combinational analysis of CNV and SNV. Over 12.02% of patients were diagnosed based on CNV, which was comparable with the published CMA diagnostic rate, while 0.74% were traditionally elusive cases who had dual diagnosis or apparently homozygous mutations that were clarified. The diagnostic rates among subgroups ranged from 21.82% to 50.32%. The top three recurrent cytobands with diagnostic CNVs were 15q11.2-q13.1, 22q11.21 and 7q11.23. The top three genes with diagnostic SNVs were: MECP2, SCN1A and SCN2A. Both the diagnostic rate and spectrums of CNVs and SNVs showed differences among the phenotype subgroups.ConclusionWith a higher diagnostic rate, more comprehensive observation of variations and lower cost compared with conventional strategies, simultaneous analysis of CNVs and SNVs based on CES showed potential as a new first-tier choice to diagnose DD.

Roll-to-Roll imprint process is considered to be the most promising technology for manufacturing large-area micro-structured surface. However, the traditional turning technique was considered to be incapable of machining radial Fresnel lenses on roller mold. This study deals with the problem of machining the radial Fresnel lens on a roller mold, which is achieved by using the diamond cutting tools mounted on a multiple axis control ultra-precision machining center. In addition, this study simulates the effect of the deviation of the tool tip position from the rotation center of the platform and the deviation from the vertical plane of the roller axis on the machining results.

Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM). Hepatic stellate cells (HSCs) are the primary cells that produce ECM in response to hepatic injury, and transforming growth factor-beta (TGF-β) has been regarded as the central stimulus responsible for HSC-mediated ECM production. In the present study, we attempted to identify a critical factor in HSC activation and the underlying mechanism. By analyzing online microarray expression profiles, we found that the expression of high-affinity cationic amino acid transporter 1 (CAT1) was upregulated in hepatic fibrosis models and activated HSCs. We isolated and identified mouse HSCs (MHSCs) and found that in these cells, CAT1 was most highly upregulated by TGF-β1 stimulation in both time- and dose-dependent manners. In vitro, CAT1 overexpression further enhanced, while CAT1 silencing inhibited, the effect of TGF-β1 in promoting MHSC activation. In vivo, CAT1 silencing significantly improved the hepatic fibrosis induced by both CCl4 and non-alcoholic fatty liver disease (NAFLD). In summary, CAT1 was significantly upregulated in TGF-β1-activated MHSCs and mice with hepatic fibrosis. CAT1 silencing inhibited TGF-β1-induced MHSC activation in vitro and fibrogenic changes in vivo. CAT1 is a promising target for hepatic fibrosis treatment that requites further investigation in human cells and clinical practice.

Gene therapy has shown promise in antitumor strategies for advanced cancer. However, efficient and safe delivery of potent therapeutic gene expressing in specific tumor tissues remains elusive, especially when there exist stromal obstacles. Here we report a non-viral gene delivery approach targeting pancreatic stellate cells (PSCs) as the transfection host in the fibroblast-enriched tumor microenvironment of pancreatic cancer. Plasmid DNA (pDNA) encapsulated in branched polyethylenemine (BPEI) was found to selectively transfect PSCs rather than pancreatic cancer cells and other fibroblast cell lines. Mechanism investigations reveal that the highly expressed fibroblast growth factor receptors (FGFRs) in PSCs facilitated the cellular uptake of polyplexes in PSCs. This delivery platform carrying gene encoding of TNF-related apoptosis-inducing ligand (TRAIL) displayed effective by-stander effect and tumor cell-selective cytotoxicity. More importantly, the therapeutic efficacy was proved in a PSC-enriched orthotopic pancreatic tumor model. Thus, this gene delivery strategy smartly converts PSCs as the microenvironment obstacle for drug delivery into the producer and reservoir of selective tumor-killing proteins.

The removal of sulfapyridine (SPY) by ferrate(VI) in aqueous solutions under a broad range of reaction conditions, including ferrate(VI) dosage, solution pH, natural organic matter and coexisting inorganic ions, was systematically investigated and the oxidation pathway of SPY by ferrate(VI) was deeply explored. Results showed that 500 µg/L of SPY was efficiently decomposed (86%) within 1 min by 5 mg/L ferrate(VI) at pH 5.6. The increment in ferrate(VI) dosage was surely favorable for SPY removal. The best SPY degradation was achieved at pH 5.6, under or above which the removal decreased. The introduction of inorganic ions in solutions retarded SPY removal. Ten oxidation intermediates were identified and the cleavages of C-S and S-N bonds might be the primary ways of SPY oxidation by ferrate(VI).

This study aimed to investigate the effect of sevoflurane on serum levels of interleukin (IL)-6 and IL-8 in patients who underwent cardiopulmonary bypass (CPB). The strength of the association between sevoflurane treatment and serum level of IL-6 and IL-8 was determined in patients who underwent CPB by summary standard mean differences (SMDs); 95% confidence interval (CI) was used. In total, seven case-control studies showed decreased IL-6 and IL-8 levels in sevoflurane-treated patients than in controls (IL-6: SMD = 1.56, 95%CI: 0.95-2.17, P < 0.001; IL-8: SMD = 1.63, 95%CI: 0.30-2.96, P < 0.001, respectively). Further, IL-6 and IL-8 levels were significantly higher in sevoflurane-treated patients than in sevoflurane-pretreated patients (IL-6 post vs pre: SMD = 2.17, 95%CI: 1.40-2.95, P < 0.001; IL-8 post vs pre: SMD = 4.01, 95%CI: 2.80-5.21, P < 0.001, respectively). CPB-stratified analysis showed significant decrease in IL-6 and IL-8 levels in sevoflurane-treated patients than in controls, irrespective of the time after CPB surgery (P < 0.05). Moreover, sevoflurane-pretreated patients under the

The aim of this study was to investigate the role of miRNA-146a in modulating the function of vascular smooth muscle cells in a rat model of coronary heart disease. Vascular smooth muscle cells were isolated and cultured from the rat coronary heart disease model and normal rats (controls). miRNA-146a levels were measured in vascular smooth muscle cells obtained from rats with coronary heart disease and control rats. The proliferation, growth, apoptosis, and activation of the NF-κB pathway in the vascular smooth muscle cells were detected using the MTT assay and flow cytometry, respectively. The role of the NF-κB pathway in modulating the apoptosis of vascular smooth muscle cells was investigated by measuring the reactivity of the cells to an NF-κB pathway inhibitor (TPCA-1). Vascular smooth muscle cells from the disease model exhibited higher levels of miRNA-146a than that by the normal controls (P = 0.0024). The vascular smooth muscle cells obtained from rats with coronary heart disease showed decreased proliferation and growth and increased apoptosis. miRNA-146a overexpression elevated the rate of cell apoptosis. The NF-κB pathway was activated in vascular smooth muscle cells obtained from rats with coronary heart disease. Inhibition of the NF- κB pathway significantly decreased the rate of vascular smooth muscle cell apoptosis in coronary heart disease rats (P = 0.0038). In conclusion, miRNA- 146a was found to induce vascular smooth muscle cell apoptosis in rats with coronary heart disease via the activation of the NF-κB signal pathway.

Background A bran-new landscape of immuno-oncology (IO) is arising in China rapidly, with IO development a hotspot in biopharmaceutical industries. Moreover, a paucity of data on the panorama of IO clinical trials in China inspired us to present the systemic analysis for stakeholders in this field. Methods Based on the Platform for Registry and Publicity of Drug Clinical Trials, a national authoritative database by China Food and Drug Administration, the trials for IO agents issued from 2013 to 2018 were explored using newly developed agents (by six types of mechanism and targets) and the number of initiated trials as key indicators. The clinical development stages of all agents were presented by targets. In addition, time trends in annually initiated trials and cumulative indication distribution were investigated. Results There were 62 IO agents and 230 initiated trials in China from 2013 to 2018, with 46 (74.2%) agents and 154 (67.0%) trials from domestic firms. The 62 agents modulated 18 targets focusing on PD-1 (17, 27.4%), PD-L1 (12, 19.4%) and unspecified tumor-associated antigens (5, 8.1%). Only 8 agents of cell therapy were ever developed for registration purpose. PD-1/L1 targets were most extensively investigated with a total of 180 (78.3%) trials and 4 agents approved. The annual number of trials showed an upward trend, and the sharp increase for trials of T-cell targeted immuno-modulators was seen with an average growth rate of 199.1% since 2016. In terms of cancer types, solid tumor (56, 24.3%), non-small cell lung cancer (45, 19.6%) and hepatocellular cancer (20, 8.7%) were the most common. Only 14 (6.1%) trials applied a biomarker enrichment strategy. Table . 1293P The landscape of immuno-oncology targets in clinical development in China since 2013 Types Targets Agents N = 62 (%) Trials N = 230 (%) Total Phase I Phase II/III Approv ed T-cell targeted immuno- modulator PD-1 17 (27.4) 6 7 4 129 (56.1) PD-L1 12 (19.4) 5 7 51 (22.2) CTLA-4 3 (4.8) 1 2 11 (4.8) IDO1/TDO 2 2 2 IDO1 1 1 1 CD137 1 1 1 LAG3 1 1 1 OX40 1 1 1 PD-1/CTLA-4 1 1 1 PD-L1/CTLA-4 1 1 1 PD-L1/ TGF-βRII 1 1 1 Other immuno- modulator Unspecified 1 1 5 (2.2) CD47 1 1 1 MUC1 1 1 1 Cancer vaccine TLR 2 2 2 EGF 1 1 1 MUC1 1 1 1 Cell Therapy Unspecified 4 (6.5) 2 2 4 (1.7) CD19 3 (4.8) 3 3 (1.3) BCMA 1 1 1 Oncolytic virus GM-CSFR 4 (6.5) 1 3 9 (3.9) CD3-targeted bispecific mAb CD19 1 1 1 HER2 1 1 1 Conclusions Though a gap exists in the number of agents and targets between China and the global pipeline, the rising capability of IO has been achieved in China recently. Efforts should be further made in novel targets, cell therapy for registration purpose, Chinese unique cancers and new trial designs. Legal entity responsible for the study National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

A novel indigo derivative ( 1 ) was synthesized and fully characterized. Its structure, confirmed by X-ray crystallography, showed that compound 1 is a planar molecule. Interestingly, compound 1 only has response to fluoride ions among six different anions (F − , Cl − , Br − , I − , AcO − , and HSO 4 − ) in an anhydrous methylene chloride solution and this response can be detected by the ‘naked eyes’.

Published online: December 28, 2015 (DOI: 10.4238/2015.December.28.19). Corrected after publication: June 24, 2016 (DOI: 10.4238/gmr.150267961). There is a change in the corresponding author, who should be Y.F. Liu.

Eight new 9,10-anthraquinones (1–8) including three acetonide derivatives of 3-hydroxy-2-hydroxymethyl-9,10-anthraquinones (6–8) were isolated from an ethanol extract of the roots of Knoxia valerianoides. On the basis of chemical transformation reactions of the co-occurring 14 and 15 combined with HPLC–DAD–ESI–MS analysis of the extracts, the previously and newly isolated 2-methoxymethyl- and 2-ethoxymethyl-9,10-anthraquinones (4, 5, and 9–13), as well as the 3-hydroxy-2-hydroxymethyl-9,10-anthraquinone acetonide derivatives (6–8), were shown to be solvolytic artifacts. In the in vitro assays, compound 4 was active to protect hepatocyte (WB-F344) damage.