Clinical application of dual-layer spectral CT multi-parameter feature to predict microvascular invasion in hepatocellular carcinoma.

OBJECTIVE: This study aimed to investigate the feasibility of using dual-layer spectral CT multi-parameter feature to predict microvascular invasion of hepatocellular carcinoma. METHODS: This retrospective study enrolled 50 HCC patients who underwent multiphase contrast-enhanced spectral CT studies preoperatively. Combined clinical data, radiological features with spectral CT quantitative parameter were constructed to predict MVI. ROC was applied to identify potential predictors of MVI. The CT values obtained by simulating the conventional CT scans with 70 keV images were compared with those obtained with 40 keV images. RESULTS: 50 hepatocellular carcinomas were detected with 30 lesions (Group A) with microvascular invasion and 20 (Group B) without. There were significant differences in AFP,tumer size, IC, NIC,slope and effective atomic number in AP and ICrr in VP between Group A ((1000(10.875,1000),4.360±0.3105, 1.7750 (1.5350,1.8825) mg/ml, 0.1785 (0.1621,0.2124), 2.0362±0.2108,8.0960±0.1043,0.2830±0.0777) and Group B (4.750(3.325,20.425),3.190±0.2979,1.4700 (1.4500,1.5775) mg/ml, 0.1441 (0.1373,0.1490),1.8601±0.1595, 7.8105±0.7830 and 0.2228±0.0612) (all p < 0.05). Using 0.1586 as the threshold for NIC, one could obtain an area-under-curve (AUC) of 0.875 in ROC to differentiate between tumours with and without microvascular invasion. AUC was 0.625 with CT value at 70 keV and improved to 0.843 at 40 keV. CONCLUSION: Dual-layer spectral CT provides additional quantitative parameters than conventional CT to enhance the differentiation between hepatocellular carcinoma with and without microvascular invasion. Especially, the normalized iodine concentration (NIC) in arterial phase has the greatest potential application value in determining whether microvascular invasion exists, and can offer an important reference for clinical treatment plan and prognosis assessment.

Celastrol inhibits angiogenesis and the biological processes of MDA-MB-231 cells via the DEGS1/S1P signaling pathway.

Celastrol (Cel) shows potent antitumor activity in various experimental models. This study examined the relationship between Cel's antivascular and antitumor effects and sphingolipids. CCK-8 assay, transwell assay, Matrigel, PCR-array/RT-PCR/western blotting/immunohistochemistry assay, ELISA and HE staining were used to detect cell proliferation, migration and invasion, adhesion and angiogenesis, mRNA and protein expression, S1P production and tumor morphology. The results showed that Cel could inhibit proliferation, migration or invasion, adhesion and angiogenesis of human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 cells by downregulating the expression of degenerative spermatocyte homolog 1 (DEGS1). Transfection experiments showed that downregulation of DEGS1 inhibited the above processes and sphingosine-1-phosphate (S1P) production of HUVECs and MDA-MB-231 cells, while upregulation of DEGS1 had the opposite effects. Coculture experiments showed that HUVECs could promote proliferation, migration and invasion of MDA-MB-231 cells through S1P/sphingosine-1-phosphate receptor (S1PR) signaling pathway, while Cel inhibited these processes in MDA-MB-231 cells induced by HUVECs. Animal experiments showed that Cel could inhibit tumor growth in nude mice. Western blotting, immunohistochemistry and ELISA assay showed that Cel downregulated the expression of DEGS1, CD146, S1PR1-3 and S1P production. These data confirm that DEGS1/S1P signaling pathway may be related to the antivascular and antitumor effects of cel.

Porous and Partially Dehydrogenated Fe2+ -Containing Iron Oxyhydroxide Nanosheets for Efficient Electrochemical Nitrogen Reduction Reaction (ENRR).

The design and development of efficient catalysts for electrochemical nitrogen reduction reaction (ENRR) under ambient conditions are critical for the alternative ammonia (NH3 ) synthesis from N2 and H2 O, wherein iron-based electrocatalysts exhibit outstanding NH3 formation rate and Faradaic efficiency (FE). Here, the synthesis of porous and positively charged iron oxyhydroxide nanosheets by using layered ferrous hydroxide as a starting precursor, which undergoes topochemical oxidation, partial dehydrogenated reaction, and final delamination, is reported. As the electrocatalyst of ENRR, the obtained nanosheets with a monolayer thickness and 10-nm mesopores display exceptional NH3 yield rate (28.5 µg h-1 mgcat. -1 ) and FE (13.2%) at a potential of -0.4 V versus RHE in a phosphate buffered saline (PBS) electrolyte. The values are much higher than those of the undelaminated bulk iron oxyhydroxide. The larger specific surface area and positive charge of the nanosheets are beneficial for providing more exposed reactive sites as well as retarding hydrogen evolution reaction. This study highlights the rational control on the electronic structure and morphology of porous iron oxyhydroxide nanosheets, expanding the scope of developing non-precious iron-based highly efficient ENRR electrocatalysts.

Effect of biochar with different particle sizes on the sorption-desorption characteristics of soil phosphorus.

The size of particles determines the adsorption reaction. In this study, three different particle sizes of biochar (0.25-1 mm, 0.075-0.25 mm, <0.075 mm) were produced from rapeseed straw (SBC) and chicken manure (MBC). The biochar was mixed with high phosphorus (P) soil and low P soil and then incubated for 30 days. We conducted isothermal P sorption and desorption experiments to evaluate the effects of biochar particle size on sorption-desorption characteristics of soil P, and analyzed soil properties associated with P sorption. The results showed that P sorption capacity of SBC and MBC in the water system was highest for the smallest particle size (<0.075 mm) (SBC: 43125 mg·kg-1, MBC: 20083 mg·kg-1), followed by the intermediate particle size (0.075-0.25 mm) (SBC: 37376 mg·kg-1, MBC: 13199 mg·kg-1) and the largest particle size (0.25-1 mm) (SBC: 27749 mg·kg-1, MBC: 12251 mg·kg-1). However, there was little difference in soil P sorption between the three particle sizes of the same biochar in the soil system. In comparison with no biochar treatment, the addition of SBC increased the Langmuir P sorption maximum (Smax) by 236.8%-755.7%, and decreased soil P desorption rate. The addition of MBC increased Smax, but the enhancement was less than that of SBC. Soil P desorption rate was increased by 7.2%-295.9%. Both SBC and MBC significantly increased the contents of soil total P, available P, and exchangeable calcium (Ca) and magnesium (Mg). The increases in Ca and Mg contents due to biochar addition was 64.0%-257.1% (SBC) and 39.1%-205.3% (MBC), respectively. The contents of soil exchangeable Ca and Mg were positively correlated with Smax. These results suggested that biochar particle size had little effect on soil P sorption, but the enrichment of Ca and Mg due to biochar addition played a critical role in regulating soil P sorption. The rapeseed straw biochar had a high adsorption capacity for soil P, making it suitable for improving the P fixation capacity of soil rich in P and reducing the loss of excess P. Chicken manure biochar could be used to improve the P availability of low P soils and increase the contents of available P.

UPLC-MS based integrated plasma proteomic and metabolomic profiling of TSC-RAML and its relationship with everolimus treatment.

Aim: To profile the plasma proteomics and metabolomics of patients with renal cysts, sporadic angiomyolipoma (S-AML) and tuberous sclerosis complex related angiomyolipoma (TSC-RAML) before and after everolimus treatment, and to find potential diagnostic and prognostic biomarkers as well as reveal the underlying mechanism of TSC tumorigenesis. Materials and Methods: We retrospectively measured the plasma proteins and metabolites from November 2016 to November 2017 in a cohort of pre-treatment and post-treatment TSC-RAML patients and compared them with renal cyst and S-AML patients by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS). The tumor reduction rates of TSC-RAML were assessed and correlated with the plasma protein and metabolite levels. In addition, functional analysis based on differentially expressed molecules was performed to reveal the underlying mechanisms. Results: Eighty-five patients with one hundred and ten plasma samples were enrolled in our study. Multiple proteins and metabolites, such as pre-melanosome protein (PMEL) and S-adenosylmethionine (SAM), demonstrated both diagnostic and prognostic effects. Functional analysis revealed many dysregulated pathways, including angiogenesis synthesis, smooth muscle proliferation and migration, amino acid metabolism and glycerophospholipid metabolism. Conclusion: The plasma proteomics and metabolomics pattern of TSC-RAML was clearly different from that of other renal tumors, and the differentially expressed plasma molecules could be used as prognostic and diagnostic biomarkers. The dysregulated pathways, such as angiogenesis and amino acid metabolism, may shed new light on the treatment of TSC-RAML.

Quantitative proteomics identifies and validates urinary biomarkers of rhabdomyosarcoma in children.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma with poor prognosis in children. The 5-year survival rate for early RMS has improved, whereas it remains unsatisfactory for advanced patients. Urine can rapidly reflect changes in the body and identify low-abundance proteins. Early screening of tumor markers through urine in RMS allows for earlier treatment, which is associated with better outcomes. METHODS: RMS patients under 18 years old, including those newly diagnosed and after surgery, were enrolled. Urine samples were collected at the time points of admission and after four cycles of chemotherapy during follow-up. Then, a two-stage workflow was established. (1) In the discovery stage, differential proteins (DPs) were initially identified in 43 RMS patients and 12 healthy controls (HCs) using a data-independent acquisition method. (2) In the verification stage, DPs were further verified as biomarkers in 54 RMS patients and 25 HCs using parallel reaction monitoring analysis. Furthermore, a receiver operating characteristic (ROC) curve was used to construct the protein panels for the diagnosis of RMS. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) software were used to perform bioinformatics analysis. RESULTS: A total of 251 proteins were significantly altered in the discovery stage, most of which were enriched in the head, neck and urogenital tract, consistent with the most common sites of RMS. The most overrepresented biological processes from GO analysis included immunity, inflammation, tumor invasion and neuronal damage. Pathways engaging the identified proteins revealed 33 common pathways, including WNT/ß-catenin signaling and PI3K/AKT signaling. Finally, 39 proteins were confirmed as urinary biomarkers for RMS, and a diagnostic panel composed of 5 candidate proteins (EPS8L2, SPARC, HLA-DRB1, ACAN, and CILP) was constructed for the early screening of RMS (AUC: 0.79, 95%CI = 0.66 ~ 0.92). CONCLUSIONS: These findings provide novel biomarkers in urine that are easy to translate into clinical diagnosis of RMS and illustrate the value of global and targeted urine proteomics to identify and qualify candidate biomarkers for noninvasive molecular diagnosis.

Current status and quality of radiomic studies for predicting KRAS mutations in colorectal cancer patients: A systematic review and meta­analysis.

PURPOSE: The purpose of this study was to evaluate the methodological quality of radiomics-based studies for noninvasive, preoperative prediction of Kirsten rat sarcoma (KRAS) mutations in patients with colorectal cancer; furthermore, we systematically evaluate the diagnostic accuracy of predicting models. METHODS: We systematically searched PubMed, Embase, Cochrane Library and Web of Science databases up to 20 April 2022 for eligible studies. The methodological quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) and Radiomics Quality Score (RQS) tools. A meta-analysis of studies on the prediction of KRAS status in colorectal cancer patients was performed. RESULT: Twenty-nine studies were identified in the systematic review, including three studies on the prediction of KRAS status in colorectal cancer liver metastases. All studies had an average RQS score of 9.55 (26.5% of the total score), ranging from 3 to 17. Most studies demonstrated a low or unclear risk of bias in the domains of QUADAS-2. Nineteen studies were included in the meta-analysis, mostly imaged with magnetic resonance imaging (MRI), followed by computed tomography (CT), positron emission tomography-CT (PET/CT). With pooled sensitivity, specificity and area under the curve (AUC) of the training cohorts were 0.80(95% confidence interval(CI), 0.75-0.84), 0.80(95% CI, 0.74-0.85) and 0.87(95% CI, 0.84-0.90),respectively. The pooled sensitivity, specificity, and AUC for the validation cohorts (13 studies) were 0.78(95% CI, 0.71-0.84), 0.84(95% CI, 0.74-0.90), and 0.86(95% CI, 0.83-0.89), respectively. CONCLUSION: Radiomics is a potential noninvasive technology that has a moderate preoperative diagnosis and prediction effect on KRAS mutations. However, it has not been implemented as a clinical decision-making tool. Future researchers should pay more attention to the methodological quality of the study and further externally validate the model using multicenter datasets.

[18F]FAPI-42 PET/CT in differentiated thyroid cancer: diagnostic performance, uptake values, and comparison with 2-[18F]FDG PET/CT.

PURPOSE: This study aimed to assess the diagnostic performance of [18F]FAPI-42 PET/CT and compare it with that of 2-[18F]FDG PET/CT in patients with differentiated thyroid cancer (DTC) with biochemical elevations in Tg or anti-Tg antibodies. METHODS: A total of 42 patients with DTC with biochemical elevations in Tg or anti-Tg antibodies underwent [18F]FAPI-42 PET/CT as part of this study; of which, 11 additionally underwent 2-[18F]FDG PET/CT within 7 days. Images were semi-quantitatively and visually interpreted, and the quantity, location, and uptake values of lesions were noted. The diagnostic capacity of [18F]FAPI-42 PET/CT and biomarkers affecting the uptake of [18F]FAPI-42 were evaluated. In addition, the diagnostic performance and uptake of [18F]FAPI-42 and 2-[18F]FDG were compared, and the correlation between lesion diameter and quantitative parameters was investigated. RESULTS: A total of 161 lesions were detected in 27 (64%) patients on [18F]FAPI-42 PET/CT. FAPI-positive local recurrence showed the highest uptake intensity, followed by lymphatic, other site-associated (bone and pleura), and pulmonary lesions (mean SUVmax, 4.7 versus 3.7 versus 3.0 versus 2.2, respectively; P < 0.0001). The levels of TSH, Tg, and Tg-Ab did not affect the uptake value of lesions (median SUVmax: 2.4 versus 3.2, P = 0.56; 2.9 versus 2.4, P = 0.0935; 2.8 versus 2.6, P = 0.0525, respectively). A total of 90 positive lesions were detected in 7 patients using both modalities. All positive lesions showed statistically higher uptake of 2-[18F]FDG than that of [18F]FAPI-42 (SUVmax, 2.6 versus 2.1; P = 0.026). However, the SUVmax of [18F]FAPI-42 was higher than that of 2-[18F]FDG in local recurrences and lymphatic lesions (SUVmax, 4.2 versus 2.9 and 3.9 versus 3.4, respectively; P > 0.05). CONCLUSION: [18F]FAPI-42 can be used for detecting lesions and reflecting FAP expression during local recurrence and metastasis in patients with DTC with biochemical elevations in Tg or anti-Tg antibodies. The diagnostic performance of [18F]FAPI-42 PET/CT is comparable with that of 2-[18F]FDG PET/CT in such patients.

Cost-effectiveness analysis of dasatinib versus imatinib in pediatric philadelphia chromosome-positive acute lymphoblastic leukemia patients in China.

BACKGROUND: Dasatinib and imatinib are the recommended tyrosine kinase inhibitors (TKIs) for treating pediatric Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), and the one which has been approved indication in China is imatinib. Recently, clinical demand for Ph + ALL treatment is becoming unmet gradually with the increasing resistance of imatinib. There are some studies reporting the better efficacy and comparative safety of dasatinib compared with imatinib, but no economic comparison has been published. This study aims to supplement economic evidence by comparing the cost-effectiveness between imatinib and dasatinib in treating pediatric patients with Ph+ ALL in China, and to help clinical rational drug use via multi-dimensional value assessment. METHODS: A decision tree model combined with a 10-year Markov model were established based on the disease progression. The parameters were collected from published literatures and our hospital's electronic medical records. From the health system perspective, the incremental cost-effectiveness ratio (ICER) between the two treatment groups was calculated through cost-effectiveness analysis and then compared with the willingness-to-pay (WTP) threshold. The set WTP threshold in this study was 1 times per capita gross domestic product (GDP) of China, as recommended by the World Health Organization. Direct medical costs and quality-adjusted life years (QALYs) were calculated and discounted at 5%. The sensitivity analyses were conducted to assess the uncertainty and robustness of the results. RESULTS: The total costs were CNY 1,020,995.35 and CNY 1,035,788.50 in imatinib group and dasatinib group during the 10-year simulation, and the total QALYs were 2.59 and 4.84. Compared with the imatinib treatment group, the ICER was around CNY 6,575.78/ QALY, which was less than the set threshold CNY 70,892/ QALY. The sensitive analyses indicated the robustness of the results. CONCLUSIONS: The cost-effectiveness analysis shows the potential cost-effective advantages of adding dasatinib comparing with adding imatinib for pediatric Ph + ALL patients in China under the set WTP threshold, which indicates that those patients could achieve more QALYs by paying acceptable fee.

Triptolide Inhibits the Biological Processes of HUVECs and HepG2 Cells via the Serine Palmitoyltransferase Long Chain Base Subunit 2/Sphingosine-1-Phosphate Signaling Pathway.

Triptolide (TP) has demonstrated innumerous biological effects and pharmacological potential against different cancer types. Hepatocellular carcinoma has a high incidence in men, and its incidence is increasing year by year. Studies have shown that angiogenesis plays an important role in the formation of tumors and that angiogenesis is closely related to tumor growth and metastasis. Deregulation of sphingolipids signaling has been associated with several pathological conditions, including cancer. In the present study, we aimed at exploring the potential molecular mechanism of TP's antivascular and antitumor effects in vitro from the perspective of sphinolipids. Human umbilical vein endothelial cells (HUVECs) and HepG2 cells were, respectively, treated with different concentrations of TP and transfected. Then, the effect of HUVECs on HepG2 cells was investigated using a three-dimensional coculture model system. CCK-8 assay was performed for cell proliferation. Cell migration and invasion abilities were assessed using the transwell assay. Cell adhesion and tube formation were detected by Matrigel. RT-PCR and western blotting were used to detect the mRNA and protein expression. The S1P production was measured via ELISA assay. Our results showed that TP inhibited HUVECs and HepG2 cells proliferation, migration, invasion, adhesion, angiogenesis, and serine palmitoyltransferase long chain base subunit 2 (SPTLC2) expression; upregulating SPTLC2 facilitated the proliferation, migration, invasion, adhesion, angiogenesis, and sphingosine-1-phosphate (S1P) production of HUVECs and HepG2 cells, while interfering with SPTLC2 expression inhibited them; HUVECs facilitated the proliferation, migration, invasion, S1P production, S1PR1, and S1PR2 expression of HepG2 cells, while S1PR3 expression was decreased. In conclusion, SPTLC2 may be associated with the antivascular and antitumor effects of TP, and SPTLC2 is expected to become a new marker for tumor therapy. HUVECs can promote the proliferation, migration, and invasion of HepG2 cells, which may be related to the S1P/sphingosine-1-phosphate receptor (S1PR) signaling pathway.

Artificial intelligence with magnetic resonance imaging for prediction of pathological complete response to neoadjuvant chemoradiotherapy in rectal cancer: A systematic review and meta-analysis.

Purpose: The purpose of this study was to evaluate the diagnostic accuracy of artificial intelligence (AI) models with magnetic resonance imaging(MRI) in predicting pathological complete response(pCR) to neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer. Furthermore, assessed the methodological quality of the models. Methods: We searched PubMed, Embase, Cochrane Library, and Web of science for studies published before 21 June 2022, without any language restrictions. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) and Radiomics Quality Score (RQS) tools were used to assess the methodological quality of the included studies. We calculated pooled sensitivity and specificity using random-effects models, I2 values were used to measure heterogeneity, and subgroup analyses to explore potential sources of heterogeneity. Results: We selected 21 papers for inclusion in the meta-analysis from 1562 retrieved publications, with a total of 1873 people in the validation groups. The meta-analysis showed that AI models based on MRI predicted pCR to nCRT in patients with rectal cancer: a pooled area under the curve (AUC) 0.91 (95% CI, 0.88-0.93), sensitivity of 0.82(95% CI,0.71-0.90), pooled specificity 0.86(95% CI,0.80-0.91). In the subgroup analysis, the pooled AUC of the deep learning(DL) model was 0.97, the pooled AUC of the radiomics model was 0.85; the pooled AUC of the combined model with clinical factors was 0.92, and the pooled AUC of the radiomics model alone was 0.87. The mean RQS score of the included studies was 10.95, accounting for 30.4% of the total score. Conclusions: Radiomics is a promising noninvasive method with high value in predicting pathological response to nCRT in patients with rectal cancer. DL models have higher predictive accuracy than radiomics models, and combined models incorporating clinical factors have higher diagnostic accuracy than radiomics models alone. In the future, prospective, large-scale, multicenter investigations using radiomics approaches will strengthen the diagnostic power of pCR. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021285630.

A multi­omics study of diagnostic markers and the unique inflammatory tumor micro­environment involved in tuberous sclerosis complex­related renal angiomyolipoma.

Tuberous sclerosis complex (TSC) is a rare disease that threatens multiple organs in the human body. TSC­associated renal angiomyolipoma (TSC­RAML) has potentially life­threatening complications and a generally poor prognosis. The present study aimed to find plasma proteomic diagnostics and disease­associated markers, and explore the tumor microenvironment using multi­omics. To achieve this goal, the plasma proteomics as well as tissue proteomics, bulk and single­cell RNA transcriptome from patients with TSC­RAML were examined and analyzed. The results suggested that plasma proteins such as MMP9 and C­C motif chemokine ligand 5 were able to differentiate TSC­RAML from sporadic angiomyolipoma and renal cyst. A correlation analysis revealed that plasma proteomics were associated with lymphangioleiomyomatosis, TSC­RAML grading and whole­body disease burden. Tissue proteomics of participants with TSC­RAML revealed disturbed small molecule catabolic process, mitochondrial matrix component and actin binding function. Bulk and single­cell RNA sequencing suggested a greater number of tumor­like cells, fibroblasts and mononuclear macrophages within the tumor microenvironment. The above results indicated that TSC­RAML exhibited a characteristic and disease­associated plasma proteomic profile. The unique microenvironment, made up of fibroblasts and mono­macrophages, may promote tumorigenesis and TSC­RAML progression.

LC-MS-Based Urine Metabolomics Analysis for the Diagnosis and Monitoring of Medulloblastoma.

Medulloblastoma (MB) is the most common type of brain cancer in pediatric patients. Body fluid biomarkers will be helpful for clinical diagnosis and treatment. In this study, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was used to identify specific urine metabolites of MB in a cohort, including 118 healthy controls, 111 MB patients, 31 patients with malignant brain cancer, 51 patients with benign brain disease, 29 MB patients 1 week postsurgery and 80 MB patients 1 month postsurgery. The results showed an apparent separation for MB vs. healthy controls, MB vs. benign brain diseases, and MB vs. other malignant brain tumors, with AUCs values of 0.947/0.906, 0.900/0.873, and 0.842/0.885, respectively, in the discovery/validation group. Among all differentially identified metabolites, 4 metabolites (tetrahydrocortisone, cortolone, urothion and 20-oxo-leukotriene E4) were specific to MB. The analysis of these 4 metabolites in pre- and postoperative MB urine samples showed that their levels returned to a healthy state after the operation (especially after one month), showing the potential specificity of these metabolites for MB. Finally, the combination of two metabolites, tetrahydrocortisone and cortolone, showed diagnostic accuracy for distinguishing MB from non-MB, with an AUC value of 0.851. Our data showed that urine metabolomics might be used for MB diagnosis and monitoring.

Dual function metal-organic frameworks based ratiometric electrochemical sensor for detection of doxorubicin.

Cancer is one of the main diseases threatening human health in the world. Doxorubicin (DOX) is a common anti-cancer drug that can be used for chemotherapy to extend a cancer patient's life. It is our common wish that treatment process of cancer is efficient and secure. Therefore, it is of great significance to develop sensitive, rapid and accurate techniques for anti-cancer drug doxorubicin (DOX) detection. Herein, in our work, a ratiometric electrochemical sensor for DOX detection was designed, which based on MB@MWCNTs/UiO-66-NH2 composites. The porous materials UiO-66-NH2 magically shoulder double function in our ratiometric electrochemical strategy, which can reduce the interior error caused by the various complex materials. Specifically, on the one hand, it can be used to catalyze DOX, which can provide a great current signal to be detected, on the other hand, its special property of absorbing molecules was utilized to load materials as internal reference. Consequently, we chose methylene blue (MB) as the substance that can generate an internal reference signal, because it is a specific and stable electroactive substance. Then, we added MWCNTs as a part of the material modified on the ratiometric electrochemical platform to enhance the signal of the target due to its feature of good electrical conductivity. Under the optimized conditions, the ratiometric electrochemical sensor displayed a wide linear detection with the range from 0.1 µM to 75 µM and the limit of detection (LOD) of 0.051 µM. The applicability of this method in the analysis of actual human saliva samples has been confirmed by the results of selectivity, stability, and reproducibility tests, which was prospective in clinical application.

Parabens and bisphenol A and its structural analogues in over-the-counter medicines from China.

Pharmaceuticals, such as over-the-counter (OTC) medicines, may be an important source of human exposure to several endocrine disruptors, though unnoticed to date. In the present study, we investigated the presence of six parabens and nine bisphenol A (BPA) and its analogues in OTC medicines manufactured in China. Parabens and bisphenols were present in more than 90% of the samples. The total measured concentrations of parabens and bisphenols were in the range of non-detectable (ND) to 213 ng/g and ND to 415 ng/g, respectively. Regarding parabens, methyl paraben (MeP) was the predominant analog, accounting for 43 ± 36% of the total amount, followed by ethyl paraben (EtP) (39 ± 35%), and others (< 10%). Bisphenol F and BPA were the predominant bisphenols, accounting for 24 ± 28% and 22 ± 26% of the total amount, respectively. The median values of estimated daily intakes (EDIs) of parabens and bisphenols were the highest for infants (2.96 and 3.14 ng/kg_bw/day, respectively) and the lowest for adults (0.69 and 0.25 ng/kg_bw/day, respectively); moreover, the EDIs of parabens and bisphenols were higher in Chinese patent medicines than in western pediatric medicines. The hazard quotient (HQ) for sum of MeP and EtP (∑(MeP + EtP)) and BPA in three age groups were within the safe zone (HQ < 0.0004). Monte Carlo simulation was applied to predict the human exposure risk of parabens and bisphenols. The predicted ranges of EDIs of parabens and bisphenols were much wider, and the extreme predicted values were observed in all four age groups, which were higher than the acceptable daily intake. The extreme predicted values of ∑(MeP + EtP) and BPA were indicative of carcinogenic risk in toddlers. These results implied potential risks for the Chinese people existed. Considering the huge export of Chinese traditional medicines and western medicines worldwide, and easy access to OTC medicines for the general population, the presence of parabens, bisphenols, and other environmental contaminants in medicines still need to be monitored.

Clinical Features and Survival of Chinese Children With Trilateral Retinoblastoma During 2006-2019: A Retrospective Multicenter Study.

PURPOSE: To summarize the clinical features and survival of Chinese patients with trilateral retinoblastoma (TRb), which may help guide early diagnosis and more effective treatments. DESIGN: Retrospective case series. METHODS: Clinical records of patients with TRb were reviewed to identify clinical characteristics and outcomes. TRb was diagnosed mainly based on imaging findings of an enlarged solid pineal or sellar mass. Mutation screening was performed using peripheral blood leucocyte DNA from 3 patients. RESULTS: Fourteen patients with TRb were identified from among 3,789 patients with retinoblastoma (0.4%). Thirteen patients had bilateral retinoblastoma and 1 patient had unilateral disease. The follow-up results revealed that 2 patients survived, 3 patients were lost to follow-up, and 9 patients died. The mean overall survival was 9.8 months (95% confidence interval: 2.3-17.2), and the 2-year survival rate was 18.8% (95% confidence interval: 2.9-45.1) based on Kaplan-Meier estimates. Cox regression multivariate analysis showed metastasis at TRb diagnosis was an independent variable of overall survival (hazard ratio: 15.8; 95% confidence interval: 0.24-5.29; P = .032). Three germline mutations in the RB1 gene were detected via next-generation sequencing. CONCLUSIONS: TRb is a rare intracranial mid-line neuroblastic disease. Increased awareness of this disease could guide early detection, which has been associated with improved outcomes.

Bioengineered human pseudoislets form efficiently from donated tissue, compare favourably with native islets in vitro and restore normoglycaemia in mice.

AIMS/HYPOTHESIS: Islet transplantation is a treatment option that can help individuals with type 1 diabetes become insulin independent, but inefficient oxygen and nutrient delivery can hamper islet survival and engraftment due to the size of the islets and loss of the native microvasculature. We hypothesised that size-controlled pseudoislets engineered via centrifugal-forced-aggregation (CFA-PI) in a platform we previously developed would compare favourably with native islets, even after taking into account cell loss during the process. METHODS: Human islets were dissociated and reaggregated into uniform, size-controlled CFA-PI in our microwell system. Their performance was assessed in vitro and in vivo over a range of sizes, and compared with that of unmodified native islets, as well as islet cell clusters formed by a conventional spontaneous aggregation approach (in which dissociated islet cells are cultured on ultra-low-attachment plates). In vitro studies included assays for membrane integrity, apoptosis, glucose-stimulated insulin secretion assay and total DNA content. In vivo efficacy was determined by transplantation under the kidney capsule of streptozotocin-treated Rag1-/- mice, with non-fasting blood glucose monitoring three times per week and IPGTT at day 60 for glucose response. A recovery nephrectomy, removing the graft, was conducted to confirm efficacy after completing the IPGTT. Architecture and composition were analysed by histological assessment via insulin, glucagon, pancreatic polypeptide, somatostatin, CD31 and von Willebrand factor staining. RESULTS: CFA-PI exhibit markedly increased uniformity over native islets, as well as substantially improved glucose-stimulated insulin secretion (8.8-fold to 11.1-fold, even after taking cell loss into account) and hypoxia tolerance. In vivo, CFA-PI function similarly to (and potentially better than) native islets in reversing hyperglycaemia (55.6% for CFA-PI vs 20.0% for native islets at 500 islet equivalents [IEQ], and 77.8% for CFA-PI vs 55.6% for native islets at 1000 IEQ), and significantly better than spontaneously aggregated control cells (55.6% for CFA-PI vs 0% for spontaneous aggregation at 500 IEQ, and 77.8% CFA-PI vs 33.4% for spontaneous aggregation at 1000 IEQ; p < 0.05). Glucose clearance in the CFA-PI groups was improved over that in the native islet groups (CFA-PI 18.1 mmol/l vs native islets 29.7 mmol/l at 60 min; p < 0.05) to the point where they were comparable with the non-transplanted naive normoglycaemic control mice at a low IEQ of 500 IEQ (17.2 mmol/l at 60 min). CONCLUSIONS/INTERPRETATION: The ability to efficiently reformat dissociated islet cells into engineered pseudoislets with improved properties has high potential for both research and therapeutic applications.

Licorice root extract and magnesium isoglycyrrhizinate protect against triptolide-induced hepatotoxicity via up-regulation of the Nrf2 pathway.

Triptolide, the predominant biologically active component of the Chinese herb Tripterygium wilfordii Hook f., possesses numerous pharmacological activities, including anti-inflammatory, anti-fertility, anti-neoplastic, and immunosuppressive effects. However, toxicity and severe adverse effects, particularly hepatotoxicity, limit the clinical application of triptolide. Licorice root extract contains various bioactive compounds and is potent hepatoprotective. Magnesium isoglycyrrhizinate, a magnesium salt of the 18α-glycyrrhizic acid stereoisomer of glycyrrhizic acid, is used clinically in China to treat chronic viral hepatitis and acute drug-induced liver injury. The aim of this study was to investigate the role of the factor erythroid 2-related factor 2 pathway in the protective effects of LE and MIG against triptolide-induced hepatotoxicity. Hepatotoxicity models were established in L-02 cells and rats using triptolide, and the protective effects of LE and MIG were investigated in vitro and in vivo, respectively. LE and MIG significantly protected against triptolide-induced cytotoxicity. Additionally, triptolide decreased the mRNA and protein levels of Nrf2 and down-regulated Nrf2 target genes, including UGT1A, BSEP, and MRP2, while pretreatment with LE and MIG reversed these effects. Finally, Nrf2-involved antioxidant responses were activated in the presence of LE and MIG.

Comparison at the peptide level with post-translational modification consideration reveals more differences between two unenriched samples.

RATIONALE: In shotgun strategies, peptide sequences are first identified from tandem mass (MS/MS) spectra, and the existence and abundance of the proteins are then inferred from the peptide information. However, the protein inference step can produce errors and a loss of information. To identify the information that is lost using the traditional approaches, this study compared the proteomic data of two leukemia cell lines (Jurkat and K562) at the peptide level with consideration of post-translational modifications (PTMs). METHODS: The raw files from the two cell lines were searched against the decoy IPI-human database version 3.68, which contains forward and reverse sequences. Then the observed modification name in the results was matched with the modification classification on the Unimod website by a manual search. Only the peptides with 'post-translational' modifications were compared between the two cell lines. RESULTS: After searching the database with consideration of PTMs, a total of 44046 non-redundant peptides were identified in both the Jurkat and K562 cell lines. Of these peptides, even without specific PTM enrichment, 11.43% of them (with at least two spectra in one cell line) existed in different PTM forms between the two cell lines, and 1.73% of the peptides were modified in both cell lines, but with different modifications or possibly on different sites. CONCLUSIONS: Comparing proteomic data at the peptide level with consideration of PTMs can reveal more differences between two unenriched samples.