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BackgroundCoptis deltoidea C.Y. Cheng et Hsiao (CD), commonly used in the treatment of heat-toxin congestion and excessiveness. However, CD needs to be processed with wine for alleviating the bitter and cold of CD, meanwhile, reducing the gastrointestinal damage. The research assessed the discrepant effects of CD on gastrointestinal system before and after processing with wine, and explore the potential mechanisms.MethodsThe ingredients in CD and CD processed with wine (PCD) were performed on Ultra Performance Liquid Chromatography Mass Spectrometry (UPLC-MS). The mice were treated with CD and PCD once a day for 6 weeks (0.65 and 2.6 g/kg, i.g.). The pathological changes of gastrointestinal tract were evaluated, and the serum inflammatory factors and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) RelA (p65) protein of tissues were determined. The short chain fatty acids (SCFAs) of feces were analyzed by UPLC-MS, the gut microbiota (GM) changes were performed on 16 S rRNA sequencing.ResultsIngredients analysis declared that the alkaloids, flavonoids, phenylpropanoid compounds were the main metabolites in CD and PCD. CD reduced body weight and food intake, and the effect of CD on fecal water content increased first and then decreased with the prolongation of administration time, while its effect on intestinal transport time was exactly the opposite, reduced the SCFAs contents of feces. CD caused different degree of damage to the gastrointestinal tract, and the effect on the small intestine and colon was more obvious, which increased the expression of NF-κB p65 and elevated the inflammatory factors levels. PCD were weaker than that of CD. In addition, CD and PCD can change the composition of GM, and reduced the levels of Lactobacillus, Allobaculum, Ruminococcus, and norank_f_S24-7, increased the levels of Akkermansia, Dorea, Bacteroides, and Blautia at the genus level. However, PCD induced a milder effect of GM dysregulation than that of CD.ConclusionCD can cause damage to the gastrointestinal tract, which may be related to the GM disorders, SCFAs changes-mediated by GM, abnormal NF-κB p65 expression and increased inflammatory factors levels, interestingly, PCD had a lower effect than CD, which may be related to the differences in the types and contents of ingredients in CD after processing. And this study provided data support for the mechanism of processing with wine to alleviate “bitter-cold injury the stomach” of CD.

To date, despite extensive research, the prognosis of advanced osteosarcoma has not improved significantly. Thus, patients experience a reduced survival rate, suggesting that a reevaluation of current treatment strategies is required. Recently, in addition to routine surgery, chemotherapy and radiotherapy, researchers have explored more effective and safer treatments, including targeted therapy, immunotherapy, anti-angiogenesis therapy, metabolic targets therapy, and nanomedicine therapy. The tumorigenesis and development of osteosarcoma is closely related to angiogenesis. Thus, anti-angiogenesis therapy is crucial to treat osteosarcoma; however, recent clinical trials found that it has insufficient efficacy. To solve this problem, the causes of treatment failure and improve treatment strategies should be investigated. This review focuses on summarizing the pathophysiological mechanisms of angiogenesis in osteosarcoma and recent advances in anti-angiogenesis treatment of osteosarcoma. We also discuss some clinical studies, with the aim of providing new ideas to improve treatment strategies for osteosarcoma and the prognosis of patients.

BackgroundThere is a link between cardiovascular diseases and intestinal permeability, but it is not clear. This review aimed to elucidate intestinal permeability in cardiovascular diseases by meta-analysis.MethodsMultidisciplinary electronic databases were searched from the database creation to April 2023. All included studies were assessed for risk of bias according to the Joanna Briggs Institute Critical Appraisal Checklist. The heterogeneity of each study was estimated using the I2 statistic, and the data were analyzed using Review Manager 5.3 and Stata 16.0.ResultsIn total, studies in 13 pieces of literature were included in the quantitative meta-analysis. These studies were conducted among 1,321 subjects mostly older than 48. Patients had higher levels of intestinal permeability markers (lipopolysaccharide, d-lactate, zonulin, serum diamine oxidase, lipopolysaccharide-binding protein, intestinal fatty acid binding protein, and melibiose/rhamnose) than controls (standard mean difference SMD = 1.50; 95% CI = 1.31–1.88; p

Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is an exceedingly rare variant of renal cell carcinoma that has only recently been acknowledged. This neoplasm exhibits a distinct follicular morphology resembling that of the thyroid gland. Immunohistochemical analysis reveals positive expression of PAX8, Vimentin, and EMA, while thyroid-specific markers TG and TTF1 are consistently absent. Furthermore, there is a notable absence of any concurrent thyroid pathology on clinical evaluation. Previous reports have suggested that TLFRCC is an indolent, slow-growing malignancy with infrequent metastatic potential. In this report, we present a case of TLFRCC characterized by remarkable ossification and widespread metastasis, including multifocal pulmonary lesions, involvement of the abdominal wall, and infiltration into the psoas muscle. To our knowledge, this represents only the third documented instance of distant metastasis in thyroid follicular renal carcinoma. The current case demonstrates a therapeutic approach that combines radiotherapy with the utilization of toripalimab, a programmed cell death 1 (PD-1) receptor inhibitor, and pazopanib. This treatment regimen was tailored based on comprehensive genomic profiling, which identified mutations in the POLE (catalytic subunit of DNA polymerase epsilon) and ATM (ataxia-telangiectasia mutated) genes, both of which have been implicated in the pathogenesis of various malignant tumors. These findings represent a novel discovery, as such mutations have never been reported in association with TLFRCC. Thus far, this therapeutic approach has proven to be the most efficacious option for treating metastatic TLFRCC among previously reported, and it also marks the first mention of the potential benefits of radiotherapy in managing this particular subtype of renal cell carcinoma.

Background and aimStandardized approach to postoperative adjuvant therapy for hepatocellular carcinoma (HCC) remains elusive. This study endeavors to examine the effects of postoperative PD-1 adjuvant therapy on the short-term and long-term prognosis of patients at a heightened risk of post-surgical recurrence.MethodsThe data of HCC patients who underwent hepatectomy at our center from June 2018 to March 2023 were collected from the hospital database. Propensity score matching (PSM) was employed to perform a 1:1 match between the postoperative anti-PD-1 antibody group and the postoperative non-anti-PD-1 antibody group. Kaplan-Meier method was utilized to compare the overall survival (OS) and recurrence-free survival (RFS) between the two groups. Cox regression analysis was conducted to identify the prognostic factors affecting patient outcomes. Subgroup analyses were performed for different high-risk factors.ResultsAmong the 446 patients included in the study, 122 patients received adjuvant therapy with postoperative anti-PD-1 antibodies. After PSM, the PD-1 group had postoperative 1-year, 2-year, 3-year, and 4-year OS rates of 93.1%, 86.8%, 78.2%, and 51.1%, respectively, while the non-PD-1 group had rates of 85.3%, 70.2%, 47.7%, and 30.0%. The PD-1 group had postoperative 1-year, 2-year, 3-year, and 4-year RFS rates of 81.7%, 77.0%, 52.3%, and 23.1%, respectively, whereas the non-PD-1 group had rates of 68.4%, 47.7%, and 25.8% in 1-year, 2-year, 3-year. A multifactorial Cox regression analysis revealed that postoperative PD-1 use was a prognostic protective factor associated with OS and RFS. Subgroup analysis results indicated that HCC patients with high recurrence risks significantly benefited from postoperative anti-PD-1 antibody treatment in terms of OS and RFS.ConclusionFor HCC patients with high-risk recurrence factors and undergoing hepatectomy, postoperative adjuvant therapy with anti-PD-1 antibodies can effectively improve their survival prognosis.

BackgroundWith the rapid development of technology, artificial intelligence (AI) has been widely used in the diagnosis and prognosis prediction of a variety of diseases, including cardiovascular disease. Facts have proved that AI has broad application prospects in rapid and accurate diagnosis.ObjectiveThis study mainly summarizes the research on the application of AI in the field of cardiovascular disease through bibliometric analysis and explores possible future research hotpots.MethodsThe articles and reviews regarding application of AI in cardiovascular disease between 2000 and 2023 were selected from Web of Science Core Collection on 30 December 2023. Microsoft Excel 2019 was applied to analyze the targeted variables. VOSviewer (version 1.6.16), Citespace (version 6.2.R2), and a widely used online bibliometric platform were used to conduct co-authorship, co-citation, and co-occurrence analysis of countries, institutions, authors, references, and keywords in this field.ResultsA total of 4,611 articles were selected in this study. AI-related research on cardiovascular disease increased exponentially in recent years, of which the USA was the most productive country with 1,360 publications, and had close cooperation with many countries. The most productive institutions and researchers were the Cedar sinai medical center and Acharya, Ur. However, the cooperation among most institutions or researchers was not close even if the high research outputs. Circulation is the journal with the largest number of publications in this field. The most important keywords are “classification”, “diagnosis”, and “risk”. Meanwhile, the current research hotpots were “late gadolinium enhancement” and “carotid ultrasound”.ConclusionsAI has broad application prospects in cardiovascular disease, and a growing number of scholars are devoted to AI-related research on cardiovascular disease. Cardiovascular imaging techniques and the selection of appropriate algorithms represent the most extensively studied areas, and a considerable boost in these areas is predicted in the coming years.

Cardiovascular disease (CVD) has no socioeconomic, topographical, or sex limitations as reported by the World Health Organization (WHO). The significant drivers of CVD are cardio-metabolic, behavioral, environmental, and social risk factors. However, some significant risk factors for CVD (e.g., a pitiable diet, tobacco smoking, and a lack of physical activities), have also been linked to an elevated risk of cardiovascular disease. Lifestyles and environmental factors are known key variables in cardiovascular disease. The familiarity with smoke goes along with the contact with the environment: air pollution is considered a source of toxins that contribute to the CVD burden. The incidence of myocardial infarction increases in males and females and may lead to fatal coronary artery disease, as confirmed by epidemiological studies. Lipid modification, inflammation, and vasomotor dysfunction are integral components of atherosclerosis development and advancement. These aspects are essential for the identification of atherosclerosis in clinical investigations. This article aims to show the findings on the influence of CVD on the health of individuals and human populations, as well as possible pathology and their involvement in smoking-related cardiovascular diseases. This review also explains lifestyle and environmental factors that are known to contribute to CVD, with indications suggesting an affiliation between cigarette smoking, air pollution, and CVD.

BackgroundColorectal cancer (CRC) remains a major global health concern, with significant morbidity and mortality rates. In this study, we aimed to develop a comprehensive blood indicator based on systemic inflammation and nutritional condition to predict the prognosis of resectable CRC patients.MethodsA retrospective cohort of 210 CRC patients who underwent radical resection at the First Affiliated Hospital of Chongqing Medical University, China, between January 2015 and December 2017, was included in the analysis. Baseline characteristics, preoperative blood markers, including neutrophil count, monocyte count, lymphocyte count, platelets, albumin, and CEA were retrospectively reviewed. Various blood indicators, such as NLR, PLR, MLR, SIRI and OPNI were calculated. The least absolute shrinkage and selection operator (LASSO) method was employed to select indicators to establish a novel comprehensive biomarker (named PSI). Kaplan-Meier survival curves and log-rank tests were used to evaluate the prognostic impact of preoperative OPNI, SIRI, and PSI. Univariate and multivariate Cox regression model were conducted to identify independent prognostic factors for CRC. The receiver operating characteristic (ROC) method assessed the predictive ability of PSI, stage, OPNI, and SIRI.ResultsPatients with higher preoperative OPNI and lower SIRI values had significantly better overall survival (OS). PSI was identified as an independent prognostic factor for OS in both univariate and multivariate analysis. Patients with medium (28.3-43.4) and high (>43.4) PSI scores exhibited superior OS compared to those with low (≤ 28.3) PSI scores. PSI showed higher predictive ability (AUC: 0.734) than individual indicators alone (OPNI: 0.721, SIRI: 0.645, stage: 0.635).ConclusionThe novel indicator, PSI, based on preoperative SIRI and OPNI, demonstrated significant prognostic value for resectable CRC patients. PSI outperformed individual indicators and could serve as a reliable tool for prognostic evaluation in CRC patients.

IntroductionTo investigate the effects of no-tillage with straw mulching on the absorption and utilization of soil nitrogen (N), fertilizer N, and straw N by rice under paddy-upland rotations.MethodsA field experiment with three cropping systems: fallow–rice rotation without straw mulching (FRN), wheat–rice rotation with wheat mulching in rice season (WRS), and oilseed rape–rice rotation with oilseed rape straw mulching in rice season (ORS) was conducted from 2015 to 2017, along with a mini-plot experiment with 15N-labeled urea and straws, which was conducted in 2017.ResultsNo-tillage with straw reduced rice N uptake up to 20 days after transplanting, the total amount of fertilizer N uptake of WRS and ORS rice plants was 46.33 and 61.67 kg/ha, respectively, which was 9.02 and 45.10% higher than that of FRN plants. Soil N was the main source for rice growth, followed by fertilizer N. Soil N uptake by WRS and ORS rice plants was 21.75 and 26.82% higher than that of FRN plants, accounting for 72.37 and 65.47%, respectively, of the total N accumulated in rice plants. Straw mulching increased the N utilization efficiency of tillering, panicle, and total fertilizer by 2.84–25.30%; however, base fertilizer was dependent on straw mulching. The total amount of N released from WRS and ORS straw mulching in the rice season was 34.97 and 24.82 kg/ha, respectively; however, only 3.04 and 4.82% of it was absorbed by the rice plants, accounting for only 0.62 and 0.66% of the total accumulated N.DiscussionNo-tillage with straw mulching under paddy-upland rotations increased the N utilization of rice, especially for the absorption of soil N. These results provide theoretical information for the effective utilization of straw and rational N application practices in rice-based cropping systems.

ObjectivesThis research aims to investigate if cataract extraction lowers the risk of all-cause dementia.MethodsOriginal literature on cataract surgery associated with all-cause dementia as of November 27, 2022, was searched in several commonly used databases. Manual review was used to include eligible studies. Stata software (version 16) was used to perform statistical analysis on pertinent data. Publication bias can be precisely evaluated using funnel plots and Egger's test.ResultsIn the meta-analysis of 4 cohort studies with 245,299 participants. Pooled analysis indicated that cataract surgery was linked to a lower incidence of all-cause dementia (OR = 0.77, 95%CI: 0.66–0.89; I2= 54.7%; P < 0.001). Cataract surgery was linked to a lower risk of AD (OR = 0.60, 95%CI: 0.35–1.02; I2= 60.2%; P < 0.001).ConclusionsCataract surgery is linked to a lower incidence of all-cause dementia and Alzheimer's disease. A cataract is a reversible visual impairment. Cataract surgery may be a protective factor against the onset of all-cause dementia and can reduce the economic and family burden caused by all-cause dementia worldwide. Given the restricted pool of included studies, our findings necessitate meticulous interpretation.Systematic review registrationhttp://www.crd.york.ac.uk/prospero retrieve registration details by searching CRD4202379371.

Inflammatory bowel disease (IBD) mainly includes Crohn’s disease and ulcerative colitis. These diseases have a progressive course of chronic relapse and remission and affect a large number of children and adults worldwide. The burden of IBD is rising worldwide, with levels and trends varying greatly in countries and regions. Like most chronic diseases, the costs associated with IBD are high, including hospitalizations, outpatient and emergency visits, surgeries, and pharmacotherapies. However, there is no radical cure for it yet, and its therapeutic targets still need further study. Currently, the pathogenesis of IBD remains unclear. It is generally assumed that the occurrence and development of IBD are related to the environmental factors, gut microbiota, immune imbalance, and genetic susceptibility. Alternative splicing contributes to a various diseases, such as spinal muscular atrophy, liver diseases, and cancers. In the past, it has been reported that alternative splicing events, splicing factors, and splicing mutations were associated with IBD, but there were no reports on the practical application for clinical diagnosis and treatment of IBD using splicing-related methods. Therefore, this article reviews research progress on alternative splicing events, splicing factors, and splicing mutations associated with IBD.

IntroductionIn China and other Asian nations, Geum japonicum (GJ) is used as functional vegetables or as a type of folk medicine. Ellagic acid (EA) is one of the main active ingredients in GJ and has been utilized in food, cosmetics, and medicinal goods worldwide. Natural deep eutectic solvents (NADESs) have gradually replaced organic solvents for efficient extraction of plant-derived active compounds due to its environmental protection, low toxicity, low solubility, reusability, etc.MethodsNADES with the highest EA yield was selected and the extraction conditions were optimized by response surface methodology (RSM), the antioxidant activity of NADES extract was determined, and finally Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) were used to explain the mechanism for the increase of EA yield in GJ.ResultsIn this work, several NADESs were tailored for the ultrasound assisted extraction (UAE) of EA from GJ, among which choline chloride-oxalic acid (ChCl:Oa) was the most effective. In optimal conditions, ChCl:Oa extract produced higher EA yields than common organic solvents including methanol, ethanol, and acetone. In vitro antioxidant experiments showed that ChCl:Oa extract had stronger DPPH radical scavenging ability than other solvent extracts. Mechanically, FT-IR results indicated that ChCl:Oa could form a hydrogen bonding with EA, which enhanced the stability of EA. Meanwhile, ChCl:Oa-UAE treatment could destroy the tissue structure of GJ, thereby improving EA yield.DiscussionIn conclusion, these results imply that the ChCl:Oa-UAE method might be an environmentally friendly approach for extracting EA from GJ.

Mammalian target of rapamycin (mTOR) inhibitors (sirolimus or everolimus) have been demonstrated effective in reducing the size of tuberous sclerosis complex (TSC)-associated retinal astrocytic hamartoma (RAH) in short term. To investigate the long-term efficacy and safety of sirolimus on TSC-associated RAH, 13 TSC-associated RAH patients (59 RAH lesions) who received sirolimus therapy for at least 2 years were retrospectively enrolled in this study. Changes in the maximal thickness (MT) of RAH on optical coherence tomography and the longest base diameter (LBD) of RAH on color fundus photography were assessed. The results showed that for a mean follow-up of 39 months, sirolimus was associated with a mean reduction of 14.6% in MT and 6.8% in LBD of RAHs. The main impacts of sirolimus occurred within the first 6–12 months, with 14.8% reduction in MT and 4.7% reduction in LBD. Mouth ulceration (10 [76.9%]) and acne (9 [69.2%]) were the most common adverse events. These follow-up data support the long-term use of sirolimus in TSC-associated RAH patients, and persistent use of sirolimus possibly prevents tumor regrowth.

BackgroundOpportunely screening for diabetes is crucial to reduce its related morbidity, mortality, and socioeconomic burden. Machine learning (ML) has excellent capability to maximize predictive accuracy. We aim to develop ML-augmented models for diabetes screening in community and primary care settings.Methods8425 participants were involved from a population-based study in Hubei, China since 2011. The dataset was split into a development set and a testing set. Seven different ML algorithms were compared to generate predictive models. Non-laboratory features were employed in the ML model for community settings, and laboratory test features were further introduced in the ML+lab models for primary care. The area under the receiver operating characteristic curve (AUC), area under the precision-recall curve (auPR), and the average detection costs per participant of these models were compared with their counterparts based on the New China Diabetes Risk Score (NCDRS) currently recommended for diabetes screening.ResultsThe AUC and auPR of the ML model were 0·697and 0·303 in the testing set, seemingly outperforming those of NCDRS by 10·99% and 64·67%, respectively. The average detection cost of the ML model was 12·81% lower than that of NCDRS with the same sensitivity (0·72). Moreover, the average detection cost of the ML+FPG model is the lowest among the ML+lab models and less than that of the ML model and NCDRS+FPG model.ConclusionThe ML model and the ML+FPG model achieved higher predictive accuracy and lower detection costs than their counterpart based on NCDRS. Thus, the ML-augmented algorithm is potential to be employed for diabetes screening in community and primary care settings.

Lung cancer is the malignant tumor with high invasion and metastasis, which seriously threatens public health. Previous study showed that NLRP3 could promote the occurrence of lung tumors in B(a)P-induced mice. MicroRNAs are closely related to the progression and metastasis of lung cancer by regulating target genes. However, which miRNAs affect the migration and invasion of lung cancer cells through regulating NLRP3 remains poorly defined. In this study, the miRNAs targeting NLRP3 were selected from TargetScan and miRDB database and finally miR-223-3p was chosen due to the consistent expression in both A549 and H520 cells. Then, the migration and invasion of lung cancer cells were detected with miR-223-3p mimic and inhibitor using Transwell assay, at the same time the expression of NLRP3, cleaved caspase-1, IL-1β and IL-18 was determined using Western Blot and immunohistochemistry assay. Our data demonstrated that miR-223-3p was upregulated in both A549 and H520 cells. Furthermore, the migration and invasion of A549 and H520 cells were promoted after inhibiting miR-223-3p. Besides, the levels of NLRP3, cleaved caspase-1, IL-1β and IL-18 were increased in the two lung cancer cells. And the corresponding results were contrary in miR-223-3p mimic group. Taken together, miR-223-3p attenuates the migration and invasion of NSCLC cells by regulating NLRP3, which provides evidence for the prevention and targeted treatment of NSCLC.

BackgroundProgression of freezing of gait (FOG), a common pathological gait in Parkinson’s disease (PD), has been shown to be an important risk factor for falls, loss of independent living ability, and reduced quality of life. However, previous evidence indicated poor efficacy of medicine and surgery in treating FOG in patients with PD. Music-based movement therapy (MMT), which entails listening to music while exercising, has been proposed as a treatment to improve patients’ motor function, emotions, and physiological activity. In recent years, MMT has been widely used to treat movement disorders in neurological diseases with promising results. Results from our earlier pilot study revealed that MMT could relieve FOG and improve the quality of life for patients with PD.ObjectiveTo explore the effect of MMT on FOG in patients with PD.Materials and methodsThis was a prospective, evaluator-blinded, randomized controlled study. A total of 81 participants were randomly divided into music-based movement therapy group (MMT, n = 27), exercise therapy group (ET, n = 27), and control group (n = 27). Participants in the MMT group were treated with MMT five times (1 h at a time) every week for 4 weeks. Subjects in the ET group were intervened in the same way as the MMT group, but without music. Routine rehabilitation treatment was performed on participants in all groups. The primary outcome was the change of FOG in patients with PD. Secondary evaluation indicators included FOG-Questionnaire (FOG-Q) and the comprehensive motor function.ResultsAfter 4 weeks of intervention, the double support time, the cadence, the max flexion of knee in stance, the max hip extension, the flexion moment of knee in stance, the comprehensive motor function (UPDRS Part III gait-related items total score, arising from chair, freezing of gait, postural stability, posture, MDS-UPDRS Part II gait-related items total score, getting out of bed/a car/deep chair, walking and balance, freezing), and the FOG-Q in the MMT group were lower than that in the control group and ET group (p < 0.05). The gait velocity, the max ankle dorsiflexion in stance, ankle range of motion (ROM) during push-off, ankle ROM over gait cycle, the knee ROM over gait cycle, and the max extensor moment in stance (ankle, knee) in the MMT group were higher than that in the control group and ET group (p < 0.05). However, no significant difference was reported between the control group and ET group (p > 0.05). The stride length and hip ROM over gait cycle in the MMT group were higher than that in the control group (p < 0.05), and the max knee extension in stance in the MMT group was lower than that in the control group (p < 0.05). Nevertheless, there was no significant difference between the ET group and MMT group (p > 0.05) or control group (p > 0.05).ConclusionMMT improved gait disorders in PD patients with FOG, thereby improving their comprehensive motor function.

PurposeThe aim of this study was to assess the safety and efficacy of microwave ablation combined with apatinib [vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor] and camrelizumab [anti-programmed death-1 (PD-1) antibody] in patients with advanced hepatocellular carcinoma (HCC).Patients and methodsPatients (age, >18 years) with histologically confirmed HCC and refractory to at least the standard first-line therapy were enrolled from 2 September 2018 to 17 January 2022. They first received ultrasound-guided subtotal microwave ablation. Then, beginning at 7–14 days after ablation, they were given apatinib (250 mg once daily) and camrelizumab (200 mg once every 2 weeks) until unacceptable toxicity or disease progression or death. The coprimary end points were progression-free survival (PFS) and overall survival (OS).ResultsFourteen HCC patients with Barcelona Clinic of Liver Cancer (BCLC) B and C stages were retrospectively enrolled. At data cutoff, follow-up period ranged from 3.8 to 41.3 months (median, 17.4 months), and the median (95% confidence interval) duration of exposure (DE) was 6.4 (4.0–8.9) months. The PFS and OS were 10.8 (0–23.5) months and 19.3 (2.4–36.2) months, respectively. Three (21.4%) patients achieved a confirmed complete response (CR). Confirmed partial response (PR), stable disease (SD), and progression of disease (PD) were achieved in four (28.6%), four (28.6%), and three (21.4%) patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were 50.0% (20.0%-80.0%) and 78.6% (54.0%-100%), respectively. The serious treatment-related adverse events included one (7.1%) case with reactive capillary hemangiomas (grade 4), one (7.1%) with hypertension (grade 3), two (14.3%) with elevated transaminase and bilirubin (grade 4), one (7.1%) with platelet count decrease (grade 4), one (7.1%) with hepatic failure (grade 4), and two (14.3%) with gastrointestinal bleeding (grades 3 and 4).ConclusionsMicrowave ablation combined with apatinib and camrelizumab treatment in advanced HCC patients demonstrated intriguing clinical activity and resulted in durable antitumor responses and significantly improved PFS and OS. The combination therapy is well tolerated, enabling further clinical studies.

Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is the first enzyme in the de novo purine nucleotide synthesis pathway and is essential for cell development. However, the effect of PRPS1 on melanoma proliferation and metastasis remains unclear. This study aimed to investigate the regulatory mechanism of PRPS1 in the malignant progression of melanoma. Here, we found PRPS1 was upregulated in melanoma and melanoma cells. In addition, our data indicated that PRPS1 could promote the proliferation and migration and invasion of melanoma both in vitro and in vivo. PRPS1 also could inhibit melanoma cell apoptosis. Furthermore, we found NRF2 is an upstream transcription factor of PRPS1 that drive malignant progression of melanoma.

Leuprolide acetate microspheres developed by Shanghai Livzon Pharmaceutical Co., Ltd. (T) have been marketed in China for more than 10 years, benefiting a large number of patients, and will continue to play an important role in China. However, as a generic drug, it is unclear whether there is a difference in efficacy between T and the original product Enantone® (R). This study compared the differences in efficacy and safety of two 1-month depot formulations in 48 healthy Chinese male subjects by comparing multiple pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The main research indicators were the PK parameters of leuprolide (Cmax, AUC0-t, AUC0-D7, and AUCD7-t) and the PD parameters of testosterone (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) after 42 days of administration. The Cmax, AUC0-t, AUC0-D7 and AUCD7-t of leuprolide were slightly higher in the T group than in the R group with 90% confidence intervals (CIs) of 94.43–118.53%, 109.13–141.88%, 109.53–139.54%, and 105.17–145.74%, respectively. No significant differences in the PD parameters (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) existed between the T and R groups, and 90% CIs were 62.80–93.57%, 88.17–110.55, 95.72%–118.50%, and 79.77–105.63, respectively. At 672 h (D28), the castration rate of T was 91.30% (21/23) and that of R was 60.87% (14/23). The PK characteristics were consistent and the inhibitory effects on testosterone levels were similar in both T and R groups; further, clinical safety was observed for both T and R formulations, suggesting that these two products can replace each other in clinical practice.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier CTR20200641.

BackgroundThe status of circulating tumor cells (CTCs) is related to the recurrence of hepatocellular carcinoma (HCC), which is also one of the reasons for the poor prognosis of HCC. The purpose of this study was to explore whether CTCs can help guide the choice of treatment methods for HCC.MethodsThis study is a multicenter retrospective study, including 602 patients with HCC. CTCs were detected in the overall cohort before operation. There were 361 patients in the training cohort and 241 patients in the validation cohort. Patients were divided into CTC-negative group (CTCs = 0/5 mL) and the CTC-positive group (CTCs ≥ 1/5 mL) according to CTCs status. Subgroup analysis was performed according to CTCs status. We compared overall survival, and recurrence outcomes for HCC patients with different CTC statuses after undergoing radiofrequency ablation (RFA) or surgical resection (SR)ResultsThere was no significant difference in overall survival (OS) and recurrence-free survival (RFS) between the RFA group and SR group for CTC-negative patients in both the training cohort and the validation cohort (P > 0.05). However, among CTC-positive patients, the clinical outcome of patients in the SR group was significantly better than those in the RFA group. CTC-positive patients who underwent RFA had increased early recurrence compared to those who underwent SR. RFA is an independent risk factor for survival and recurrence in CTC-positive HCC patientsConclusionsThe CTC status could serve as an indicator to guide the choice between surgical resection or radiofrequency ablation for early hepatocellular carcinoma. Surgical resection is recommended for CTC-positive patients.

Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders.

Chalkiness, which is highly affected by nitrogen (N) management during grain filling, is critical in determining rice appearance quality and consumer acceptability. We investigated the effects of N application rates 75 (N1), 150 (N2), and 225 (N3) kg ha−1 on the source-sink carbohydrate accumulation and grain filling characteristics of two indica hybrid rice cultivars with different chalkiness levels in 2019 and 2020. We further explored the relationship between grain filling and formation of chalkiness in superior and inferior grains. In this study, carbohydrates in the functional leaves and grains of the two varieties, and grain filling parameters, could explain 66.2%, 68.0%, 88.7%, and 91.6% of the total variation of total chalky grain rate and whole chalkiness degree, respectively. They were primarily concentrated in the inferior grains. As the N fertilizer application rate increased, the chalky grain rate and chalkiness degree of both the superior and inferior grains decreased significantly. This interfered with the increase in total chalky grain rate and chalkiness. Moreover, the carbohydrate content in the functional leaves increased significantly in N2 and N3 compared with that in N1. The transfer of soluble sugar from the leaves to the grains decreased the soluble sugar and increased total starch contents, accelerated the development of grain length and width, increased grain water content, and effectively alleviated the contradiction between source and sink. These changes promoted the carbohydrate partition in superior and inferior grains, improved their average filling rate in the middle and later stages, optimized the uniformity of inferior grain fillings, and finally led to the overall reduction in rice chalkiness.

Background and AimRuptured hepatocellular carcinoma (rHCC) is classified as T4 according to the TNM staging system with a very poor (does not achieve expected) prognosis, which has always been controversial. This study aimed at assessing the specific impact of different tumor diameters on the posttreatment prognosis of BCLC stage 0/A rHCC patients.MethodsData from 258 patients with BCLC stage 0/A HCC treated in our center from January 2008 to December 2017 were collected, including 143 rHCC patients and 115 patients with non-ruptured HCC (nrHCC). With the help of X-tile software, we determined the cutoff value of the tumor diameter in patients with rHCC. Using 8 cm as the cutoff, we divided rHCC patients into Small-rHCC (n = 96) and Large-rHCC (n = 47) groups, compared the prognoses of the S-rHCC and L-rHCC groups, as well as the prognoses of the two groups with the nrHCC group using the Kaplan–Meier method, and screened the prognostic factors of rHCC patients using the multivariate Cox risk model.ResultsThe OS of the S-rHCC group was significantly higher than that of the L-rHCC group [HR = 2.41 (1.60–3.63)], and the OS of the nrHCC group was comparable to that of the S-rHCC group (P = 0.204). In patients treated with surgery only, OS and RFS were also comparable in the S-rHCC nrHCC group. Meanwhile, multivariate Cox regression analysis revealed that alpha-fetoprotein (AFP), alkaline phosphatase (ALP), and the main method of treatment were also prognostic factors for OS in patients with rHCC.ConclusionsRuptured HCC with a relatively small diameter (≤8 cm) can also achieve the same prognosis as nrHCC patients after aggressive treatment. It is also not recommended to include all patients with rHCC in stage T4.

BackgroundLarge hepatocellular carcinoma (LHCC) is highly malignant and prone to recurrence, leading to a poor long-term prognosis for patients. There is an urgent need for measures to intervene in postoperative recurrence. Preoperative Transcatheter Arterial Embolization (TACE) is an effective treatment. However, there is a lack of reliable preoperative indicators to guide the application of preoperative TACE. We, therefore, investigated whether the preoperative status of circulating tumor cells (CTCs) could be used to guide preoperative TACE for HCC treatment.MethodsThis study recruited 361 HCC patients and compared recurrence-free survival (RFS) and overall survival (OS) in patients treated with TACE prior to surgery and those not treated with TACE. Patients were divided into CTC-positive group and CTC-negative group according to CTC status, and the effect of preoperative TACE on RFS and OS was compared in each subgroup.ResultsIn CTC-positive patients, preoperative TACE reduces early recurrence and improves long-term survival. However, HCC patients did not benefit from preoperative TACE for the overall population and CTC-negative patients.ConclusionsPreoperative CTC testing is a reliable indicator of whether HCC patients received TACE preoperatively. CTC positivity was associated with early tumor recurrence, and preoperative TACE could reduce early recurrence and long-term prognosis in CTC-positive patients.

Organizational citizenship behavior (OCB) can foster organizational competitiveness and survival especially, facing a rapidly changing environment. There are some empirical pieces of research that shed light on the effects of OCB on extrinsic rewards, since OCB, through performance appraisal, affects extrinsic rewards which will influence OCB as well. However, researchers have overlooked the reverse effect of extrinsic rewards (i.e., positive verbal rewards) on OCB. It is necessary to explore the mechanism between positive verbal rewards and OCB. This study integrated psychological ownership and affective commitment to form a structural model based on social exchange theory and cognitive evaluation theory. These results show that positive verbal rewards are positively correlated with psychological ownership, psychological ownership is positively correlated with affective commitment and OCB, and affective commitment is positively correlated with OCB. As refers to the mediating effects, psychological ownership fully mediates the relationship between positive verbal rewards and affective commitment. Furthermore, affective commitment plays a partial mediating role in the effect of psychological ownership on OCB. Accordingly, this psychological mechanism between positive verbal rewards and OCB reveals important theoretical and practical implications.

Background and AimTo investigate the effect of preoperative circulation tumor cells (CTCs) on postoperative recurrence and overall survival prognosis of pancreatic head cancer after pancreaticoduodenectomy (PD).MethodsFrom March 2014 to January 2018, 73 patients with pancreatic head cancer underwent radical resection (R0) in Zhongshan People's Hospital. CTCs in peripheral blood of patients with pancreatic head cancer were detected by “Cyttel” method before PD. Seventy-three patients were divided into positive and negative groups according to the positive criteria. To explore the relationship between the clinical data of CTCs and disease-free survival (DFS) and overall survival (OS). Cox proportional hazards model was used to analyzing the risk factors affecting the postoperative recurrence and the survival prognosis of patients.Results41 patients (56.2%) were in the CTC-positive group. Preoperative CTCs were correlated with tumor vascular invasion, CA199 level and postoperative liver metastasis (P < 0.05). Preoperative CTC-positive, lymph node metastasis, vascular invasion, and nerve invasion were independent risk factors for DFS (P < 0.05). Preoperative CTC-positive, tumor diameter > 2 cm and vascular invasion were independent risk factors for OS of patients (P < 0.05).ConclusionThe detection of CTCs before PD is an important factor affecting the DFS and OS of pancreatic head cancer, which is significant in guiding clinical work.

Background and AimThe effect of perioperative blood transfusion (PBT) on the prognosis of patients with ruptured hepatocellular carcinoma (rHCC) with different Barcelona Clinic Liver Cancer (BCLC) stages is not clear. We identified the independent predictors of PBT for postoperative rHCC and investigated the effects of PBT on the prognosis of patients with rHCC at different BCLC stages.MethodsA total of 340 patients who underwent curative hepatectomy for rHCC between January 2010 and March 2018 were abstracted from the databases of two centers. A total of 166 patients underwent PBT. The prognosis of patients who received PBT and those who did not was compared before and after propensity score matching (PSM) in different BCLC stages. Univariate and multivariate Cox regression analyses were also used to identify independent predictors of PBT.ResultsWe divided the 340 patients into two groups: early tumor stage (BCLC-A) n = 196 and advanced tumor stage (BCLC-B/C) n = 144. Overall, the median survival time of the PBT group was lower than that of the nonPBT group before and after PSM. However, in the BCLC-BC group, the prognosis of patients with PBT was not statistically different from that of patients without blood transfusion. Univariate Cox analysis showed that PBT was a risk factor affecting the overall survival (OS) and recurrence-free survival (RFS) in BCLC-A, and PBT was not a risk factor for poor OS and RFS in BCLC-B/C.ConclusionPerioperative blood transfusion has a negative impact on the postoperative prognosis of patients with rHCC in the early stage, but has no significant impact on the postoperative prognosis of patients with rHCC in the advanced stage.

BackgroundThe current diagnosis of Parkinson's disease (PD) is mainly based on the typical clinical manifestations. However, 60% dopaminergic neurons have died when the typical clinical manifestations occur. Predictive neurobiomarkers may help identify those PD patients having non-motor disorders or in different stage and achieving the aim of early diagnosis. Up to date, few if any neuroimaging techniques have been described useful for non-movement disorders diagnosis in PD patients. Here, we investigated the alteration of metabolites in PD patients in different stage of PD and non-motor symptoms including sleep, gastrointestinal and cognitive dysfunction, by using the 1H-MRS.MethodsA total of 48 subjects were included between 2017 and 2019: 37 PD (15 men, age 47–82 years) and 11 healthy people (8 men, age 49–74 years). All participants underwent MRI and multi-voxel 1H-MRS examination within 3 days in admission. Six kinds of metabolites, such as creatine (Cr), N-acetyl aspartate/creatine (NAA/Cr), N-acetyl aspartate/choline (NAA/Cho), choline/creatine (Cho/Cr), lipid/creatine (LL/Cr), and myo-Inositol/creatine ratio (mI/Cr) were tested among the PD group and the control groups. Statistical analyses and correlation analyses were performed by using SPSS. The p < 0.05 was considered statistically significant.ResultsCompared late PD group with a control group or early group, higher Cr ratio and lower NAA/Cr ratio were observed in the late PD group (p < 0.05). The mI/Cr in the late PD group was also lower than that in the early PD group (p < 0.05). Regarding the relationship between metabolites and NMS, Cho/Cr was higher in the sleep disorder group, whereas mI/Cr was lower in the gastrointestinal dysfunction group in comparison with the non-symptom groups. Moreover, Cr, Cho/Cr, mI/Cr, and LL/Cr were identified to have higher concentrations in the cognitive group in thalamus.ConclusionsProton magnetic resonance spectroscopy is an advanced tool to quantify the metabolic changes in PD. Three biomarkers (Cr, NAA/Cr, and mI/Cr) were detected in the late stage of PD, suggesting that these markers might be potential to imply the progression of PD. In addition, subgroups analysis showed that MRS of thalamus is a sensitive region for the detection of cognitive decline in PD, and the alteration of neurochemicals (involving Cr, Cho, mI, and LL) may be promising biomarkers to predict cognitive decline in PD.

Objective: The aim of the study was to develop the early diagnostic criteria for Wilson’s disease (WD) in young children in southern China by using alanine aminotransferase (ALT) elevation as the first manifestation.Methods: A cross-sectional retrospective analysis of the clinical data and genetic test results of children with WD in southern China in the past 4 years and the follow-up of their short-term prognosis were performed in this study.Results: A total of 30 children (5.08 ± 2.06 years old) with elevated ALT as the first manifestation of WD in southern China were enrolled in this study, including 14 females and 16 males. Specifically, in all of the 30 cases (100%), the serum ceruloplasmin (CP) level was decreased, whereas the 24-h urinary copper level was increased. The genetic mutation test of the ATP7B gene was used to confirm the diagnosis. In particular, the two mutation sites, including p.R778L and p.I1148T, had the highest mutation frequencies, approximately 23.0 and 10.7%, respectively. Through follow-up, most of the children had good recovery.Conclusion: Early diagnosis and treatment of WD would substantially increase the survival rate and have a better prognosis. In addition, in 5-year-old children from southern China, early diagnosis could be performed quickly by referring to the following three parameters: elevated ALT, decreased ceruloplasmin level, and increased 24-h urinary copper level. It lays a foundation for further studies with a larger sample size.

Aim: To comprehensively profile the landscape of the mRNA N6-methyladenosine (m6A) modification in human colorectal cancer (CRC).Methods: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was explored to compare the difference in mRNA N6-methyladenosine (m6A) methylation between CRC tissues and adjacent normal control (NC) tissue. RNA-sequencing (RNA-seq) was performed to transcribe differentially expressed mRNAs. Conjoint analysis of MeRIP-seq and RNA-seq data was conducted to predict RNA-binding proteins (RBPs).Results: MeRIP-seq identified 1110 differentially m6A methylated sites (DMMSs) and 980 differentially m6A methylated genes (DMMGs) in CRC, with 50.13% of all modified genes showing unique m6A-modified peaks in CRC. RNA-seq showed 915 upregulated genes and 1463 downregulated genes in CRC. QRT-PCR verified the RNA-seq results by detecting the expression of some mRNAs. Conjoint analysis of MeRIP-seq and RNA-seq identified 400 differentially m6A methylated and expressed genes (DEGs), and pathway analysis detected that DMMGs and DEGs were closely related to cancer. After analyzing these DMMGs and DEGs through the GEPIA database, we found that the expression of B3GNT6, DKC1, SRPK1, and RIMKLB were associated with prognosis, and the expression of B3GNT6 and RIMKLB were associated with clinical stage. 17 RBPs were identified based on the DMMGs and DEGs, among which FXR1, FXR2, FMR1, IGF2BP2, IGF2BP3, and SRSF1 were obviously highly expressed in CRC, and FMR1, IGF2BP2, and IGF2BP3 were closely related to methylation, and might be involved in the development of CRC.Conclusion: This study comprehensively profiled m6A modification of mRNAs in CRC, which revealed possible mechanisms of m6A-mediated gene expression regulation.

Background: The neurological manifestation of Behcet's disease (BD) is known as Neuro-Behcet's disease (NBD). The lack of a specific diagnostic method for NBD renders the diagnosis and treatment of NBD challenging.Methods and Results: We report a boy aged 11 years and 11 months who underwent right-eye intraocular lens implantation, appendectomy, perianal abscess removal, thalidomide therapy, and infliximab infusions for his Crohn disease. Magnetic resonance venography (MRV) and magnetic resonance imaging (MRI) were performed to address the onset of headache during the course of his treatment, and cerebral venous sinus thrombosis was detected. After the diagnosis of NBD, the patient was treated with anticoagulation therapy (nadroparin calcium), low-dose corticosteroids, and an immunosuppressant (cyclophosphamide), and consequently, he recovered.Conclusion: This case report shows that NBD is prone to misdiagnosis and missed diagnosis and should be diagnosed based on clinical manifestations and results from colonoscopy, pathological examination, and MRI or MRV.

Objective: The primary aim of this systematic review was to examine the relationship of polycyclic aromatic hydrocarbon (PAH) exposure with cardiovascular diseases (CVDs) and elaborate the current knowledge and recent advances in the area of PAH and its effects on CVDs and discuss the growing epidemiological evidence linking PAH to CVDs on the health of human populations. In this systematic review, the increased risk of cardiovascular diseases and their relationship with PAHs were discussed in detail.Methods: On 05th April 2021, a systematic literature search was conducted using PubMed/Medline and Web of Science search engines in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The search was limited to articles that were written in English and dealt with human issues. All original peer-review publications were considered for inclusion. Comments, case reports, reviews, duplicated papers, and conference reports were excluded. Data was collected from included papers by two independent reviewers.Results: Conclusively, 20 research articles published between 2005 and 2021 were chosen for the final analysis. The systemic review included 20 studies with a variety of geographical studies. The most common research category among the nominated studies were time-series studies followed by retrospective cohort, cross-sectional, quasi-experimental, panel, and case-control studies. Most of the studies were conducted in the United States, whereas others were showed in various geographical countries around the world, such as Denmark, Germany, Finland, Netherlands, France, China, Norway, Korea, Sweden, Saudi Arabia, and Belgium. Eight studies assessed the association between PAH exposure and CVDs, four articles observed this relationship with blood pressure (BP), two observed association between atherosclerotic CVD and PAH, one congenital heart disease, cardiovascular events, and two with obesity. Furthermore, in some investigations, a favorable association between PAH exposure and hypertension as well as PAH exposure and obesity was found.Conclusion: In conclusion, this systematic review examined the relationship of PAH exposure with CVDs and CVD-related risk factors by searching several digital databases. After a comprehensive literature searches and summarizing findings from 20 articles, the authors concluded that a positive relationship was observed between PAH exposure and CVD risks.

Sepsis and acute lung injury (ALI) are linked to mitochondrial dysfunction; however, the underlying mechanism remains elusive. We previously reported that c-Jun N-terminal protein kinase 2 (JNK2) promotes stress-induced mitophagy by targeting small mitochondrial alternative reading frame (smARF) for ubiquitin-mediated proteasomal degradation, thereby preventing mitochondrial dysfunction and restraining inflammasome activation. Here we report that loss of JNK2 exacerbates lung inflammation and injury during sepsis and ALI in mice. JNK2 is downregulated in mice with endotoxic shock or ALI, concomitantly correlated inversely with disease severity. Small RNA sequencing revealed that miR-221-5p, which contains seed sequence matching to JNK2 mRNA 3’ untranslated region (3’UTR), is upregulated in response to lipopolysaccharide, with dynamically inverse correlation with JNK2 mRNA levels. miR-221-5p targets the 3’UTR of JNK2 mRNA leading to its downregulation. Accordingly, miR-221-5p exacerbates lung inflammation and injury during sepsis in mice by targeting JNK2. Importantly, in patients with pneumonia in medical intensive care unit, JNK2 mRNA levels in alveolar macrophages flow sorted from non-bronchoscopic broncholaveolar lavage (BAL) fluid were inversely correlated strongly and significantly with the percentage of neutrophils, neutrophil and white blood cell counts in BAL fluid. Our data suggest that miR-221-5p targets JNK2 and thereby aggravates lung inflammation and injury during sepsis.

BackgroundThe clinical role of deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) in gastric cancer (GC) is still controversial. We aimed to analyze the relationship between dMMR/MSI-H and clinicopathological features along with survival.MethodsPatients who were diagnosed with GC at the three big cancer centers in China from 2015 to 2020 were evaluated retrospectively. MMR/MSI status was assessed using immunohistochemistry/PCR. Clinical and pathological data were collected from the medical record system.ResultsA total of 196 patients with dMMR/MSI-H status were enrolled for analysis. The prevalence of MSI-H/dMMR in GC was 6.6%. Another 694 proficient MMR (pMMR) GC patients were enrolled for comparison. Compared with pMMR patients, dMMR/MSI-H patients were associated with older age, female predominance, distal location in the stomach, earlier TNM stage, intestinal subtype, better differentiation, and more negative HER2 status. The median overall survival (OS) of the dMMR/MSI-H group was better than that of the pMMR/microsatellite stability (MSS) group (not reached vs. 53.9 months, p = 0.014). Adjuvant chemotherapy had no impact in both disease-free survival (DFS) and OS of dMMR/MSI-H patients (p = 0.135 and 0.818, respectively). dMMR/MSI-H patients had poorer response and progression-free survival (PFS) of first-line chemotherapy, though they were statistically significant (p = 0.361 and 0.124, respectively).ConclusionsdMMR/MSI-H GC patients have specific clinicopathological characteristics and better prognosis than pMMR patients.

The COVID-19 outbreak caused by the Severe Acute Respiratory Syndrome CoronaVirus type 2 (SARS-CoV-2) has spread across the world. However, our understanding of the public responses, in particular in adopting protective behaviors, has been limited. The current study aimed to determine the level of protective behaviors adopted by the residents in China and its association with their cultural attributes. A national cross-sectional online survey was conducted in mainland China from 4th to 13th August 2020. Protective behaviors were assessed as a summed score (ranging from 0 to 40) measured by ten items. The self-report tendency of study participants toward the four cultural attributes (individualism, egalitarianism, fatalism, hierarchy) was rated on a seven-point Likert scale. A total of 17651 respondents returned a valid questionnaire, representing 47.9% of those who accessed the online survey. Most (89.8%) respondents aged between 18 and 45 years in the age range of and 47.7% were male. High levels of protective behaviors (34.04 ± 5.78) were reported. The respondents had high scores in the cultural attributes of hierarchy (Median = 5) and egalitarianism (Median = 5), compared with low scores in individualism (Median = 1) and fatalism (Median = 1). High levels of protective behaviors were associated a higher tendency toward egalitarianism (AOR = 2.90, 95% CI 2.67–3.15) and hierarchy (AOR = 1.66, 95% CI 1.53–1.81) and a low tendency toward fatalism (AOR = 1.79, 95% CI 1.63–1.97) and individualism (AOR = 2.62, 95% CI 2.41–2.85). The cultural attributes explained 17.3% of the variations in the protective behavioral scores. In conclusion, the adoption of protective behaviors is associated a risk culture characterized by high levels of hierarchy and egalitarianism and low levels of individualism and fatalism. Government actions and communication strategies need to adapt to the cultural characteristics of their target audience.

Background: Trichohepatoenteric syndrome (THES) is a rare disease that mainly causes intractable diarrhea. It is classified into THES1 and THES2, which are associated with the tetratricopeptide repeat domain 37 (TTC37) gene and Ski2-like RNA helicase (SKIV2L) gene, respectively. THES is not very prevalent in China or worldwide, but new cases have increasingly been reported.Methods and Results: Here, we report the clinical and genetic information of a 1.5-month-old girl who was admitted to our hospital due to diarrhea and failure to thrive. Whole-exome sequencing (WES) revealed novel compound-heterozygous variants of the SKIV2L gene, c.3602_3609delAGCGCCTG (p.Q1201Rfs*2), and c.1990A > G (p.T664A) as the causative factors, which were confirmed via Sanger sequencing. Upon continuous feeding with an amino-acid formula through a gastric tube and parenteral nutrition, the patient resumed thriving and her stool frequency decreased.Conclusion: We report a girl carrying novel variants of the SKIV2L gene that cause THES2, thereby providing valuable information on the diagnosis of THES2 and expanding the spectrum of disease-causing SKIV2L mutations.

Objective: The aim of this study was to evaluate the treatment efficacy of lateral spinal stenosis through the decompression of the nerve root under a multiple planar endoscope.Methods: From January 2017 to March 2019, 52 patients with lumbar spinal stenosis or lumbar spinal stenosis combined with intervertebral disc herniation had been treated via transforaminal approach spinal endoscopy. Our study retrospectively analyzed the treatment outcome. All patients experienced complications with different degrees of facet joint hyperplasia and ligamentum flavum hyperplasia and hypertrophy. Some patients suffered disc herniation. All patients were treated with percutaneous transforaminal approach multiple planar endoscopic decompression. The visual analog scale (VAS) and the Oswestry Disability Index (ODI) were compared before and after the operation, as were the horizontal foramen areas of the medial margins of the upper and lower pedicles of the vertebral arch. The treatment effectiveness was evaluated.Results: VAS and ODI scores were significantly improved at postoperative 3 days, 3 months, 6 months, and the last follow-up (P < 0.05). The area of the intervertebral foramen was 422.5 ± 159.2 mm2 preoperatively and 890.8 ± 367.7 mm2 postoperatively, the difference was statistically significant (P < 0.05).Conclusion: Percutaneous transforaminal approach multiple planar endoscopic decompression could achieve an accurate and effective decompression of the lumbar lateral spinal canal. This procedure has good short-term effects, and is especially suitable for elderly patients.

In order to explore the clinical characteristics of pediatric patients admitted to the pediatric intensive care unit (PICU) who suffered from hematological neoplasms complicated with acute respiratory distress syndrome (ARDS), we retrospectively analyzed 45 ARDS children with hematological neoplasms who were admitted to the PICU of Shanghai Children's Medical Center from January 1, 2014, to December 31, 2020. The 45 children were divided into a survival group and a non-survival group, a pulmonary ARDS group and an exogenous pulmonary ARDS group, and an agranulocytosis group and a non-agranulocytosis group, for statistical analysis. The main clinical manifestations were fever, cough, progressive dyspnea, and hypoxemia; 55.6% (25/45) of the children had multiple organ dysfunction syndrome (MODS). The overall mortality rate was 55.6% (25/45). The vasoactive inotropic score (VIS), pediatric critical illness scoring (PCIS), average fluid volume in the first 3 days and the first 7 days, and the incidence of MODS in the non-survival group were all significantly higher than those in the survival group (P < 0.05). However, total length of mechanical ventilation and length of hospital stay and PICU days in the non-survival group were significantly lower than those in the survival group (P < 0.05). The PCIS (OR = 0.832, P = 0.004) and the average fluid volume in the first 3 days (OR = 1.092, P = 0.025) were independent risk factors for predicting death. Children with exogenous pulmonary ARDS were more likely to have MODS than pulmonary ARDS (P < 0.05). The mean values of VIS, C-reactive protein (CRP), and procalcitonin (PCT) in children with exogenous pulmonary ARDS were also higher (P < 0.05). After multivariate analysis, PCT was independently related to exogenous pulmonary ARDS. The total length of hospital stay, peak inspiratory pressure (PIP), VIS, CRP, and PCT in the agranulocytosis group were significantly higher than those in the non-agranulocytosis group (P < 0.05). Last, CRP and PIP were independently related to agranulocytosis. In conclusion, children with hematological neoplasms complicated with ARDS had a high overall mortality and poor prognosis. Children complicated with MODS, positive fluid balance, and high VIS and PCIS scores were positively correlated with mortality. In particular, PCIS score and average fluid volume in the first 3 days were independent risk factors for predicting death. Children with exogenous pulmonary ARDS and children with agranulocytosis were in a severely infected status and more critically ill.

BackgroundUniversal salt iodization (USI) was implemented in mainland China in 1996. The prevalence of hyperthyroidism and its risk factors now require examination.MethodsData were acquired from a nationwide Thyroid, Iodine, and Diabetes Epidemiological survey (TIDE 2015–2017) of 78,470 subjects from 31 provinces. Iodine status, and thyroid hormones and antibodies were measured. ResultsAfter two decades of USI, the prevalence of overt hyperthyroidism (OH), Graves’ disease (GD), severe subclinical hyperthyroidism (severe SCH), and mild subclinical hyperthyroidism (mild SCH) in mainland China was 0.78%, 0.53%, 0.22%, and 0.22%, respectively. OH and GD prevalence were higher in women than in men (OH: 1.16% vs. 0.64%, P

The global spread of the novel coronavirus SARS-CoV-2 urgently requires discovery of effective therapeutics for the treatment of COVID-19. The spike (S) protein of SARS-CoV-2 plays a key role in receptor recognition, virus-cell membrane fusion and virus entry. Our previous studies have reported that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) serves as a viral entry inhibitor to prevent several kinds of virus infection. Here, our results reveal that HP-OVA can effectively inhibit SARS-CoV-2 replication and S protein-mediated cell-cell fusion in a dose-dependent manner without obvious cytopathic effects. Further analysis suggests that HP-OVA can bind to both the S protein of SARS-CoV-2 and host angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and disrupt the S protein-ACE2 interaction, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that HP-OVA can serve as a potential therapeutic agent for the treatment of deadly COVID-19.

Immune checkpoint inhibitors (ICIs) have shown potential to improve the prognosis of patients with brain metastasis (BM) caused by advanced cancers. However, controversies still exist in regard to its survival benefits. In the present work, a time series-based meta-analysis based on the phase I/II/III trials and observational studies were performed to investigate the differences in mortality of ICI-treated BM patients. A number of public library databases, including MEDLINE, EMBASE, OVID, and COCHRANE, were systemically searched by March 2019. The quality of included studies was evaluated by the Newcastle-Ottawa Scale (NOS) scoring. Outcome measures here established were mortality and progression-free survival (PFS) at different follow-up endpoints. Survival rates and curve data were pooled for further analysis. To detect the data heterogeneity, subgroup analyses were conducted according to tumor and ICI types. Eighteen studies, 6 trials, and 12 controlled cohorts were assessed, involving a total of 1330 ICI-treated BM patients. The 6-month survival rate and PFS were 0.67 (95%CI: 0.59–0.74) and 0.36 (95%CI: 0.24–0.49), respectively. According to the tumor type (melanoma, NSCLC, and RCC), subgroup analyses indicated that melanoma presented the lowest survival rates among the three groups here selected. In regard to the type of ICIs, the anti-CTLA-4 combined with the anti-PD-1/PD-L1 showed the best survival outcome among these groups. The 12-month survival rate and PFS showed a consistent pattern of findings. In the long-term, the 24-month survival rate and PFS were 0.20 (95%CI: 0.12–0.31) and 0.18 (0.05–0.46) in BM patients. Hence, ICI therapy may be associated with an improved prognosis of BM patients. Nevertheless, current research presented a limited study design. Multicenter randomized trials may later assist in validating ICI-based therapies for a better outcome of BM patients.

Purpose: The expressions of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) are very common in the sera of patients with autoimmune thyroid diseases (AITD). The relationship between thyroid autoantibodies and the occurrence of glucose and lipid metabolic disorders remains unclear. This study was performed to investigate the correlation between the presence of serum TPOAb/TgAb and those metabolic disorders in euthyroid general population.Methods: The data of this study were derived from the Thyroid Disease, Iodine status, and Diabetes National epidemiological (TIDE) survey from all 31 provinces of mainland China. A total of 17,964 euthyroid subjects including 5,802 males (4,000 with TPOAb−TgAb− and 1,802 with TPOAb+/TgAb+) and 12,162 females (8,000 with TPOAb−TgAb− and 4,162 with TPOAb+/TgAb+) were enrolled in this study. The blood glucose and lipid levels were compared between individuals with TPOAb−TgAb− and those with TPOAb+TgAb−, TPOAb−TgAb+, TPOAb+TgAb+.Results: Both fasting blood glucose (FBG) concentration and the proportion of individuals with impaired FBG (IFG) showed the decreased trends in TPOAb−TgAb+ males as compared with TPOAb−TgAb− men. There were significantly lower FBG and higher HDL-C levels as well as tendencies toward decreased incidences of IGT and hypertriglyceridemia in TPOAb−TgAb+ females when compared with TPOAb−TgAb− women. Binary logistic regression analysis further showed that serum TgAb single positivity in males was an independent protective factor for IFG with an OR of 0.691 (95% CI, 0.503–0.949). For females, serum TgAb single positivity was an independent protective factor for hypertriglyceridemia with an OR of 0.859 (95% CI, 0.748–0.987). Trend test showed that with the increase of serum TgAb level, there were significant decreases in the prevalence of IFG among the men with TSH ≤ 2.5 mIU/L and that of hypertriglyceridemia in the women, especially among non-obese females.Conclusion: Serum TgAb single positivity may imply a reduced risk of IFG in euthyroid men and that of hypertriglyceridemia in euthyroid women. The mechanisms for the independent protective roles of TgAb await further investigation.

The broad spectrum of intellectual disability (ID) patients’ clinical manifestations, the heterogeneity of ID genetic variation, and the diversity of the phenotypic variation represent major challenges for ID diagnosis. By exploiting a manually curated systematic phenotyping cohort of 3803 patients harboring ID, we identified 704 pathogenic genes, 3848 pathogenic sites, and 2075 standard phenotypes for underlying molecular perturbations and their phenotypic impact. We found the positive correlation between the number of phenotypes and that of patients that revealed their extreme heterogeneities, and the relative contribution of multiple determinants to the heterogeneity of ID phenotypes. Nevertheless, despite the extreme heterogeneity in phenotypes, the ID genes had a specific bias of mutation types, and the top 44 genes that ranked by the number of patients accounted for 39.9% of total patients. More interesting, enriched co-occurrent phenotypes and co-occurrent phenotype networks for each gene had the potential for prioritizing ID genes, further exhibited the convergences of ID phenotypes. Then we established a predictor called IDpred using machine learning methods for ID pathogenic genes prediction. Using10-fold cross-validation, our evaluation shows remarkable AUC values for IDpred (auc = 0.978), demonstrating the robustness and reliability of our tool. Besides, we built the most comprehensive database of ID phenotyped cohort to date: IDminer http://218.4.234.74:3100/IDminer/, which included the curated ID data and integrated IDpred tool for both clinical and experimental researchers. The IDminer serves as an important resource and user-friendly interface to help researchers investigate ID data, and provide important implications for the diagnosis and pathogenesis of developmental disorders of cognition.

Neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation. However, the mechanism of neuritin in modulating neurite growth has not been elucidated. Here, using yeast two-hybrid we screened and discovered the interaction of neuritin and neuralized (NEURL1), which is an important regulator that can activate Notch signaling through promoting endocytosis of Notch ligand. And then we identified the interaction of neuritin and neuralized by co-immunoprecipitation (IP) assays, and clarified that neuritin and NEURL1 were co-localized on the cell membrane of SH-SY5Y cells. Moreover, neuritin significantly suppressed Notch ligand Jagged1 (JAG1) endocytosis promoted by NEURL1, and then inhibited the activation of Notch receptor Notch intracellular domain (NICD) and decreased the expression of downstream gene hairy and enhancer of split-1 (HES1). Importantly, the effect of neuritin on inhibiting Notch signaling was rescued by NEURL1, which indicated that neuritin is an upstream and negative regulator of NEURL1 to inhibit Notch signaling through interaction with NEURL1. Notably, recombinant neuritin restored the retraction of neurites caused by activation of Notch, and neurite growth stimulated by neuritin was partially blocked by NEURL1. These findings establish neuritin as an upstream and negative regulator of NEURL1 that inhibits Notch signaling to promote neurite growth. This mechanism connects neuritin with Notch signaling, and provides a valuable foundation for further investigation of neuritin’s role in neurodevelopment and neural plasticity.

Leuprolide acetate microspheres developed by Shanghai Livzon Pharmaceutical Co., Ltd. (T) have been marketed in China for more than 10 years, benefiting a large number of patients, and will continue to play an important role in China. However, as a generic drug, it is unclear whether there is a difference in efficacy between T and the original product Enantone® (R). This study compared the differences in efficacy and safety of two 1-month depot formulations in 48 healthy Chinese male subjects by comparing multiple pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The main research indicators were the PK parameters of leuprolide (Cmax, AUC0-t, AUC0-D7, and AUCD7-t) and the PD parameters of testosterone (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) after 42 days of administration. The Cmax, AUC0-t, AUC0-D7 and AUCD7-t of leuprolide were slightly higher in the T group than in the R group with 90% confidence intervals (CIs) of 94.43–118.53%, 109.13–141.88%, 109.53–139.54%, and 105.17–145.74%, respectively. No significant differences in the PD parameters (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) existed between the T and R groups, and 90% CIs were 62.80–93.57%, 88.17–110.55, 95.72%–118.50%, and 79.77–105.63, respectively. At 672 h (D28), the castration rate of T was 91.30% (21/23) and that of R was 60.87% (14/23). The PK characteristics were consistent and the inhibitory effects on testosterone levels were similar in both T and R groups; further, clinical safety was observed for both T and R formulations, suggesting that these two products can replace each other in clinical practice. [ABSTRACT FROM AUTHOR]