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To investigate radiotherapy (RT)-related brain network changes in patients with nasopharyngeal carcinoma (NPC) over time and develop least absolute shrinkage and selection operator (LASSO)-based multivariable normal tissue complication probability (NTCP) models to predict RT-related brain network changes.36 NPC patients were followed up at four timepoints: baseline, within 3 months (acute), 6 months (subacute), and 12 months (delayed) post-RT. 15 comparable healthy controls (HCs) were finally included and followed up in parallel. Functional neuroimaging data, dose-volume parameters of bilateral temporal lobes and Montreal Cognitive Assessment (MoCA) were acquired. Graph theoretical analysis and mixed-design analysis of variance were performed to investigate how the brain global and nodal changes were affected by RT. Multivariate logistic regression NTCP models were developed. LASSO with nested cross-validation strategy was used to select features. The relationships between network changes and MoCA changes were also examined.Significant changes were detected in nodal efficiency (NE) in NPC patients but not in HCs over time. Altered NE was distributed in the bilateral frontal, temporal lobes and the right insula, which showed a "decrease-increase/recovery" pattern over time. Among all models, the model for predicting NE changes of STG.R showed a relatively good performance (area under the receiver operating curve: 0.68), and DOur findings indicate that RT-induced brain injury begin at the acute period and follow a recovery over time. Furthermore, our study presents prediction models for brain dysfunction based on the dosimetric and clinical parameters.

New mononuclear and dinuclear Ru(II) coordination compounds with the 2,7-bisbenzoimidazolyl-naphthyridine ligand have been synthesized and characterized by UV-vis, NMR, and MALDI-TOF. The molecular structures for Ru(II) compounds were determined by single-crystal X-ray diffraction. With the expansion of ligand π-conjugation and the increase in the complexed Ru number, the maximum emission wavelength red-shifted from 696 to 786 nm. The binding mode between complexes and DNA was predicted by molecular docking, which is intercalations and π-π stacking interactions with the surrounding bases. The intercalation mode of DNA binding was then determined by DNA titration and ethidium bromide (EB) displacement experiments. The antigrowth effects of complexes

The mechanism of insulin signaling on browning of white preadipocytes remains unclear. Human and mouse primary subcutaneous white preadipocytes (hsASCs and WT lean and obese msASCs, respectively) were induced to transdifferentiate into beige adipocytes under conditions of intact or blocked insulin signaling, respectively. Level of phosphoinositide-3-kinase (PI3K) after induction of beige adipocytes under conditions of normal insulin signaling, phosphorylated protein kinase B (pAKT), peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC-1α), zinc-fifinger transcriptional factor PRD1-BF1-RIZ1 homologous domain-containing protein 16 (PRDM16), uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein beta (C/EBPβ) were significantly increased. Conversely, when insulin signaling is incompletely inhibited, the expression of the thermogenic and adipogenic factors is significantly reduced, with obvious impairment of adipogenesis. However, phosphorylation level of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and expression level of sirtuin type 1 (SIRT1) had increased. These white preadipocytes from different donors showed similar dynamic change in morphology and molecular levels during the browning. The present data indicate that insulin signaling plays a important role in regulation of browning of hsASCs and msASCs through PI3K-AKT-UCP1 signaling pathway. The insulin-AMPK-SIRT1 pathway was also involved in the adipocytes browning, while its effect is limited.

OBJECTIVE The dynamic adaptive immune responses elicited by the inactivated virus vaccine, CoronaVac, remain elusive. METHODS In a prospective cohort of 100 SARS-CoV-2 naïve healthcare professionals who received two doses of CoronaVac, we analyzed SARS-CoV-2-specific humoral and cellular responses at four different timepoints, including before vaccination (T1), 2 weeks after the first dose (T2), 2 weeks after the booster dose (T3), and 8-10 weeks post the booster dose (T4). SARS-CoV-2-specific antibodies, serum neutralizing activities, peripheral B cells, CD4+ and CD8+ T cells, and their memory subsets were simultaneously measured in this cohort. RESULTS SARS-CoV-2 Spike-specific IgG responses reached the peak (geometric mean titer [GMT] 54827, 30969-97065) after two doses and rapidly declined (GMT 502, 212-1190) at T4, whereas suboptimal IgA responses were detected (GMT 5, 2-9). Spike-specific circulating B cells (0.60%, 0.46-0.73% of total B cells) and memory B cells (1.18%, 0.92-1.44% of total memory B cells) were effectively induced at T3 and sustained over time (0.33%, 0.23-0.43%; 0.87%, 0.05-1.67%, respectively). SARS-CoV-2-specific circulating CD4+ T cells (0.57%, 0.47-0.66%) and CD8+ T cells (1.29%, 1.04-1.54%) were detected at T3. At T4, 0.78% (0.43-1.20%) of memory CD4+ T cells and 0.68% (0.29-1.30%) of memory CD8+ T cells were identified as SARS-CoV-2 specific, while 0.62% (0.51-0.75%) of CD4+ T cells and 0.47% (0.38-0.58%) of CD8+ T cells were SARS-CoV-2 specific terminally differentiated effector memory cells. Furthermore, age and interval between doses affected the magnitude of CoronaVac induced immune responses. SARS-CoV-2 memory CD4+ T cells was strongly associated with both RBD-specific memory B cells (r=0.87, p, Graphical abstract Image 1

Background and Objective. White matter lesions (WMLs) are imaging changes characterized by hyperintensities on T2-weighted or FLAIR images, which are closely related to the decline of cognitive function. However, the etiology and pathogenesis of WMLs remain undetermined. The aim of this study was to analyze the relationship between adiponectin levels and cognitive decline in persons with or without white matter lesions. Method. In the present study, 126 patients, 90 cases in the WML group and 36 cases in the control group, were analyzed to explore the relationship between adiponectin and WMLs. All patients underwent an MRI scan to assess whether white matter lesions happened. And the serum levels of adiponectin were detected by ELISA. Results. In this study, according to Fazekas criteria, WMLs were divided into different severity groups. With the increase of WML score, the level of adiponectin decreased, and linear correlation analysis shows that adiponectin is negatively correlated with the severity of white matter lesions ( p < 0.001 ). And adiponectin level was significantly positively correlated with MoCA score ( p < 0.05 ). Moreover, adiponectin in the WMLs combined with the cognitive impairment group was significantly reduced ( p < 0.01 ). Conclusion. The level of adiponectin is independently associated with WMLs and cognitive function, which suggests that adiponectin may be a protective factor for WMLs and cognitive function.

The change in the left atrial anteroposterior diameter (LAD) after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) has become an independent factor in predicting the postoperative curative effect; however, whether the specific time point of this change is related to the postoperative curative effect is unclear. The purpose of this study was to explore the correlation between the specific time point of LAD change and the recurrence of AF 1 year after RFCA.Patients with AF who underwent RFCA in our hospital from July 2016 to May 2020 were enrolled in the study. The patients were divided into four groups according to the time point when the LAD decreased by 10% after RFCA: group A, first month after RFCA; group B, second month after RFCA; group C, third month after RFCA; group D, unchanged or changed 3 months after RFCA.In the multivariable Cox analyses, the duration of AF, LAD, and persistent AF were independent risk factors for the recurrence of AF. The recurrence rate of AF 1 year after RFCA were significantly lower in groups A (odds ratio [OR], 0.160; 95% confidence interval [CI]: 0.073-0.352; P 0.001) and C (OR, 0.388; 95% CI: 0.156-0.963; P = 0.041) than in the control group.Reduction of LAD within 3 months after operation predicts the success rate of RFCA, with reduction within 1 month after operation having a higher success rate. This indicates the necessity of treatment in patients with AF who do not experience an early reduction in the LAD after RFCA.

Linked colour imaging (LCI) is a novel new image-enhanced endoscopy (IEE) technology that produces bright and vivid images. The aim of this study was to assess the ability of LCI to improve the diagnostic accuracy of early gastric cancer (EGC) relative to white light imaging (WLI). We performed this study on patients undergoing screening endoscopy from 12 medical institutions in China. Patients were randomly assigned to receive WLI followed by LCI or LCI followed by WLI. The primary outcome was to compared the diagnostic accuracy between LCI and WLI for EGC/high-grade intraepithelial neoplasms. Secondary outcomes included the numbers of suspicious lesions, neoplastic lesions and examination time by using LCI detected versus using WLI. A total of 1924 patients were randomly selected, and 1828 were included in the analysis. The diagnostic accuracy for EGC, which was 78.8% by using LCI and 68.4% by using WLI (p < .0001). More suspicious lesions were detected by LCI than by WLI (n = 1235 vs. 1036, p = .031), especially among differentiated EGC (p = .013). LCI greatly shortened the examination time compared with WLI (p = .019). LCI has better accuracy and shorter examination time in diagnosing EGC than WLI (Clinical trial registration: NCT03092414).Key messagesCompared with white light imaging (WLI), the diagnostic accuracy, sensitivity and specificity increased by using LCI.More lesions were detected by LCI alone than by WLI alone, especially among differentiated EGC.LCI may be used as a screening tool for routine clinical observation. Compared with white light imaging (WLI), the diagnostic accuracy, sensitivity and specificity increased by using LCI. More lesions were detected by LCI alone than by WLI alone, especially among differentiated EGC. LCI may be used as a screening tool for routine clinical observation.

Background Serum uric acid (SUA) acts as an antioxidant and abnormally low SUA may raise the risk of developing atherosclerotic disorders. There is a U-shaped association between SUA with cardiovascular diseases (CVDs) in general population. However, the prevalence of hypouricemia and its influence on CVDs in rheumatoid arthritis (RA) remains unclear. Methods This cross-sectional study collected clinical data from a Chinese RA cohort. Hypouricemia was defined as SUA ≤ 3.0 mg/dL, and hyperuricemia was defined as SUA ≥ 7.0 mg/dL. CVDs were defined as a history of angina pectoris, myocardial infarction, heart failure, stroke and peripheral arterial disease. Restricted cubic spline regression and logistic regression analysis were conducted to evaluate the associations between SUA levels and CVDs. Results Among 1130 RA patients recruited, the mean age was 53.2 years and 79.0% were female. The prevalence of hypouricemia and hyperuricemia were 10.6% and 12.0%, respectively. RA patients with hyperuricemia had a higher rate of CVDs than normouricemic patients (27.9% vs. 7.1%, P P Pnon-linear Conclusions Hypouricemia may be a potential risk factor of CVDs in RA patients

Dysregulation of alternative splicing (AS) induced by serine/arginine-rich proteins has recently been linked to cancer metastasis. Nonetheless, as a member of the serine/arginine-rich protein family, the involvement of SRSF11 in colorectal cancer (CRC) is unknown.The TCGA dataset and clinical samples were used to assess SRSF11 expression levels in CRC. For SRSF11, functional experiments were conducted both in vitro and in vivo. RNA-seq technology was used to analyze and screen SRSF11-triggered AS events, which were then confirmed by in vivo UV crosslinking and immunoprecipitation (CLIP) and mini-gene reporter assays. Jalview software was used to determine the preferential binding motif with relation to exon skipping (ES) events. Furthermore, coimmunoprecipitation (Co-IP) and Phospho-tag SDS-PAGE experiments were used to investigate PAK5-mediated phosphorylation regulation on SRSF11, and in vitro kinase experiments validated the interaction.In CRC, SRSF11 was discovered to be overexpressed and associated with a poor prognosis. And SRSF11 played a pro-metastatic role in vitro and in vivo. By screening SRSF11-regulated AS events, we identified the binding motif of SRSF11-triggered splicing-switching of HSPA12A AS, which specifically regulated HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the HSPA12A transcript with exon 2 retention increased N-cadherin expression by promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated SRSF11 at serine 287, protecting it from ubiquitination degradation.SRSF11 exerts pro-metastatic effects in CRC by inhibiting the AS of HSPA12A pre-RNA. Our findings point to SRSF11-regulated HSPA12A splicing as a novel relationship between SRSF11-regulated splicing and CRC metastasis and suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and prognostic biomarker in CRC.

Industrialization and urbanization are critical paths to modernization for a country or region. The coordination of industrialization and urbanization fosters the development of a regional economy. In academic circles, this is usually measured by the IU ratio (ratio of labor industrialization rate to urbanization rate) and the NU ratio (ratio of non-agricultural employment rate to urbanization rate). However, these methods are inapplicable to large countries’ inland areas. The traditional methods failed to explain the real situation and produced contradictory results. The IU ratio shows that industrialization lags behind urbanization, while the NU ratio shows that industrialization is ahead of urbanization. According to studies conducted in the Sichuan Province of China, through comparison with Jiangsu Province, it is found that the non-agricultural employment growth is not dependent on the development of local industrialization, and rural-urban migration is not entirely dependent on the evolution of the non-agricultural employment rate. Other factors that promote urbanization, such as the country’s capital policies and funds for migrant labor force transfer, should also be considered. This research attempts to improve the traditional methods for measuring the degree of urbanization and industrialization synergy in inland areas. The new empirical approach can effectively identify the critical characteristics of urbanization in inland provinces, such as the development of non-agricultural employment with external assistance and urban migrants “unrelated to employment opportunities”. Based on these key characteristics, it can provide the basis for local urbanization policy formulation.

The main contents of the Clinical Practice Guidelines on Image-Guided Thermal Ablation (IGTA) of Primary and Metastatic Lung Tumors (2022 Edition) include the following: epidemiology of primary and metastatic lung tumors; the concepts of the IGTA and common technical features; procedures, indications, contraindications, outcomes evaluation, and related complications of IGTA on primary and metastatic lung tumors; and limitations and future development.

Aberrant expression of long noncoding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) has been detected in human colorectal cancer (CRC). This study aimed to investigate the role of CDKN2B-AS1 and the underlying mechanism in human CRC. Gain- and loss-of-function assays were performed to explore the role of CDKN2B-AS1 in the malignant behavior of HCT116 and SW480 CRC cells in vitro and in vivo. RNA pull-down assay was conducted to identify the target of CDKN2B-AS1 in CRC cells. The physical and functional interactions between CDKN2B-AS1 and the target were examined. CDKN2B-AS1 inhibited CRC cell proliferation and migration while promoting apoptosis in vitro via activation of mitogen-activated protein kinase kinases (MEK)/extracellular signal-regulated kinase (ERK)/p38 signaling. CDKN2B-AS1 bound to mitogen-activated protein kinase (MAPK) inactivator dual-specificity phosphatase 1 (DUSP1) in CRC cells. In contrast to CDKN2B-AS1, DUSP1 promoted CRC cell proliferation, suppressed apoptosis and inactivated MEK/ERK/p38 signaling in CRC cells. Furthermore, CDKN2B-AS1 overexpression attenuated DUSP1 expression in normal colonic myofibroblasts and CRC cells. Overexpression of DUSP1 effectively countered the activation of MEK/ERK/p38 signaling induced by CDKN2B-AS1 overexpression or further blocked MEK/ERK/p38 signaling suppressed by CDKN2B-AS1 silencing. In the mouse xenograft model, CDKN2B-AS1 suppressed CRC growth, whereas DUSP1 promoted CRC growth. CDKN2B-AS1 induced cell apoptosis while suppressing EMT (epithelial–mesenchymal transition), whereas DUSP1 suppressed cell apoptosis while inducing EMT in CRC, as evidenced by the alterations in the protein levels of apoptosis and EMT markers in tumor tissue samples. CDKN2B-AS1 regulates CRC cell growth and survival by targeting MAPK inactivator DUSP1.

[Formula: see text] Alternative splicing (AS) can generate distinct transcripts and subsequent isoforms that play differential functions from the same pre-mRNA. Recently, increasing numbers of studies have emerged, unmasking the association between AS and cancer. In this review, we arranged AS events that are closely related to cancer progression and presented promising treatments based on AS for cancer therapy. Obtaining proliferative capacity, acquiring invasive properties, gaining angiogenic features, shifting metabolic ability, and getting immune escape inclination are all splicing events involved in biological processes. Spliceosome-targeted and antisense oligonucleotide technologies are two novel strategies that are hopeful in tumor therapy. In addition, bioinformatics applications based on AS were summarized for better prediction and elucidation of regulatory routines mingled in. Together, we aimed to provide a better understanding of complicated AS events associated with cancer biology and reveal AS a promising target of cancer treatment in the future.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second most common cause of cancer deaths. This study aimed to explore the inhibitory effect and mechanism of Aidi injection (ADI) combined with doxorubicin (DOX) in HCC treatment. The drug concentrations in the combined therapy was determined by investigating the effect of various concentrations of ADI and DOX on the viability of H22 cells. The combination index was also calculated. A metabolomic strategy based on a ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform was established to analyze the metabolites. As a result, the combination index values were less than 1, indicating that the combination of ADI and DOX exerted a synergistic effect on HCC treatment. The combination of 40‰ ADI and 1 μmol/l DOX had the strongest inhibitory effect and was used for subsequent metabolomic analysis. A total of 19 metabolic markers were obtained in metabolomic analysis, including amino acids (l-glutamic acid, l-arginine and l-tyrosine), organic acids (succinic acid and citric acid), adenosine and hypoxanthine. Compared with the treatment using DOX or ADI alone, the combined therapy further regulated the levels of metabolic markers in HCC, which may be the reason for the synergistic effect. Seven metabolic pathways were significantly enriched, including phenylalanine, tyrosine and tryptophan biosynthesis, d-glutamine and d-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, the tricarboxylic acid cycle and purine metabolism. These findings demonstrated that ADI combined with DOX can effectively inhibit the viability of H22 cells, which may exert a synergistic antitumor effect by balancing the metabolism of amino acids and energy-related substances.

Antioxidants are healthy substances that are beneficial to the human body and exist mainly in natural and synthetic forms. Among many kinds of antioxidants, the natural antioxidants have great applications in many fields such as food chemistry, medical care, and clinical application. In recent years, many efforts have been made for the determination of natural antioxidants. Nano-electrochemical sensors combining electrochemistry and nanotechnology have been widely used in the determination of natural antioxidants due to their unique advantages. Therefore, a large number of nanomaterials such as metal oxide, carbon materials, and conducting polymer have attracted much attention in the field of electrochemical sensors due to their good catalytic effect and stable performance. This review mainly introduces the construction of electrochemical sensors based on different nanomaterials, such as metallic nanomaterials, metal oxide nanomaterials, carbon nanomaterials, metal-organic frameworks, polymer nanomaterials, and other nanocomposites, and their application to the detection of natural antioxidants, including ascorbic acid, phenolic acids, flavonoid, tryptophan, citric acid, and other natural antioxidants. In the end, the limitations of the existing nano-sensing technology, the latest development trend, and the application prospect for various natural antioxidant substances are summarized and analyzed. We expect that this review will be helpful to researchers engaged in electrochemical sensors.

Dyslipidemia is one of the complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and it is often underestimated and undertreated. Dyslipidemia in allo-HSCT recipients has been confirmed to be associated with endocrine dysfunction, acute and chronic graft-versus-host disease (aGVHD and cGVHD), immunosuppressive agent application, etc. However, few studies have illustrated the accurate molecular signaling pathways involved in dyslipidemia, and there are no standard guidelines for dyslipidemia management after HSCT. This review will discuss the pathogenesis of dyslipidemia, especially the association with aGVHD and/or cGVHD. Comprehensive treatment methods for dyslipidemia after HSCT will also be summarized.

BackgroundAssociations between rheumatoid arthritis (RA) and reduced skeletal muscle have been studied, and we firstly reported myopenia independently predict one-year radiographic progression in RA. Myokine myostatin can negatively regulate skeletal muscle mass and promote osteoclast differentiation. However, there is no report about their relationships in RA patients. We firstly explored the relationship of serum myostatin and disease characteristics, as well as aggravated joint destruction during one-year follow-up.MethodsConsecutive RA patients were recruited from a real-world prospective cohort and completed at least one-year follow-up. Baseline serum level of myostatin was measured by enzyme-linked immunosorbent assay. Clinical data in RA patients as well as muscle index in both RA patients and healthy controls were collected. One-year radiographic progression as primary outcome was defined by a change in the total Sharp/van der Heijde modified score ≥0.5 units.ResultsTotally 344 RA patients (age 47.9 ± 12.5 years, 84.0% female) and 118 healthy control subjects (age 42.8 ± 11.3 years, 74.6% female) were recruited. Compared with healthy controls, RA patients showed a higher level of serum myostatin at baseline (3.241 ± 1.679 ng/ml vs. 1.717 ± 0.872 ng/ml, P2vs. 6.5 ± 1.0 kg/m2, Pvs. 18.6%, Pvs. 10.3%-31.4%, PAOR=3.451, 95%CI: 2.016-5.905) and myopenia (AOR=2.387, 95%CI: 1.416-4.022) at baseline were risk factors for one-year radiographic progression, especially for those with high myostatin overlapping myopenia (AOR=10.425, 95%CI: 3.959-27.450) as the highest-risk individuals among four subgroups. Significant synergistic interaction effect was observed between high myostatin and myopenia on one-year radiographic progression (AP=66.3%, 95%CI: 43.2%-89.3%).ConclusionMyostatin is a novel predictor of aggravated joint destruction in RA patients which has synergistic interaction with myopenia for predicting value.

Hydrogen peroxide (HThe H5 min bleaching treatment contributed to 60% of the bleaching effect maximum, the 10 min effect was close to 15 min effect. Meanwhile, the microhardness reduced and roughness increased under a treatment which was longer than 20 min. Tooth pulp chamber temperature was keeping in a safe range within 20 min treatment.5-10 min was the best treatment time from which we can get an ideal tooth bleaching effect and less influence on tooth enamel and pulp tissue when using cold plasma and H

Photothermal therapy (PTT) is an emerging paradigm for the degradation of amyloid-β (Aβ) aggregations and has become an effective way of treating Alzheimer's disease (AD). A promising PTT therapeutic option requires control of at least two key functional aspects: controllable photoactivity and specific activation. In this work, a near-infrared (NIR)-activated thermo-switchable biopolymeric PTT agent was designed and synthesized by conjugating a molecular rotor-based boron dipyrromethene photosensitizer (BDP) to a temperature-responsive polymer backbone of biopolymeric hydroxypropyl cellulose (HPC). The as-synthesized BDP-HPC exhibited an ultra-high PCE of 78.1% along with prominent cycling stability of phase-transition behavior under NIR irradiation in the light of the lower critical solution temperature (LCST at 42.5 °C). Importantly, the NIR irradiation can manipulate the reversible phase transition behavior of the resultant BDP-HPC that reveals high effectiveness in inhibiting Aβ aggregation together with the obvious ability to dissociate Aβ aggregations. Our work reveals an accurate modulation strategy for versatile and high-performance AD treatment.

Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.

Objective The aim of this study was to investigate whether treatment with minimally invasive transforaminal lumbar interbody fusion (Mis‐TLIF) causes patients suffering from lumbar spinal stenosis (LSS) to experience less anxiety and better clinical efficacy than open transforaminal lumbar interbody fusion (TLIF). Methods In this retrospective cohort study, we analyzed 86 patients, including 46 male patients and 41 female patients, who suffered from single‐segmental lumbar spinal stenosis in our department between January 2016 and January 2018. They were divided into two groups: a control group (n = 46), for patients who underwent open TLIF surgery, and an experimental group (n = 40), for patients who underwent Mis‐TLIF surgery. All patients were evaluated based on operation time, intraoperative blood loss, hospital stay, visual analogue scale (VAS), Oswestry disability index (ODI), hospital anxiety depression scale (HADS), fusion rate, and complications (screw misplacement and loosening, cerebrospinal fluid leakage, infection, and delayed wound healing). Patient characteristics were compared within and between groups. Results The average incision length was 3.64 ± 0.476 cm in the experimental group, which was smaller than that (8.11 ± 2.406 cm) in the control group (P 0.05). The low back pain VAS scores on postoperative day 3 and at 3, 6, and 12 months postoperatively were 5.000 ± 0.987, 4.075 ± 0.997, 2.150 ± 0.834, and 1.450 ± 0.639 in the experimental group, respectively; these scores were lower than those in the control group (6.870 ± 1.572, P 0.05). The ODI scores at postoperative months 3, 6, and 12 were 25.225% ± 5.554%, 20.150% ± 7.698%, and 16.125% ± 9.565% in the experimental group; these scores were lower than those in the control group (49.130% ± 14.805%, P 0.05). However, the mean HADS scores on postoperative day 3 in the experimental group was 8.500 ± 2.000, decreasing obviously compared to the preoperative scores (P 0.05). The HADS scores in the experimental group was lower than that in the control group on postoperative day 3 (P, Mis‐TLIF could result in patients experiencing less anxiety than those undergoing open TLIF because of the smaller incision required. The reduced anxiety is correlated with better outcomes.

Age-related macular degeneration (AMD) is resulted from choroidal neovascularization (CNV)-mediated cicatrization and vision loss. The sustained retinal hypoxia in retinal pigment epithelium (RPE) cells was reported to contribute to CNV. However, the underlying genetic regulatory network of hypoxia response in RPE is not fully understood. In this study, human ARPE-19 RPE cells were cultured under the anoxia for 24 h and later re-oxygenated in normoxia. Then the transcriptome was investigated via high throughput sequencing. We observed that long non-coding RNA (lncRNA) histone deacetylase 4 antisense RNA 1 (HDAC4-AS1) was increased in hypoxic condition compared to normal control and decreased after re-oxygenation addition, while the change of HDAC4 expression was reduced in hypoxic condition compared to normal control and up-regulated after re-oxygenation addition in ARPE-19 cells. Furthermore, HDAC4-AS1 knockdown could suppress the transcription activity of HDAC4 only in hypoxia condition, and fluorescence in situ hybridization and pull down assay indicated that transcripts of HDAC4-AS1 could substantially bind to the promoter of HDAC4 and facilitate the recruitment of HIF-1α. Finally, we also determined the specific regions of HDAC4-AS1 that contribute to the interaction with HIF-1α and the promoter of HDAC4. Taken together, these outcomes declared that HDAC4-AS1 could inhibit HDAC4 expression through regulating HIF-1α in human ARPE-19 cells with hypoxic stress., Graphical abstract

Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.

CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.

Background Few safety and effectiveness results have been published regarding the administration of tenofovir alafenamide fumarate (TAF) during pregnancy for the prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV). Methods In this multicenter prospective observational study, pregnant women with HBV DNA levels higher than 200 000 IU/mL who received TAF or tenofovir disoproxil fumarate (TDF) from gestational weeks 24–35 to delivery were 1:1 enrolled and followed until postpartum month 6. Infants received immunoprophylaxis. The primary endpoint was the safety of mothers and infants. The secondary endpoint was the hepatitis B surface antigen (HBsAg)-positive rate at 7 months for infants. Results In total, 116 and 116 mothers were enrolled, and 117 and 116 infants were born, in the TAF and TDF groups, respectively. TAF was well tolerated during a mean treatment duration of 11.0 weeks. The most common maternal adverse event was nausea (19.0%). One (0.9%), 3 (2.6%), and 9 (7.8%) mothers had abnormal alanine aminotransferase levels at delivery and at postpartum months 3 and 6, respectively. The TDF group had safety profiles that were comparable to those of the TAF group. No infants had birth defects in either group. The infants’ physical and neurological development at birth and at 7 months in the TAF group were comparable with those in the TDF group. The HBsAg positive rate was 0% at 7 months in all 233 infants. Conclusions Antiviral prophylaxis with TAF was determined to be generally safe for both mothers and infants and reduced the MTCT rate to 0%.

Drug–drug interactions (DDIs) prediction is a challenging task in drug development and clinical application. Due to the extremely large complete set of all possible DDIs, computer-aided DDIs prediction methods are getting lots of attention in the pharmaceutical industry and academia. However, most existing computational methods only use single perspective information and few of them conduct the task based on the biomedical knowledge graph (BKG), which can provide more detailed and comprehensive drug lateral side information flow. To this end, a deep learning framework, namely DeepLGF, is proposed to fully exploit BKG fusing local–global information to improve the performance of DDIs prediction. More specifically, DeepLGF first obtains chemical local information on drug sequence semantics through a natural language processing algorithm. Then a model of BFGNN based on graph neural network is proposed to extract biological local information on drug through learning embedding vector from different biological functional spaces. The global feature information is extracted from the BKG by our knowledge graph embedding method. In DeepLGF, for fusing local–global features well, we designed four aggregating methods to explore the most suitable ones. Finally, the advanced fusing feature vectors are fed into deep neural network to train and predict. To evaluate the prediction performance of DeepLGF, we tested our method in three prediction tasks and compared it with state-of-the-art models. In addition, case studies of three cancer-related and COVID-19-related drugs further demonstrated DeepLGF’s superior ability for potential DDIs prediction. The webserver of the DeepLGF predictor is freely available at http://120.77.11.78/DeepLGF/.

Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 μg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.

Creatinine, as a significant biomarker for kidney, thyroid, and muscle dysfunction-related diseases, detection is of great important meaning. In this paper, an enzyme-nanozyme cascade sensing platform was developed for visual creatinine detection. Perovskite oxide BiFeO

PURPOSE: To establish a machine-learning (ML) model based on coronary computed tomography angiography (CTA) images for evaluating myocardial ischemia in patients diagnosed with coronary atherosclerosis. METHODS: This retrospective analysis includes CTA images acquired from 110 patients. Among them, 58 have myocardial ischemia and 52 have normal myocardial blood supply. The patients are divided into training and test datasets with a ratio 7 : 3. Deep learning model-based CQK software is used to automatically segment myocardium on CTA images and extract texture features. Then, seven ML models are constructed to classify between myocardial ischemia and normal myocardial blood supply cases. Predictive performance and stability of the classifiers are determined by receiver operating characteristic curve with cross validation. The optimal ML model is then validated using an independent test dataset. RESULTS: Accuracy and areas under ROC curves (AUC) obtained from the support vector machine with extreme gradient boosting linear method are 0.821 and 0.777, respectively, while accuracy and AUC achieved by the neural network (NN) method are 0.818 and 0.757, respectively. The naive Bayes model yields the highest sensitivity (0.942), and the random forest model yields the highest specificity (0.85). The k-nearest neighbors model yields the lowest accuracy (0.74). Additionally, NN model demonstrates the lowest relative standard deviations (0.16 for accuracy and 0.08 for AUC) indicating the high stability of this model, and its AUC applying to the independent test dataset is 0.72. CONCLUSION: The NN model demonstrates the best performance in predicting myocardial ischemia using radiomics features computed from CTA images, which suggests that this ML model has promising potential in guiding clinical decision-making.

Introduction The basis of orthodontic tooth movement (OTM) is the reconstruction of periodontal tissue under stress. Increasing the speed of OTM has always been the focus of attention. Objectives Periodontal ligament stem cells (PDLSCs) are direct effector cells of mechanical force, but the mechanism by which PDLSCs sense mechanical stimuli is unclear. Methods Human PDLSCs (hPDLSCs) were analyzed in the presence or absence of force loading with the Flexcell loading system in vitro. Then, periodontal tissues were analyzed after mechanical stimulation in vivo. In addition, cells in a confined microenvironment were analyzed to observe changes in the cytoskeleton and migration. Finally, TRPC6−/− mice were used to further verify the effect of TRPC6. After force application, the OTM distance, bone marrow density (BMD), TRPC6 and COL1 expression, and TRAP staining were evaluated in periodontal tissues. Results RNA sequencing (RNA-seq) and western blot analyses revealed that TRPC6 was important during mechanical force application to hPDLSCs. Appropriate mechanical force application also induced TRPC6 activation in the OTM model and the confined microenvironment. Under a slightly confined microenvironment, treatment with the TRPC6 inhibitor SKF96365 and TRPC6 knockout decreased the migration speed of hPDLSCs and mouse bone marrow mesenchymal stem cells (mBMSCs). In addition, TRPC6−/− mice showed lower OTM distances and reduced osteogenic and osteoclastic differentiation. Conclusion In summary, TRPC6 activation in PDLSCs mediated by appropriate mechanical force application contributes to periodontal tissue reconstruction. Graphical abstract PDLSCs modulate periodontal tissue remodeling under appropriate mechanical stimulation through TRPC6; however, under excessive stress, alveolar bone and tooth roots are readily absorbed. Under this condition, environmental factors play a leading role, and the regulatory effect of TRPC6 is not obvious.

Conventional methods used to control bacterial biofilm infection in root canals have poor efficacy, causing repeated and chronic infections, which pose a great challenge to clinical treatment. Microbubbles, due to their small size and ultrasound (US)-enhanced cavitation effects, have attracted considerable clinical attention. They possess the potential for therapeutic application in restricted spaces. We address the above problem with a strategy for the restricted space of root canals. Herein, phase-change nanodroplets (P-NDs) exposed to US are combined with common antibacterial drugs to disrupt a 7 day

The ratio of mean platelet volume (MPV) to count (PC) (MPV/PC) has been applied in the diagnosis and prognosis of various malignancies. However, the prognostic value of MPV/PC in gastric cancer has not been studied yet. This study aims to explore the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), combined neutrophil-platelet score (CNPS), systemic immune-inflammation index (SII) and MPV/PC in patients with resectable gastric cancer. In this study, the medical records of patients with gastric cancer in two centers were retrospectively analyzed. Kaplan–Meier and log-rank were tests applied to analyze the survival differences of patients with various inflammation indexes. A nomogram prognostic model was established to predict the 3- and 5-year survival rate of patients with resectable gastric cancer. In the two cohorts, Kaplan–Meier analysis that the postoperative survival time of gastric cancer patients with low MPV/PC, high NLR, high PLR and high SII was significantly shorter than that of patients with high MPV/PC, low NLR, low PLR or low SII. Compared with NLR, PLR, SII and CNPS, MPV/PC was more accurate in determining the prognosis of patients with gastric cancer than other indexes, and multivariate analysis confirmed that MPV/PC was an independent prognostic factor for patients with resectable gastric cancer. The nomogram model established based on tumor size, TNM stage and MPV/PC was more accurate than TNM stage in predicting the 3- and 5-year survival rate of patients with resectable gastric cancer. Preoperative MPV/PC is a new independent prognostic index and a potential marker for treatment response monitoring in patients with resectable gastric cancer. The nomogram model for postoperative prognosis of gastric cancer established based on MPV/PC, tumor size and TNM stage is helpful for developing more accurate and timely individualized therapeutic regimens.

Among the most common types of brain tumor, gliomas are the most aggressive and have the poorest prognosis. Dolichyl-diphosphooligosaccharide protein glycosyltransferase non-catalytic subunit (DDOST) encodes a component of the oligosaccharide transferase complex and is related to the N-glycosylation of proteins. The role of DDOST in gliomas, however, is not yet known. First, we performed a pan cancer analysis of DDOST in the TCGA cohort. The expression of DDOST was compared between glioma and normal brain tissues in the GEO and Chinese Glioma Genome Atlas (CGGA) databases. In order to explore the role of DDOST in glioma, we analyze the impact of DDOST on the prognosis of glioma patients, with the CGGA 325 dataset as a test set and the CGGA 693 dataset as a validation set. Immunohistochemistry was performed on tissue microarrays to examine whether DDOST has an impact on glioma patient survival. Next, using single-cell sequencing analysis, GSEA, immune infiltration analysis, and mutation analysis, we explored how DDOST affected the glioma tumor microenvironment. Finally, we evaluated the clinical significance of DDOST for glioma treatment by constructing nomograms and decision curve analysis (DCA) curves. We found that DDOST was overexpressed in patients with high grade, IDH wild type, 1p19q non-codel and MGMT un-methylated, which was associated with poor prognosis. Patients with high levels of DDOST, regardless of their clinical characteristics, had a worse prognosis. Immunohistochemical analysis confirmed the results of the above bioinformatics analysis. Mechanistic analysis revealed that DDOST was closely associated with the glioma microenvironment and negatively related to tumor-infiltrating B cells and CD4+ T cells and positively related to CAFs and tumor-associated macrophages. In conclusion, these findings suggested that DDOST mediated the immunosuppressive microenvironment of gliomas and could be an important biomarker in diagnosing and treating gliomas.

Background Orthodontic treatment is commonly more time-consuming in adults than in teenagers, especially when it comes to the maxillary en-masse retraction, which may take 9 months or even longer. As to solve this concern, orthodontists have been striving to seek new methods for shortening orthodontic treatment time. Piezocision, as a popular alternative treatment, has been widely used in different types of tooth movement. However, its effect on en-masse retraction of maxillary anterior teeth remains unclear. This randomized controlled trial intends to figure out the role piezocision plays in accelerating en-masse retraction. Methods This protocol is designed for a prospective, single-center, assessor-blinded and parallel-group randomized controlled trial. Twenty adult patients aged from 18 to 40 whose orthodontic treatment required bilateral maxillary first premolars extraction will be randomly assigned to the piezocision group and the control group at a ratio of 1:1. The piezocision group will undergo en-masse retraction immediately after the piezo surgery, while the control group will start en-masse retraction directly. Both groups will be followed up every 2 weeks to maintain the retraction force until the end of space closure. The space closing time is set as the primary endpoint. Meanwhile, the secondary endpoints include the change of root length, labial and palatal alveolar bone thickness, vertical bone height, probing depth of maxillary anterior teeth, cephalometric measurements, visual analogue scale, and postoperative satisfaction questionnaire. Discussion This study will attempt to provide more convincing evidence to verify whether piezocision will shorten the time of en-masse retraction or not. Distinguished with previous studies, our study has made some innovations in orthodontic procedure and primary outcome measurement, aiming to clarify the efficacy and safety of piezocision-assisted en-masse retraction in Chinese population. Trial registration Chinese Clinical Trial Registry ChiCTR 1900024297. Registered on 5 July 2019

Background: Dabigatran etexilate (DE) was approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in adults with Non-valvular Atrial Fibrillation (NVAF). Compared with warfarin, a traditional anticoagulant drug, DE exhibits a shorter half-life, improved dose-effect relationship, fewer food and drug interactions, and can be taken orally without monitoring the conventional coagulation index. DE can also prevent or reduce the severity of adverse events, such as attenuated drug efficacy or bleeding. It is convenient for patients to take DE due to low levels of individual variation. This review aims to application of Dabigatran etexilate in specific populations. Methods: Fifty-five papers were included in the review. Results: We review the pharmacological mechanisms, pharmacokinetics and drug interactions, as well as the application of DE for different clinical populations, and provide clinical guidelines. Conclusion: When using DE, one should consider the risk of bleeding, age, renal function, drug interactions, and other factors.

Background & Aims: A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD. Methods: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0–18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses. Results: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 years and 2.3% of children aged 6–18 years. Of the 17 patients with monogenic Crohn’s disease, 35% had abdominal pain, 24% had nonbloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD-unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 years (odds ratio [OR], 6.30; P = .020), family history of autoimmune disease (OR, 5.12; P = .002), extra-intestinal manifestations (OR, 15.36; P < .0001), and surgery (OR, 3.42; P = .042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation. Conclusions: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare, but should be considered in analysis of all patients with pediatric onset of IBD.

Objectives: Breast cancer has been the second most prevalent and fatal malignancy due to its frequent metastasis to other organs. We aim to study the effects of a key miRNA-mRNA signaling in breast cancer. Results: CNN1 was identified as the key gene in breast cancer by the bioinformatics analysis, and the downregulation of CNN1 in breast cancer tissues and cell lines was observed. Upregulating CNN1 inhibited cell survival, migration, invasion, and adhesion, but enhanced cell apoptosis. miR-106b-5p not only bound to CNN1 mRNA 3’UTR, but also promoted lung metastasis in vivo. Besides, the miR-106b-5p mimic enhanced breast cancer canceration by targeting CNN1 and activating Rho/ROCK1 signaling pathway. Conclusion: Overall, our results proved that miR-106b-5p promoted the metastasis of breast cancer by suppressing CNN1 and activating Rho/ROCK1 pathway. Methods: Bioinformatics analysis was performed to select the key gene in breast cancer. The overexpression and knockdown of Calponin 1 (CNN1) in breast cancer cell lines were performed to conduct cell viability, migrating, invasion, proliferation, adhesion, and apoptosis experiments. To identify the role of miR-106b-5p and Rho/ROCK1 in CNN1-induced breast cancer, a dual-luciferase assay, tumor lung metastasis assay, transcript half-life assay, and Rho/ROCK1 inhibition assay were performed.

Objectives Soluble programmed death-1 (sPD-1) plays an essential role in the pathogenesis and progression of various diseases, including chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). Currently, there is no Food and Drug Administration–approved sPD-1 immunoassay available for routine clinical testing. Most sPD-1 detections employed enzyme-linked immunosorbent assay (ELISA) method for research purpose, which is complicated by intensive manual operation and cannot achieve automatic detection. Therefore, we aimed to develop an automated, rapid immunoassay for sPD-1 measurement based on testing-on-a-probe (TOP) biosensors and evaluate its performance in patients with hepatic diseases. Methods We developed an automatic fluorescent immunoassay using TOP biosensors using a pair of mouse anti-PD-1 monoclonal antibodies (mAbs), which were evaluated by biolayer interferometry. The sensitivity, linearity, and repeatability of the novel immunoassay were analyzed, and its compatibility with an established ELISA kit was evaluated. Further, we quantified sPD-1 level in healthy individuals as well as patients with CHB, hepatic cirrhosis, and HCC. Results The TOP assay to quantify sPD-1 was developed and performed on an automatic fluorescent analyzer within 20 min, which showed good precision with coefficients of variation less than 10% and good linearity ranging from 2 to 3,000 pg/mL. The results tested by our TOP assay correlated well with the established ELISA assay (r=0.92, p Conclusions An automated, rapid fluorescent immunoassay to quantify serological sPD-1 protein using TOP biosensors was developed and showed acceptable analytical performance including precision, linearity, and good correlation with the established ELISA assay, with the great potential in clinical practice.

Fenbendazole, a broad-spectrum anti-parasitic drug, can be a potential anti-tumor agent. In this study, we synthesized and purified its derivative, analog 6, intending to achieve improved efficacy in cancer cells and decreased toxicity in normal cells. To evaluate in vitro anti-tumor activities of fenbendazole and analog 6 in different cancer cell lines, a CCK-8 assay was performed, and we found that human cervical cancer HeLa cells were more sensitive to analog 6 than to fenbendazole. Furthermore, we explored the associated mechanism, and our results showed that analog 6 and fenbendazole could induce oxidative stress by accumulating ROS. It not only activated the p38-MAPK signaling pathway, thereby inhibiting the proliferation of HeLa cells and enhancing the apoptosis of HeLa cells, but also significantly induced impaired energy metabolism and restrained their migration and invasion. In addition, the modified analog 6 showed reduced toxicity to normal cells without decreased anti-cancer effect. In conclusion, fenbendazole and analog 6 have multiple targets and strong anti-tumor effects on HeLa cells in vitro and in vivo. The optimized analog 6 could inhibit the viability of HeLa cells with lower toxicity than normal human cells, promising to be developed as an antitumor active compound.

Background This study aimed to analyze associations between genetic variants and plasma concentrations along with clinical outcomes in dabigatran in patients with non-valvular atrial fibrillation (NVAF). Methods We conducted a prospective study and enrolled NVAF patients treated with dabigatran in the real world. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration. All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up. Results Eighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. There was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran (P = 0.013). Our results showed that the CES1 SNP rs8192935 significantly influenced dabigatran trough concentrations in the Chinese population, and carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 SNP c.2482-2236G > A (rs4148738) was associated with major bleeding events in the addictive model (P = 0.046, OR = 3.29) and dominant model (P = 0.040, OR = 8.17). Additionally, the ABCB1 SNP c.3435 C > T (rs1045642) was associated with the incidence of major bleeding events in the addictive model (P = 0.043, OR = 3.34) and dominant model (P = 0.046, OR = 7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events. Conclusion Our results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events for the first time in a Chinese population.

In atrial fibrillation (AF) patients, complex electrograms during sinus rhythm (C-EGMs) could be pathological or not. We aimed to demonstrate whether local pacing was helpful to discern pathological C-EGMs. 126 persistent AF patients and 27 patients with left-side accessory pathway (LAP) underwent left atrial mapping during sinus rhythm. If C-EGMs were detected, local pacing was performed. If the electrograms turned normal, we defined them as non-fixed C-EGMs, otherwise as fixed C-EGMs. No difference was detected in the incidence and proportion of non-fixed C-EGMs between AF patients and LAP patients (101/126 vs. 19/27, P = 0.26; 9.1 ± 6.0% vs. 7.7 ± 5.7%, P = 0.28). However, the incidence and proportion of fixed C-EGMs were higher in persistent AF patients (87/126 vs. 1/27, P P P = 0.011). Among patients without fixed C-EGMs ablation, the proportion of fixed C-EGMs was an independent predictor of ablation outcomes (HR for per percent: 1.13, 95% CI 1.01–1.28, P = 0.038). C-EGMs could be classified into fixed and non-fixed C-EGMs through local pacing. Fixed rather than non-fixed C-EGMs might indicate abnormal atrial substrates and fixed C-EGMs ablation improve outcomes of persistent AF ablation.

BackgroundThe prevalence of rheumatoid arthritis (RA) has significant gender and age difference. The peak age of RA is consistent with the age of menopause, which is accompanied by a sharp increase in serum follicle-stimulating hormone (FSH) level. This study aims to identify the FSH levels in female RA patients and the relationship with diseases activity.MethodsIn total, 79 female RA patients and 50 age-matched controls were included in our study. Serum sex hormones levels were measured using chemiluminescence. RA patients were grouped by FSH quartile. Disease activity and inflammatory marks were analyzed among groups.ResultsLower sex hormones and higher gonadotropin were found in RA patients. Serum FSH level was significantly higher in RA patients than in the age-match controls (57.58 ± 15.94 vs. 43.11 ± 19.46, p=0.025). Even after adjusting for age (OR: 1.071; 95%CI: 1.006-1.139; p = 0.031), luteinizing hormone (LH), estradiol (E), and testosterone (T) OR: 1.066; 95%CI: 1.003-1.133; p = 0.039), the OR were still more than one. RA patients in the higher quartiles had higher ESR, DAS28-ESR and DAS28-CRP (pConclusionHigh FSH appears to be a risk factor for RA and is positively associated with their disease activity. Early menopause might be an essential factor of RA.

Background A novel scoring system and screening procedure for gastric cancer (GC) screening was proposed based on the national conditions of China, which state that endoscopy professionals and facilities are relatively limited compared with the large Chinese population. Methods A novel scoring system for gastric cancer screening was used to retrospectively analyse the patients who met the screening procedure from April 2017 to December 2019 in our hospital. We divided all of the patients into three groups: low-risk group (0–11 scores), medium-risk group (12–16 scores), and high-risk group (17–23 scores). Statistical analysis was performed on the detection rate of gastric cancer and precursors of gastric cancer among these three groups. Results A total of 6701 patients were enrolled in this study, including 4,352(64.95%) in the low-risk group, 1,948 patients (29.07%) in the medium-risk group, and 401 patients (5.98%) in the high-risk group. The total detection rate of gastric cancer was 2.84% (190/6,701), with a 0.94% rate (41/4,352) in the low-risk group, a 5.18% rate (101/1,948) in the medium-risk group, and a 11.97% rate (48/401) in the high-risk group. There were statistically significant differences in the detection rate of gastric cancer among these three groups (all P Conclusion The screening strategy based on the novel scoring system can significantly improve the efficiency of gastric cancer opportunistic screening in hospital visits. Gastroscopy should be strongly recommended for patients in the medium-risk group and high-risk group, and detailed gastroscopy should be adopted as early as possible to improve the detection rate of early gastric cancer.

It is important to predict the risk of gastric cancer (GC) for endoscopists because early detection of GC determines the selection of the best treatment strategy and the prognosis of patients. The study aimed to evaluate the utility of a predictive nomogram based on the Kyoto classification of gastritis for GC.It was a retrospective study that included 2639 patients who received esophagogastroduodenoscopy and serum pepsinogen (PG) assay from January 2019 to November 2019 at the Endoscopy Center of the Department of Gastroenterology, Wenzhou Central Hospital. Routine biopsy was conducted to determine the benign and malignant lesions pathologically. All cases were randomly divided into the training set (70%) and the validation set (30%) by using the bootstrap method. A nomogram was formulated according to multivariate analysis of the training set. The predictive accuracy and discriminative ability of the nomogram were assessed by concordance index (C-index), area under the curve (AUC) of receiver operating characteristic curve (ROC) as well as calibration curve and were validated by the validation set.Among all patients enrolled, 102 of 2636 cases showed LGIN, HGIN and gastric cancer pathology results, whereas the rest cases showed benign pathological results. Multivariate analysis indicated that age, sex, PG I/II ratio and Kyoto classification scores were independent predictive variables for GC. The C-index of the nomogram of the training set was 0.79 (95% CI: 0.74 to 0.84) and the AUC of ROC is 0.79. The calibration curve of the nomogram demonstrated an optimal agreement between predicted probability and observed probability of the risk of GC. The C-index was 0.86 (95% CI: 0.79 to 0.94) with a calibration curve of better concurrence in the validation set.The nomogram formulated was proven to be of high predictive value for GC.

Background To investigate the diagnostic efficacy of long noncoding RNA metastasis-associated in lung adenocarcinoma transcript l (MALAT1) as a candidate serological biomarker for non-small cell lung cancer (NSCLC). Methods Diagnostic studies relevant to circulation long noncoding RNA MALAT1 as a candidate serological biomarker for NSCLC were electronically systematically searched in PubMed, EMBASE, EBSCO and CNKI databases. Suitable studies were included in the meta-analysis by pooling the diagnostic sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR), diagnostic odds ratio (DOR) and area under the symmetric ROC curve (AUC) through a random or fixed effects model. Deeks' funnel plot was applied for publication bias evaluation. Results Six studies with eight datasets were finally included in the meta-analysis after a systematic search of the databases was performed. The pooled diagnostic sensitivity, specificity, +LR, -LR and DOR were 0.81 (95% CI:0.78-0.84), 0.67 (95% CI:0.63-0.71), 2.61 (95% CI:1.81-3.71), 0.28 (95% CI:0.19-0.43) and 13.73 (95% CI:6.19-30.44), respectively. The pooled area under the ROC curve (AUC) were 0.8663 and 0.8658, respectively by symmetric and asymmetric methods. Conclusion Based on the results of our study, serum long noncoding RNA MALAT1 is a promising biomarker for NSCLC screening. However, due to its low specificity, MALAT1 positive cases need further validation for NSCLC by other diagnostic methods such as radiology, cytology, etc.

Alveolar bone defects can arise as a consequence of trauma, infection, periodontal disease, or congenital alveolar fenestration. Many approaches have been employed in an effort to treat or overcome such defects, but the ability to effectively achieve alveolar regeneration remains elusive. Platelet-derived growth factor-BB (PDGF-BB) has been shown to serve as a key factor capable of orchestrating cell proliferation, angiogenesis, and chemoattraction in the context of osteogenic processes. Exactly how PDGF-BB affects human periodontal ligament stem cells (hPDLSCs), however, requires further exploration. In this report, we utilized a lentiviral construct to achieve PDGF-BB overexpression in hPDLSCs, allowing us to establish that this gene was able to enhance the proliferation of these cells and to mediate osteogenic gene upregulation therein. In addition, we established a rat model of alveolar defects that were implanted using different complexes, and then monitored through histological and micro-CT analyses 4 and 8 weeks postsurgery to assess bone repair outcomes. These analyses revealed that a thermosensitive hydrogel was an effective 3D cell culture scaffold, while PDLSCs overexpressing PDGF-BB enhanced bone growth in the context of alveolar bone defects. Together, these results thus indicate that PDGF-BB represents a potent means of promoting stem cell-based alveolar bone tissue regeneration.

The way of co-administration of drugs is a sensible strategy for treating complex diseases efficiently. Because of existing massive unknown interactions among drugs, predicting potential adverse drug–drug interactions (DDIs) accurately is promotive to prevent unanticipated interactions, which may cause significant harm to patients. Currently, numerous computational studies are focusing on potential DDIs prediction on account of traditional experiments in wet lab being time-consuming, labor-consuming, costly and inaccurate. These approaches performed well; however, many approaches did not consider multi-scale features and have the limitation that they cannot predict interactions among novel drugs. In this paper, we proposed a model of BioDKG–DDI, which integrates multi-feature with biochemical information to predict potential DDIs through an attention machine with superior performance. Molecular structure features, representation of drug global association using drug knowledge graph (DKG) and drug functional similarity features are fused by attention machine and predicted through deep neural network. A novel negative selecting method is proposed to certify the robustness and stability of our method. Then, three datasets with different sizes are used to test BioDKG–DDI. Furthermore, the comparison experiments and case studies can demonstrate the reliability of our method. Upon our finding, BioDKG–DDI is a robust, yet simple method and can be used as a benefic supplement to the experimental process.

The Expert Consensus reviews current literatures and provides clinical practice guidelines for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The main contents include the following: (1) clinical evaluation of GGN; (2) procedures, indications, contraindications, outcomes evaluation, and related complications of thermal ablation for GGN; and (3) future development directions.

Background Many studies have demonstrated efficacy of casein phosphopeptide (CPP) containing products for dentin tubule occlusion for treatment of dentin sensitivity, but their effectiveness under dynamic erosive challenges remains to be elucidated. The purpose of the present study was to investigate the effectiveness of a desensitizing dentifrice containing CPP in occluding dentin tubules and resisting erosive challenges in comparison to that containing polyvinyl methyl ether/maleic acid (PVM/MA) copolymers. Methods A total of 33 dentin discs were prepared from coronal sections of human third molars and divided into 3 groups: a toothpaste containing CPP; a toothpaste containing PVM/MA and submicron silica; and a regular toothpaste (Controls). A soft-bristle toothbrush was used to brush the dentin discs with the dentifrices for 45 strokes in 30 s at a force of approximately 200 g. The brushing cycle was repeated after immersion of the dentin discs in artificial saliva overnight. The dentin discs were then challenged in orange juice for 10 min in an incubator rocking at 120 rpm. Three fields were randomly selected on each dentin disk surface to assess dentin tubule occlusions after each brushing cycle and after orange juice challenge with a 3D laser scanning microscope. Specimen cross sections were examined with a scanning electron microscope equipped with energy dispersive spectroscopy (SEM/EDS). Results After the first and second cycles of brushing, dentin tubules were occluded on average by 56.3% and 85.7% in CPP group, 66.2% and 88.1% in PVM/MA group, and 0.0 and 13.0% in the controls, respectively. There were no statistically significant differences in dentin tubule occlusions between the CPP and PVM/MA groups after two cycles of brushing (p>0.05). After dynamic erosive challenges with orange juice, 20.3% of the dentin tubules in the CPP group, 79.1% in the PVM/MA group and none in the control remained occluded (P Conclusions Desensitizing dentifrices containing CPP or PVM/MA could effectively occlude dentin tubules after two cycles of brushing. PVM/MA in combination with submicron silicon dioxide exhibited stronger resistance to dynamic erosive challenges by acidic beverages. Inorganic fillers that can enter dentin tubules and resist erosive challenges may be key for desensitizing dentifrices.