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Background This study was designed to compare diagnostic categories of thyroid fine needle aspiration cytology (FNAC) and incidence of thyroid tumors in the multi-institutional Asian series with a special focus on diagnostic category IV (suspicious for a follicular neoplasm) and follicular thyroid carcinomas (FTCs). Methods Distribution of FNAC categories, incidence of thyroid tumors in resection specimens and cytologic diagnoses of surgically confirmed follicular adenomas (FAs) and FTCs were collected from 10 institutes from five Asian countries and were compared among countries and between FAs and FTCs. Results The frequency of category IV diagnoses (3.0%) in preoperative FNAC were significantly lower compared to those in Western countries (10.1%). When comparing diagnostic categories among Asian countries, category IV was more frequent in Japan (4.6%) and India (7.9%) than in Taiwan (1.4%), Korea (1.4%), and China (3.6%). Similarly, incidence of FAs and FTCs in surgical resection specimens was significantly higher in Japan (10.9%) and India (10.1%) than in Taiwan (5.5%), Korea (3.0%), and China (2.5%). FTCs were more commonly diagnosed as category IV in Japan (77.5%) than in Korea (33.3%) and China (35.0%). Nuclear pleomorphism, nuclear crowding, microfollicular pattern, and dyshesive cell pattern were more common in FTCs compared with FAs. Conclusions Our study highlighted the difference in FNAC diagnostic categories of FTCs among Asian countries, which is likely related to different reporting systems and thyroid cancer incidence. Cytologic features such as nuclear pleomorphism, nuclear crowding, microfollicular pattern, and dyshesive cell pattern were found to be useful in diagnosing FTCs more effectively.

Abstract Purpose This study aimed to use propensity score matching (PSM) to explore the long-term outcomes and failure patterns in locally advanced rectal cancer (LARC) patients with positive versus negative lateral pelvic lymph node (LPLN). Materials and methods Patients with LARC were retrospectively divided into LPLN-positive and LPLN-negative groups. Clinical characteristics were compared between the groups using the chi-square test. PSM was applied to balance these differences. Progression-free survival (PFS) and overall survival (OS), and local–regional recurrence (LRR) and distant metastasis (DM) rates were compared between the groups using the Kaplan–Meier method and log-rank tests. Results A total of 651 LARC patients were included, 160 (24.6%) of whom had positive LPLN and 491 (75.4%) had negative LPLN. Before PSM, the LPLN-positive group had higher rates of lower location (53.1% vs. 43.0%, P = 0.025), T4 stage (37.5% vs. 23.2%, P = 0.002), mesorectal fascia (MRF)-positive (53.9% vs. 35.4%, P

As a prevalent industrial material and component of consumer products, bisphenol A (BPA) is linked to hormone homeostasis disruption and potential carcinogenicity. However, the precise mechanisms through which BPA contributes to thyroid carcinogenesis, especially in papillary thyroid carcinoma (PTC), are not fully understood. This study investigates how BPA boosts the proliferation and tumorigenic characteristics of thyroid cells. BPA exposure significantly increased cell proliferation in a duration-dependent manner at a concentration of 0.5 μM, which is slightly higher than human exposure levels. Therefore, this study utilized BPA treatment concentrations of 0.1 µM and 0.5 µM. BPA augmented the invasiveness of PTC cells with a dependency on both dosage and temporal factors. RNA-seq and gene expression analysis from normal human thyroid follicular epithelial cells suggested that BPA upregulated genes related to oxidative stress and thyroid cancer. Concurrently, our study revealed significant upregulation of NOX4 in thyroid tumors compared to normal thyroid tissues, with higher expression levels observed in advanced carcinomas by analyses of the TCGA database. BPA induces the upregulation of NOX4 in human thyroid cells, thereby triggering the activation of MAPK and PI3K/AKT pathways. In xenograft models, BPA treatment resulted in increased tumor size and Ki-67 proliferation index, accompanied by upregulated NOX4 expression. Additionally, BPA exposure led to higher levels of free triiodothyronine (FT3), indicating thyroid hormone disruption. Mechanistically, BPA activates the MAPK and PI3K/AKT pathways via NOX4, leading to increased ROS production and cell proliferation. This was further demonstrated through the use of ROS scavenger treatment and si-NOX4, which showed that BPA stimulates ROS generation by activating NOX4/MAPK and NOX4/PI3K/AKT pathways in thyroid cells. This finding enhances our understanding of the pathogenesis of PTC related to BPA exposure and highlights the necessity for rigorous health risk assessments regarding BPA exposure.

BackgroundThe involvement of mitochondrial and programmed cell death (mtPCD)–related genes in the pathogenesis of pre-eclampsia (PE) remains inadequately characterized.MethodsThis study explores the role of mtPCD genes in PE through bioinformatics and experimental approaches. Differentially expressed mtPCD genes were identified as potential biomarkers from the GSE10588 and GSE98224 datasets and subsequently validated. Hub genes were determined using support vector machine, least absolute shrinkage and selection operator, and Boruta based on consistent expression profiles. Their performance was assessed through nomogram and artificial neural network models. Biomarkers were subjected to localization, functional annotation, regulatory network analysis, and drug prediction. Clinical validation was conducted via real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, and Western blot.ResultsFour genes [solute carrier family 25 member 5 (SLC25A5), acyl-CoA synthetase family member 2 (ACSF2), mitochondrial fission factor (MFF), and phorbol-12-myristate-13-acetate–induced protein 1 (PMAIP1)] were identified as biomarkers distinguishing PE from normal controls. Functional analysis indicated their involvement in various biological pathways. Immune analysis revealed associations between biomarkers and immune cell activity. A regulatory network was informed by biomarker expression and database predictions, in which KCNQ1OT1 modulates ACSF2 expression via hsa-miR-200b-3p. Drug predictions, including clodronic acid, were also proposed. Immunofluorescence, RT-qPCR, and Western blot confirmed reduced expression of SLC25A5, MFF, and PMAIP1 in PE, whereas ACSF2 was significantly upregulated.ConclusionThese four mtPCD-related biomarkers may play a pivotal role in PE pathogenesis, offering new perspectives on the disease’s diagnostic and mechanistic pathways.

The Pearl River Estuary, a vital ecological and economic zone in Southern China, has been heavily impacted by industrial discharges, leading to significant heavy metal contamination. To address the ecological implications of different chemical forms of heavy metals, this study systematically evaluated the total concentrations and chemical speciation of Cu, Zn, Cd, and Pb in surface sediments (0–2 cm) collected from 17 sites. Chemical speciation was determined using a modified BCR sequential extraction procedure, and pollution and ecological risks were assessed via the geo-accumulation index (Igeo), potential ecological risk index (RI), and risk assessment code (RAC). The results showed that all four metals exceeded background values, with Cd presenting the highest enrichment (39 times) and contributing 97% of the ecological risk. Speciation analysis revealed that Cd predominantly exists in bioavailable forms, posing severe ecological threats. This study highlights the urgent need for targeted remediation strategies to mitigate Cd contamination and its ecological impact on the estuary.

Abstract Background Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. Methods Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. Results Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor β (IR-β) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-β phosphorylation, ultimately resulting in IR-β inactivation. This inactivation of IR-β suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. Conclusions These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

BackgroundCerebral radiation necrosis (RN), a severe complication of stereotactic radiotherapy (SRT), has been shown to significantly decrease patient survival time and quality of life. The purpose of this study was to analyze whether bevacizumab can prevent or reduce the occurrence of SRT-induced cerebral RN in non-small cell lung cancer (NSCLC) patients with brain metastases.Materials and methodsWe retrospectively reviewed the clinical records of NSCLC patients with brain metastases from March 2013 to June 2023 who were treated with SRT. Patients were divided into two groups: those in the bevacizumab group received SRT with four cycles of bevacizumab, and patients in the control group received SRT only. Inverse probability of treatment weighting (IPTW) was performed based on a multinomial propensity score model to balance the baseline characteristics. The chi-square test was used. A Cox model was used to evaluate overall survival (OS).ResultsA total of 80 patients were enrolled, namely, 28 patients in the bevacizumab group and 52 patients in the control group. The possibility of developing cerebral RN and/or symptomatic edema (RN/SE) was significantly decreased in patients treated with bevacizumab compared to those who did not receive bevacizumab before IPTW (p=0.036) and after IPTW (p=0.015) according to chi-square analysis. The IPTW-adjusted median OS was 47.7 months (95% CI 27.4-80.8) for patients in the bevacizumab group and 44.1 months (95% CI 36.7-68.0) (p=0.364) for patients in the control group.ConclusionThe application of bevacizumab concurrent with SRT may prevent or reduce the occurrence of cerebral RN in NSCLC patients with brain metastases.

PurposeRepeated cone-beam CT (CBCT) scans for image-guided radiotherapy (IGRT) increase the health risk of radiation-induced malignancies. Patient-enrolled studies to optimize scan protocols are inadequate. We proposed a virtual clinical trial-based approach to evaluate projection-reduced low-dose CBCT for IGRT.Materials and methodsA total of 71 patients were virtually enrolled with 26 head, 23 thorax and 22 pelvis scans. Projection numbers of full-dose CBCT scans were reduced to 1/2, 1/4, and 1/8 of the original to simulate low-dose scans. Contrast-to-noise ratio (CNR) values in fat and muscle were measured in the full-dose and low-dose images. CBCT images were registered to planning CT to derive 6-degree-of-freedom couch shifts. Registration errors were statistically analyzed with the Wilcoxon paired signed-rank test.ResultsAs projection numbers were reduced, CNR values descended and the magnitude of registration errors increased. The mean CNR values of full-dose and half-dose CBCT were >3.0. For full-dose and low-dose CBCT (i.e. 1/2, 1/4 and 1/8 full-dose), the mean registration errors were< ± 0.4 mm in translational directions (LAT, LNG, VRT) and ±0.2 degree in rotational directions (Pitch, Roll, Yaw); the mean magnitude of registration errors were< 1 mm in translation and< 0.5 degree in rotation. The couch shift differences between full-dose and low-dose CBCT were not statistically significant (p>0.05) in all the directions.ConclusionThe results indicate that while the impact of dose-reduction on CBCT couch shifts is not significant, the impact on CNR values is significant. Further validation on optimizing CBCT imaging dose is required.

Abstract C-type lectin-like receptor-2 (CLEC-2) is a member of the C-type lectin superfamily of cell surface receptors. The first confirmed endogenous and exogenous ligands of CLEC-2 are podoplanin and rhodocytin, respectively. CLEC-2 is expressed on the surface of platelets, which participates in platelet activation and aggregation by binding with its ligands. CLEC-2 and its ligands are involved in pathophysiological processes, such as atherosclerosis, cancer, inflammatory thrombus status, maintenance of vascular wall integrity, and cancer-related thrombosis. In the last 5 years, different anti- podoplanin antibody types have been developed for the treatment of cancers, such as glioblastoma and lung cancer. New tests and new diagnostics targeting CLEC-2 are also discussed. CLEC-2 mediates thrombosis in various pathological states, but CLEC-2-specific deletion does not affect normal hemostasis, which would provide a new therapeutic tool for many thromboembolic diseases. The CLEC-2-podoplanin interaction is a target for cancer treatment. CLEC-2 may be applied in clinical practice and play a therapeutic role.

Dawn and dusk land surface temperature (LST) is important for constructing subdaily LSTs and understanding diurnal temperature cycles. In this study, a dawn–dusk LST was developed using the medium-resolution spectral imager-low-light (MERSI-LL) instrument onboard Fengyun-3E. A temperature and emissivity separation algorithm was first implemented using the three thermal infrared bands of MERSI-LL. The retrieved LST was validated against in situ measurements at 46 sites. An RMSE of 2.07 K was obtained for vegetated surfaces, while a large negative bias (–3.63 K) and high RMSE (4.09 K) were observed at one barren site. Then, intercomparisons with LST products from two geostationary satellites indicated that the proposed LST exhibited a reasonable performance over two sample regions with varying vegetation densities. Finally, the emissivity intercomparison showed close agreement with other low Earth orbit (LEO) sensors at the sites, supporting the reasonability of the retrieved LST. This dawn–dusk time LST could potentially be combined with other LEO satellite-based LSTs to achieve gapless LST products in the future.

The Asian Thyroid Working Group was founded in 2017 at the 12th Asia Oceania Thyroid Association (AOTA) Congress in Busan, Korea. This group activity aims to characterize Asian thyroid nodule practice and establish strict diagnostic criteria for thyroid carcinomas, a reporting system for thyroid fine needle aspiration cytology without the aid of gene panel tests, and new clinical guidelines appropriate to conservative Asian thyroid nodule practice based on scientific evidence obtained from Asian patient cohorts. Asian thyroid nodule practice is usually designed for patient-centered clinical practice, which is based on the Hippocratic Oath, “First do not harm patients,” and an oriental filial piety “Do not harm one’s own body because it is a precious gift from parents,” which is remote from defensive medical practice in the West where physicians, including pathologists, suffer from severe malpractice climate. Furthermore, Asian practice emphasizes the importance of resource management in navigating the overdiagnosis of low-risk thyroid carcinomas. This article summarizes the Asian Thyroid Working Group activities in the past 7 years, from 2017 to 2023, highlighting the diversity of thyroid nodule practice between Asia and the West and the background reasons why Asian clinicians and pathologists modified Western systems significantly.

Abstract Purpose Manual clinical target volume (CTV) and gross tumor volume (GTV) delineation for rectal cancer neoadjuvant radiotherapy is pivotal but labor-intensive. This study aims to propose a deep learning (DL)-based workflow towards fully automated clinical target volume (CTV) and gross tumor volume (GTV) delineation for rectal cancer neoadjuvant radiotherapy. Materials & methods We retrospectively included 141 patients with Stage II-III mid-low rectal cancer and randomly grouped them into training (n = 121) and testing (n = 20) cohorts. We adopted a divide-and-conquer strategy to address CTV and GTV segmentation using two separate DL models with DpuUnet as backend-one model for CTV segmentation in the CT domain, and the other for GTV in the MRI domain. The workflow was validated using a three-level multicenter-involved blind and randomized evaluation scheme. Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (95HD) metrics were calculated in Level 1, four-grade expert scoring was performed in Level 2, and head-to-head Turing test in Level 3. Results For the DL-based CTV contours over the testing cohort, the DSC and 95HD (mean ± SD) were 0.85 ± 0.06 and 7.75 ± 6.42 mm respectively, and 96.4% cases achieved clinical viable scores (≥ 2). The positive rate in the Turing test was 52.3%. For GTV, the DSC and 95HD were 0.87 ± 0.07 and 4.07 ± 1.67 mm respectively, and 100% of the DL-based contours achieved clinical viable scores (≥ 2). The positive rate in the Turing test was 52.0%. Conclusion The proposed DL-based workflow exhibited promising accuracy and excellent clinical viability towards automated CTV and GTV delineation for rectal cancer neoadjuvant radiotherapy.

IntroductionAntibiotics frequently induce abnormal liver function. Omadacycline is a novel aminomethylcycline antibiotic, which shows potent activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical (including Legionella pneumophila) bacteria. Of note, omadacycline is tolerable in most patients with liver impairment. However, evidence regarding the application of omadacycline in patients with Legionella pneumophila pneumonia after experiencing liver dysfunction is scarce.MethodsThe current study reported 6 cases of patients with Legionella pneumophila pneumonia receiving omadacycline as subsequent antibiotics after experiencing liver dysfunction.ResultsThese 6 cases were admitted to the hospital for pneumonia and received antibiotic therapy, including piperacillin-tazobactam, imipenem, meropenem, and moxifloxacin. After receiving these antibiotics, increased liver enzymes were noted. Although hepatoprotective therapy (such as magnesium isoglycyrrhizinate and glutathione) was given, the liver function was still abnormal. According to metagenomic next-generation sequencing, these patients were diagnosed with Legionella pneumophila pneumonia. Considering the abnormal liver function, the antibiotic therapy was switched to omadacycline-containing antibiotic therapy. After that, liver function was improved, and the infection was ameliorated. Ultimately, all patients discharged from the hospital, including 2 patients who achieved complete clinical symptomatic improvement and 4 patients who achieved partial clinical symptomatic improvement.DiscussionThis study emphasizes the successful treatment of switching to omadacycline after experiencing abnormal liver function in patients with Legionella pneumophila pneumonia. This study suggests that omadacycline may serve as an optional antibiotic for patients with Legionella pneumophila pneumonia, especially when occurring liver dysfunction. However, more clinical studies are required to validate our findings.

Abstract Background Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound Qiying Granules (CQYG) for DPN. Methods Rats and RSC96 cells of DPN models were established to evaluate the therapeutic effects of CQYG. Then the morphology and apoptotic changes of sciatic nerves were detected. Further, tandem mass tag based quantitative proteomics technology was used to identify differentially expressed proteins (DEPs) and the underlying molecular mechanisms. Protein expression of key signaling pathways was also detected. Results CQYG treatment significantly improved blood glucose and oxidative stress levels, and further reduced nerve fiber myelination lesions, denervation, and apoptosis in DPN rats. Further, 2176 DEPs were found in CQYG treated DPN rats. Enrichment analysis showed that protein processing in the endoplasmic reticulum (ER), and apoptosis were all inhibited after CQYG treatment. Next, CQYG treatment reduced inflammatory factor expression, mitochondrial damage, and apoptosis in RSC96 cells which induced by high glucose. Transmission electron microscopy results found that CQYG treatment improved the morphology of nerve myelin, mitochondria, and ER. CQYG treatment decreased ER stress and apoptosis pathway proteins that were highly expressed in DPN models. In addition, we also predicted the potential targets of CQYG in DEPs. Conclusions CQYG exerts neuroprotective effects in experimental diabetic neuropathy through anti-ER stress and anti-apoptosis.

This study evaluated the feasibilities and outcomes following four-dimensional magnetic resonance imaging (4D-MRI) assisted stereotactic body radiation therapy (SBRT) for unresectable colorectal liver metastases (CRLMs). From March 2018 to January 2022, we identified 76 unresectable CRLMs patients with 123 lesions who received 4D-MRI guided SBRT in our institution. 4D-MRI simulation with or without abdominal compression was conducted for all patients. The prescription dose was 50–65 Gy in 5–12 fractions. The image quality of computed tomography (CT) and MRI were compared using the Clarity Score. Clinical outcomes and toxicity profiles were evaluated. 4D-MRI improved the image quality compared with CT images (mean Clarity Score: 1.67 vs 2.88, P

Background: Osteosarcoma, the most common primary malignant bone tumor, is currently treated with surgery combined with chemotherapy, but the limited availability of targeted drugs contributes to a poor prognosis. Identifying effective therapeutic targets is crucial for improving the prognosis of osteosarcoma patients. Methods: We screened the DepMap database to identify essential genes as potential therapeutic targets for osteosarcoma. Gene Set Enrichment Analysis (GSEA) was employed to elucidate the biological roles of these essential genes. Promising candidates were filtered through univariate and multivariate Cox analyses, as well as Kaplan-Meier survival analyses using the GSE21257-OSA and TARGET-OSA datasets. The functional role of the target gene was assessed through cell experiments. Additionally, an in situ nude mice model was established to observe the gene's function, and RNA sequencing was utilized to explore the underlying molecular mechanism. Results: A total of 934 essential genes were identified based on their effects (Chronos) using the DepMap database. These genes were primarily enriched in the ribosome pathway according to GSEA analysis. Among them, 195 genes were associated with the ribosome pathway. Rps28, Rps7, and Rps25 were validated as promising candidates following univariate and multivariate Cox analyses of the TARGET-OSA and GSE21257-OSA datasets. Kaplan-Meier survival analyses indicated Rps28 represented an especially promising target, with high expression correlating with poor prognosis. Knockdown of small ribosomal subunit protein eS28, the protein of Rps28, inhibited proliferation, migration, and invasion in both in vitro and in vivo experiments. Silencing RPS28 affected the MAPK signaling pathway in osteosarcoma. Conclusion: In summary, Rps28 has been identified as an essential gene for osteosarcoma cell survival and eS28 may serve as a potential vulnerability in osteosarcoma.

BackgroundThe aim of this article was to establish the clinical prognostic models and identify the predictive radiation dosimetric parameters for thrombocytopenia during concurrent chemoradiotherapy for rectal cancer.MethodsIn this retrospective cohort study, patients with rectal adenocarcinoma undergoing concurrent long-term chemoradiotherapy were included. The primary outcome of interest was grade 2 or higher (2+) thrombocytopenia (platelet(PLT) count

Background As Industry 4.0 debuted roughly a decade ago, it is now necessary to examine how it affects various aspects of the discipline. It is the responsibility of the education sector to guarantee that the next generation is equipped mentally, physically, and cognitively to face unforeseen challenges. Numerous educational institutions are outfitted with Industry 4.0 technology-based learning. Industry 4.0 fosters advancements in learning methodologies, especially for language enhancements. Learners may gain knowledge at their base, providing them an opportunity for independent study. The majority of subjects have been acquired through Industry 4.0. This research chapter explores the intersection of Industry 4.0 and education, specifically focusing on the SmallTalk AI tool. It investigates how technological and digital innovations within the context of Industry 4.0 can serve as powerful tools to enhance language learning outcomes. Methods This article presents a comprehensive analysis of statistical data and empirical evidence to support the positive impact of Industry 4.0 technology of SmallTalk on language acquisition particularly speaking. The study also determines the relationship among participants’ usage through the technology acceptance model (TAM). Furthermore, it examines the challenges and opportunities associated with integrating these innovations into language learning pedagogies, offering insights for educators and policymakers to harness the potential of Industry 4.0 in fostering language proficiency. The research employs quantitative analysis. The data obtained from educational institutions has been analyzed using the SPSS and AMOS software. Results The results indicate that Industry 4.0 has had an important effect on English language acquisition. This self-supported adaptable system of education facilitates effective student learning. This study also suggests that future research into the utility of Industry 4.0 be conducted elsewhere internationally.

Abstract Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid carcinoma originating from follicular epithelial cells. No explicit consensus can be achieved to date due to sparse clinical data, potentially compromising the outcomes of patients. In this comprehensive review from a clinician’s perspective, the epidemiology and prognosis are described, diagnosis based on manifestations, pathology, and medical imaging are discussed, and both traditional and emerging therapeutics are addressed as well. Turin consensus remains the mainstay diagnostic criteria for PDTC, and individualized assessments are decisive for treatment option. The prognosis is optimal if complete resection is performed at early stage but dismal in nearly half of patients with locally advanced and/or distant metastatic diseases, in which adjuvant therapies such as 131I therapy, external beam radiation therapy, and chemotherapy shou ld be incorporated. Emerging therapeutics including molecular targeted therapy, differentiation therapy, and immunotherapy deserve further investigations to improve the prognosis of PDTC patients with advanced disease.

Introduction Many smokers have not accessed professional smoking cessation assistance due to limited smoking cessation services. We developed a novel mHealth-based integrated modality for smoking cessation (WeChat + Quitline modality, WQ modality) and applied it to a large public welfare project (China Western-QUIT Program) in western China. This study evaluated the usage, acceptability, and preliminary effectiveness of the WQ modality in the population of western China. Methods A prospective cohort study was conducted between April and August 2021. Smokers or their relatives were recruited through online advertisements and medical staff referrals. After using the services of the WQ modality for one month, the self-reported awareness, use, and satisfaction with each service among the participants were collected by a telephone interview. We also evaluated the self-reported 7-day point prevalence of abstinence (PPA) and quit attempt rate among baseline current smokers. The usage data of each service were downloaded from quitline and WeChat platforms. Results Of the 17326 people from western China using the WQ modality, the largest number of users was WeChat official account (11173), followed by WeChat mini program (3734), WeChat group (669), and quitline (541 inbound calls, 605 outbound calls). At one month follow-up, over 70% of participants who completed the baseline survey (n=2221) were aware of WeChat-based services, and over 50% used them. However, the awareness rate (11.1%) and utilization rate (0.5%) of quitline were relatively low. The median satisfaction scores across all services were 9 out of 10 points (IQR: 8–9). Among the baseline current smokers (n=1257), self-reported 7-day PPA was 41.8% (526/1257), and another 225 smokers (17.9%) reported making a quit attempt. Conclusions The WQ modality could be well used and accepted, and it has great potential to motivate and aid short-term smoking cessation in smokers from western China.

Abstract Background Novel biomarkers for personalizing anticoagulation remain undetermined. We aimed to investigate the association of plasma miRNAs with pharmacokinetic–pharmacodynamic (PK-PD) profiles of rivaroxaban. Methods This is a multicenter, exploratory study of miRNAs in a Chinese population. Healthy volunteers and patients receiving rivaroxaban were enrolled in the study. The area under the plasma concentration–time curve from time 0-t h (AUC0-t) and anti-Xa activity at 3 h (AXA3h) were measured in healthy volunteers, and AXA3h was measured in patients. MiRNAs were detected by miRNA microarray in 26 healthy volunteers with 20 mg rivaroxaban, and quantitative reverse transcription polymerase chain reaction was used to exclude undetectable ones. MiR-320a-3p and miR-483-5p were then quantified in 65 healthy volunteers and 71 patients. MiRNA levels at 3 h were compared between high and low AXA3h or AUC0-t subjects and in matched patients with or without bleeding during follow-up. The miRNA targets were predicted by TargetScan, miRTarBase, and miRDB. Validated genes were included in GO enrichment and KEGG analyses. The protein–protein interaction network was established by STRING and visualized by Cytoscape. Results A total of 136 Chinese subjects completed the study. In healthy volunteers taking 15 mg rivaroxaban, the miR-320a level at 3 h was significantly positively correlated with AXA3h and AUC0-t (r = 0.359, p = 0.025; r = 0.370, p = 0.02, respectively). A positive correlation was also observed between miR-483 and AXA3h or AUC0-t (r = 0.372, p = 0.02; r = 0.523, p = 0.001, respectively). MiR-320a and miR-483 levels at 3 h in the higher AUC0-t group were significantly higher than those at 0 h. MiR-483 levels at 3 h may distinguish healthy volunteers with high or low AXA3h or AUC0-t. In the 10 mg fed subgroup, higher 3 h mir-483 levels were also observed compared with the control group. No significant differences were found in the comparisons among patients. Bioinformatic analysis showed that these miRNAs may play a regulatory role by targeting ABCG2, ITGB3, PTEN, MAPK1/3, etc. Conclusions MiR-320a and miR-483 levels were found to be associated with PK and PD profiles of rivaroxaban in healthy Chinese subjects. Further studies are required to verify these findings and explore the mechanisms.

Abstract Surface flashover of insulating materials induced by pollution and moisture environment is one of the main reasons for the damage of power system and electrical equipment. The improvement of the insulating materials surface hydrophobicity is key important, which can prevent the pollutants and water attachment, and enhance the insulating performance. In this paper, the super‐hydrophobic film is formed on the surface of epoxy resin by a one‐dimensional (1D) argon (Ar) jet array driven by nanosecond pulse power supply with hexamethyldisiloxane (HMDSO) addition. The influences of the processing time and HMDSO content on the epoxy resin surface hydrophobicity are investigated. It shows that with 0.04 % HMDSO, the jet array achieves a best hydrophobic treatment effect on the epoxy resin surface. After 60 s treatment, the apparent contact angle (ACA) of the epoxy resin surface increases from 60.3° of the untreated surface to 150.0°. The wettability of epoxy resin surface does not change too much as the treatment time beyond 60 s. The maximum ACA value 153.4° appears at 120 s processing time, which is just slightly higher than that of 60 s treatment time. The epoxy resin surface morphology and chemical feature before and after plasma processing are characteristics by the scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier transform infra‐red spectroscopy and X‐ray photoelectron spectroscopy. It shows that the treated epoxy resin surface is covered with dense coral like particles in nanoscales, the original C=O、C‐H and other organic functional groups are replaced by Si‐(CH3), Si‐O‐Si and other silicon containing groups, and the Si content increases from 0.4% to 28.0%. The experimental results provide important references to develop jet array as an efficient tool to enhance the surface hydrophobicity and insulating performance of insulating materials.

BackgroundDecabromodiphenyl ether (BDE209), an essential industrial flame retardant that is widely used, has recently been reported to be increasing in human serum. Due to the structural similarity between BDE209 and thyroid hormones, its toxic effects on the thyroid are of particular concern.MethodsOriginal articles in the PubMed database were collected using the terms “BDE209”, “decabromodiphenyl ether”, “endocrine disrupting”, “thyroid”, “carcinogenesis”, “polybrominated diphenyl ethers”, “PBDEs,” and their synonyms from inception up to October of 2022.ResultsOf the 748 studies initially identified, 45 were selected, which emphasized the adverse effects of BDE209 on endocrine system. BDE209 may have a toxic effect not only on thyroid function but also on thyroid cancer tumorigenesis at multiple levels, such as by directly interfering with the TR, hypothalamic-pituitary-thyroid (HPT) axis, enzyme activity, and methylation. However, it is impossible to draw a definitive conclusion on the exact pathway of thyroid toxicity from BDE209.ConclusionsAlthough the toxic effects of BDE209 on the thyroid have been well investigated, its tumorigenic effects remain unclear and further research is necessary.

Abstract Introduction Individual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF). Materials and Methods From June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti‐Factor Xa (anti‐FXa) level 3 h after rivaroxaban administration as peak concentration. Whole‐exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496). Results The bleeding events within 12 months were significantly related to the peak anti‐FXa level (p = .027). SUSD3 rs76292544 was associated with 12‐month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17–8.14, p = 6.43×10−5). Five SNPs including NCMAP rs4553122 (p = 2.29×10−5), PRF1 rs885821 (p = 7.02×10−5), PRKAG2 rs12703159 (p = 7.97×10−5), PRKAG2 rs13224758 (p = 8.70×10−5), and POU2F3 rs2298579 (p = 8.24×10−5) were associated with peak anti‐FXa level. Genetic variants of 52 SNPs from 36 genes including GOT2 rs14221 and MMP13 rs640198 were potentially related to 12‐month bleeding events caused by rivaroxaban's efficacy. Conclusions Peak anti‐FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban. SUSD3 rs76292544 was suggestively associated with 12‐month bleeding events and five SNPs (NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, rs13224758 and POU2F3 rs2298579) were suggestively associated with peak anti‐FXa level.

Abstract Background Multimodal therapies based on surgical resection have been recommended for the treatment of adenocarcinoma of the oesophagogastric junction (AEG). We aimed to evaluate prognostic factors in AEG patients receiving neoadjuvant chemoradiotherapy and to build predictive models. Methods T3 − T4N + M0 AEG patients with resectable Siewert type II/III tumours were enrolled in this study. All patients underwent neoadjuvant chemoradiation, followed by radical surgery or systemic therapy according to clinical response. Survival analysis was performed using the Kaplan–Meier method; multivariate analysis using the Cox proportional hazards method was also conducted. The Harrell concordance index (C-index) was used to test the prognostic value of models involving prognostic factors, and consistency between actual and predicted survival rates was evaluated by calibration curves. Results From February 2009 to February 2018, 79 patients were treated with neoadjuvant chemoradiotherapy; 60 patients of them underwent radical surgery. The R0 resection rate was 98.3%, and 46.7% of patients achieved a major pathologic response (MPR), namely, a residual tumour issue less than 10%. The 5-year overall survival (OS) rate was 63%, and the 5-year progression-free survival (PFS) rate was 48%. The incidence of grade 3 complications was 21.5%, and no grade 4 complications were reported. According to the results of univariate and multivariate analyses, we included the neutrophil–lymphocyte ratio (NLR), prognostic nutrition index (PNI), eosinophilic granulocyte (EOS) and postoperative pathologic stage in nomogram analysis to establish prediction models for OS and PFS; the C-index of each model was 0.814 and 0.722, respectively. Both the C-index and calibration curves generated to validate consistency between the actual and predicted survival indicated that the models were well calibrated and of good predictive value. Conclusions AEG patients achieved favourable downstaging and pathologic response after neoadjuvant chemoradiation, with acceptable adverse effects. Inflammation-based and nutrition-related factors and postoperative pathologic stage had a significant influence on OS and PFS, and the predictive value was verified through prognostic models.

Abstract Background Studies show inconsistent results regarding the impact of CYP2C19 genotype on the pharmacodynamics (PD) and clinical outcomes of ticagrelor. With the implementation of genotype-guided individualized antiplatelet therapy, the association between CYP2C19 polymorphism and the efficacy and safety of ticagrelor for patients is still worthy of exploring and studying. Methods This systematic review protocol has been registered in the PROSPERO network (No. CRD 42020158920). Electronic databases of PubMed, EmBase, and the Cochrane Library were systematically searched from inception to January 6th, 2022 to select studies investigating the impact of CYP2C19 genotype on PD and clinical outcomes of ticagrelor. The results were presented as odds ratio (OR) or weight mean difference with its 95% confidence interval (CI) by using the random-effects model. Trial sequential analysis (TSA) was used to control risk of random errors and detect the robustness of outcomes. Results Eight studies recruited a total of 6405 patients treated with ticagrelor. Mostly trials reported no significant effect of any or no CYP2C19 loss-of-function (LOF) allele (*2 or *3) on all the endpoints. Compared with no LOF allele carriers, subgroup analysis suggested any LOF allele in Asian patients was associated with a significant decreased risk of bleeding events (OR: 0.41; 95% CI: 0.22–0.75; P = 0.004). Furthermore, any LOF allele carriers didn’t yield any impact on the risk of MACEs (OR: 1.11; 95% CI: 0.76–1.64; P = 0.586), stroke (OR: 1.71; 95% CI: 0.99–2.96; P = 0.054), definite stent thrombosis (OR: 0.88; 95% CI: 0.17–4.60; P = 0.882), bleeding (OR: 0.63; 95% CI: 0.27–1.46; P = 0.281), myocardial infarction (OR: 0.81; 95% CI: 0.30–2.20; P = 0.682), and revascularization (OR: 0.81; 95% CI: 0.33–2.00; P = 0.649) in all patients. The results of TSA were indicated that more further trials would be required. Conclusions This qualitative and quantitative study suggested Asian patients carrying any CYP2C19 LOF allele might have a lower risk of bleeding events comparing with no LOF allele carriers when treated with ticagrelor. However, we did not prove an important role of CYP2C19 genotype on the risk of PD and clinical endpoints in the whole cohort. In future, more large-scale prospective studies and more different ethnic populations should be included.

Crop plant diseases are a significant threat to productivity and sustainable development in agriculture. Early prediction of disease attacks is useful for the effective control of the disease by taking proactive actions against their attacks. Modern Information and Communication Technologies (ICTs) have a predominant role in Precision Agriculture (PA) applications to support sustainable developments. There is an immense need for solutions for the early prediction of the disease attack for proactive control against the plant disease attack. The present solution of disease detection using the computer vision approach can only detect the existence of the disease once the disease has already appeared. This study aims to propose a Machine Learning (ML) approach for the early prediction of the probability of disease attack based on Internet of Things (IoT) directly sensed crop field environmental conditions. Plant disease life cycles are strongly correlated with environmental conditions. The crop field environmental conditions are used to predict the occurrence of plant diseases. The Multiple Linear Regression (MLR) is applied as the ML model due to the existence of a linear relationship between disease attack and environmental conditions. Internet of Things (IoT) based crop field environmental conditions help to accurately predict the occurrence of plant diseases using the ML approach. The proposed model is implemented for the prediction of blister blight (Exobasidium vexans) for tea (Camellia sinensis) plant to check the effectiveness of the proposed solution. The implementation of the proposed model from 2015 to 2019 reveals that the accuracy of prediction of occurrence of the disease reached up to 91% in 2019.

Aims: A histone H3F3A (H3.3) mutation involving a substitution in H3.3 G34 recently has been reported in GCTB within the frequency range (from 69 % to 96 %) and is a helpful diagnostic indicator of GCTB. However, the relationship between H3F3A mutations and the clinicopathological feature of GCTB involving non-long bones (irregular bones and small bones) is unclear. Methods and results: H3F3A mutations were observed in a cohort of specimens (230 samples of GCTB) using immunohistochemistry and Sanger sequencing. The relationship between H3F3A mutations and the clinicopathological characteristics of patients with GCTB occurring in the non-long bones of the appendicular skeleton was investigated. No significant difference between H3F3A mutations in GCTB arising in non-long bones and the classic sites was found (P = 0.483). GCTB in non-long bones occurred more common in female (31/49, 63.3 %) than in male patients (P = 0.016). GCTB with H3.3 G34L/V/R mutation occurred more often in younger patients compared with those with H3.3 G34W mutation (P = 0.009). The majority of GCTB with soft tissue extension developed in irregular bones but not in small bones (P = 0.061). The H3.3 G34L/V/R mutations rate (7/45) in the non-long bones was significantly higher than that in long bones. The recurrence rate of the GCTB in long bones and non-long bones was 23.3 % (45/193) including 43 cases with local recurrene and 2 cases with lung metastasis. No recurrence occurred in cases with G34V/L/R mutations. Conclusions: H3F3A was an effective diagnostic marker for GCTB of the non-long bones. The younger patients with GCTB of the non-long bones harboured H3.3 G34L/V/R mutations and may had a female preference and rarely recurrent.

BackgroundFew studies have evaluated the significance of sarcopenia in predicting the outcomes of patients with adenocarcinoma of the esophagogastric junction (AEG), especially those who received neoadjuvant chemoradiotherapy (NCRT). We aimed to identify the sarcopenic status and its impact on the outcomes of patients with locally advanced AEG who received NCRT followed by radical surgery or systemic therapy.Materials and methodsPatients with T3-4N+M0 AEG with accessible abdominal computed tomography (CT) before and after NCRT were retrospectively analyzed. Body composition parameters, particularly the skeletal muscle index (SMI), were assessed using a CT-based method, and sarcopenia was defined using a predetermined SMI cutoff value. Survival analysis was conducted using the Kaplan–Meier method. A Cox proportional hazards regression model was used to identify independent prognostic factors. Receiver operating characteristic curve analysis was carried out, and the area under the curve (AUC) was calculated to test the prognostic accuracy of different factors.ResultsA total of 63 patients were enrolled, 65.1 and 79.4% of whom developed pre- and post-NCRT sarcopenia, respectively. Patients with pre-NCRT sarcopenia had lower radical surgery rates (70.7 vs. 95.5%, p = 0.047) than those without sarcopenia; however, sarcopenic status did not affect other short-term outcomes, including treatment-related toxicity and efficacy. Pre-NCRT sarcopenia was identified as an independent predictive factor for poor overall survival (OS) [adjusted hazard ratio (HR), 6.053; p = 0.002] and progression-free survival (PFS) (adjusted HR, 2.873; p = 0.031). Compared with nutritional indices such as the Nutritional Risk Screening 2002, weight loss during NCRT, and post-NCRT sarcopenia, pre-NCRT sarcopenia was regarded as the best predictive index for the 5-year OS (AUC = 0.735) and PFS rates (AUC = 0.770).ConclusionPre-NCRT sarcopenia may be an independent predictive factor for OS and PFS rates in patients with locally advanced AEG receiving multimodal treatment.

The characterisation of the papillary thyroid carcinoma (PTC) tumour microenvironment remains crucial. Here, the authors perform single-cell RNA sequencing in 11 patients and identify potential opportunities for the use of immunotherapy and its combination with anti-angiogenic therapy in PTC.

Abstract Introduction To identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF). Materials and methods Chinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2‐year follow‐up were evaluated. Peak and trough PD parameters (anti‐FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole‐exome sequencing, genome‐wide sequencing and candidate gene association analyses were performed. Results There were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single‐nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99–25.83, p = 7.77 × 10−5 at sixth month visit) and FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87–23.89, p = 9.08 × 10−5 at 12th month visit), as well as with increased trends at other visits (p

Primary thyroid osteosarcoma is an extremely rare tumor which is associated with a poor prognosis. In this study, we describe an additional case. A 4.5 × 3.8 cm irregular heterogeneous nodule was examined in the left thyroid gland of a 72-year-old woman. Cytological smears and histopathological specimens showed typical features of osteosarcoma with a neoplastic lesion rich in spindle cells with occasional multinucleated cells and lace-like osteoid matrix. Negative immunoreaction with epithelial markers and positive immunoreaction with SATB2 and low Ki-67 labeling index suggested the diagnosis of osteosarcoma. Multiple KMT2C gene mutations determined by next-generation sequencing further confirmed the diagnosis.

Abstract Background The impact of smokeless tobacco (SLT) use on the risk of oral cavity cancer (OCC) has been confirmed; however, the sex-based difference in this association remains inconclusive. Therefore, this study aimed to estimate the association between SLT use and OCC risk in women and compared it to that in men. Methods PubMed, Embase, and Cochrane Library databases were systematically searched for eligible studies from their inception up to August 2020. Studies reporting the effect estimates of SLT use on OCC risk in men and women, were eligible for inclusion. The relative risk ratio (RRR) was applied to calculate the sex-based difference in the relationship between SLT use and OCC risk, and pooled analysis was conducted using a random-effects model with inverse variance weighting. Results Nineteen studies reporting a total of 6593 OCC cases were included in the final meta-analysis. The pooled relative risk (RR) suggested that SLT use was associated with an increased risk of OCC in both men (RR, 2.94; 95% confidence interval [CI], 2.05–4.20; P

Subjective well-being (SWB) is an important part of positive psychology research. Compared with other countries and regions, Chinese adolescents’ well-being level is relatively lower. Under the guidance of ecological systems theory, this study is based on the survey data of PISA 2018, with 10,805 middle school students from four provinces and cities in China (Beijing, Shanghai, Jiangsu, and Zhejiang) as the research samples, and examines the theoretical model of the influence of family capital on adolescents’ subjective well-being by means of structural equation modeling, in which the effects of family capital, school climate and academic achievement on adolescents’ subjective well-being are discussed. The empirical results show that family capital directly and indirectly negatively influences adolescents’ subjective well-being through academic achievements, and indirectly positively influences adolescents’ subjective well-being through school climate. School climate directly positively affects adolescents’ subjective well-being and indirectly negatively influences adolescents’ subjective well-being through their academic achievement. Academic achievement negatively affects adolescents’ subjective well-being. The research results strongly support the correctness of the theoretical framework, indicating the complexity of the formation of adolescents’ subjective well-being.

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, several variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged and have consistently replaced the previous dominant variant. Therapeutics against variants of SARS-CoV-2 are urgently needed. Ideal SARS-CoV-2 therapeutic antibodies would have high potency in viral neutralization against several emerging variants. Neutralization antibodies targeting SARS-CoV-2 could provide immediate protection after SARS-CoV-2 infection, especially for the most vulnerable populations. In this work, we comprehensively characterize the breadth and efficacy of SARS-CoV-2 RBD-targeting fully human monoclonal antibody (mAb) MW3321. MW3321 retains full neutralization activity to all tested 12 variants that have arisen in the human population, which are assigned as VOC (Variants of Concern) and VOI (Variants of Interest) due to their impacts on public health. Escape mutation experiments using replicating SARS-CoV-2 pseudovirus show that escape mutants were not generated until passage 6 for MW3321, which is much more resistant to escape mutation compared with another clinical staged SARS-CoV-2 neutralizing mAb MW3311. MW3321 could effectively reduce viral burden in hACE2-transgenic mice challenged with either wild-type or Delta SARS-CoV-2 strains through viral neutralization and Fc-mediated effector functions. Moreover, MW3321 exhibits a typical hIgG1 pharmacokinetic and safety profile in cynomolgus monkeys. These data support the development of MW3321 as a monotherapy or cocktail against SARS-CoV-2-related diseases.

PurposeDabigatran concentrations monitoring are gaining importance of special situations, but limited data are available for the expected peak and trough levels. The hemoclot thrombin inhibitor (HTI) is dabigatran-calibrated quantitative determination of dabigatran concentration. This study aims to validate HTI assay as the quantification choice of dabigatran, and providing the expected peak and trough levels.Materials and MethodsThis is a multi-center methodology validate study, including seven hospitals from Beijing, Shanghai, Henan, Hunan, Chongqing, and Fujian. We retrospectively analyzed plasma samples taken from 118 healthy subjects and 183 patients receiving dabigatran. Dabigatran concentrations were measured with HTI assay and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Linear regression, Spearman correlation and Bland-Altman analysis were used in this study.ResultsThe mean concentration ratio of HPLC-MS/MS and HTI assays was 1.03 and 0.98 at 2 and 12 h, and the acceptance ranges for both the ratio limit as well as the limit of agreement were met, suggesting good agreement between the HTI-derived plasma concentrations and HPLC-MS/MS. The reference detection range of single dose dabigatran 150 mg in healthy subjects was 33–159 ng/ml. About 500 blood samples were taken from 183 patients suggested that the expected peak and trough levels range of dabigatran 110 mg was about 95–196 and 36–92 ng/ml.ConclusionHemoclot thrombin inhibitor assay can be a good quantitative detection method of dabigatran. Expected peak and trough levels provide a basis for the rational use of dabigatran, and provide important Asian population data for the update of the international clinical guidelines for hematological testing.Clinical Trial Registration[https://clinicaltrials.gov], identifier [NCT03161496].

Background Assessing nuclear features is diagnostically challenging in the aspect of thyroid pathology. The aim of this study was to determine whether pathologists could distinguish BRAF-like and RAS-like nuclear features morphologically and identify morphological features to differentiate thyroid tumors with RAS-like mutations from encapsulated papillary thyroid carcinoma (PTC) with predominant follicular growth and BRAFV600E mutation. Methods Representative whole slide images of 16 encapsulated thyroid tumors with predominant follicular growth were reviewed by 12 thyroid pathologists using a web browser-based image viewer. Total nuclear score was calculated from semi-quantitatively scored eight nuclear features. The molecular profile of RAS and BRAF genes was determined by Sanger sequencing. Results Total nuclear score ranging 0 to 24 could differentiate BRAF-like tumors from RAS-like tumors with a cut-off value of score 14. The interobserver agreement was the highest for the assessment of nuclear pseudoinclusions (NPIs) but the lowest for nuclear elongation and sickle-shaped nuclei. NPIs were found in tumors with BRAFV600E mutation, but not in tumors with RAS-like mutations. Total nuclear scores were significantly higher for tumors with BRAFV600E than for those with RAS-like mutations (P

Abstract Background In 1997, the Radiation Therapy Oncology Group (RTOG) put forward the recursive partitioning analysis classification for the prognosis of brain metastases (BMs), but this system does not take into account the epidermal growth factor receptor (EGFR) mutations. The aim of the study is to assess the prognosis of patients with EGFR-mutated non-small cell lung cancer (NSCLC) and BMs in the era of tyrosine kinase inhibitor (TKI) availability. Methods This was a retrospective study of consecutive patients with EGFR-mutated (exon 19 or 21) NSCLC diagnosed between 01/2011 and 12/2014 at the Tianjin Medical University Cancer Institute & Hospital and who were ultimately diagnosed with BMs. The patients were stage I-III at initial presentation and developed BMs as the first progression. Overall survival (OS), OS after BM diagnosis (mOS), intracranial progression-free survival (iPFS), response to treatment, and adverse reactions were analyzed. Results Median survival was 35 months, and the 1- and 2- year survival rates were 95.6% (108/113) and 74.3% (84/113). The 3-month CR + PR rates of radiotherapy(R), chemotherapy(C), targeted treatment(T), and targeted treatment + radiotherapy(T+R) after BMs were 63.0% (17/27), 26.7% (4/15), 50.0% (7/14), and 89.7% (35/39), respectively. The median survival of the four treatments was 20, 9, 12, and 25 months after BMs, respectively (P = 0.001). Multivariable analysis showed that

Abstract Background Progressive bone pain and fracture and abnormal positron emission tomography combined with a computed tomography are main reasons for the oncologists suspecting bone tumor. During the patient’s medical treatment, the oncologists’ unfamiliarity with adverse reactions to anti-HBV drugs were main reason for the long-term exposure to the drug and the adverse reaction (ADR) experienced by the patient. Case presentation A 63-year-old Chinese man had a 27-month history of progressive generalized bone pain combined with spontaneous fractures. Positron emission tomography combined with a computed tomography, revealed an abnormal increase in ribose metabolism and low positron serum inorganic phosphorus concentration (0.7; 0.78–1.65 mmol/L). Serum creatinine level was 252 μmol/L (53–97) μmol/L, and glomerular filtration rate was 22.79 mL/min/1.73 m2. The patient was referred to a multidisciplinary clinic to clarify the diagnosis of myeloma or bone tumor for further treatment in 2017. His medical history revealed that he had a 30-year history of chronic hepatitis B infection. He had received lamivudine at a daily dose of 100 mg for 19 years (1990 to 2009), which had been changed to adefovir (10 mg/day) owing to lamivudine resistance in 2009. Based on the changes in the patient’s laboratory markers and the results of emission computed tomography and other radiographic findings, adefovir-induced hypophosphatemic osteomalacia due to acquired renal Fanconi syndrome was suspected by the clinical pharmacist. Considerable clinical improvement was observed after adefovir discontinuation and the administration of entecavir (1.0 mg, every other day). Conclusion Fanconi syndrome with osteomalacia can develop in patients with chronic hepatitis B infection being treated with adefovir at a conventional low dosage of 10 mg/day. This case highlights the importance of ADR as a differential diagnosis and the need of pharmacists with drug safety expertise expert in the patient management.

BackgroundSmoking and secondhand smoke (SHS) exposure rates are much higher in China than in other countries. A smoke-free policy was implemented in Xi'an, a city in Shaanxi Province, China, on November 1, 2018. This study aimed to evaluate the effect of the smoke-free policy on changes in hospital admissions for acute ischemic heart disease (AIHD) and stroke in Xi'an.MethodsAll subjects had been hospitalized for AIHD or stroke from February 9, 2017 to December 25, 2019 (study period: 150 weeks) in six randomly selected public hospitals out of 36 tertiary hospitals in Xi'an. A generalized additive model developed using an interrupted time series design was used to compare immediate and annual percent changes in hospital admissions before and after policy implementation.ResultsThe study included 31,400 cases (16,656 cases of AIHD and 14,744 cases of stroke) from 6 hospitals in Xi'an. Immediately after implementation of the smoke-free policy, AIHD admissions were reduced significantly (−31.66%, 95% CI: – 39.45 to −22.86%), but stroke admissions were not (−4.94%, 95% CI: −13.26 to 4.17%). The annual reduction in stroke-related admissions (−14.54%, 95% CI: −23.53 to −4.49%) and the annual increase in AIHD-related admissions (40.58%, 95% CI: 22.08 to 61.87%) were significant. Although there was no significant reduction in AIHD admissions, stroke admissions were significantly reduced by −15.73% (from 7,350 to 6,194) after implementation of the smoke-free policy in Xi'an.ConclusionThe smoke-free policy had different effects on hospital admissions for AIHD and stroke in Xi'an. Xi'an should improve its smoke-free legislation and expand the measures to maintain or achieve additional significant health benefits. These findings can guide the formulation and implementation of regional and national smoke-free policies.

BackgroundDrug–drug interactions (DDIs) pose new challenges beyond traditional pharmacodynamics in the context of optimizing the treatment options with immune checkpoint inhibitors (ICIs). To alleviate cancer-related pain, analgesics are of absolute vital importance as chronic medications used by cancer patients. However, the possible outcome of ICI treatment concomitant with analgesics remains unclear.MethodsOriginal articles describing the possible influence of analgesics use on ICI treatment published before December 1, 2021 were retrieved from PubMed, Embase, and the Cochrane Library. Odds ratio (OR) with 95% confidence interval (CI) for objective response rate (ORR), hazard ratio (HR) with 95% CI for progression-free survival (PFS), and overall survival (OS) were calculated using the random-effects or fixed-effects model, and heterogeneity was assessed using the χ2-based Q-test. Publication bias was examined by funnel plot analysis.ResultsA total of 11 studies involving 4,404 patients were included. The pooled OR showed that opioid use decreased the response of opioid users to ICIs compared to non-opioid users (OR = 0.49, 95% CI = 0.37–0.65, p < 0.001). Compared to patients who did not receive opioids, opioid users had an increased risk of progression and mortality (HR = 1.61, 95% CI = 1.37–1.89, p < 0.001; HR = 1.67, 95% CI =1.30–2.14, p < 0.001, respectively). Furthermore, the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) was not significantly associated with differences in ORR, PFS, and OS in patients treated with ICIs (OR = 1.40, 95% CI = 0.84–2.32, p = 0.190; HR = 0.90, 95% CI = 0.77–1.06, p = 0.186; HR = 0.90, 95% CI = 0.71–1.14, p = 0.384, respectively).ConclusionThe concomitant use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs.

Background: The purpose of this study was to identify genetic variations associated with the metabolism of dabigatran in healthy Chinese subjects, with particular focus given to pharmacokinetics (PK) and pharmacodynamics (PD).Methods: Healthy Chinese adults aged 18–65 years with unknown genotypes from a bioequivalence trial were included according to the protocol registered at ClinicalTrial.org (NCT03161496). All subjects received a single dose (150 mg) of dabigatran etexilate. PK (main outcomes: area under the concentration-time, AUC0-t, of total and free dabigatran) and PD (main outcomes: anti-FIIa activity, APTT, and PT) parameters were evaluated. Whole-exome sequencing and genome-wide association analyses were performed. Additionally, candidate gene association analyses related to dabigatran were conducted.Results: A total of 118 healthy Chinese subjects were enrolled in this study. According to the p-value suggestive threshold (1.0 × 10−4), the following three SNPs were found to be associated with the AUC0–t of total dabigatran: SLC4A4 SNP rs138389345 (p = 5.99 × 10−5), FRAS1 SNP rs6835769 (p = 6.88 × 10−5), and SULT1A1 SNP rs9282862 (p = 7.44 × 10−5). Furthermore, these SNPs were also found to have significant influences on the AUC0–t of free dabigatran, maximum plasma concentration, and anti-FIIa activity (p < 0.05). Moreover, we identified 30 new potential SNPs of 13 reported candidate genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP1A2, CYP2C19, CYP3A5, CES1, SLCO1B1, SLC22A1, UGT1A1, UGT1A9, and UGT2B7) that were associated with drug metabolism.Conclusion: Genetic variations were indeed found to impact dabigatran metabolism in a population of healthy Chinese subjects. Further research is needed to explore the more detailed functions of these SNPs. Additionally, our results should be verified in studies that use larger sample sizes and investigate other ethnicities.

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration.Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters.Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%–95% PI)) of 20 and 15 mg were 309 ng/ml (139–597 ng/ml) and 296 ng/ml (138–604 ng/ml), both median values were within the expected range. For patients with CrCL 30–49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range.Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF.

BackgroundNuclear protein in testis (NUT) carcinoma (NC) is a rare and aggressive undifferentiated carcinoma that typically arises from midline supradiaphragmatic structures. It is uniquely driven by a NUT gene rearrangement on chromosome 15q14. Few thyroid NCs have been reported and there are no established treatment guidelines for NUT carcinoma.MethodUltrasound-guided fine needle aspiration smear was performed for the preoperative diagnosis of thyroid lesions. Cytopathology, histology, and immunochemical staining all indicated NC. Fluorescence in situ hybridization (FISH), qRT-PCR, and next-generation sequencing (NGS) were used to analyze the genetic characteristics of NC.ResultsWe describe a rare case of thyrogenic NC in a 38-year-old male with cytological, histological, immunohistochemical, and genetic features. Cytological smears and histopathological specimens showed typical features of NC. Immunohistochemistry confirmed strong immunoreactivity with NUT, EMA, P63, TTF-1, and c-myc. CK19 was positive exclusively in sudden keratosis. No immunoreactivity was found for neuroendocrine markers. FISH was applied to isolate the NUT gene on chromosome 15q14. The NGS results revealed a BRD4-NUT gene fusion, which was further confirmed by RT-qPCR. Structural variation (SV) of NUTM1 occurred in the exon region, and the mutation site was 15q14. Moreover, BRD4 single-nucleotide variation (SNV) occurs in the 3′ UTR at mutation site 19p13.12. The PD-L1 combined predictive score was over 30%. The patient received chemotherapy, followed by programmed cell death 1 (PD-1) inhibition with camrelizumab, and died 10 months after surgery.ConclusionThyroid NC is an extremely rare and fatal malignant tumor. It is necessary to consider NC when squamous differentiation is observed cytologically or histologically. NGS is an effective tool for obtaining the final diagnosis and obtaining a better understanding of tumor pathogenesis. A large number of IGKV gene fusions in addition to the BRD4-NUT fusion may play a role in the pathogenesis and immunotherapy response of NC. Immunotherapy for NC remains to be explored due to the rarity of this aggressive malignancy.

Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its influence on platelet ADP-P2Y12 receptor inhibitors lack consistency. Thus, we conducted a systematic review and meta-analysis of already existing data/studies to further explore this issue. PubMed, Web of science, EMBASE, Clinical Trials, and the Cochrane Library were searched from inception to March 2018. Studies investigating the residual platelet reactivity categorized by smoking status and patients treated with platelet ADP-P2Y12 receptor inhibitors qualified the inclusion criteria. The primary outcome was P2Y12 reaction unit (PRU) value measured by VerifyNow P2Y12 assay, compared with different smoking status in ADP-P2Y12 receptor inhibitors treatment groups. Secondary outcome was post-treatment with 5 μmol/L ADP-inhibition of platelet aggregation (ADP-IPA) measured by light transmittance aggregometry (LTA). Of the 4954 citations retrieved, 12 studies involving 16 296 patients with acute coronary syndrome and/or stent deployment using platelet ADP-P2Y12 receptor inhibitors were included for meta-analysis. Pooled analysis revealed that PRU values of current smokers were 25.70 lower than nonsmokers (95% CI −38.81 to −12.60, p = 0.0001), getting better effects of antiplatelet treatment. In the smoking extent subgroup analysis, patients smoking >10 cigarettes/day shown about 46.49 lower of PRU values than patients smoking

Background: This study aims to investigate isocitrate dehydrogenase gene mutations in patients with the non-hereditary skeletal disorders of Ollier disease and Maffucci syndrome, particularly in the extraosseous tumours. Methods: A total of 16 tumours from three patients with Ollier disease and three patients with Maffucci syndrome were collected. Sanger sequencing was applied to determine the hotspot mutations of IDH1 and IDH2 genes in multiple neoplastic tissues. Results: A majority of the tumours displayed an IDH1 mutation (p.R132C in 11 tumours including the paediatric ovarian tumour from one patient with Ollier disease, 4 cutaneous haemangiomas from three patients with Maffucci syndrome, 5 enchondromas and 1 chondrosarcoma; p.R132H in 2 cartilaginous tumours from one patient). Conclusions: IDH1 mutations were demonstrated in multiple cartilaginous tumours and extraskeletal neoplasms in this case series. Specifically, identical IDH1 mutations were confirmed in the separate lesions of each patient. These results are in concordance with findings that have been reported. However, here, we additionally reported the first case of Ollier disease with an ovarian tumour, which harboured the identical IDH1 mutation with the corresponding cartilaginous tumour. We further provided evidence that IDH mutations are the potential genetic links among the multiple neoplastic lesions of Ollier disease and Maffucci syndrome.

This study analyzes the spectral characteristics of desert surface emissivity according to soil classification and the influence of mineral materials and soil texture information using simulation results from the microwave land emissivity model (MLEM). It also aims at exploring the feasibility of reducing the simulation error in MLEM by refining the soil classification characteristic parameters (such as soil composition content, distribution of particle size, etc.). The surface emissivity of the Taklimakan Desert is derived, to our knowledge for the first time, from FY-3B/MWRI (FengYun-3B Microwave Radiation Imager), and then the spectral characteristics of the study area for different soil types are further analyzed according to soil classification. In addition, emissivity spectra of the four most widely mineral materials in the desert area are reproduced using an MLEM under different conditions. Results showed that microwave land emissivity is highly correlated with the soil type and changes are markedly affected by the soil water content, soil texture, mineral composition, and soil particle size. For the desert soil, the emissivity of horizontal/vertical polarization is affected by the frequency in those soils dominated by large-size particles. However, for those dominated by smaller particles, the surface emissivity is almost constant or appears to be somehow dependent on the frequency. Moreover, the season effect on emissivity characteristics is clear, especially for soils composed of small-size particles. The emissivity of horizontal polarization shows stronger seasonal variation than that of vertical polarization. The study findings also showed that refining soil texture information (soil component content, distribution of particle size) improves the simulation accuracy in desert areas. For example, for the soil dominated by clay and clay loam, the simulation error is reduced from 6–9% to less than 6%. The latter is evident, especially for soil types containing a large number of small particles, such as clay and clay loam, for which the simulation error is reduced. All in all, our study contributes to a better understanding of the influencing factors of soil texture and stratification of the near-surface soil, helping to improve microwave land surface emissivity prediction by the studied here model. As MLEM consists of an important part of the global meteorological data assimilation and weather forecast system, results can also help towards increasing the use of satellite data in desert areas and in improving the accuracy of numerical weather forecast models.