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Although various anti-osteoporosis drugs are available, the limitations of these therapies, including drug resistance and collateral responses, require the development of novel anti-osteoporosis agents. Rhizoma Drynariae displays a promising anti-osteoporosis effect, while the effective component and mechanism remain unclear. Here, we revealed the therapeutic potential of Rhizoma Drynariae-derived nanovesicles (RDNVs) for postmenopausal osteoporosis and demonstrated that RDNVs potentiated osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) by targeting estrogen receptor-alpha (ERα). RDNVs, a natural product isolated from fresh Rhizoma Drynariae root juice by differential ultracentrifugation, exhibited potent bone tissue-targeting activity and anti-osteoporosis efficacy in an ovariectomized mouse model. RDNVs, effectively internalized by hBMSCs, enhanced proliferation and ERα expression levels of hBMSC, and promoted osteogenic differentiation and bone formation. Mechanistically, via the ERα signaling pathway, RDNVs facilitated mRNA and protein expression of bone morphogenetic protein 2 and runt-related transcription factor 2 in hBMSCs, which are involved in regulating osteogenic differentiation. Further analysis revealed that naringin, existing in RDNVs, was the active component targeting ERα in the osteogenic effect. Taken together, our study identified that naringin in RDNVs displays exciting bone tissue-targeting activity to reverse osteoporosis by promoting hBMSCs proliferation and osteogenic differentiation through estrogen-like effects.

ABSTRACTThe synergistic disruption of intracellular redox homeostasis through the combination of ferroptosis/gas therapy shows promise in enhancing the antitumor efficacy. However, the development of an optimal delivery system encounters significant challenges, including effective storage, precise delivery, and controlled release of therapeutic gas. In this study, we propose the utilization of a redox homeostasis disruptor that is selectively activated by the tumor microenvironment (TME), in conjunction with our newly developed nanoplatforms (MC@HMOS@Au@RGD), for highly efficient ferroptosis therapy of tumors. The TME-triggered degradation of HMOS initiates the release of MC and AuNPs from the MC@HMOS@Au@RGD nanoplatform. The released MC subsequently reacts with endogenous hydrogen peroxide (H2O2) and H+ to enable the on-demand release of CO gas, leading to mitochondrial damage. Simultaneously, the released AuNPs exhibit GOx-like activity, catalyzing glucose to generate gluconic acid and H2O2. This process not only promotes the decomposition of MnCO to enhance CO production but also enhances the Fenton-like reaction between Mn2+ and H2O2, generating ROS through the modulation of the H+ and H2O2-enriched TME. Moreover, the generation of CO bubbles enables the monitoring of the ferroptosis treatment process through ultrasound (US) imaging. The efficacy of our prepared MC@HMOS@Au@RGD disruptors in ferroptosis therapy is validated through both in vitro and in vivo experiments.

Quantifying the impacts of climate change, vegetation greening and human activities (CVH) on evapotranspiration (ET), surface drought intensity (ET divided by precipitation, SDI), and vegetation available water (precipitation minus ET, VAW) would improve our understanding of water cycle processes. The Yellow River Basin (YRB) is a significant climate-sensitive region in China, resulting in an obvious spatiotemporal heterogeneity of ET, SDI, and VAW in response to driving variables. In this study, we analysed the spatiotemporal variation characteristics of ET, SDI, and VAW in the YRB from 1984 to 2018. We also quantified the direct and indirect contributions of the CVH to the changes in ET, SDI, and VAW, and revealed the influence mechanism of each link. Finally, water resource risks were assessed from a probabilistic perspective. The results indicated that vegetation greening was the primary driver of ET with an increase rate of 1.60 mm/a, which was also the most important influencing factor of SDI increase and VAW decrease. Leaf area index (LAI) and relative humidity (RH) jointly dominated the ET changes in 66 % of the YRB, temperature (Temp) dominated the SDI changes in nearly half of the basin, precipitation (Pre) and LAI jointly dominated the VAW changes in 66 % of the YRB. Temp indirectly influenced ET primarily through LAI, whereas LAI primarily influenced ET directly. Temp had a significant direct impact on SDI, while LAI mainly influenced SDI through RH and wind speed (WS). Temp exhibited the most substantial negative influence on VAW. LAI was identified as the primary factor contributing to water resource risks, with a probability reaching 0.8, while the probabilities associated with other factors inducing such risks were similar at the basin level, but disparities existed among different land use types. The findings of the study significantly enhanced our understanding of the role that the CVH played in hydrological processes, serving as a crucial foundation for achieving a balance between ecological restoration and socio-economic development in the YRB.

Relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is associated with poor prognosis. As such, a comprehensive analysis of intratumoral components, intratumoral heterogeneity, and the immune microenvironment is essential to elucidate the mechanisms driving the progression of DLBCL and to develop new therapeutics. Here, we used single-cell transcriptome sequencing and conventional bulk next-generation sequencing (NGS) to understand the composite tumor landscape of a single patient who had experienced multiple tumor recurrences following several chemotherapy treatments. NGS revealed several key somatic mutations that are known to contribute to drug resistance. Based on gene expression profiles at the single-cell level, we identified four clusters of malignant B cells with distinct transcriptional signatures, showing high intra-tumoral heterogeneity. Among them, heterogeneity was reflected in activating several key pathways, human leukocyte antigen (HLA)-related molecules’ expression, and key oncogenes, which may lead to multi-drug resistance. In addition, FOXP3+ regulatory CD4+ T cells and exhausted cytotoxic CD8+ T cells were identified, accounted for a significant proportion, and showed highly immunosuppressive properties. Finally, cell communication analysis indicated complex interactions between malignant B cells and T cells. In conclusion, this case report demonstrates the value of single-cell RNA sequencing for visualizing the tumor microenvironment and identifying potential therapeutic targets in a patient with treatment-refractory DLBCL. The combination of NGS and single-cell RNA sequencing may facilitate clinical decision-making and drug selection in challenging DLBCL cases.

Abstract Plant-derived nanovesicles (NVs) and extracellular vesicles (EVs) are the next generation of nanocarrier platforms for biotherapeutics and drug delivery. EVs exist not only in the extracellular space, but also within the cell wall. Due to the limitations of existing isolation methods, the EVs extraction efficiency is low, and a large amount of plant material is wasted, which is of concern for rare and expensive medicinal plants. We proposed and validated a novel method for isolation of plant EVs by enzyme degradation of the plant cell wall to release the EVs. The released EVs can easily be collected. The new method was used for extraction of EVs from the roots of Morinda officinalis (MOEVs). For comparison, nanoparticles from the roots (MONVs) were extracted using the grinding method. The new method yielded a greater amount of MOEVs, and the vesicles had a smaller diameter compared to MONVs. Both MOEVs and MONVs were readily absorbed by endothelial cells without cytotoxic effect and promoted the expression of miR-155. The promotion of miR-155 by MOEVs was dose-dependent. More importantly, we found that MOEVs and MONVs were enriched toward bone tissue. These results support our hypothesis that EVs in plants could be efficiently extracted by enzymatic cell wall digestion and confirm the potential of MOEVs as therapeutic agents and drug carriers.

Abstract Background To assess the predictive values of primary tumor FDG uptake for patients with inoperable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). Methods A total of 107 patients with diagnosis of stage III NSCLC and CCRT were enrolled. The tumor maximum uptake value (SUVmax) was standardized by calculating several ratios between tumor and each background tissues. The receiver operating characteristics curve (ROC) was used to compare the predictive power of prognostic models. The tumor objective response rate (ORR) and overall survival (OS) were compared and analyzed by the Kaplan–Meier method and univariate and multivariate Cox regression models. Results The areas under ROC curve (AUCs) ranged from 0.72 to 0.81 among these tumor SUVmax and standardized SUVmax ratios, and the tumor SUVmax and tumor SUVmax-to-liver SUVmean ratio (TLMR) were more predictive of ORR (AUC, 0.81; 95% CI, 0.73–0.88 for tumor SUVmax and AUC, 0.84; 95%CI, 0.76–0.91 for TLMR) than any of other SUVmax ratios. The patients with lower tumor SUVmax, SUVmean and SUVmax ratios had a significantly better OS than those with their corresponding higher ones. Moreover, both univariate and multivariable analyses revealed that TLMR was significantly associated with better ORR and OS after adjustment with other prognostic variables. Conclusions TLMR, a standardized tumor SUVmax, was an independent prognostic predictor for tumor ORR and OS of patients with stage III NSCLC after CCRT.

Abstract The interplay between immune cells/macrophages and fibroblast‐like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single‐cell RNA sequencing (scRNA‐seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients’ synovial macrophage infiltration and polarization. In addition, the yes‐associated protein 1 (YAP1)/thioredoxin‐interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)‐dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule‐1 (ICAM‐1) which may subsequently fine‐tune the infiltration of M1‐polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane‐camouflaged Verteporfin (Vt)‐loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1‐polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

Purpose: For systematic athletic training and targeted talent development, it is essential to know the physical fitness and motor competencies of top athletes in detail. However, it can be difficult to identify differences in performance requirements and thus to provide adequate support, especially for sports that at first glance appear to have similar demands—such as track and field throwing disciplines. Therefore, the aim of the study was to examine the physical fitness and motor competence of top athletes from different throwing disciplines and to check whether the athletes’ performance parameters match the specific requirements of the respective sport.Methods: The study involved 289 male youth athletes (aged 14–18 years) across four distinct throwing disciplines: shot put (n = 101), hammer throw (n = 16), discus throw (n = 63), and javelin throw (n = 109). The performance evaluation comprised three anthropometric measurements and twelve motor performance prerequisites applicable to the throwing disciplines. Discriminant analysis and neural networks (Multilayer Perceptron) were implemented to determine the possibility of distinguishing among athletes from the four sports.Results: The study’s findings indicate that in male throwing athletes, disparities in general physical fitness and motor proficiency assessments discern the majority of talented young athletes based on their specific sport (discriminant analysis: 68.2%; multilayer perceptron analysis: 72.2%). This remains applicable irrespective of the classification method employed. Discus throwers possessed a height advantage, while shot putters and hammer throwers exhibited superior arm strength. Javelin throwers displayed better explosive strength and sprinting speed. Except for the hammer throwers, all events demonstrated a high level of explosive power in the medicine ball forward or backward throw test, which was especially crucial for shot put and discus athletes.Conclusion: The significance of physical fitness and motor competence tests in identifying and transferring talented athletes in track and field throwing disciplines has been affirmed. Using linear and non-linear classification methods, most athletes could be assigned to their correct sport. However, this also shows that slightly different training and talent identification is required for each of these sports. Furthermore, non-linear analysis methods can provide useful support for the development processes in junior competitive sports.

Abstract Clinically, activated EGFR mutation associated chemo-drugs resistance has severely threaten NSCLC patients. Nanoparticle based small interfering RNA (siRNA) therapy representing another promising alternative by silencing specific gene while still suffered from charge associated toxicity, strong immunogenicity and poor targetability. Herein, we reported a novel EGFR-mutant NSCLC therapy relying on edible and cation-free kiwi-derived extracellular vesicles (KEVs), which showed sevenfold enhancement of safe dosage compared with widely used cationic liposomes and could be further loaded with Signal Transducer and Activator of Transcription 3 interfering RNA (siSTAT3). siSTAT3 loaded KEVs (STAT3/KEVs) could be easily endowed with EGFR targeting ability (STAT3/EKEVs) and fluorescence by surface modification with tailor-making aptamer through hydrophobic interaction. STAT3/EKEVs with a controlled size of 186 nm displayed excellent stability, high specificity and good cytotoxicity towards EGFR over-expressing and mutant PC9-GR4-AZD1 cells. Intriguingly, the systemic administration of STAT3/EKEVs significantly suppressed subcutaneous PC9-GR4-AZD1 tumor xenografts in nude mice by STAT3 mediated apoptosis. This safe and robust KEVs has emerged as the next generation of gene delivery platform for NSCLC therapy after multiple drug-resistance. Graphical Abstract

Efficient photoprotection is vital for the maintenance of photosynthetic efficiency during photodamage. Here, the authors reveal that m6A writer VIRILIZER acts as a molecular switch of photoprotection by post-transcriptional regulation in plants.

BackgroundThe present study sought to understand how clinical factors and inflammatory biomarkers affected the prognosis of mucosa-associated lymphoid tissue (MALT) lymphoma and develop a predictive nomogram to assist in clinical practice.MethodsWe conducted a retrospective study on 183 cases of newly diagnosed MALT lymphoma from January 2011 to October 2021, randomly divided into two groups: a training cohort (75%); and a validation cohort (25%). The least absolute shrinkage and selection operator (LASSO) regression analysis was combined with multivariate Cox regression analysis to construct a nomogram for predicting the progression-free survival (PFS) in patients with MALT lymphoma. To evaluate the accuracy of the nomogram model, the area under the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used.ResultsThe PFS was significantly associated with the Ann Arbor Stage, targeted therapy, radiotherapy, and platelet-to-lymphocyte ratio (PLR) in MALT lymphoma. These four variables were combined to establish a nomogram to predict the PFS rates at three and five years. Importantly, our nomogram yielded good predictive value with area under the ROC curve (AUC) values of 0.841 and 0.763 in the training cohort and 0.860 and 0.879 in the validation cohort for the 3-year and 5-year PFS, respectively. Furthermore, the 3-year and 5-year PFS calibration curves revealed a high degree of consistency between the prediction and the actual probability of relapse. Additionally, DCA demonstrated the net clinical benefit of this nomogram and its ability to identify high-risk patients accurately.ConclusionThe new nomogram model could accurately predict the prognosis of MALT lymphoma patients and assist clinicians in designing individualized treatments.

Purpose: The aims of this study were: (1) to profile anthropometric, physical fitness, and specific throwing strength characteristics among 14–18 years boys and girls throwers; (2) to evaluate which factors vary with age, and which correlate with specific throwing strength; (3) to identify the measured variables that best predict specific throwing strength. Methods: Anthropometric, physical fitness, and specific throwing strength of 154 boys and 104 girls, who participated in track-and-field throw (Shot put, Javelin, Discus and Hammer throw) from four age categories (U15, U16, U17, U18), were measured in September 2022. The differences and correlations in parameters among different age, sex and throwing groups were analyzed using parametric and non-parametric testing. Multivariate linear regression analysis was used to identify the variables that best explain the specific throwing strength. Results: Disparities in height between boys and girls of the same age have consistently existed, however, the dissimilarity in weight tends to diminish as they grow older. Boys and girls of identical age groups exhibit noteworthy disparities in terms of speed, agility, and jumping prowess. These disparities tend to amplify as they advance in age. Significant differences were observed among boys of different ages in Height (p = 0.038), Body Mass (p = 0.02), BMI (p = 0.025), sit and reach test (p = 0.035), standing long jump (p = 0.012), standing triple jump (p < 0.01), forward overhead medicine ball throw (p = 0.002) and the hexagon agility test (p < 0.01). No differences were found in anthropometric measurements among girls, but differences were found in the hexagon agility test (p = 0.017) and plank test (p = 0.041). Specific throwing strength exhibits variations due to differences in events, age, and gender. Additionally, physical fitness performance, especially lower limb power, linear sprint speed, forward overhead medicine ball throw and backward overhead shot throw, have a high correlation with specific throwing strength. Conclusions: These findings broaden the existing knowledge base for coaches and practitioners, enabling them to discern the distinctive attributes of track and field throwers and capture the crucial physical markers that are pivotal for nurturing the progression of track-and-field throwers. The study suggests that throwers aged 14 to 18 should strive to comprehensively cultivate their athletic abilities.

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants and pose a severe threat to human health. Here, 38 surface sediment samples collected from the Gaoqiao mangrove wetland in Zhanjiang, south China, were analyzed to determine 16 Environmental Protection Agency (EPA) priority PAHs. Total PAHs concentrations ranged from 33.5 µg/kg to 404.8 µg/kg with an average of 147.7 ± 77.7 µg/kg, inferring a moderate pollution level. Three and four-ring compounds dominated the PAHs composition patterns. Significant positive correlations were observed between the PAHs and the physicochemical properties of the sediments. According to the characteristic molecular ratio method, PAHs in sediments were mainly derived from combustion sources, including the incomplete combustion of liquid fossil fuels, grass, wood, and coal. The result based on the PMF model indicates that the primary combustion sources of PAHs are coal combustion, diesel-powered vehicles, biomass combustion and gasoline-powered vehicles, with a share of 39.01%, 25.21%, 12.72% and 10.48%, respectively. The petrogenic source contributes 12.58% PAHs to the sediments. The mean effects range median quotient (m-ERM-Q) and toxic equivalent method (TEQ) indicate a low comprehensive ecological risk of PAHs in the study area. Still, the evaluation results of effects range low (ERL) suggest that PAHs in the sediment would occasionally have adverse biological effects. Therefore, this situation demands attention and calls for protection strategies in the processes of urbanization and industrialization in south China.

Extracellular vesicles (EVs) are nano-sized membrane vesicles released by various cell types. Mammalian EVs have been studied in-depth, but the role of plant EVs has rarely been explored. For the first time, EVs from Drynariae Rhizoma roots were isolated and identified using transmission electron microscopy and a flow nano analyzer. Proteomics and bioinformatics were applied to determine the protein composition and complete the functional analysis of the EVs. Seventy-seven proteins were identified from Drynariae Rhizoma root-derived EVs, with enzymes accounting for 47% of the proteins. All of the enzymes were involved in important biological processes in plants. Most of them, including NAD(P)H-quinone oxidoreductase, were enriched in the oxidative phosphorylation pathway in plants and humans, and Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, which are associated with oxidative stress in humans. These findings suggested that EVs from Drynariae Rhizoma roots could alleviate such neurological diseases and that enzymes, especially NAD(P)H-quinone oxidoreductase, might play an important role in the process.

BackgroundUncommon epidermal growth factor receptor (EGFR) mutations consist of a heterogeneous population of molecular alterations, and the available clinical data on the outcomes of patients with non-small-cell lung cancer (NSCLC) harboring uncommon EGFR mutations following afatinib treatment are limited. The purpose of this pooled analysis was to investigate the clinicopathological features of patients with uncommon EGFR mutations (um-EGFRms) along with their treatment response and survival outcomes following afatinib treatment.MethodsWe performed a literature search in the NCBI PubMed database to identify relevant articles and conducted this pooled analysis based on 70 studies. The relationships between patient clinical characteristics, EGFR mutation type and the response to afatinib treatment were analyzed using univariate chi-square analysis, and survival analysis was performed using the Kaplan–Meier method.ResultsData from a total of 99 patients were included in the pooled analysis. The objective response rate (ORR) to treatment with afatinib was53.5%, with a median progression-free survival (mPFS) of 9.0 months. For patients administered first-line afatinib treatment, the ORR and median PFS were 73.5% and 15.6 months, respectively, which were both superior to those of patients treated with second- or later-line treatments (ORR:37.0%, p < 0.001; mPFS: 6.0months, p = 0.001). Moreover, patients with a single um-EGFRm were more likely to have a favorable response and prognosis benefit after treatment with afatinib than patients with multiple one (ORR: 63.3% vs 38.5%, p=0.017; mPFS: 15.6 months vs 6.0 months,p=0.010). Moreover, single um-EGFRm were independent predictive factors for better treatment response and superior PFS. Subgroup analysis indicated that patients harboring major um-EGFRms (i.e., L861Q, G719X, and S768I) exhibited the best treatment responses and prognoses (ORR: 74.1%, mPFS: 15.6 months), by contrast, patients harboring multiple um-EGFRms comprising 19del/L858R had the worst treatment responses and prognoses (ORR: 23.5%, mPFS: 5.6months).ConclusionsPatients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following afatinib treatment, which closely related to the mutation pattern and cooccurring partner mutant genes. Administering afatinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances, but this recommendation requires further clinical studies for verification.

BackgroundPituitary metastasis accounts for a very low percentage of cases of brain metastasis from lung cancer, and there are uncertainties and challenges in diagnosis and treatment. We hope to shed some light on the diagnosis and treatment by reporting a case of ALK fusion mutation-positive lung cancer pituitary metastasis.Case presentationWe report a 48-year-old female patient with an initial diagnosis of stage IVB lung adenocarcinoma with ALK fusion. The patient developed headache, dizziness, hypopituitarism and hyperprolactinemia one year after treatment with crizotinib. Later, the patient underwent neurosurgical resection of the pituitary tumor and then symptomatic relief. Postoperative pathology suggested pituitary metastasis, and the next-generation gene sequencing conducted on the pituitary metastasis indicated that secondary drug resistance mutation ALK-I1171s occurred after the ALK fusion gene.ConclusionIn this article, we present a patient with suspected pituitary metastases with lung cancer. The progression to pituitary mass resection and next-generation gene sequencing of the pituitary metastasis are suggestive for further diagnosis and treatment.

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread to many countries around the world. In addition to lung disease, severe cases also displayed varying degrees of liver injury. This article will describe the latest developments regarding coronavirus and the pathogenesis of liver injury, the prone population and clinical characteristics of these patients, as well as providing some suggestions for clinical treatment.

Background: In this pooled analysis, the aim was to investigate the clinicopathological characteristics of patients with uncommon epidermal growth factor receptor (EGFR) (ucm-EGFRms) along with their treatment responses and survival following osimertinib treatment.Methods: Univariate chi-square analysis was conducted to analyze the correlation between clinical characteristics, EGFR mutation type, and treatment response, and the Kaplan-Meier method was applied for survival analysis. Univariate logistic regression model and Cox proportional hazards model were performed to compare the efficacy and prognosis in subgroup analysis.Results: Seventy-two NSCLC patients in total were included in this pooled analysis. The objective response rate (ORR) for osimertinib treatment was 57.0%, with a median PFS of 7.1 months. Twenty-eight patients received osimertinib as first-line therapy with an ORR of 67.9%, which was higher than that in patients who received osimertinib as second- or later-line therapy, and their response rate was 50%, nevertheless, no statistically significant differences were found (p = 0.139). However, patients who received first-line osimertinib showed a more significant PFS benefit than those who received second- or later-line therapy (mPFS: 16.8 months vs 6.0 months HR: 2.453, 95%CI: 1.285-4.682, p =0.004). Subgroup analysis showed that patients with a single, non-ex20ins, ucm-EGFRm displayed a superior efficacy advantage and favorable survival benefit following osimertinib treatment, with an ORR of 68.8% and an mPFS at 15.1 months. By contrast, patients with a multiple ucm-EGFRm that contain T790M exhibited the worst outcome of osimertinib treatment, with an ORR of 47.6% and an mPFS of only 3.6 months, respectively.Conclusion: Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following osimertinib treatment, which is closely related to the mutation pattern and cooccurring partner mutant genes. Administering osimertinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances.

Background: Pressure-strain loop (PSL) analysis provides a novel, less load-dependent non-invasive method to quantify myocardial work and demonstrates a significant correlation with the contractile reserve in adult athletes. We aim to validate PSL-derived markers in characterizing LV function in pre-adolescent basketball players by comparing results before and after the cardiopulmonary exercise test (CPX) and explore its association with CPX-derived aerobic capacity.Methods: Cardiac morphology and function in 20 pre-adolescent basketball players were assessed at 9.7 years old (9.7 ± 1.1 year) before and after cardiopulmonary exercise testing. Echocardiography was performed in all subjects, including two-dimensional speckle-tracking echocardiography (STE). Simultaneous brachial-cuff-measured blood pressure was recorded to perform PSL analysis.Results: Nineteen subjects were included in the final analysis. Exercise training in pre-adolescent males was associated with lower global work index (GWI) and global work efficiency (GWE) at rest. GWE at stress was significantly correlated with VO2max and peak O2 pulse (p = 0.0122, r = 0.56; p = 0.00122, r = 0.69, respectively). When indexed by body mass, GWI and GWE both significantly correlated with relative VO2max (p = 0.0086 and 0.0011 respectively, r = 0.58 and 0.69 respectively); GWI and GWE at baseline and stress were all significantly correlated with peak O2 pulse (GWI at baseline, p< 0.0001, r = −0.90; GWE at baseline, p< 0.0001, r = −0.89; GWI at stress, p= 0.0289, r = −0.50; GWE at stress, p< 0.0001, r = −0.83).Conclusion: PSL-analysis-derived GWI and GWE at rest indexed by body mass are associated with cardiopulmonary exercise test-derived peak oxygen consumption and oxygen pulse in pre-adolescent athletes.

Background: Mesenchymal Stem Cells (MSCs) therapy has become a new coming focus of clinical research in regenerative medicine. However, only a small number of implanted MSCs could successfully reach the injured areas. The previous studies have shown that fracture healing time is inversely proportional to concentration of MSCs in injured tissue. Methods: The migration and osteogenesis of MSCs were assessed by transwell assay and Alizarin Red S staining. Levels of gene and protein expression were checked by qPCR and Western Blot. On the other hand, the enhanced migration ability of MSCs induced by Cyasterone was retarded by CXCR4 siRNA. In addition, the rat model of femoral fracture was established to evaluate the effect of Cyasterone on fracture healing. What's more, we also checked the effect of Cyasterone on mobilisation of MSCs in vivo. Results: The results showed that Cyasteron increased the number of MSCs in peripheral blood. The concentrations of SDF-1α in serum at different time points were determined by ELISA assay. Micro-CT and histological analysis were used to evaluate the fractured femurs.Our results showed that Cyasterone could promote the migration and osteogenesis capacities of MSCs. The fractured femurs healed faster with treatment of Cyasterone. Meanwhile, Cyasterone could significantly increase the level of SDF-1α in rats with femur fracture. Conclusion: Cyasterone could promote migration and osteogenesis of MSCs, and most importantly, it could accelerate bone fracture healing.Translational Potential statement: These findings provide evidence that Cyasterone could be used as a therapeutic reagent for MSCs mobilisation and osteogenesis. What's more, it could acclerate fracture healing.

Abstract Background We evaluated the prognostic potential of tumor 18F-fluorodeoxyglucose (FDG) uptake derived from positron emission tomography (PET) and known inflammatory hematological markers, both individually and in combination, for chemosensitivity and survival in patients with stage IIIB-IV non-small cell lung cancer (NSCLC) receiving first-line chemotherapy. Methods A total of 149 patients with stage IIIB and IV NSCLC (based on TNM 7th edition) were retrospectively reviewed. Maximum standardized uptake value (SUVmax) were used to quantitatively assess FDG uptake. The lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were selected as hematological markers. Receiver operating characteristic (ROC) curves were constructed for the determination of optimal cut-off values to predict chemotherapeutic response. Results Patients with SUVmax > 11.6 or LMR ≤3.73 exhibited a significantly lower objective response rate (ORR) to chemotherapy (p 11.6) and low LMR (≤3.73) as independent predictors of poor PFS (p

Abstract Background We conducted this study to combine the mean standardized uptake value (SUVmean) and neutrophil to lymphocyte ratio (NLR) to establish a strong predictive model for patients with esophageal squamous cell carcinoma (ESCC) after concurrent chemoradiotherapy (CCRT). Methods We retrospectively analyzed 163 newly diagnosed ESCC patients treated with CCRT. Eighty patients (training set) were randomly selected to generate cut-off SUVmean and NLR values by receiver operating characteristic (ROC) curve analysis and to establish a predictive model by using the independent predictors of treatment outcomes. Then, we evaluated the performance of the prediction model regarding treatment outcomes in the testing set (n = 83) and in all sets. Results A high SUVmean (> 5.81) and high NLR (> 2.42) at diagnosis were associated with unfavorable treatment outcomes in patients with ESCC. The prediction model had a better performance than the simple parameters (p

Abstract Background Perfusion CT can offer functional information about tumor angiogenesis, and 18F-FDG PET/CT quantifies the glucose metabolic activity of tumors. This prospective study aims to investigate the value of biologically relevant imaging biomarkers for predicting treatment response and survival outcomes in patients with locally advanced esophageal squamous cell cancer (LA ESCC). Methods Twenty-seven patients with pathologically proven ESCC were included. All patients had undergone perfusion CT and 18F-FDG PET/CT using separate imaging systems before receiving definitive chemoradiotherapy (dCRT). The perfusion parameters included blood flow (BF), blood volume (BV), and time to peak (TTP), and the metabolic parameters included maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The flow-metabolism ratio (FMR) was defined as BF divided by SUVmax. Statistical methods used included Spearman’s rank correlation, Mann–Whitney U test or two-sample t test, receiver operating characteristic (ROC) curve analysis, the Kaplan–Meier method, and Cox proportional hazards models. Results The median overall survival (OS) and progression-free survival (PFS) were 18 and 11.6 months, respectively. FMR was significantly positively correlated with BF (r = 0.886, p < 0.001) and negatively correlated with SUVmax (r = − 0.547, p = 0.003) and TTP (r = − 0.462, p = 0.015) in the tumors. However, there was no significant correlation between perfusion and PET parameters. After dCRT, 14 patients (51.9%) were identified as responders, and another 13 were nonresponders. The BF and FMR of the responders were significantly higher than those of the nonresponders (42.05 ± 16.47 vs 27.48 ± 8.55, p = 0.007; 3.18 ± 1.15 vs 1.84 ± 0.65, p = 0.001). The ROC curves indicated that the FMR [area under the curve (AUC) = 0.846] was a better biomarker for predicting treatment response than BF (AUC = 0.802). Univariable Cox analysis revealed that of all imaging parameters, only the FMR was significantly correlated with overall survival (OS) (p = 0.015) and progression-free survival (PFS) (p = 0.017). Specifically, patients with a lower FMR had poorer survival. Multivariable analysis showed that after adjusting for age, clinical staging, and treatment response, the FMR remained an independent predictor of OS (p = 0.026) and PFS (p = 0.014). Conclusions The flow-metabolism mismatch demonstrated by a low FMR shows good potential in predicting chemoradiotherapy sensitivity and prognosis in ESCC.

IntroductionOsimertinib resistance is inevitable. The purpose of this study was to explore the predictive value of pretreatment clinical characteristics in T790M-positive non-small cell lung cancer NSCLC patients for the resistance pattern of osimertinib during tumor progression as well as the treatment strategy.MethodsWe performed a literature search in the NCBI PubMed database to identify relevant articles and completed a pooled analysis based on 29 related published studies. The relationship between clinical characteristics, EGFR mutation type, previous treatment history and the gene mutation pattern at resistance to osimertinib was analyzed.ResultsA total of 38 patients were included in the pooled analysis. Patients with an initial epidermal growth factor receptor EGFR mutation status of 19 deletions were more likely to have T790M loss (HR: 12.187, 95% CI: 2.186–67.945, p = 0.004). Patients with an initial EGFR mutation of L858R were more likely to have C797S mutations (HR: 0.063, 95% CI: 0.011–0.377, p = 0.002). The other factors (age, gender, ethnicity, smoking history, previous EGFR-TKI targeted therapy history, history of radiotherapy and chemotherapy) were not associated with the resistance pattern of osimertinib (all p > 0.05).ConclusionsThe type of EFGR mutation in T790M-positive NSCLC patients prior to treatment can predict the resistance pattern to osimertinib. This finding plays a vital role and theoretical basis in guiding clinicians to formulate treatment strategies at the early stage of treatment and rationally combine drugs to overcome EGFR-TKI resistance.

Background. Myocardial infarction (MI) is cardiac tissue necrosis caused by acute and persistent ischemic hypoxia of the coronary arteries. This study is aimed at investigating the expression of long noncoding RNA (lncRNA) LINC00261 in MI and its effect on myocardial cells. Methods. qRT-PCR was performed to detect the expression levels of LINC00261, miR-522-3p, and TNRC6A in normal and MI cells. Western blotting analysis was performed to detect the expression of TNRC6A protein. Viability and apoptosis of myocardial cells after MI with the knockout of LINC00261 or TNRC6A were detected. The relationships among miR-522-3p, LINC00261, and TNRC6A in cardiomyocytes were evaluated using a double luciferase reporter gene assay. Hypoxic preconditioning in normal cells was used to construct a simulated MI environment to investigate the effect of LINC00261 on apoptosis of cardiac cells. Results. LINC00261 and TNRC6A were upregulated, while miR-522-3p was downregulated in coronary heart disease tissues with MI. Knockout of LINC00261 can increase the viability of cardiomyocytes and inhibit cell apoptosis. LINC00261 targets miR-522-3p in cardiomyocytes. In addition, miR-522-3p targets TNRC6A in cardiomyocytes. TNRC6A regulates cell viability and apoptosis of cardiomyocytes after MI, and TNRC6A-induced MI can be reversed by overexpression of miR-522-3p. Conclusions. LINC00261 downregulated miR-522-3p in cardiomyocytes after MI by directly targeting miR-522-3p. TNRC6A is the direct target of miR-522-3p. Our results indicated that LINC00261 might serve as a therapeutic target for the treatment of MI.

Background: The maximum standardized uptake values (SUVmax) derived from 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) have some well-known shortcomings in predicting treatment response and prognosis in oncology. The standardized SUVmax with an appropriate reference background may overcome this problem in some instances. This study explored the prognostic value of the tumor-to-liver SUVmax ratio (SUVTLR) and the tumor-to-blood pool SUVmax ratio (SUVTBR) in predicting the objective response (OR) and overall survival (OS) in patients with locally advanced esophageal cancer after concurrent chemoradiotherapy (CCRT).Methods: We retrospectively analyzed 128 newly diagnosed esophageal squamous cell carcinoma (ESCC) patients who were treated with CCRT. The SUVmax of primary tumor, SUVTLR, SUVTBR and clinicopathologic features data were analyzed. Univariate and multivariate analyses were used to determine the predictors of tumor response. Survival analysis was performed using the Kaplan–Meier method and Cox proportional hazards model.Results: Receiver operating characteristic (ROC) curve analysis demonstrated that SUVTLR was superior to SUVmax and SUVTBR in predicting treatment response. Univariate and multivariate analyses revealed that advanced tumor stage (hazard ratio [HR] = 9.67; 95% CI: 1.15-81.28; P = 0.037) and high SUVTLR (HR = 21.92; 95% CI: 2.26-212.96; P = 0.008) were independent predictors of poor treatment response. Cox regression analysis showed that good clinical tumor response (p < 0.014, HR =0.501; 95% CI: 0.288–0.871) was a favorable independent predictive factor for OS, while an advanced tumor stage (p = 0.018, HR = 1.796; 95% CI: 1.107-2.915) and a high SUVTLR (p < 0.002, HR = 2.660; 95% CI: 1.425–4.967) were prognostic factors for poor OS. The median OS of patients in the low SUVTLR and high SUVTLR groups was 13.47 vs. 19.30 months, respectively.Conclusions: PET-derived SUVTLR is superior to tumor SUVmax and SUVTBR in predicting treatment response and overall survival in patients with ESCC undergoing CCRT. High SUVTLR was an independent predictor of poor treatment response and shorter overall survival.

Training in elite sport aims at the optimization of the athletic performance, and to control the athletes`progress in physiological, anthropometrical and motor performance prerequisites. However, in most sports, the value of longitudinal testing is unclear. This study evaluates the longitudinal development and the influence of intense training over 2-years on specific physiological performance prerequisites, as well as certain body dimensions and motor abilities in elite youth athletes. Recruited between 11-13 years of age at Shanghai Elite Sport school, the sample of student-athletes (N = 21) was categorized as the swimming group (10 athletes), and the racket sports group (11 players: 7 table tennis and 4 badminton players). The performance monitoring took place over two years between September 2016 and September 2018 and included 5 test waves. In all the test waves, the athletes were assessed by means of three physiological measurements (vital capacity, hemoglobin concentration, heart rate at rest), three anthropometric parameters (body height, body weight, chest girth), and two motor tests (back strength, complex reaction speed). Seven out of eight diagnostic methods exhibit medium to high validity to discriminate between the different levels of performance development in the two sports groups. The investigated development of the performance characteristics is attributed partly to the inherited athletic disposition as well as to the different sport-specific training regimens of the two sports groups.

Background/Aims: Circular RNAs (circRNAs) serve as potential diagnostic biomarkers. In this study, we aimed to identify a potential biomarker from peripheral blood mononuclear cells (PBMCs) of patients with postmenopausal osteoporosis (PMOP). Methods: CircRNA expression in PBMCs from three pairs of samples from PMOP patients and controls was initially detected by circRNA microarray. The changes in selected circRNAs in PBMCs from 28 PMOP patients and 21 age- and sex-matched controls were confirmed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Next, samples from 30 PMOP patients and 20 controls were used for further verification. Pearson correlation test was performed to assess the correlation between circRNAs and clinical variables. The area under the receiver operator characteristic (ROC) curve was calculated to evaluate the diagnostic value. Results: Six differentially expressed circRNAs were identified by chip microarray analysis, of which only hsa_circ_0001275 showed consistency and statistical significance in qRT-PCR. The correlation analysis between age, body weight, height, WBC, lymphocyte and monocyte count, bone density, T-score, β-CROSSL, OSTEOC, and TP1NP showed that hsa_circ_0001275 was negatively correlated with T-score. ROC curves showed that hsa_circ_0001275 has significant diagnostic value in PMOP (AUC=0.759, P< 0.001). Conclusion: This study suggests that hsa_circ_0001275 may serve as a potential diagnostic biomarker for PMOP.

Hypoxic training has been reported to lower obesity morbidity without clear underlying mechanisms. This study investigates the effect of hypoxic training on metabolic changes, particularly, on liver metabolism of high fat diet (HFD)-induced obese mice. We compared the hypoxic training group with normoxic sedentary, normoxic training, and hypoxic sedentary groups. Body weight, fat mass, glucose tolerance and liver physiology were determined after 4 weeks intervention. In both normoxic training and hypoxic training groups, body weight was lower than the normoxic sedentary group, with less fat mass. Insulin sensitivity was improved after hypoxic training. Moreover, liver metabolomics revealed insights into the protective effect of hypoxic training on HFD-induced fatty liver. Taken together, these findings provide a molecular metabolic mechanism for hypoxic training.

Several talent selection programs in elite sport schools are based on motor diagnostics for the purpose of recommending or transferring promising talents to general groups of sports; game sports, combat sports or endurance sports, and to more concrete sports such as gymnastics, skiing, or tennis. However, the predictive value of such testing is unclear. This study evaluated the concurrent validity of physiological performance prerequisites, body dimensions, as well as specific motor performances. The sample consisted of N = 97 youth athletes from all ninth grade classes of a Shanghai Elite Sport school belonging to six different sports including basketball (n = 7), fencing (n = 23), judo (n = 20), swimming (n = 10), table tennis (n = 15), and volleyball (n = 22). The performance diagnosis took place between September 2016 and March 2017, and comprised five physiological measurements of the heart rate at rest, vital capacity, systolic and diastolic blood pressure, and hemoglobin concentration in the blood, eighteen anthropometric parameters, and two motor tests on back strength and complex reaction speed. The aim of the study was to investigate whether U15 age group athletes participating in six different sports already at this age show a sport specific anthropometric, motor performance, and physiological profile which is in line with the specific requirements of each of the sports. A discriminant analysis and a Neural Network (Multilayer Perceptron) were used to test whether it is possible to discriminate between athletes of the six sports and to assign each individual of the Under-15 athletes to his own sport on the basis of a unique profile of the morphological, motor, and physiological prerequisites. All diagnostic methods exhibited medium to high validity to discriminate between the six different sports. The relevance of the eighteen body dimensions, five physiological measures, and two motor tests for talent identification was confirmed.

In the last few decades, transgenic animal technology has witnessed an increasingly wide application in animal breeding. Reproductive traits are economically important to the pig industry. It has been shown that the bone morphogenetic protein receptor type IB (BMPR1B) A746G polymorphism is responsible for the fertility in sheep. However, this causal mutation exits exclusively in sheep and goat. In this study, we attempted to create transgenic pigs by introducing this mutation with the aim to improve reproductive traits in pigs. We successfully constructed a vector containing porcine BMPR1B coding sequence (CDS) with the mutant G allele of A746G mutation. In total, we obtained 24 cloned male piglets using handmade cloning (HMC) technique, and 12 individuals survived till maturation. A set of polymerase chain reactions indicated that 11 of 12 matured boars were transgene-positive individuals, and that the transgenic vector was most likely disrupted during cloning. Of 11 positive pigs, one (No. 11) lost a part of the terminator region but had the intact promoter and the CDS regions. cDNA sequencing showed that the introduced allele (746G) was expressed in multiple tissues of transgene-positive offspring of No.11. Western blot analysis revealed that BMPR1B protein expression in multiple tissues of transgene-positive F1 piglets was 0.5 to 2-fold higher than that in the transgene-negative siblings. The No. 11 boar showed normal litter size performance as normal pigs from the same breed. Transgene-positive F1 boars produced by No. 11 had higher semen volume, sperm concentration and total sperm per ejaculate than the negative siblings, although the differences did not reached statistical significance. Transgene-positive F1 sows had similar litter size performance to the negative siblings, and more data are needed to adequately assess the litter size performance. In conclusion, we obtained 24 cloned transgenic pigs with the modified porcine BMPR1B CDS using HMC. cDNA sequencing and western blot indicated that the exogenous BMPR1B CDS was successfully expressed in host pigs. The transgenic pigs showed normal litter size performance. However, no significant differences in litter size were found between transgene-positive and negative sows. Our study provides new insight into producing cloned transgenic livestock related to reproductive traits.

To solve the problem of passenger travel cost and full load rate balance before and after the implementation of cross-line operation in the peak period of urban rail transit (URT) passenger flow. This paper introduces the concept of section full load rate balance. According to the division of different types of passenger flow in the intersection mode of "X" and "Y" lines, based on the characteristics of passenger flow in peak passenger flow period, a mathematical model with cross-line operation mode turn-back station and operation frequency of train as decision variables is constructed to minimize passenger travel cost, full load rate balance objective function and enterprise operation cost. Taking the Changping Line and Line 8 in the Beijing URT system as examples, the validity of the model is verified. The results show that the operation mode of the cross-line train can alleviate the passenger flow pressure of the transfer station, reduce the overload of the original train on the line, improve the full load rate balance of the train, make the utilization of the transport capacity more balanced, and optimize the passenger ride experience. In addition, considering the operation of cross-line trains may increase the operating costs of enterprises. [ABSTRACT FROM AUTHOR]

The nitrogen isotopes of the organic matter preserved in fossil fish otoliths (ear stones) are a promising tool for reconstructing past environmental changes. We analyzed the 15N/14N ratio (d15N) of fossil otolith-bound organic matter in Late Cretaceous fish otoliths (of Eutawichthys maastrichtiensis, Eutawichthys zideki and Pterothrissus sp.) from three deposits along the US east coast, with two of Campanian (83.6 to 77.9 Ma) and one Maastrichtian (72.1 to 66 Ma) age. d15N and N content were insensitive to cleaning protocol and the preservation state of otolith morphological features, and N content differences among taxa were consistent across deposits, pointing to a fossil-native origin for the organic matter. All three species showed an increase in otolith-bound organic matter d15N of ~4‰ from Campanian to Maastrichtian. As to its cause, the similar change in distinct genera argues against changing trophic level, and modern field data argue against the different locations of the sedimentary deposits. Rather, the lower d15N in the Campanian is best interpreted as an environmental signal at the regional scale or greater, and it may be a consequence of the warmer global climate. A similar decrease has been observed in foraminifera-bound d15N during warm periods of the Cenozoic, reflecting decreased water column denitrification and thus contraction of the ocean's oxygen deficient zones (ODZs) under warm conditions. The same d15N-climate correlation in Cretaceous otoliths raises the prospect of an ODZ-to-climate relationship that has been consistent over the last ~80 My, applying before and after the end-Cretaceous mass extinction and spanning changes in continental configuration. [ABSTRACT FROM AUTHOR]