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Abstract This study aims to develop a super-resolution (SR) algorithm tailored specifically for enhancing the image quality and resolution of early cervical cancer (CC) magnetic resonance imaging (MRI) images. The proposed method is subjected to both qualitative and quantitative analyses, thoroughly investigating its performance across various upscaling factors and assessing its impact on medical image segmentation tasks. The innovative SR algorithm employed for reconstructing early CC MRI images integrates complex architectures and deep convolutional kernels. Training is conducted on matched pairs of input images through a multi-input model. The research findings highlight the significant advantages of the proposed SR method on two distinct datasets at different upscaling factors. Specifically, at a 2× upscaling factor, the sagittal test set outperforms the state-of-the-art methods in the PSNR index evaluation, second only to the hybrid attention transformer, while the axial test set outperforms the state-of-the-art methods in both PSNR and SSIM index evaluation. At a 4× upscaling factor, both the sagittal test set and the axial test set achieve the best results in the evaluation of PNSR and SSIM indicators. This method not only effectively enhances image quality, but also exhibits superior performance in medical segmentation tasks, thereby providing a more reliable foundation for clinical diagnosis and image analysis.

Abstract Background Alzheimer’s disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. Main content Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron–glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. Conclusion Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.

Extraction and purification of polysaccharides from the seed kernel of Acer truncatum Bungeto investigate their physicochemical properties and hypoglycemic activity. In the study, the polysaccharide was obtained by water extraction and ethanol precipitation from seed kernel of Acer truncatum Bunge, and the extraction process was optimized by response surface method. The polysaccharide was purified by Sevage deproteinization and column chromatography. The composition and structure of the purified polysaccharide were characterized by infrared spectroscopy, thermogravimetric analysis and ion chromatography, and its hypoglycemic activity was further investigated by the insulin resistance model of liver cancer cell (IR-HepG2). The results showed that the yield of crude polysaccharide (PATM) was 18.17% under the conditions of extraction times 1, liquid-solid ratio 30:1 mL/g, extraction temperature 80 ℃ and extraction time 3.5 h. The purified polysaccharide (PATM-3-1) obtained by the Sevage deproteinization, DEAE-DE cellulose 52 column and SephadexG-100 gel column had the characteristic peak of infrared spectrum of polysaccharide component, and was composed of D-galacturonic acid, L-arabinose, D-galactose, L-rhamnose, D-glucose, D-xylose, D-mannose, D-glucuronic acid, L-fucose, D-ribose and D-glucosamine. The results of hypoglycemic activity experiment in vitro showed that PATM-3-1 had strong α-amylase inhibitory activity, and could significantly (P

Abstract Objective To assess stress distribution in peri-implant bone and attachments of mandibular overdentures retained by small diameter implants, and to explore the impact of implant distribution on denture stability. Methods Through three-dimensional Finite Element Analysis (3D FEA), four models were established: three models of a two mandibular implants retained overdenture (IOD) and one model of a conventional complete denture (CD). The three IOD models consisted of one with two implants in the bilateral canine area, another with implants in the bilateral lateral incisor area, and the third with one implant in the canine area, and another in the lateral incisor area. Three types of loads were applied on the overdenture for each model: a 100 N vertical load and a inclined load on the left first molar, and a100N vertical load on the lower incisors. The stress distribution in the peri-implant bone, attachments, and the biomechanical behaviors of the overdentures were analyzed. Results Despite different distribution of implants, the maximum stress values in peri-implant bone remained within the physiological threshold for all models across three loading conditions. The dispersed implant distribution design (implant in the canine area) exhibited the highest maximum stress in peri-implant bone (822.8 µe) and the attachments (275 MPa) among the three IOD models. The CD model demonstrated highest peak pressure on mucosa under three loading conditions (0.8188 Mpa). The contact area between the denture and mucosa of the CD model was smaller than that in the IOD models under molar loading, yet it was larger in the CD model compared to the IOD model under anterior loading. However, the contact area between the denture and mucosa under anterior loading in all models was significantly smaller than those under molar loading. The IOD in all three models exhibited significantly less rotational movement than the complete denture. Different implant positions had minimal impact on the rotational movement of the IOD. Conclusion IOD with implants in canine area exhibited the highest maximum stress in the peri-implant bone and attachments, and demonstrated increased rotational movement. The maximum principal stress was concentrated around the neck of the small diameter one-piece implant, rather than in the abutment. An overdenture retained by two implants showed better stability than a complete denture.

ObjectiveThis study aims to analyze the value of prenatal ultrasound in the screening, diagnosis, and treatment of double aortic arch (DAA) malformations.MethodsA retrospective analysis was conducted on 31 fetal cases with double aortic arch anomalies over a 12-year period from June 1, 2011 to June 1, 2023. The assessment included combined measurements of fetal tracheal internal diameter Z-score and DAA pinch angle, along with ultrasonographic findings, associated anomalies, genetic abnormalities, postnatal CTA images, and long-term postnatal outcomes.ResultsOf the 31 fetal double aortic arch cases, 15 were right aortic arch dominant, 2 were left aortic arch dominant, and 14 had a balanced double arch. Genetic testing was performed on 19 cases, revealing abnormalities in 2 cases, including one Turner syndrome, and one carrier of ichthyosis gene with heterozygous deletion. Out of the total cases, 29 were delivered, and 2 cases were terminated. Prenatal diagnosis accurately identified 29 cases (29/31, 93.5%), which was confirmed by postnatal pathological anatomy, echocardiography, surgery or CTA. Fetal tracheal internal diameter Z-scores were significantly smaller in the symptomatic group than in the asymptomatic group (−1.27 ± 0.49 vs −0.68 ± 0.60, P = 0.018). The area under the curve was 0.776 (95% confidence interval, 0.593–0.960) using a tracheal internal diameter z-score cutoff of −0.73 with a sensitivity of 90% and specificity of 64.7%. The double arch pinch angle was significantly smaller in the symptomatic group than in the asymptomatic group [52.50° (38.25° to 59.00°) vs 60.00° (53.50° to 70.50°), P = 0.035]. The area under the curve was 0.744 (95% confidence interval, 0.554–0.935), and the sensitivity for determining the presence or absence of symptoms was 90% when the cutoff value was 62.5°, with a specificity of 47.1%. Fifteen cases opted for surgery with favorable surgical outcome.ConclusionPrenatal echocardiography demonstrates good diagnostic efficacy for fetal double aortic arch. It is also essential to detect the presence of other underlying intra- and extracardiac malformations and genetic abnormalities. There is a significant difference in prenatal tracheal internal diameter Z-scores and double arch pinch angle between asymptomatic and symptomatic DAA infants. Symptomatic infants require early surgery, while asymptomatic infants should be monitored.

Abstract To classify early endometrial cancer (EC) on sagittal T2-weighted images (T2WI) by determining the depth of myometrial infiltration (MI) using a computer-aided diagnosis (CAD) method based on a multi-stage deep learning (DL) model. This study retrospectively investigated 154 patients with pathologically proven early EC at the institution between January 1, 2018, and December 31, 2020. Of these patients, 75 were in the International Federation of Gynecology and Obstetrics (FIGO) stage IA and 79 were in FIGO stage IB. An SSD-based detection model and an Attention U-net-based segmentation model were trained to select, crop, and segment magnetic resonance imaging (MRl) images. Then, an ellipse fitting algorithm was used to generate a uterine cavity line (UCL) to obtain MI depth for classification. In the independent test datasets, the uterus and tumor detection model achieves an average precision rate of 98.70% and 87.93%, respectively. Selecting the optimal MRI slices method yields an accuracy of 97.83%. The uterus and tumor segmentation model with mean IOU of 0.738 and 0.655, mean PA of 0.867 and 0.749, and mean DSC of 0.845 and 0.779, respectively. Finally, the CAD method based on the calculated MI depth reaches an accuracy of 86.9%, a sensitivity of 81.8%, and a specificity of 91.7% for early EC classification. In this study, the CAD method implements an end-to-end early EC classification and is found to be on par with radiologists in terms of performance. It is more intuitive and interpretable than previous DL-based CAD methods.

Effective separation of cellulose and hemicellulose from lignocellulosic biomass is an essential step for creating high-value products. In this study, a modified treatment process was proposed for cellulose purification via microwave-assisted formic acid catalytic hydrolysis followed by cold caustic extraction. The sugar content in the extract was determined using UV spectrophotometer and dual-wavelength visible spectrophotometry. Combined microwave-assisted formic acid (M-FA) with cold caustic extraction (CCE) treatments achieved rapid separation and removal of hemicelluloses from waste hardwood pulp fibers. The hemicelluloses content decreased from 28.6% to 2.3%, and the lignin content changed from 27.8% to 6.1%, which resulted in a maximal cellulose content of 91.5% under the optimal M-FA/CCE treatment conditions. In addition, the crystallinity index of pulp fibers increased from 54.3% to 67.1%, and the initial decomposition temperature decreased from 335.4 to 270.2 °C with the decrease of hemicellulose and lignin content. The modified process provided a sustainable and effective method for hemicellulose separation and lignin removal from cellulosic fibers.

Objective To design and simulate routine serological experiments in transfusion techniques using RhD blood group, so as to solve the problem of difficult to obtain positive specimens in experimental teaching. Methods RhD positive red blood cells, RhD negative red blood cells and anti-D reagent were used to design and simulate the enzyme treatment experiment, absorption and elution test, antibody identification experiment and cross matching experiment of polybrene technology in transfusion techniques. Results Papain treatment of red blood cells made the agglutination of RhD positive red blood cells and IgG anti-D visible. Absorption and elution test were successfully simulated with RhD positive red blood cells and IgG anti-D reagent. The antibody identification of anti-Jka and anti-Fya was successfully simulated by creating different identification panel and panel cells made by RhD positive cells and negative cells. Cross matching test of polybrene method can also be simulated using RhD negative and positive red blood cells and IgG anti-D reagent. Conclusion RhD blood group can be used to simulate most of the routine serological experiments of blood transfusion, which can be used in the serological laboratory teaching of transfusion.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health issue closely associated with multiple extrahepatic cancers. The association between MAFLD and clinical outcomes of endometrial cancer (EC) remains unknown. Methods: We retrospectively included 725 EC patients between January 2012 and December 2020. The odds ratios (ORs) were calculated using logistic regression analyses. Kaplan–Meier survival curves were used for survival analysis. Results: Among EC patients, the prevalence of MAFLD was 27.7% (201/725, 95% confidence interval (Cl) = 0.245–0.311). MAFLD was significantly associated with cervical stromal involvement (CSI) (OR = 1.974, 95% confidence interval (Cl) = 1.065–3.659, p = 0.031). There was a significant correlation between overall survival (OS) and CSI (HR = 0.31; 95%CI: 0.12–0.83; p = 0.020), while patients with MAFLD had a similar OS to those without MAFLD (p = 0.952). Moreover, MAFLD was significantly associated with CSI in the type I EC subgroup (OR = 2.092, 95% confidence interval (Cl) = 1.060–4.129, p = 0.033), but not in the type II EC subgroup (p = 0.838). Further logistic regression analysis suggested that the hepatic steatosis index (HSI) was significantly associated with CSI among type I EC patients without type 2 diabetes mellitus (T2DM) (OR = 1.079, 95% confidence interval (Cl) = 1.020–1.139, p = 0.012). Conclusions: About one-quarter of our cohort had MAFLD. MAFLD was associated with the risk of CSI in EC patients, and this association existed in type I EC patients but not in type II EC patients. Furthermore, the HSI can help predict CSI in type I EC patients without T2DM.

Abstract Objective Acute kidney injury (AKI) is one of the most frequent complications in patients treated with extracorporeal membrane oxygenation (ECMO) support. The aim of this study was to investigate the risk factors of AKI in patients undergoing ECMO support. Methods We performed a retrospective cohort study which included 84 patients treated with ECMO support at intensive care unit in the People’s Hospital of Guangxi Zhuang Autonomous Region from June 2019 to December 2020. AKI was defined as per the standard definition proposed by the Kidney Disease Improving Global Outcome (KDIGO). Independent risk factors for AKI were evaluated through multivariable logistic regression analysis with stepwise backward approach. Results Among the 84 adult patients, 53.6% presented AKI within 48 h after initiation of ECMO support. Three independent risk factors of AKI were identified. The final logistic regression model included: left ventricular ejection fraction (LVEF) before ECMO initiation (OR, 0.80; 95% CI, 0.70–0.90), sequential organ failure assessment (SOFA) score before ECMO initiation (OR, 1.41; 95% CI, 1.16–1.71), and serum lactate at 24 h after ECMO initiation (OR, 1.27; 95% CI, 1.09–1.47). The area under receiver operating characteristics of the model was 0.879. Conclusion Severity of underlying disease, cardiac dysfunction before ECMO initiation and the blood lactate level at 24 h after ECMO initiation were independent risk factors of AKI in patients who received ECMO support.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy with poor patient prognosis. Current treatment for ESCC, including immunotherapy, is only beneficial for a small subset of patients. Better characterization of the tumor microenvironment (TME) and the development of novel therapeutic targets are urgently needed. Methods In the present study, we hypothesized that integration of single-cell transcriptomic sequencing and large microarray sequencing of ESCC biopsies would reveal the key cell subtypes and therapeutic targets that determine the prognostic and tumorigenesis of ESCC. We characterized the gene expression profiles, gene sets enrichment, and the TME landscape of a microarray cohort including 84 ESCC tumors and their paired peritumor samples. We integrated single-cell transcriptomic sequencing and bulk microarray sequencing of ESCC to reveal key cell subtypes and druggable targets that determine the prognostic and tumorigenesis of ESCC. We then designed and screened a blocking peptide targeting Chemokine C–C motif ligand 18 (CCL18) derived from tumor associated macrophages and validated its potency by MTT assay. The antitumor activity of CCL18 blocking peptide was validated in vivo by using 4-nitroquinoline-1-oxide (4-NQO) induced spontaneous ESCC mouse model. Results Comparative gene expression and cell–cell interaction analyses revealed dysregulated chemokine and cytokine pathways during ESCC carcinogenesis. TME deconvolution and cell interaction analyses allow us to identify the chemokine CCL18 secreted by tumor associated macrophages could promote tumor cell proliferation via JAK2/STAT3 signaling pathway and lead to poor prognosis of ESCC. The peptide Pep3 could inhibit the proliferation of EC-109 cells promoted by CCL18 and significantly restrain the tumor progression in 4-NQO-induced spontaneous ESCC mouse model. Conclusions For the first time, we discovered and validated that CCL18 blockade could significantly prevent ESCC progression. Our study revealed the comprehensive cell–cell interaction network in the TME of ESCC and provided novel therapeutic targets and strategies to ESCC treatment.

Purpose – This paper aims to study the influence of aerodynamics force of trains passing each other on the dynamic response of vehicle bridge coupling system based on numerical simulation and multi-body dynamics and put forward the speed threshold for safe running of train under different crosswind speeds. Design/methodology/approach – The computational fluid dynamics method is adopted to simulate the aerodynamic force in the whole process of train passing each other by using dynamic grid technology. The dynamic model of vehicle-bridge coupling system is established considering the effects of aerodynamic force of train passing each other under crosswind, the dynamic response of train intersection on the bridge under crosswind is computed and the running safety of the train is evaluated. Findings – The aerodynamic force of trains' intersection has little effects on the derailment factor, lateral wheel-rail force and vertical acceleration of train, but it increases the offload factor of train and significantly increases the lateral acceleration of train. The crosswind has a significant effect on increasing the derailment factor, lateral wheel-rail force and offload factor of train. The offload factor of train is the key factor to control the threshold of train speed. The impact of the aerodynamic force of trains' intersection on running safety cannot be ignored. When the extreme values of crosswind wind speed are 15 m·s−1, 20 m·s−1 and 25 m·s−1, respectively, the corresponding speed thresholds for safe running of train are 350 km·h−1, 275 km·h−1 and 200 km·h−1, respectively. Originality/value – The research can provide a more precise numerical method to study the running safety of high-speed trains under the aerodynamic effect of trains passing each other on bridge in crosswind.

Abstract Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 μg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma.

ObjectivesThis study aims to investigate the efficacy of prenatal ultrasonography in diagnosing the anomalous origin of the fetal pulmonary artery (AOFPA).MethodsA total of 26 AOFPA cases were retrospectively analyzed from January 2014 to January 2023. The features of the AOFPA were characterized by comparing the prenatal ultrasonic data with the results of anatomical casting after pregnancy termination or postnatal imaging and surgical intervention. Missed diagnoses and misdiagnoses were expounded.ResultsOf the 26 AOFPA cases, there were 13 cases of pulmonary artery sling, 8 cases of anomalous origin of the unilateral pulmonary artery, and five cases of unilateral absence of the pulmonary artery; 17 cases received pathological anatomy and casting after pregnancy termination, and nine cases were confirmed by postnatal imaging and surgery. Nineteen cases were accurately prenatally diagnosed (19/26, 73.1%), and seven cases were missed or misdiagnosed (7/26, 26.9%).ConclusionsPrenatal ultrasonography has a favorable diagnostic efficacy for anomalous origin of the fetal pulmonary artery. The absence of either the left or right pulmonary artery from the image of pulmonary artery bifurcation may indicate origin abnormalities of the pulmonary artery in fetuses, which signifies the necessity to detect the abnormal origin of the pulmonary artery on the affected side and other potential intracardiac malformation complications.

Background Aside from immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), intervention of CD47/Sirpα mediated ‘don’t eat me’ signal between macrophage and tumor cell is considered as a promising therapeutic approach for cancer immunotherapy. Compared with CD47, the novel immune checkpoint CD24/Siglec-10 can also deliver ‘don’t eat me’ signal and CD24 shows much lower expression level in normal tissue which might avoid unwanted side effects.Methods Cell-based phage display biopanning and D-amino acid modification strategy were used to identify the CD24/Siglec-10 blocking peptide. Cell-based blocking assay and microscale thermophoresis assay were used to validate the blocking and binding activities of the peptide. Phagocytosis and co-culture assays were used to explore the in vitro function of the peptide. Flow cytometry was performed to assess the immune microenvironment after the peptide treatment in vivo.Results A CD24/Siglec-10 blocking peptide (CSBP) with hydrolysis-resistant property was identified. Surprisingly, we found that CSBP could not only block the interaction of CD24/Siglec-10 but also PD-1/PD-L1. CSBP could induce the phagocytosis of tumor cell by both the macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs), which can further activate CD8+ T cells. Besides, combination of radiotherapy and CSBP synergistically reduced tumor growth and altered the tumor microenvironment in both anti-PD-1-responsive MC38 and anti-PD-1-resistant 4T1 tumor models.Conclusions In summary, this is the first CD24/Siglec-10 blocking peptide which blocked PD-1/PD-L1 interaction as well, functioned via enhancing the phagocytosis of tumor cells by macrophages and M-MDSCs, and elevating the activity of CD8+ T cells for cancer immunotherapy.

Background: Sophoridine, the major active constituent of Sophora alopecuroides and its roots, is a bioactive alkaloid with a wide range of pharmacological effects, including antitumor, anti-inflammatory, antiviral, antibacterial, analgesic, cardioprotective, and immunoprotective activities. Sophora flavescens Aiton is a traditional Chinese medicine that is bitter and cold. Additionally, it also exhibits the effects of clearing heat, eliminating dampness, and expelling insects.Aims of the study: To summarize the pharmacological research and associated mechanisms of sophoridine, we compiled this review by combining a huge body of relevant literature.Materials and methods: The information related to this article was systematically collected from the scientific literature databases including PubMed, Google Scholar, Web of Science, Science Direct, Springer, China National Knowledge Infrastructure, published books, PhD and MS dissertations.Results: Its antitumor activity is particularly remarkable, as it can inhibit cancer cell proliferation, invasion, and metastasis while inducing cell cycle arrest and apoptosis. Additionally, sophoridine also holds therapeutic potential for myocardial ischemia, osteoporosis, arrhythmias, and neurological disorders, primarily through the suppression of related inflammatory factors and cell apoptosis. However, sophoridine has also exhibited adverse effects such as hepatotoxicity and neurotoxicity. The antidisease effect and mechanism of sophoridine are diverse, so it has high research value.Conclusion: As an important traditional Chinese medicine alkaloid, modern pharmacological studies have demonstrated that sophoridine has prominent bioactivities, especially on anti-tumor anti-inflammation activities, and cardiovascular system protection. These activities provide prospects for novel drug development for cancer and some chronic diseases. Nevertheless, the understanding of the multitarget network pharmacology, long-term in vivo toxicity, and clinical efficacy of sophoridine require further detailed research.

Neurodegenerative disorders are known to be associated with neuroinflammation caused by microglia. Therefore, regulation of microglia activation and polarization to inhibit neuroinflammatory reactions seems to hold promise as a therapeutic approach in neurodegenerative disorders. Spatholobus suberectus Dunn (SSD) has been utilized as a traditional Chinese medicine remedy for brain diseases for thousands of years. SSD possesses various pharmacological activities, such as circulation invigoration, neuroprotection, and anti-inflammatory. The objective of this research was to examine the anti-neuroinflammatory effects and molecular mechanisms of an active fraction from SSD (ASSD) in vitro culture BV2 cells, a type of mouse microglia cell line. The inflammatory responses in BV2 cells were induced by stimulating them with 1 μg/mL lipopolysaccharide (LPS) and the effects of ASSD on LPS-stimulated inflammation were monitored. Besides, by using the methods of Western blot, immunofluorescence, and RT-PCR, the mechanisms of ASSD on microglia activation, M1/M2 polarization, and the TLR4/MyD88/NF-κB pathway were investigated. Our findings demonstrate that the treatment doses of ASSD neither induce cytotoxicity nor promote the production of inflammatory cytokines. In addition, immunofluorescence analysis show that ASSD inhibited the expression of ionized calcium-binding adapter molecule 1(Iba1) and inducible nitricoxide synthase (iNOS), and induced arginase 1 (Arg1) expression. Moreover, Western blot analysis indicated that ASSD significantly down-regulated TLR4, MyD88, p-IκB, NF-κB p65, and NF-κB p-p65 protein expression levels. Furthermore, RT-qPCR assay show that ASSD significantly down-regulated iNOS, TLR4, MyD88, and NF-κB mRNA expression levels, and up-regulated Arg1 mRNA expression level. According to the findings, ASSD can suppress microglia-mediated inflammatory responses by modulating microglia activation, inducing a shift from M1 to M2 polarization, and inhibiting the TLR4/MyD88/NF-κB signaling pathway.

Abstract Background Metastasis is the leading cause of mortality in human cancers, including esophageal squamous cell carcinoma (ESCC). As a pro-inflammatory cytokine, IL-32 was reported to be a poor prognostic factor in many cancers. However, the role of IL-32 in ESCC metastasis remains unknown. Methods ESCC cells with ectopic expression or knockdown of IL-32 were established and their effects on cell motility were detected. Ultracentrifugation, Transmission electron microscopy and Western blot were used to verify the existence of extracellular vesicle IL-32 (EV-IL-32). Coculture assay, immunofluorescence, flow cytometry, and in vivo lung metastasis model were performed to identify how EV-IL-32 regulated the crosstalk between ESCC cells and macrophages. Results Here, we found that IL-32 was overexpressed and positively correlated to lymph node metastasis of ESCC. IL-32 was significantly higher in the tumor nest compared with the non-cancerous tissue. We found that IL-32β was the main isoform and loaded in EV derived from ESCC cells. The shuttling of EV-IL-32 derived from ESCC cells into macrophages could promote the polarization of M2 macrophages via FAK-STAT3 pathway. IL-32 overexpression facilitated lung metastasis and was positively correlated with the proportion of M2 macrophages in tumor microenvironment. Conclusions Taken together, our results indicated that EV-IL-32 derived from ESCC cell line could be internalized by macrophages and lead to M2 macrophage polarization via FAK-STAT3 pathway, thus promoting the metastasis of ESCC. These findings indicated that IL-32 could serve as a potential therapeutic target in patients with ESCC.

Pre-harvest application of elicitors improves grape quality, specifically the phenolic compounds and color characteristics. Limited research has been conducted on the impact of elicitors on the C6 compounds found in grapes. This is due to lack of comprehensive studies examining the combined effects of bound aroma compounds, enzyme activity, and substrate availability. This study aimed to assess the impact of benzothiadiazole (BTH) on the physicochemical properties and C6 compounds of Cabernet Gernischt grapes during ripening. Compared with the control group (CK), BTH treatment significantly increased the 100-berry weight, skin/berry ratio, pH, total phenolic content, and total flavonoid content in ripe grapes. Additionally, BTH treatment led to significant reductions in reducing sugar, total soluble solids, titratable acidity, linoleic acid, linolenic acid, and free C6 aldehydes. Furthermore, BTH treatment significantly decreased the contents of free C6 alcohols and increased the levels of free and bound C6 esters. BTH treatment also increased the activities of lipoxygenase, alcohol dehydrogenase, and alcohol acetyltransferase enzymes, while it decreased the activity of hydroperoxide lyase enzyme. The application of BTH resulted in changes to the physicochemical properties and levels of C6 compounds in Cabernet Gernischt grapes by up-regulating enzyme activity and down-regulating precursors.

Tryptophan 2,3-dioxygnease 2 (TDO2) is specific for metabolizing tryptophan to kynurenine (KYN), which plays a critical role in mediating immune escape of cancer. Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers, its tumor-promoting role in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we observed that TDO2 was overexpressed in ESCC tissues and correlated significantly with lymph node metastasis, advanced clinical stage, and unfavorable prognosis. Functional experiments showed that TDO2 promoted tumor cell proliferation, migration, and colony formation, which could be prevented by inhibition of TDO2 and aryl hydrocarbon receptor (AHR). Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model, tumor burden of C57BL/6 mice with ESCC induced by 4-NQO, enhance the expression of phosphorylated AKT, with subsequent phosphorylation of GSK3β, and polarization of M2 macrophages by upregulating interleukin-8 (IL-8) to accelerate tumor progression in the tumor microenvironment (TME). Collectively, our results discovered that TDO2 could upregulate IL-8 through AKT/GSK3β to direct the polarization of M2 macrophages in ESCC, and suggested that TDO2 could represent as an attractive therapeutic target and prognostic marker to ESCC.

Background The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet.Methods The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression.Results Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (KD=65 nM) and effectively inhibit its deaminase activity (IC50=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade.Conclusions This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.

Abstract Pulmonary fibrosis is a devastating disease, and the pathogenesis of this disease is not completely clear. Here, the medical records of 85 Covid-19 cases were collected, among which fibrosis and progression of fibrosis were analyzed in detail. Next, data independent acquisition (DIA) quantification proteomics and untargeted metabolomics were used to screen disease-related signaling pathways through clustering and enrichment analysis of the differential expression of proteins and metabolites. The main imaging features were lesions located in the bilateral lower lobes and involvement in five lobes. The closed association pathways were FcγR-mediated phagocytosis, PPAR signaling, TRP-inflammatory pathways, and the urea cycle. Our results provide evidence for the detection of serum biomarkers and targeted therapy in patients with Covid-19.

Early treatment increases the 5-year survival rate of patients with endometrial cancer (EC). Deep learning (DL) as a new computer-aided diagnosis method has been widely used in medical image processing which can reduce the misdiagnosis by radiologists. An automatic staging method based on DL for the early diagnosis of EC will benefit both radiologists and patients. To develop an effective and automatic prediction model for early EC diagnosis on magnetic resonance imaging (MRI) images, we retrospectively enrolled 117 patients (73 of stage IA, 44 of stage IB) with a pathological diagnosis of early EC confirmed by postoperative biopsy at our institution from 1 January 2018, to 31 December 2020. Axial T2-weighted image (T2WI), axial diffusion-weighted image (DWI) and sagittal T2WI images from 117 patients have been classified into stage IA and stage IB according to the patient’s pathological diagnosis. Firstly, a semantic segmentation model based on the U-net network is trained to segment the uterine region and the tumor region on the MRI images. Then, the area ratio of the tumor region to the uterine region (TUR) in the segmentation map is calculated. Finally, the receiver operating characteristic curves (ROCs) are plotted by the TUR and the results of the patient’s pathological diagnosis in the test set to find the optimal staging thresholds for stage IA and stage IB. In the test sets, the trained semantic segmentation model yields the average Dice similarity coefficients of uterus and tumor on axial T2WI, axial DWI, and sagittal T2WI were 0.958 and 0.917, 0.956 and 0.941, 0.972 and 0.910 respectively. With pathological diagnostic results as the gold standard, the classification model on axial T2WI, axial DWI, and sagittal T2WI yielded an area under the curve (AUC) of 0.86, 0.85 and 0.94, respectively. In this study, an automatic DL-based segmentation model combining the ROC analysis of TUR on MRI images presents an effective early EC staging method.

Landslides are geohazards of major concern that can cause casualties and property damage. Short-term landslide displacement prediction is one of the most critical and challenging tasks in landslide deformation analysis, and is beneficial for future hazard mitigation. In this research, a novel short-term displacement prediction approach using spatial-temporal correlation and a gated recurrent unit (GRU) is proposed. The proposed approach is a unified framework that integrates time-series instant displacements collected from multiple monitoring points on a failing slope. First, a spatial-temporal correlation matrix, including the pairwise Pearson’s correlation coefficients, was studied based on the temporal instant displacement data. Then, the extracted spatial features were integrated into the time-series prediction model using GRU. This approach combines both spatial and temporal features simultaneously and provides enhanced prediction performance. In the last step, a comparative analysis against other benchmark algorithms is performed in two case studies including the conventional time-series modeling approach and the spatial-temporal modeling approach. The computational results show that the proposed model performs best in terms of performance evaluation metrics.

Abstract Background TIGIT, as a novel immune checkpoint molecule involved in T cell and NK cell anergy, could induce the immune tolerance and escape through binding with its ligand PVR. Blockade of TIGIT/PVR is considered as a promising strategy in cancer immunotherapy. However, to facilitate the design of inhibitors targeting TIGIT/PVR, the structural characteristics and binding mechanism still need to be further studied. Methods In this study, molecular dynamics (MD) simulations and in silico mutagenesis were used to analyze the interaction between TIGIT and its ligand PVR. Then, PVR mutants were designed and their activities were determined by using TIGIT overexpressed Jurkat cells. Results The results suggested that the loops of PVR (CC′ loop, C′C″ loop, and FG loop) underwent a large intra-molecular rearrangement, and more hydrogen bond crosslinking between PVR and TIGIT were formed during MD simulations. The potential residues for PVR to interact with TIGIT were identified and utilized to predict high affinity PVR mutants. Through the biological activity evaluation, four PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) with enhanced affinity to TIGIT were discovered, which could elicit more potent inhibitory effects compared with the wild type PVR. Conclusions The MD simulations analysis provided new insights into the TIGIT/PVR interaction model, and the identified PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) could serve as new candidates for immunotherapy to block TIGIT/PVR. Video Abstract

Background: Neoadjuvant therapy (NAT) for T1/T2 pancreatic adenocarcinoma (PDAC) prior to pancreaticoduodenectomy remains controversial. We compared positive margin rates in patients with clinical T1&T2 tumors who did and did not receive NAT. Methods: The National Cancer Database (NCDB) found clinical T1&T2 PDAC patients who underwent pancreaticoduodenectomy from 2004 to 2014. Univariate and multivariate regression determined factors associated with a positive margin and survival. Results: 9795 patients underwent surgery for clinical T1 or T2 pancreatic head adenocarcinoma. 8472 patients had data regarding use of neoadjuvant and adjuvant therapies; of which, 774 (9.1%) received NAT and 435 (5.1%) received both chemotherapy and radiation therapy. NAT was found to lower positive margin rates from 21.8 to 15.5% (p

Background Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. Camrelizumab is a monoclonal antibody against PD-1, and famitinib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenesis and antiproliferation activities against tumor cells. We conducted an open-label, multicenter phase 2 basket study of camrelizumab and famitinib in eight cohorts of genitourinary or gynecological cancers. Here, findings in cohort of advanced or metastatic urothelial carcinoma with platinum-progressive disease (cohort 2) are presented.Methods Patients who had progressed after platinum-based chemotherapy for advanced or metastatic disease or had progressed within 12 months after completion of platinum-based (neo)adjuvant therapy were given camrelizumab (200 mg intravenously every 3 weeks) plus famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1.Results Totally, 36 patients were recruited. With a median duration from enrollment to data cut-off of 11.9 months (range 6.1–28.5), ORR was 30.6% (95% CI 16.3% to 48.1%). Median duration of response (DoR) was 6.3 months (95% CI 2.1 to not reached). Median progression-free survival (PFS) was 4.1 months (95% CI 2.2 to 8.2), and median overall survival (OS) was 12.9 months (95% CI 8.8 to not reached). Patients with bladder cancer (n=18) had numerically better outcomes, with an ORR of 38.9% (95% CI 17.3% to 64.3%) and a median PFS of 8.3 months (95% CI 4.1 to not reached). Median DoR and OS in this subpopulation had not been reached with lower limit of 95% CI of 4.2 months for DoR and 11.3 months for OS, respectively. Of 36 patients, 22 (61.1%) had grade 3 or 4 treatment-related adverse events, mainly decreased platelet count and hypertension.Conclusions Camrelizumab plus famitinib showed potent antitumor activity in advanced or metastatic urothelial carcinoma patients after platinum-based chemotherapy. Patients with bladder cancer seemed to have better response to this combination.Trial registration number NCT03827837.

Abstract Background Inhibitors targeting immune checkpoint were proved effective in cancer immunotherapy, such as PD-1/PD-L1 blockade. The novel immune checkpoint TIGIT/PVR plays critical roles in suppressing the anti-tumor effects of CD8+ T and NK cells, and dual blockade of TIGIT/PVR and PD-1/PD-L1 by antibody can elicit synergistic effects in tumor models and clinical trials. However, small molecules for TIGIT/PVR blockade have not been investigated. Methods The expression of PVR in tumors were analyzed by using TCGA, Oncomine and GEO database, and in cancer cell lines examined by flow cytometry. Natural product compounds were docked to PVR for virtual screening by using the software Molecular Operating Environment (MOE). Candidate compounds were further tested by biolayer interferometry-based binding assay, microscale thermophoresis assay and cell based blocking assay. The in vitro activity of the candidate compound was determined by MTT, peripheral blood mononuclear cells (PBMCs) activation assay and coculture assay. The anti-tumor effects and mechanism were also investigated by using MC38 tumor-bearing mice model and immune cell depletion tumor model. Results PVR was over-expressed in many tumor tissues and cancer cell lines, making it a promising therapeutic target. Through virtual screening, binding, and blocking assay, liothyronine was discovered to bind PVR and block the interaction of TIGIT/PVR. Liothyronine could enhance the function of CD4+ and CD8+ T cells in PBMCs. Besides, in the Jurkat-hTIGIT and CHOK1-hPVR coculture assay, liothyronine could reverse the IL-2 secretion inhibition resulted by TIGIT/PVR ligation. Although had no influence on the proliferation of tumor cells in vitro, liothyronine could significantly inhibit tumor growth when administrated in vivo, by enhancing CD8+ T cell infiltration and immune responses in the tumor bearing mice. The immune cell depletion model showed that the anti-tumor effects of liothyronine depends on CD4+ T cells, CD8+ T cells and NK cells. Conclusions A small molecule liothyronine was discovered to serve as a potential candidate for cancer immunotherapy by blocking the immune checkpoint TIGIT/PVR. Video abstract Graphical abstract

This study was to investigate the protective effect of hyperbaric oxygen (HBO) on HT22 and PC12 cell damage caused by oxygen-glucose deprivation/reperfusion-induced ferroptosis. A 2-h oxygen-glucose deprivation and 24-h reperfusion model on HT22 and PC12 cells was used to simulate cerebral ischemia-reperfusion injury. Cell viabilities were detected by Cell Counting Kit-8 (CCK-8) method. The levels of reactive oxygen species (ROS) and lipid reactive oxygen species (Lipid ROS) were detected by fluorescent probes Dihydroethidium (DHE) and C11 BODIPY 581/591. Iron Colorimetric Assay Kit, malondialdehyde (MDA) and glutathione (GSH) activity assay kits were used to detect intracellular iron ion, MDA and GSHcontent. Cell ferroptosis-related ultrastructures were visualized using transmission electron microscopy (TEM). Furthermore, PCR and Western blot analyses were used to detect the expressions of ferroptosis-related genes and proteins. After receiving oxygen-glucose deprivation/reperfusion, the viabilities of HT22 and PC12 cells were significantly decreased; ROS, Lipid ROS, iron ions and MDA accumulation occurred in the cells; GSH contents decreased; TEM showed that cells were ruptured and blebbed, mitochondria atrophied and became smaller, mitochondrial ridges were reduced or even disappeared, and apoptotic bodies appeared. And the expressions of Nrf2, SLC7A11 and GPX4 genes were reduced; the expressions of p-Nrf2/Nrf2, xCT and GPX4 proteins were reduced. Notably, these parameters were significantly reversed by HBO, indicating that HBO can protect HT22 cells and PC12 cells from damage caused by oxygen-glucosedeprivation/reperfusion via the inhibition of Nrf2/System Xc-/GPX4 axis-mediated ferroptosis.

The study aims to explore application of RNAIII inhibiting peptide (RIP) and image information counting algorithm in the rehabilitation treatment plan of staphylococcus aureus infection in old people’s bone and joint. A fuzzy mathematical evaluation model is established for the clinical efficacy of osteoarthritis infection, which lays a foundation for the establishment of the expert diagnosis and treatment system of the disease efficacy evaluation. The relationship between the ability of Staphylococcus aureus to form membrane and the concentration of RNAIII inhibiting peptide (RIP) was observed. Additionally, the influence of RIP on the adhesion of Staphylococcus aureus was counted and analyzed by image information counting algorithm. Furthermore, the real-time quantitative PCR (RT-q PCR) was used to detect the mRNA levels of five genes related to biofilm formation, including ica A, ica R, fnb A, atl A, and sar A. It was found that the adhesion ability of Staphylococcus aureus decreased under the effect of RIP, and the results showed that the expression level of ica A, ica R, fnb A, and atl A gene in the experimental group was significantly lower than that in the control group, with statistical difference. After culture for 2 h, 8 h, and 24 h, the expression of ica R gene in the experimental group was 1.45, 1.46, and 1.5, respectively, which were significantly higher than those in the control group, showing statistical significance. There was no significant difference between the two groups in gene expression of sar A. Through the image information counting algorithm for Staphylococcus aureus technology, it was found that RIP could inhibit the adhesion of Staphylococcus aureus and the formation of early biofilm, but the specific regulatory mechanism needs further study. To sum up, according to the results of this study, RIP can be applied to old people's bone and joint diseases caused by Staphylococcus aureus infection, such as pyogenic arthritis and osteomyelitis.

Elicitors as alternatives to agrochemicals are widely used as a sustainable farming practice. The use of elicitors in viticulture to control disease and improve phenolic compounds is widely recognized in this field. Concurrently, they also affect other secondary metabolites, such as aroma compounds. Grape and wine aroma compounds are an important quality factor that reflects nutritional information and influences consumer preference. However, the effects of elicitors on aroma compounds are diverse, as different grape varieties respond differently to treatments. Among the numerous commercialized elicitors, some have proven very effective in improving the quality of grapes and the resulting wines. This review summarizes some of the elicitors commonly used in grapevines for protection against biotic and abiotic stresses and their impact on the quality of volatile compounds. The work is intended to serve as a reference for growers for the sustainable development of high-quality grapes.

In this manuscript, a new approach to study the fractionalized Oldroyd-B fluid flow based on the fundamental symmetry is described by critically examining the Prabhakar fractional derivative near an infinitely vertical plate, wall slip condition on temperature along with Newtonian heating effects and constant concentration. The phenomenon has been described in forms of partial differential equations along with heat and mass transportation effect taken into account. The Prabhakar fractional operator which was recently introduced is used in this work together with generalized Fick’s and Fourier’s law. The fractional model is transfromed into a non-dimentional form by using some suitable quantities and the symmetry of fluid flow is analyzed. The non-dimensional developed fractional model for momentum, thermal and diffusion equations based on Prabhakar fractional operator has been solved analytically via Laplace transformation method and calculated solutions expressed in terms of Mittag-Leffler special functions. Graphical demonstrations are made to characterize the physical behavior of different parameters and significance of such system parameters over the momentum, concentration and energy profiles. Moreover, to validate our current results, some limiting models such as fractional and classical fluid models for Maxwell and Newtonian are recovered, in the presence of with/without slip boundary wall conditions. Further, it is observed from the graphs the velocity curves for classical fluid models are relatively higher than fractional fluid models. A comparative analysis between fractional and classical models depicts that the Prabhakar fractional model explains the memory effects more adequately.

Background Immunotherapy has achieved remarkable advances via a variety of strategies against tumor cells that evade immune surveillance. As important innate immune cells, macrophages play important roles in maintaining homeostasis, preventing pathogen invasion, resisting tumor cells and promoting adaptive immune response. CD47 is found to be overexpressed on tumor cells and act as a don’t eat me’ signal, which contributes to immune evasion. Macrophages mediated phagocytosis via blockade CD47/SIRPα (signal regulatory protein alpha) interaction was proved to induce effective antitumor immune response.Methods A novel peptide pep-20, specifically targeting CD47 and blocking CD47/SIRPα interaction, was identified via high-throughput phage display library bio-panning. The capability to enhance the macrophage-mediated phagocytosis activities and antitumor effects of pep-20 were investigated. The mechanism of pep-20 to induce T-cell response was explored by ex vivo analysis and confirmed via macrophage depleting strategy. The structure-activity relationship and D-amino acid substitution of pep-20 were also studied. The antitumor effects and mechanism of a proteolysis resistant D-amino acid derivate pep-20-D12 combined with irradiation (IR) were also investigated.Results Pep-20 showed remarkable enhancement of macrophage-mediated phagocytosis to both solid and hematologic tumor cells in vitro, and inhibited tumor growth in immune-competent tumor-bearing mice. Furthermore, pep-20 promoted macrophages to mobilize the antitumor T-cell response with minimal toxicity. Furthermore, systemic administration of the derivate pep-20-D12 showed robust synergistic antitumor efficacy in combination with IR.Conclusion In summary, these results demonstrated that CD47/SIRPα blocking peptides, pep-20 and its derivate, could serve as promising candidates to promote macrophages-mediated phagocytosis and immune response in cancer immunotherapy.

Ventricular remodelling leads to cardiomyocyte hypertrophy, myocardial fibrosis, endothelial vasoactive substance changes and endothelial dysfunction. Our purpose was to research the effect of an aqueous extract of Averrhoa carambola L. (AEA) on endothelial function in rats with ventricular remodelling induced by isoprenaline. Rats were subjected to injection of isoprenaline and administration of various drugs. Vasoactive substances were measured, and the ventricular remodelling index was detected by the weighing method. Immunohistochemical analysis, pathological examination, Western blot and Masson’s trichrome staining were performed. After AEA administration, the levels of transforming growth factor-β (TGF-β), angiotensin II (AngII), inducible NO synthase (iNOS), endothelin-converting enzyme (ECE), and endothelin 1 (ET-1); the ventricular remodelling index; and the collagen volume fraction were decreased, while the levels of total NO synthase (tNOS) and endothelial NO synthase (eNOS) were increased. The pathological examination results showed that apoptosis, fibrosis, necrosis and inflammatory infiltration of myocardial tissue were attenuated by AEA treatment. AEA might alleviate ventricular remodelling in rats by maintaining the balance of vasoactive substances and the function of the vascular endothelium.

Esophageal squamous cell carcinoma (ESCC), one of the deadliest gastrointestinal cancers, has had limited effective therapeutic strategies up to now. Accumulating evidence suggests that effective immunotherapy in cancer patients has been associated with T cells responsive to mutant peptides derived from neoantigens. Here, we selected 35 human leukocyte antigen-A2 (HLA-A2)-restricted mutant (MUT) peptides stemmed from neoantigens of ESCC. Among them, seven mutant peptides had potent binding affinity to HLA-A*0201 molecules and could form a stable peptide/HLA-A*0201 complex. Three mutant peptides (TP53-R267P, NFE2L2-D13N, and PCLO-E4090Q) of those were immunogenic and could induce the cytotoxic T lymphocytes (CTLs) recognizing mutant peptides presented on transfected cells in an HLA-A2-restricted and MUT peptide-specific manner. In addition, the CTL response in immunized HLA-A2.1/Kb transgenic (Tg) mice was enhanced by coupling MUT peptides to peptide WH, a peptide delivery carrier targeting Clec9a+ DCs. Then, the possible binding model conversions between the WT and MUT candidate peptides were analyzed by docking with the pockets of HLA-A*0201 molecule. We therefore propose a novel strategy and epitopes for immunotherapy of ESCC based on neoantigens.

Abstract Metastasis causes approximately 90% of breast cancer-related deaths in women. Previously, we have demonstrated that 2-dodecyl-6-methoxycyclohexa-2,5-diene- 1,4-dione (DMDD) remarkably inhibited the growth of human breast cancer cells with little toxicity. In this study, we investigated the toxicity and efficacy of DMDD to treat metastatic breast tumors using an in vivo mouse model of the 4T1 mammary carcinoma. DMDD caused no observable toxicity and significantly extended the survival of 4T1 tumor-bearing mice. DMDD effectively inhibited the growth of 4T1 cells in vitro, and suppressed the growth and metastasis of mammary tumor in vivo. The levels of inflammatory cytokines in the serum (TNF-α, IL-6, IL-12, TGF-β, and VEGF) were down regulated by DMDD. Immunohistochemical analysis demonstrated that the inhibition of tumor growth and metastasis was associated with activation of Bax, cleaved caspases-3 and -9, and down-regulation of Bcl-2, MMP-2 and -9, NF-κB and IκBα. We speculate that DMDD inhibits cytokine production in the tumor cells in mice, which leads to deactivation of NF-κB pathway, and consequently inhibits the expression of many anti-apoptosis and metastasis-promoting genes, such as Bcl-2 and MMPs. Collectively, our results demonstrate the potential of DMDD as a safe and effective antitumor agent in the treatment of late-stage breast cancer.

The article is devoted to the analysis of the role and the place of linguo-sociocultural competence in university teaching of the language and preparation for professional work of foreign language teachers, in particular, Chinese teachers of the Russian language. The invariant and variable aims of education and the communicative needs of students-philologists – future teachers in the current branches of communication are formulated: professional, socio-cultural, business, socio-political and colloquial. The modern points of view on the structure of professional competence of future foreign language teachers, the place of linguistic and socio-cultural competence in its structure are analyzed. The result of mastering a foreign language by this contingent of students should be an integrative communicative competence, which is a complex of key competencies: linguistic, conversational, socio-cultural and professional. The role of mastering the aspects of the language system, productive and receptive types of speech activity in the process of forming the professional skills of students in communication and studying in the socio-cultural sphere is described. Cultural studies components of the educational process organization are emphasized. The training of linguistic and socio-cultural competence should be carried out within the framework of the culturological approach. The most developed in the methodology aspect of this approach is linguistic and cultural studies. The linguistic-cultural knowledge, abilities and skills of foreign languages future teachers are systematized. The analysis of the main data formation of linguistic and socio-cultural competence is carried out on the example of the organization of the teaching Russian to Chinese students. Methodical solutions for the formation of professionally oriented linguistic and socio-cultural competence based on its cognitive-active model are proposed.

Background/Aims: Studies have demonstrated that 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione (DMDD), isolated from the roots of Averrhoa carambola L., has significant therapeutic potential for the treatment of diabetes. However, the protective effect of DMDD against pancreatic beta cell dysfunction has never been reported. We investigated whether DMDD protected against palmitic acid-induced dysfunction in pancreatic β-cell line Min6 cells by attenuating the inflammatory response and apoptosis and to shed light on its possible mechanism. Methods: Cell viability was assessed by CCK-8. Glucose-stimulated insulin secretion levels and inflammatory cytokines levels were examined by ELISA. Apoptosis was assessed by Annexin V-FITC/PI Flow cytometry assay, Hoechst 33342/PI double-staining assay, and Transmission electron microscopy assay. Relative quantitative real-time PCR and western blot were used to determine the expressions of genes and proteins. Results: Cell viability and glucose-stimulated insulin secretion levels were increased in DMDD-pretreated Min6 cells. DMDD inhibited inflammatory cytokines IL-6, TNF-α and MCP-1 generations in palmitic acid (PA)-induced Min6 cells. Moreover, DMDD protected against PA-induced Min6 cells apoptosis and the expression of Cleaved-Caspase-3, -8 and -9 were down-regulated and the Bcl-2/Bax ratio was increased in DMDD-pretreated Min6 cells. In addition, the expression of TLR4, MyD88 and NF-κB were down-regulated in DMDD-pretreated Min6 cells and TAK-242-pretreated group cells. Conclusions: DMDD protected Min6 cells against PA-induced dysfunction by attenuating the inflammatory response and apoptosis, and its mechanism of this protection was associated with inhibiting the TLR4-MyD88-NF-κB signaling pathway.

Background: The previous studies have demonstrated that the polysaccharide isolated from Tarphochlamys affinis (PTA) exhibits anti-tumor effect on S180 tumor-bearing mice and protective effects against hepatic injury. Methods: In this study, we investigated the anti-tumor activity and possible underlying mechanism of PTA on liver cancer using a murine H22 hepatocarcinoma model. Results: PTA was capable of repressing transplanted H22 solid hepatic tumor cell growth in vivo. The relative weight of immune organs (spleen and thymus) and lymphocyte proliferation induced by ConA or LPS were improved after PTA treatment. Furthermore, treatment with PTA promoted immune-stimulating serum cytokine secretion in H22 tumor-bearing mice. Additionally, the percentage of CD4+ T lymphocytes, CD8+ T lymphocytes and NK cells was increased in tumor-bearing mice following PTA administration. In tumor tissue, PTA significantly up-regulated the expression of Bax and p53 proteins and down-regulated the expression of Bcl-2 protein. In addition, at the therapeutic dose, PTA displayed very few toxic effects to major organs, such as the liver and kidney, in tumor-bearing mice. Conclusion: In H22 tumor-bearing mice, PTA exhibited prominent anti-tumor activity in vivo. The possible mechanism of action might be related to enhanced host immune system function and induction of H22 tumor cell apoptosis.

Background/Aims: In this study, we examined whether the combination of hyperbaric oxygen (HBO) and diltiazem therapy provided a cardioprotective effect on myocardial ischemia-reperfusion injury (MIRI) rat model. Methods: Sixty healthy Sprague-Dawley rats were randomly divided into sham, IR, diltiazem (5 mg/kg), HBO (0.25 MPa, 60 min) and combination therapy (HBO plus diltiazem) groups. MIRI model was established by ligating the left anterior descending for 30 min, followed by 60 min of reperfusion. Results: The results show that HBO and diltiazem preconditioning significantly improves cardiac function and myocardial infarction area, increases nitric oxide, endothelial nitric oxide synthase and ATPase (Na+-K+-ATPase and Ca2+-Mg2+-ATPase) activity and decreases levels of oxygen stress, myocardial enzymes and endothelin-1. Notably, HBO and diltiazem preconditioning significantly increased Bcl-2 protein expression and decreased Bax protein and caspase-3 mRNA expression. Conclusions: These data indicate that combination therapy protected against heart MIRI by reducing oxygen stress damage, correcting energy metabolism, improving endothelial function and inhibiting cell apoptosis.

The increasing consumption of regenerated cellulose, in particular the viscose fiber, has led to a significant development of dissolving pulps in the last decade. In this review paper, the current status of dissolving pulp with respects to raw materials, manufacturing processes, and some key issues are discussed. Non-wood materials and the process concept of upgrading paper-grade pulp into dissolving pulp are also included. Some recent developments related to the analytical methods of the purity and molecular weight distribution based on the ion chromatography and gel permeation chromatography are discussed. Finally, further processing improvements of purification, such as mechanical, chemical, and enzymatic treatment, and their combinations during the manufacturing process of dissolving pulp, are included.

Abstract Background It has been well accepted that glycans present in schistosomes are highly antigenic. However, it is not clear what kind of worm glycans can affect the infected host to mount IgG responses and whether mounted anti-glycan IgG responses are protective. Methods The contribution of antigenicity by glycans was measured by using competitive ELISA assay in sera from infected mice and humans. Monoclonal antibodies towards soluble Schistosoma japonicum egg antigens (SjEA) were generated from SjEA immunizated mice. The expression of glycans on surfaces of cercaria or young worm and their distributions were examined by immunofluorescence assay. The protective roles of glycans-specific mAbs were assayed by determination of the worm and egg burden in infected mice. Results Both periodate-resistant glycans and periodate-sensitive glycans are antigenic in schistosome infections. When monoclonal antibodies against either periodate-sensitive or periodate-resistant glycans were administered prior to schistosome infections in mice, both kinds of anti-glycan antibodies were found to successfully provide protective immunity to infected mice. Conclusions Both periodate-resistant and periodate-sensitive glycans are antigenic, and dominant anti-glycan IgG responses can play important roles in protective immunity in schistosome infected hosts.

Aims: Effect and mechanism of Yulangsan flavonoid (YLSF) on rat myocardial ischemia/reperfusion injury (MI/RI) has been investigated. Methods: Sprague-Dawley (SD) rats were randomly divided into seven groups (sham group, model group and NS group: 2 mL of normal saline/kg body weight was administered; diltiazem group: 5 mg of diltiazem hydrochloride/kg body weight was administered; YLSFL, YLSFM and YLSFH groups: 20, 40 and 80 mg of YLSF/kg body weight was administered) and the MI/RI model was established. Myocardial infarct area, levels of myocardial enzymes and nitric oxide synthase (NOS) were measured. Caspase-3 and adenine nucleotide translocator-1 (ANT1) mRNA expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Pathological structure and cardiocyte ultrastructure were also analysed. Results: Compared with the MI/RI group, pretreatment with YLSF or diltiazem hydrochloride decreased the infarct area, levels of inducible nitric oxide synthase (iNOS), caspase-3 as well as the leakage of myocardial enzyme and increased activities of total nitric oxide synthase (tNOS) as well as constitutive nitric oxide synthase (cNOS). Cellular edema and the infiltration of inflammatory cells were alleviated. Conclusions: The experiment showed that YLSF protected the heart against MI/RI, possibly by reducing lipid peroxidation damage, regulating NOS activity and modulating the apoptosis genes expression.

A straightforward method has been developed for the synthesis of the benzimidazole ring system through a carbon-nitrogen cross-coupling reaction. In the presence of 2.0 equiv. of K2CO3 in water at 100 °C for 30 h, the intramolecular cyclization of N-(2-iodoaryl)benzamidine provides benzimidazole derivatives in moderate to high yields. Remarkably, the procedure occurs exclusively in water and doesn’t require the use of any additional reagent/catalyst, rendering the methodology highly valuable from both environmental and economical points of view.

FOXP3 is a key transcription factor for regulatory T cell function. We report the crystal structure of the FOXP3 coiled-coil domain, through which a loose or transient dimeric association is formed and modulated, accounting for the activity variations introduced by disease-causing mutations or posttranslational modifications. Structure-guided mutagenesis revealed that FOXP3 coiled-coil-mediated homodimerization is essential for Treg function in vitro and in vivo. In particular, we identified human FOXP3 K250 and K252 as key residues for the conformational change and stability of the FOXP3 dimer, which can be regulated by protein posttranslational modifications such as reversible lysine acetylation. These studies provide structural and mechanistic explanations for certain disease-causing mutations in the coiled-coil domain of FOXP3 that are commonly found in IPEX syndrome. Overall, the regulatory machinery involving homooligomerization, acetylation, and heteroassociation has been dissected, defining atomic insights into the biological and pathological characteristics of the FOXP3 complex.

Atrial septal defect (ASD) is the third most frequent type of congenital heart anomaly, featuring shunting of blood between the two atria. Gene-environment interaction remains to be an acknowledged cause for ASD occurrence. A recent European genome-wide association study (GWAS) of congenital heart disease (CHD) identified 3 susceptibility SNPs at chromosome 4p16 associated with ASD: rs870142, rs16835979 and rs6824295. A Chinese-GWAS of CHD conducted in the corresponding period did not reveal the 3 susceptibility SNPs, but reported 2 different risk SNPs: rs2474937 and rs1531070. Therefore, we aimed to investigate the associations between the 3 European GWAS-identified susceptibility SNPs and ASD risk in the Han population in southwest China. Additionally, to increase the robustness of our current analysis, we conducted a meta-analysis combining published studies and our current case-control study. We performed association, linkage disequilibrium, and haplotype analysis among the 3 SNPs in 190 ASD cases and 225 age-, sex-, and ethnicity-matched healthy controls. Genotype and allele frequencies among the 3 SNPs showed statistically significant differences between the cases and controls. Our study found that individuals carrying the allele T of rs870142, the allele A of rs16835979, and the allele T of rs6824295 had a respective 50.1% (odds ratio (OR) = 1.501, 95% confidence interval (CI) = 1.122-2.009, PFDR-BH = 0.018), 48.5% (OR = 1.485, 95%CI = 1.109-1.987, PFDR-BH = 0.012), and 38.6% (OR = 1.386, 95%CI = 1.042-1.844, PFDR-BH = 0.025) increased risk to develop ASD than wild-type allele carriers in our study cohort. In the haplotype analysis, we identified a disease-risk haplotype (TAT) (OR = 1.540, 95%CI = 1.030-2.380, PFDR-BH = 0.016). Our meta-analysis also showed that the investigated SNP was associated with ASD risk (combined OR (95%CI) = 1.35 (1.24-1.46), P < 0.00001). Our study provides compelling evidence to motivate better understanding of the etiology of ASD.

OBJECTIVE: To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. METHODS: We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. RESULTS: A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88-4.38 mg/day) than the low-dose range (