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Background Hypertension is a kind of clinical syndrome, characterized by the increase of systemic arterial pressure. There is a lack of identifiable triggers and predictors of hypertensive disease in response to treatment at rest and during exercise. In this study, a mathematical model was used to screen and compare the indicators and related changes at rest and during exercise between normotensive and hypertensive individuals. Methods Blood pressure and ultrasound-related indicators, blood biochemical indicators and metabolic compounds were collected and logistic regression model and Principal component analysis (PCA) were used to explore the differences of indexes at rest and in different exercise states in healthy and hypertensive patients. An indicator change map for hypertension is established. Results The results reveal that hypertension is not only related to oxidative stress, inflammatory reaction and fatty acid oxidation, but also involves various amino acid metabolism. The defined mathematical models and indicators changes during exercise might be helpful for early screening of hypertension and future studies are needed to explore their value on prevention and control of hypertension. Conclusion The research shows that the main regulation indicators at different exercise states differ significantly in the normal group and the hypertensive group. The key indicators of the normal group are blood pressure and ultrasound related indicators, while those of the hypertensive group are metabolites related to lactic acid metabolism, glycolysis, aerobic oxidation and lipid metabolism.

Dipyrrolydiketones BF2 complex was synthesized and characterized by NMR, HRMS, and single crystal diffraction. In non-polar environment, this BF2 containing dye emitted bright blue-green fluorescence. No significant spectra shift was observed both in absorption and emission spectra, which indicates the insensitivity of absorption/emission toward environment. The alkyl substituted pyrrole rings lead to its highly emission character in solid state by enhancing the distance between dye molecules. Absolute quantum yields were determined to be 0.51-0.78/0.36 in selected organic medium and solid state, respectively. The emission dynamics was investigated by fluorescence lifetime and both monoexponential and bi-exponential decay was observed.

Zuogui Wan (ZGW), a well-known traditional Chinese medicine (TCM), has been used to nourish “Kidney-Yin” for a long time in China, implying a protective effect on the kidney. The aim of the present study is to investigate the effect of ZGW on high glucose-induced podocyte apoptosis and diabetic nephropathy (DN) in db/db mice. ZGW (1 g/kg−1/day−1) was administered intragastrically to db/db mice for 8 weeks. HPLC was used for identifying the components of ZGW, biochemical and histopathological approaches were used for evaluating its therapeutic effects, and cultured mouse podocytes were used for further exploring its underlying mechanism in vitro. ZGW improved renal function and podocyte loss and also normalized kidney reactive oxygen species production in db/db mice. The cytotoxicity of ZGW on mouse podocytes was assessed by the LDH assay. The effect of ZGW on podocyte viability and apoptosis was determined with CCK-8 and Annexin-V/PI staining by treatment with high glucose. ZGW attenuated podocyte apoptosis, and oxidative stress was detected by the peroxide-sensitive fluorescent probe 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA) staining in a dose-dependent manner. Furthermore, ZGW decreased the expression of caspase-3 and phospho-p38 in both the kidney cortex and high glucose-treated podocytes. Thus, our data from in vivo and in vitro studies demonstrated that ZGW improved renal injury in diabetes by inhibiting oxidative stress and podocyte apoptosis.

The identification of cone photoreceptor cells is important for early diagnosing of eye diseases. We proposed automatic deep-learning cone photoreceptor cell identification on adaptive optics scanning laser ophthalmoscope images. The proposed algorithm is based on DeepLab and bias field correction. Considering manual identification as reference, our algorithm is highly effective, achieving precision, recall, and F 1 score of 96.7%, 94.6%, and 95.7%, respectively. To illustrate the performance of our algorithm, we present identification results for images with different cone photoreceptor cell distributions. The experimental results show that our algorithm can achieve accurate photoreceptor cell identification on images of human retinas, which is comparable to manual identification.

BACKGROUND Chimeric antigen receptor T cell (CART) therapy has benefited many refractory lymphoma patients, but some patients experience poor effects. Previous studies have shown that programmed cell death protein-1 (PD-1) inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment. CASE SUMMARY A 61-year-old male presented with 15-d history of diarrhea and lower-limb edema. A large mass was detected in the pelvis, and pathology indicated non-Hodgkin diffuse large B-cell lymphoma. After three cycles of the R-CHOP chemotherapeutic regimen, the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine. Pathological examination of the nodules indicated DLBCL again. The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma. We recommended CAR-T cell treatment. Before treatment, the patient’s T cell function and expression of immune detection points were tested. Expression of PD-1 was obviously increased (52.7%) on cluster of differentiation (CD)3+ T cells. The PD-1 inhibitor (3 mg/kg) was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide. CAR-CD19 T cells of 3 × 106/kg and CAR-CD22 T cells 1 × 106/kg were infused, respectively. The therapeutic effect was significant, and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable. Presently, the patient has been disease-free for more than 12 mo. CONCLUSION This case suggests that the combination of PD-1 inhibitors and CAR-T cells improved therapeutic efficacy in B-cell lymphoma.

miRNA-223 has been previously reported to play an essential role in hepatic cholesterol homeostasis. However, its role in regulation of biliary cholesterol secretion and gallstone formation remains unknown. Hence, mice with conventional knockout (KO), hepatocyte-specific knockout (ΔHepa) / knockdown (KD) or gain expression of miRNA-223 were included in the study and were subjected to lithogenic diet (LD) for various weeks. The gall bladders and liver tissues were harvested for cholesterol crystal imaging, gallstone mass measurement and molecular analysis. Levels of cholesterol, bile salt, phospholipids, and triglyceride were determined in serum, liver tissues, and bile by enzyme color reactive assays. A 3' UTR reporter gene assay was used to verify the direct target genes for miRNA-223. LD-induced gallstone formation was remarkably accelerated in miRNA-223 KO, ΔHepa, and KD mice with concurrent enhancement in total cholesterol levels in liver tissues and bile. Key biliary cholesterol transporters ABCG5 and ABCG8 were identified as direct targets of miRNA-223. Reversely, AAV-mediated hepatocyte-specific miRNA-223 overexpression prevented gallstone progression with reduced targets expression. Therefore, the present study demonstrates a novel role of miRNA-223 in the gallstone formation by targeting ABCG5 and ABCG8 and elevating miRNA-223 would be a potentially novel approach to overcome the sternness of cholesterol gallstone disease.

Activation and migration of donor T cells to the host target organs are critical mechanisms in the pathogenesis of graft-versus-host disease (GVHD). The role of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor CCR2 in the recruitment of T cells during immune or inflammatory response is also well known. For elucidation of the mechanism of the therapeutic effect of human bone marrow derived-mesenchymal stem cells (MSC) in GVHD, we studied the effect of these cells on migration of activated donor T cells through the CCL2-CCR2 axis in vitro. MSC were expanded from donors' bone marrow mononuclear cells. After co-culturing of IL-2-activated T cells with allogeneic MSC at different ratios, the levels of CCL2 in supernatants were measured by ELISA, and CCR2 expression in CD4+/CD8+ T cells subsets were detected by flow cytometry. The effect of MSC on the migration of activated T cells in the Transwell system was studied in the absence or presence of CCL2. Our results show that CCL2 levels in supernatants of co-cultures were significantly higher than in MSC monoculture and this increase depended on the number of MSC. MSC inhibited proliferation of T cells, but did not change the percentages of CD4+ and CD8+ T cells subsets. MSC can up-regulate the CCR2 expression in CD8+ subsets rather than in CD4+ subsets; MSC enhanced migration of IL-2-activated T cells to CCL2 by increasing the expression of CCR2. The data demonstrate that MSC can enhance chemotaxis of cytokine-activated T cells through the CCL2-CCR2 axis in vitro.

Previous research has revealed the involvement of microRNA-212-5p (miR-212-5p) and cyclin T2 (CCNT2) in acute myeloid leukemia (AML). However, whether the miR-212-5p/CCNT2 axis is required for the function of decitabine in AML has not been well elucidated. Quantitative reverse transcription-polymerase chain reaction was used to examine enrichment of miR-212-5p. The relationship between CCNT2 and miR-212-5p was verified by the luciferase reporter assay. Cell apoptosis was evaluated by flow cytometry and western blot. CCK-8 assay was performed to determine cell viability. Decitabine significantly repressed cell viability, while promoted cell apoptosis. Meanwhile, the expression levels of cyclinD1, CDK4, and Bcl-2 were suppressed in cells with decitabine exposure, but Bax and caspase-3 expression levels were upregulated. Besides, miR-212-5p upregulation had the similar function with decitabine in AML cell proliferation and apoptosis. Subsequently, restoration of CCNT2 attenuated miR-212-5p overexpression-induced effects in Kasumi-1 and SKNO-1 cells. In addition, miR-212-5p depletion reversed decitabine-induced CCNT2 downregulation. The miR-212-5p/CCNT2 axis had an implication in the anti-leukemic effect of decitabine in AML.

The combination of Salvia miltiorrhiza (Danshen) and rivaroxaban is a promising treatment option in clinical practice in China, but the herb–drug interaction between Danshen and rivaroxaban remains unclear. Therefore, this study aims to reveal the interaction between Danshen and rivaroxaban. We not only investigated the inhibitory properties of Danshen tablet on rivaroxaban metabolism in rat and human liver microsomes but also evaluated the inhibitory effects of Danshen tablet and its eight active components (dihydrotanshinone I, tanshinone I, tanshinone IIA, cryptotanshinone, danshensu, salvianolic acid A, salvianolic acid B, and salvianolic acid C) on cytochrome P450 (CYP) enzymes. The results showed that Danshen tablet potently inhibited the metabolism of rivaroxaban in rat and human liver microsomes. In the CYP inhibition study, we found that dihydrotanshinone I, the active component of Danshen tablet, potently inhibited the activities of rat CYP3A and CYP2J, with IC50 values at 13.85 and 6.39 μM, respectively. In further inhibition kinetic study, we found that Danshen tablet is a mixed inhibitor in rivaroxaban metabolism in rat and human liver microsomes, with the Ki value at 0.72 and 0.25 mg/ml, respectively. In conclusion, there is a potential interaction between Danshen tablet and rivaroxaban. Danshen tablet inhibits the metabolism of rivaroxaban, which may be because its lipid-soluble components such as dihydrotanshinone I strongly inhibit the activities of CYP enzymes, especially CYP3A and CYP2J. Therefore, when Danshen tablet and rivaroxaban are used simultaneously in the clinic, it is necessary to strengthen the drug monitoring of rivaroxaban and adjust the dosage.

With the popularization of the emerging 3C products (e.g., smartwatches, smart entertainment robots, and various wearable devices), printed circuit boards (PCBs), considered as the core of electronic products, have gained more attention in terms of the performance in the quality control. Many studies have been conducted and outstanding results have been obtained. However, there are still many challenges, e.g., the complexity and diversity of the PCB small defect dataset. To further cope with the above problems, the improved YOLOv4 algorithm is designed and verified in terms of the detection performance on a public PCB small defect dataset. First, the size distributions of six class defect images are analyzed; the reasonable size of anchor boxes is re-designed and assigned to multiscale feature layers. Second, the ADD-path module and the DSCBlock-W module combined with the MobiletNetv2 module are used to construct the backbone of the YOLOv4 method. Finally, the fusion of multilevel features is enhanced and the data information of the low-level feature is fully utilized, thereby enabling YOLOv4 to better detect small defects. Compared to different state-of-the-art methods, the improved YOLOv4 method obtains an mAP as high as 99.71%, which confirms the efficiency and accuracy of the improved method.

Acute demyelinating myelopathy after allogeneic hematopoietic stem cell transplantation (HSCT) is rare, and the exact pathogenesis remains unclear. Here, we report the case of a 20-year-old patient with B-cell acute lymphocyte leukemia (B-ALL) who developed acute demyelinating myelopathy approximately 10 months after HSCT. Magnetic resonance imaging revealed high T2 signal intensity lesions from the C2-T4 levels of the spinal cord. Treatments with high doses of corticosteroids, immunoglobulins, and rituximab improved his neurologic symptoms, and he achieved 44 months of leukemia-free and graft-versus-host disease (GVHD)-free survival, with no recurrence of the demyelination myelopathy. An understanding of the contribution of immune reconstitution to the pathogenesis of demyelinating myelopathy after HSCT and the association of this disease with GVHD will require more clinical cases.

Bacterial endotoxin is considered as one of the critical risk factors in medical devices, especially implanted devices that directly or indirectly contact with blood circulating system. In that case, endotoxin limits for implanted medical devices is important in determine the safety of medical devices. According to GB/T 14233.2-2005, the requirements of endotoxin index for intrathoracic medical devices is 2.15 EU per device. However, the definition of "intrathoracic medical devices" is vague. Specifically, "for cardiovascular system application" instead of "intrathoracic application" is more reasonable. With the deeper understanding of the risk of endotoxin in medical devices and considering the internationally accepted standards, the limits of endotoxin in medical devices for cardiovascular system application is acceptable at 20 EU per device.

In this work, we developed a motion estimation and correction method which real-time obtained the direction and displacement of repetitive micro bulk motion (such as cardiac and respiratory motion) on an SS-OCT system without additional tracking hardware, and reduced the motion noise in optical coherence tomography angiography (OCTA). In the approach, the direction of repetitive micro bulk motion was considered fixed, and proportional relationships between the motion components in three directions were determined; Then we performed one-dimension cross-correlation to obtain depth displacement which was further used to obtain other two motion components, and greatly reduced the computation; The processing speed on a graphic processing unit was 478 pairs of B-Scans per second, and the measurement range was larger than the range of the angiogram-based methods. Lastly, corrupt angiograms were recovered by adaptive scan protocol, and reduced acquisition time in comparison with the previous work. This article is protected by copyright. All rights reserved.

Identification of cone photoreceptor cells (CPCs) is essential for the diagnosis and treatment of various retinal disorders. In the present work, a new automated unsupervised learning-based method is proposed for the identification of CPCs in adaptive optics scanning laser ophthalmoscope images. This method consists of the following steps: image denoising, CPC number estimation, bias field correction, unsupervised CPC identification, and merging close CPC identification data. By comparing our results with those obtained manually, it was found that the proposed method showed high effectiveness, with the precision, recall and F1 score values of 92.9%, 84.4% and 88.4%, respectively. Furthermore, healthy retinal AO-SLO images with the difference in CPC densities and pathological (diabetic retinopathy) AO-SLO images are processed by our method. The results demonstrated that our method exhibited a good accuracy for the identification of CPCs in diabetic retinopathy and healthy retinas.

Backgroud: Pressure injuries (PIs) bring a considerable physical and mental burden on immobile patients, and have put families and government under tremendous pressure to cover the cost of treatment. Therefore, this protocol proposes to identify risk factors of developing PIs in immobile patients from systematic reviews (SRs) and clinical practice guidelines (CPGs), in order to establish a risk prediction model for developing PIs and identify individual risk factors that can be modified to aid prevention. Methods: Electronic databases and specific databases for CPGs and SRs will be searched. Study selection and data collection will be performed independently by two reviewers. All included SRs and CPGs will be subject to critical appraisal. RevMan 5.3 will be used to calculate the pooled odds ratio (ORP) after appraising the quality of eligible studies, and the risk predictive model will be established using logistic regression model. A narrative synthesis, evidence summary table, and Sankey diagram will also be performed. Results: The results of this study will be submitted to a peer-reviewed journal for publication. Conclusion: This systematic review will provide a risk prediction model of PI developing. INSPLAY registration number: INPLASY2020100097

BackgroudMiRNA-223 has previously been reported to play an essential role in hepatic cholesterol homeostasis by suppressing cholesterol synthesis, attenuating cholesterol uptake by hepatocyte from and promoting cholesterol efflux into the blood. However, its role in regulation of biliary cholesterol secretion and gallstone formation remains unknown.MethodsMice with conventional knockout (KO), hepatocyte-specific knockout (ΔHepa) / knockdown (KD) or gain expression of miRNA-223 were included in the study and were subjected to lithogenic diet (LD) for various weeks. The gallbladders were harvested and subjected to cholesterol crystal imaging and gallstone mass measurement. Liver tissues were collected for western blotting, RT-qPCR, and immunohistochemistry staining. Levels of cholesterol, bile salt, phospholipids, and triglyceride were determined in serum, liver tissues, and bile by enzyme color reactive assays. 3’ UTR reporter gene assays were used to verify the direct target genes for miRNA-223.ResultsLD-induced gallstone formation was remarkably accelerated in miRNA-223 KO, ΔHepa, and KD mice with concurrent enhancement in total cholesterol levels in liver tissue and bile. Key biliary cholesterol transporters ABCG5 and ABCG8 were identified as direct targets of miRNA-223. Reversely, AAV-mediated hepatocyte-specific miRNA-223 overexpression prevented gallstone progression with reduced targets protein expression.ConclusionThe present study demonstrates a novel role of miRNA-223 in the regulation of hepatic bile cholesterol secretion pathway and gallstone formation by targeting ABCG5 and ABCG8 expression. Therefore, elevating miRNA-223 would be a potentially novel approach to overcome the sternness of cholesterol gallstone disease.Graphical Abstract

Oxidative stress plays a key role in the pathogenesis of diabetic nephropathy (DN). The anti-aging protein Klotho has been demonstrated to have antioxidant capacity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a central transcription factor regulating antioxidant responses. The present study aimed to explore the effects of Klotho on DN and the underlying mechanisms related to Nrf2. Low glucose (LG) or high glucose (HG) medium-cultured podocytes and diabetic db/db mice were overexpressed with Klotho via adenoviral transfer to evaluate the effects of Klotho on Nrf2 signaling, oxidative stress, podocyte apoptosis, and renal function and histopathology. Klotho overexpression significantly induced the expression and activation of Nrf2 as well as its downstream targets SOD2 and NQO1 in podocytes. Moreover, Klotho overexpression inhibited HG-induced oxidative stress and apoptosis in podocytes. Co-treatment with Nrf2 inhibitor trigonelline prevented Klotho-induced expression of SOD2 and NQO1, and abolished Klotho-conferred antioxidant and anti-apoptotic effects. In db/db mice, Klotho overexpression also activated Nrf2 signaling, and suppressed diabetes-induced oxidative stress and podocyte apoptosis, which were accompanied by improved renal function and decreased glomerulosclerosis. Our data highlight a novel Nrf2-mediated antioxidant mechanism underlying the protective effects of Klotho in podocytes and indicate the therapeutic potential of targeting Klotho to activate Nrf2 in DN.

The genetic variations of the apolipoprotein L1 (APOL1) gene are associated with non-diabetic kidney diseases. However, very little is known about the role of ApoL1 in glomerular damage. Here, we aimed to identify the function and mechanism of ApoL1 in glomerular damage. The mice were randomly divided into two groups: one group was intraperitoneally injected with phosphate buffer saline (PBS), while the other group was intraperitoneally injected with recombinant ApoL1 every other day for 3 months. Hematoxylin and eosin (HE) and periodic acid Schiff (PAS) staining were used to demonstrate the effects of ApoL1 on kidney inflammation and injury. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses revealed that ApoL1-treated mice exhibited enhanced expression of various inflammation markers in the kidney and serum compared to the PBS-treated mice. Immunofluorescence staining revealed that ApoL1 accumulated in kidney podocytes. Treatment with ApoL1 dose-dependently increased the expression of inflammation markers and apoptotic markers. The abnormal gene expression associated with ApoL1-mediated podocyte inflammation was evaluated using microarray analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the upregulated genes were enriched in the inflammation-related processes, such as the RIG-I/NF-κB signaling pathway. Consistently, the knockdown of RIG-I significantly mitigated the ApoL1-induced upregulation of inflammatory and apoptotic markers in the human podocytes. Additionally, the ApoL1-induced glomerular damage was attenuated in AAV-shRIG-I mice. Therefore, the effects of ApoL1 on glomerular damage may be, at least partially, through inducing abnormal expression of inflammatory molecules, which may have important implications for treatment of kidney diseases.

W2Zr intermetallic is an important reason for the brittleness of W–Zr binary system. When W–Zr alloys are used as the energetic fragment, the integrity of a projectile cannot be maintained under the explosion even propellant loading process, resulting in severe fracture of the projectile. Moreover, due to the strong atomic bonding in W2Zr intermetallic, the oxidation reactivity of the Zr atoms with oxygen in the air is significantly suppressed, limiting the effective energy release of W–Zr fragment under high-speed impacting process. In this study, based on the thermodynamic analysis, 30W-xTi-(70-x)Zr (wt.%) alloys were designed and prepared by powder metallurgy. It was found that the formation and stabilization temperature of W2Zr phase can be reduced by increasing the Ti content. The hard W-rich phase has changed from the coarse W2Zr particle to fine W2Zr precipitate and finally to the WTix solid solution with the increase of Ti content. Meanwhile, a semi-coherent interface between fine W2Zr precipitate and α matrix and even coherent interface between WTix and α matrix were formed, by which the intergranular fracture ratio between W-rich phases and α matrix was significantly decreased in the W–Ti–Zr alloys. Consequently, higher dynamic compressive strength and ductility of the W–Ti–Zr alloys were obtained by increasing the Ti content. The selected W–Ti–Zr alloys with high strength and proper failure strain exhibited good penetration and energy-releasing behaviors when they were used as reactive bullet launching at a velocity of about 1250 m/s. The relationship among the dynamic compressive strength, ductility and ballistic performance of the W–Ti–Zr reactive structural alloys was also discussed in detail.

A reliable single-image denoising method is presented for adaptive optics scanning laser ophthalmoscopy. This method firstly averaged multiple images and then used the averaged image as the reference to adjust the parameters of the filtering process that was subsequently applied to other individual images. Six filtering methods, including the mean, median, Gaussian, fast adaptive nonlocal synthetic aperture radar despeckling, K-single value decomposition, and block matching and three-dimensional filtering, were utilized. The effectiveness of our method was verified based on the comparison of sets of images without and with parameter adjustments. Furthermore, we applied the same parameter settings as those obtained from the filter adjustments of another adaptive optics scanning laser ophthalmoscope image acquired by the same instrument. The filtered images showed that the parameter-adjusted filters work well on other images, which is helpful for improving the image quality of adaptive optics scanning laser ophthalmoscope images.

The damage effect of reactive structural materials (RSMs) is one of the focuses in this field. In this study, four new Zr-Ti-W alloys were prepared by adding Ti element on the basis of W-Zr alloys. These alloys have different densities and mechanical properties. The damage effect of these alloys on 18 mm thick Q235 steel plate under the condition of 1600— 1700 m/s impacting speed was investigated. The results show that the penetration power of Zr-Ti-W alloy is mainly affected by the density of the alloy. The higher the density is, the greater the penetration depth and crater diameter of the alloy bullet are. In addition to the high penetration depth and large crater diameter, the 20Ti alloy also exhibits excellent energy-releasing behavior. This alloy has the tremendous potential to be used as reactive fragments in military application. Besides, the Zr-Ti-W alloys designed in this study maintain good integrity under extreme loading conditions, which had successfully overcome the problem of poor overload resistance of W-Zr alloys.

Cone cell identification is essential for diagnosing and studying eye diseases. In this paper, we propose an automated cone cell identification method that involves TV-L1 optical flow estimation and K-means clustering. The proposed algorithm consists of the following steps: image denoising based on TV-L1 optical flow registration, bias field correction, cone cell identification based on K-means clustering, duplicate identification removal, identification based on threshold segmentation, and merging of closed identified cone cells. Compared with manually labelled ground-truth images, the proposed method shows high effectiveness with precision, recall, and F1 scores of 93.10%, 94.97%, and 94.03%, respectively. The method performance is further evaluated on adaptive optics scanning laser ophthalmoscope images obtained from a healthy subject with low cone cell density and subjects with either diabetic retinopathy or acute zonal occult outer retinopathy. The evaluation results demonstrate that the proposed method can accurately identify cone cells in subjects with healthy retinas and retinal diseases.

Aims Podocyte apoptosis plays an important role in the pathogenesis of diabetic nephropathy (DN). Astragaloside IV (AS-IV) has been shown to protect against podocyte apoptosis. Here we aim to investigate the mechanism responsible for the protective effects of AS-IV. Main methods Diabetic db/db mice and high glucose (HG)-cultured podocytes were treated with AS-IV. Renal function and histopathological changes were measured to evaluate the therapeutic effects of AS-IV against DN. Adenovirus-mediated Klotho overexpression, Klotho siRNA, and PPARγ inhibitor were applied in vitro to investigate the potential mechanism. The expression levels of mRNA and proteins were analyzed by qRT-PCR, western blot or immunofluorescence. Intracellular ROS and mitochondrial superoxide were detected by DHE and MitoSOx Red, respectively. Cell apoptosis was evaluated by TUNEL staining and flow cytometry. Key findings AS-IV improved renal function and ameliorated podocyte injury in db/db mice accompanied with enhanced Klotho expression in glomerular podocytes. In vitro, AS-IV inhibited HG-induced podocyte apoptosis and restored HG-inhibited Klotho expression, whereas Klotho knockdown abrogated the anti-apoptosis action of AS-IV. Further study showed that adenovirus-mediated Klotho overexpression enhanced Forkhead transcription factor O1 (FoxO1)-dependent antioxidant activity and attenuated HG-evoked oxidative stress and apoptosis. AS-IV prevented HG-induced FoxO1 inhibition and oxidative stress, whereas Klotho knockdown reversed these effects. Cotreatment with PPARγ inhibitor T0070907 abolished AS-IV-induced Klotho expression and anti-apoptosis action. Significance These data suggested that AS-IV attenuated podocyte apoptosis presumably by inhibiting oxidative stress via activating PPARγ-Klotho-FoxO1 signaling pathway, thereby ameliorating DN. This study provided new insights into the molecular mechanisms of AS-IV against DN.

Background: Pressure injuries, also known as pressure ulcers, are local skin injuries. Once a pressure injury occurs, clinical treatment is relatively difficult, the treatment cycle is long, and the treatment cost is high, which brings heavy burdens to patients and society. Therefore, look for a reliable pressure injuries treatment method is 1 of the focus of clinical nursing workers. Objective: At present, there are many kinds of dressings to treat pressure injuries, and there is no uniform conclusion about which dressing is the most effective. Therefore, we systematically evaluate the effects of different dressings on the treatment of pressure injuries. Methods: We systematically searched the Chinese and English databases: PubMed, Embase, CENTRAL, CINAHL, Web of Science, CNKI, CBM, VIP, Wan Fang. Literature screening, data extraction, and quality evaluation were carried out by 2 researchers, and finally, use R software to carry out network meta-analysis. Results: This study is ongoing and the results will be submitted to a peer-reviewed journal for publication. Ethics and dissemination: Ethical approval is not applicable, since this is an overview based on published articles. Protocol registration number: INPLASY2020100087.

Background: The arrival of transcatheter mitral valve therapies has provided feasible and safe alternatives to medical and surgical treatments for mitral regurgitation. The aim of this study is to estimate the relative efficacy and safety of different transcatheter mitral valve therapies for mitral regurgitation patients through network meta-analysis. Methods: A systematic search will be performed using PubMed, EMBASE, the Cochrane Library, Web of Science, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure to include random controlled trials and nonrandom controlled trials comparing the efficacy and safety of different transcatheter mitral valve techniques. The risk of bias for the included nonrandom controlled studies will be evaluated according to Risk of Bias in Non-randomized Studies - of Interventions. For random controlled trials, we will use Cochrane Handbook version 5.1.0 as the risk of bias tool. A Bayesian network meta-analysis will be conducted using R-4.0.3 software. Grading of recommendations assessment, development, and evaluation will be used to assess the quality of evidence. Results: The results of this network meta-analysis will be submitted to a peer-reviewed journal for publication. Conclusion: This study will provide broad evidence of efficacy and safety of different transcatheter mitral valve therapies for treatment of mitral regurgitation and provide suggestions for clinical practice and future research. Protocol registration number: INPLASY2020110034.

Rare earth element (REE) geochemistry is a useful tool in delineating hydrogeochemical processes and tracing solute transport, which can be used to reveal groundwater chemical evolution in the complexed groundwater systems of the North China Plain (NCP). Groundwaters and sediments were collected approximately along a flow path in shallow and deep aquifers of the NCP to investigate REE geochemistry as a function of distance from the recharge zone. Groundwater REE concentrations are relatively low, with ranges from 81.2 to 163.6 ng/L in shallow groundwaters, and from 65.2 to 133.7 ng/L in deep groundwaters. Speciation calculation suggests that dissolved REEs mainly occur as dicarbonato (Ln(CO3)2−) and carbonato (LnCO3+) complexes. Although along the flow path groundwater REE concentrations do not vary substantially, relatively lower HREEs are observed in central plain (Zone II) compared to recharge area (Zone I) and discharge plain (Zone III). Shale-normalized REE patterns are characterized by different degrees of enrichment in the HREEs, as indicated by the variation in average (Er/Nd)NASC value. The similar REE compositions and shale-normalized REE patterns of shallow and deep groundwaters demonstrate that interactions of groundwaters between shallow and deep aquifers possibly occur, which is likely due to the long-term groundwater over-exploration. Cerium anomalies (Ce/Ce∗ = CeNASC/(LaNASC × PrNASC)0.5) generally increase from Zone I, through Zone II, to Zone III, with trends from 0.79 to 3.58, and from 1.22 to 2.43 in shallow groundwaters and deep groundwaters, respectively. This is consistent with the variations in oxidation–reduction potential and redox sensitive components (i.e., dissolved Fe, Mn, NO3− and As concentrations) along the flow path. Positive Ce anomaly and redox indicators suggest that redox conditions progressively evolve from oxic to moderate anaerobic in the direction of groundwater flow. In the recharge zone (Zone I), groundwater low positive Ce anomalies are likely due to partially oxidative scavenging of Ce(III) to Ce(IV), and HREE enrichment would result from preferential scavenging of the LREEs relative to the HREEs during Fe/Mn oxides/oxyhydroxides precipitations, which is well supported by the low concentrations of dissolved Fe and Mn. In the down-gradient (Zone II and Zone III), reductive dissolution of Fe/Mn oxides/oxyhydroxides increases positive Ce anomalies along the flow path. The positive correlations between (Er/Nd)NASC values and dissolved Fe/Mn concentrations suggest that reductive dissolution of Fe/Mn oxides/oxyhydroxides, as well as readsorption, are the geochemical controls on groundwater REE fractionation patterns. Groundwaters mostly have positive Eu anomalies (Eu/Eu∗ = EuNASC/(SmNASC × GdNASC)0.5), which would be the result of chemical weathering of feldspars (e.g., plagioclase) detected in aquifer sediments by XRD technique.

Background: Cancer patients are in a state of systemic immunosuppression and are considered a highly vulnerable population in the Corona Virus Disease 2019 (COVID-19) epidemic. However, the relationship between cancer and the severity and mortality of patients with COVID-19 remains unclear. This study aims to evaluate whether cancer patients with COVID-19 may be at an increased risk of severe illness and mortality. Methods: We will perform comprehensive searches in PubMed, EMBASE.com, Web of Science, and the Cochrane Central Register of Controlled Trials to identify studies providing prevalence of cancer between patients with severe and non-severe illness or between non-survivors and survivors. We will use the Newcastle-Ottawa quality assessment scale to assess the quality of included studies. We will conduct pairwise meta-analyses to compute the odds ratio and 95% confidence interval using the Mantel Haenszel method with the random-effects model. The statistical heterogeneity will be assessed using the I2 statistic. Subgroup analyses, sensitivity analyses, and meta-regression analyses will be performed to explore the sources of heterogeneity. Results: The results of this study will be published in a peer-reviewed journal. Conclusion: Our meta-analysis will systematically evaluate the association between cancer and the severity and mortality of patients with COVID-19. This study will provide evidence to help determine whether cancer patients should be provided with special precautions and advised to use stronger personal protection. INPLASY registration number: INPLASY202090093.

An automated superpixels identification/mosaicking method is presented for the analysis of cone photoreceptor cells with the use of adaptive optics scanning laser ophthalmoscope (AO-SLO) images. This is an image oversegmentation method used for the identification and mosaicking of cone photoreceptor cells in AO-SLO images. It includes image denoising, estimation of the cone photoreceptor cell number, superpixels segmentation, merging of superpixels, and final identification and mosaicking processing steps. The effectiveness of the presented method was confirmed based on its comparison with a manual method in terms of precision, recall, and F1-score of 77.3%, 95.2%, and 85.3%, respectively.

Background Adults with relapsed acute lymphoblastic leukemia (ALL) have a poor prognosis, especially in patients who relapsed within 6 months of complete remission 1 (CR1). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice. However, this can only be considered after complete remission 2 (CR2) is achieved. Therefore, bridging treatment is urgently needed. Case presentation In the present study, we report a relapsed adult B-cell ALL case that achieved CR2 after treatment with CD19-directed chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapy. After subsequent allo-HSCT, the patient acquired 21 months of disease-free survival. Conclusion The present results confirm that both CAR-T and allo-HSCT are effective for treating refractory or relapsed B-ALL. However, a novel sequential treatment strategy with these two therapeutic methods may achieve longer disease-free survival time.

The present case report describes a rare case of T cell acute lymphoblastic lymphoma (T-LBL) in the lymph node with myeloid sarcoma in the pericardium. A 33-year-old Chinese male was admitted to hospital on 4 July 2015 exhibiting a fever and having experienced wheezing and fatigue for the previous 7 days. Routine pathological, computed tomographic, cytological and immunophenotypic observations revealed a diagnosis of T-LBL in the lymph node on 7 August 2015, without evidence of bone marrow (BM) involvement. The patient received induction chemotherapy for T-LBL and achieved partial remission. The patient was identified to have multiple serous effusion and analysis of pericardial effusion cells revealed the diagnosis of T-LBL with extramedullary myeloid sarcoma (without BM involvement) on 25 November 2015. On 30 December 2015, the patient was identified to exhibit proliferation of primary myeloid cells in the peripheral blood and BM, and an abnormal karyotype in BM cells, indicating that the complicated myeloid sarcoma involved the BM. No matched donor was available so the patient received chemotherapy to manage the disease. The patient was discharged on 31 January 2016 and ceased treatment. The patient succumbed on 19 February 2016 at home. To the best of our knowledge, T-LBL complicated with myeloid sarcoma had not been previously reported in Chinese adult male patients. In addition, the involvement of the BM and aberrant karyotype of the complicated myeloid sarcoma in the patient were rare.

The potential developmental toxicity of environmental estrogenic endocrine disruptors have become a great concern in recent years. In this study, two typical environmental oestrogen, namely, bisphenol A (BPA) and genistein (GEN) were investigated for potential embryotoxicity using the embryonic stem cell test model. Afterwards, a 4×4 full factorial design and the estimated marginal means plot were performed to assess the combined effects of these two compounds. According to the linear discriminant functions and classification criteria, bisphenol A and genistein were classified as weakly embryotoxic and strongly embryotoxic respectively. As for combined effects, the overall interaction between BPA and GEN on embryonic stem cells (ESCs) differentiation was synergistic at low dosages, however, on ESCs and 3T3 cell proliferation, the predominate action was additive. Considering the actual daily intake of these chemicals, it is concluded that BPA alone might not have adverse reproductive or developmental effects on human being. However, given that BPA and GEN do have synergistic effect at low concentration, they may disturb normal embryo development together, which could result in birth defect and behavioral alterations later in life.

The North China Plain is one of the biggest plains in China, where municipal, agricultural and industrial water supplies are highly dependent on groundwater resources. It is crucial to investigate water chemistry and hydrogeochemical processes related to hydrogeologic settings for sustainable utilization of groundwater resources. Two hydrochemical profiles proximately along the groundwater flow paths were selected for hydrogeochemical study. Major components and 2H and 18O isotopes were analyzed in groundwater samples from the profiles. The study area was divided into three zones, including strong runoff-alluvial/pluvial fans in the piedmont area (Zone I), slow runoff-alluvial/lacustrine plain in the central area (Zone II), and discharge-alluvial/marine plain in the coastal area (Zone III). Major components of groundwater samples showed obvious zonation patterns from Zone I to Zone III. Total dissolved solid (TDS) concentrations gradually increased, and the hydrochemical type changed from HCO3–SO4–Ca–Mg and HCO3–Cl–Ca–Mg types to HCO3–SO4–Na–Ca, SO4–Cl–Na–Ca and SO4–Cl–Na types from Zone I to Zone III. Abrupt increases in concentrations of Na+, Cl− and SO 4 2 - in deep groundwater were observed around the depression cones, which indicated that overexploitation resulted in water quality deterioration. Calcite and dolomite precipitation occurred in Zone I of deep groundwater systems and shallow groundwater systems. Cation exchange was believed to take place along the entire flow paths. Gypsum tended to dissolve in groundwater systems. The depletion in D and 18O isotopes in deep groundwater was related to the recharge from precipitation in paleo-climate conditions in glacial or interglacial periods, indicating that renewal groundwater was very limited. Efficient strategies must be taken to preserve the valued water resources for sustainable development.

Bisphenol A (BPA) has been widely used in the manufacture of polycarbonate plastic, water bottles and food containers. Previous studies have established that BPA could cause developmental toxicity by inhibiting the proliferation and differentiation of rat embryonic midbrain (MB) cells in vitro. However, the underlying mechanisms have not been well studied yet. In the current study, we examined the proliferation and differentiation of MB cells treated with 10(-12)-10(-4)M BPA and found that only 10(-4)M BPA inhibited proliferation and differentiation. Then, we investigated the cell cycle progression and apoptosis of MB cells; 10(-4)M BPA caused an explicit S phase and G2/M phase arrest in the cell cycle and increased the percentage of apoptotic cells. Moreover, the phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic-AMP response binding protein (CREB) and the expression of some apoptotic regulatory genes were investigated. BPA (10(-4)M) reduced the phosphorylation of C-Jun N-terminal kinase (JNK) and CREB, and increased the mRNA expression level of Bax and p53. Our findings demonstrated that BPA could cause developmental toxicity through anti-proliferation and pro-apoptosis in MB cells. Multiple signaling pathways, such as the JNK, CREB and p53-mitochondrial apoptosis pathways, participate in these effects.

Twenty-nine wells were selected for groundwater sampling in the town of Shahai, in the Hetao basin, Inner Mongolia. Four multilevel samplers were installed for monitoring groundwater chemistry at depths of 2.5–20 m. Results show that groundwater As exhibits a large spatial variation, ranging between 0.96 and 720 μg/L, with 71% of samples exceeding the WHO drinking water guideline value (10 μg/L). Fluoride concentrations range between 0.30 and 2.57 mg/L. There is no significant correlation between As and F − concentrations. Greater As concentrations were found with increasing well depth. However, F − concentrations do not show a consistent trend with depth. Groundwater with relatively low Eh has high As concentrations, indicating that the reducing environment is the major factor controlling As mobilization. Low As concentrations ( 2 into the aquifers, and lead to reducing conditions that favor As release. Sediment composition is an additional factor in determining dissolved As concentrations. In aquifers composed of yellowish-brown fine sands at depths around 10 m, groundwater generally has low As concentrations which is attributed to the high As adsorption capacity of the yellow–brown Fe oxyhydroxide coatings. Fluoride concentration is positively correlated with pH and negatively correlated with Ca 2+ concentration. All groundwater samples are over-saturated with respect to calcite and under-saturated with respect to fluorite. Dissolution and precipitation of Ca minerals (such as fluorite and calcite), and F − adsorption–desorption are likely controlling the concentration of F − in groundwater.

Genistein (GEN) is one kind of phytoestrogen. Several studies have demonstrated the teratogenic potential of GEN in vitro by postimplantation rat whole embryo culture (WEC) assay, but GEN showed no teratogenic effects in vivo even at a dose up to 1000 mg/kg bw/day. The mechanism of such discrepancy is still unclear. Because more than 80% of total genistein (free plus glycoside form) in circulation is its glycoside metabolite, genistin (GIN), we thus hypothesize that genistin is non-teratogenic. To prove this hypothesis, rat whole embryo culture (WEC) and limbud micromass culture methods were applied to compare the teratogenic effects of GEN and GIN on developing embryos in vitro. In WEC assay, we found that the development of embryos was affected by GEN treatment dose-dependently, while GIN-treated embryos displayed slight developmental defects only at the highest dose (222 μM). In micromass culture assay, the IC50 of cell proliferation and differentiation for GEN were 15.6 and 37.2 μM, respectively, while neither was influenced by GIN treatment up to 111 μM. Collectively, our study indicated that GEN showed no teratogenic effects in vivo probably due to its transformation to the non-teratogenic metabolite, GIN.

The potential teratogenic effects and fetal toxicity of environmental estrogenic endocrine disruptors have become a great concern in recent years, and they have yet to be fully characterized. In the present study, the teratogenic effects of bisphenol A (BPA) and genistein (GEN) on rat embryos during their critical period of organogenesis were investigated using a whole-embryo culture experiment. The combined exposure effects of BPA and GEN were explored using a 4 x 4 full factorial design. Both BPA and GEN produced concentration-dependent inhibition of embryonic development, beginning at 32.0 and 10.0 microg/ml, respectively. Full factorial and isobologram analyses revealed a significant synergistic interaction between BPA and GEN for most end points (12 out of 20 tested), as indicated by the enhanced developmental toxicity of BPA after coexposure with different dose levels of GEN. In particular, serious malformations and a higher abnormal frequency of the central nervous system were induced by the combination of BPA and GEN. Our findings suggest that GEN may be embryotoxic and teratogenic to humans. BPA alone may not be a potential teratogen, but these two estrogenic chemicals have a synergistic effect on embryonic development when present together during the critical period of major organ formation. The current findings suggest that pregnant women should not take soy supplements, but more studies are necessary to provide a conclusive recommendation.

To determine if cetuximab combined with chemotherapy is beneficial for patients with advanced NSCLC after failure of first-line chemotherapy and EGFR-tyrosine kinase inhibitors (TKI). Twenty patients were treated with cetuximab in combination with pemetrexed, and 14 patients were treated with cetuximab in combination with docetaxel. Short-term response rates and long-term survival after salvage therapy were evaluated. Partial response (PR) occurred in 4 patients, stable disease (SD) occurred in 13 patients, and progressive disease (PD) occurred in 17 patients. No patient achieved a complete response (CR). The objective response rate (ORR) was 11.8% (4/34) and the disease control rate (DCR) was 50.0% (17/34). The disease progression rate (DPR) was 50% (17/34). Further analyses showed that the DCR was significantly higher in patients treated with EGFR-TKI for ≥6 months compared to patients treated with EGFR-TKI for

The present study aims to clarify whether hyaluronan binding protein 1 (HABP1/p32/C1QBP) is an indicator of peritoneal and lymph node metastasis in epithelial ovarian cancer (EOC), which to the authors' knowledge is not previously reported by others. Western blot analysis demonstrated that HABP1 was highly overexpressed in most metastatic lesions. Of 89 patients whose primary tumors showed high HABP1 expression on immunohistochemical staining, 85 (95.5%) presented peritoneal metastases and 43 (48.3%) had lymph node metastases. Univariate and multivariate logistic regression analyses revealed that HABP1 overexpression correlated with peritoneal dissemination and lymph node metastasis in EOC. The specificity and positive predictive value of HABP1 staining were shown to be better for peritoneal metastasis, while the negative and sensitivity predictive value of HABP1 staining were better for lymph node metastasis. The odds ratio of high versus low staining for peritoneal spread was 9.236 (95% confidence interval (CI), 2.705, 19.316), and that for lymph node metastasis was 8.614 (95% CI, 2.507, 21.039). Furthermore, HABP1 protein may potentially be used alone or in combination with other markers as a predictive marker of EOC patients with lymph node metastasis and/or peritoneal dissemination.

Telomerase activity (TA) is reactivated in more than 90% of all human malignant tumors and normal somatic cells that lack TA. Thus, human TERT (hTERT) is a promising target in malignant tumor treatment. RNA interference is a powerful tool for gene silencing. In this study, we constructed siRNA#1-4 to knock down hTERT. All siRNAs were able to downregulate hTERT differently and we chose siRNA#3 (most effectively) in the following experiments. We studied the effects on cell proliferation, cell cycle, cell apoptosis and radiosensitivity using SiHa cells. Our results showed that siRNA#3 was able to silence hTERT gene effectively. The silencing of hTERT could induce immediate growth arrest, enhance the S phase in cell cycle study and lead to early apoptosis in human cervical cancer cells (SiHa). In clonogenic assays, we used multitarget-single hit and linear-quadratic models to assess the radiosensitivity after knockdown of hTERT. All results of parameters (D0, Dq, α, β) indicated that downregulation of hTERT enhanced radiosensitivity in SiHa cells.

Vascular endothelial growth factor (VEGF) plays an important role in the initiation and regulation of angiogenesis in various tumor tissues. Recently, several therapeutic approaches based on the inhibition of VEGF function during angiogenesis. However, VEGF function in cervical cancer may not be limited to angiogenesis, and VEGF signaling may be important for the ability of these tumor cells to evade apoptosis and progress towards invasive and metastatic diseases. In our study, VEGF expression was knocked down using plasmid-based RNA interference (RNAi) and detected in cervical carcinoma cells using real-time RT-PCR to screen the best RNA interference plasmid and reveal the VEGF expression level by radiation. Cell apoptosis and tumor xenografts in nude mice were measured by flow cytometry and immunohistochemistry, respectively, to further verify the possibility of enhancing apoptosis and radiosensitivity of cervical carcinoma cells by inhibition of VEGF expression. VEGF expression was significantly inhibited and the apoptosis was efficiently increased by RNAi. Moreover, the expression of VEGF was increased in HeLa cells in vivo and in vitro only by radiation. Increased apoptotic cell death and knockdown of VEGF expression in HeLa cells indicated increased cellular sensitivity to radiation. The data suggested that inhibited VEGF expression enhances radiosensitivity in cervical cancer therapy.