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Abstract MAT2B works together with MAT2A to synthesize S-Adenosyl methionine (SAM) as the primary methyl donor. MAT2B, despite lacking catalytic activity, exerts regulatory control over the enzymatic activity of MAT2A. In addition to the enzymatic activity regulation, we find that, in an NADP+-dependent manner, MAT2B binds and stabilizes MAT2A. Disruption of the cellular NADP+ remodels the protein level of MAT2A. The pentose phosphatase pathway regulates the level of MAT2A protein through the interaction of NADP+ with MAT2B. Additionally, MAT2B-MAT2A interaction regulates the mRNA m6A modification and stability. In liver tumors, the Mat2a mRNA level is elevated but the protein level is decreased by the restricted NADP+. Blocking the interaction between MAT2B and MAT2A by the keto diet can suppress liver tumor growth. These findings reveal that MAT2B is essential for regulating the protein levels of MAT2A and connecting SAM synthesis to mRNA m6A.

Abstract Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.

AIM: To investigate Omicron's impact on clinical presentation of acute primary angle closure (APAC) in China. METHODS: A consecutive case series with historical controls was conducted at Shenzhen Eye Hospital, the largest specialized hospital in Shenzhen, China. Medical records from a two-month period during the Omicron pandemic (December 1, 2022, to January 31, 2023) were compared with records from two control groups (12/2018–1/2019 and 12/2021–1/2022) before pandemic. Patients with APAC were included, and the prevalence of APAC and demographic characteristics in Omicron-infected and non-infected patients were compared. RESULTS: Seventy-one (23.43%) out of 303 patients were diagnosed with APAC in the pandemic cohort, which was 2.98 and 2.61 times higher than that in control cohorts (7.87% in 2019, 8.96% in 2022, P

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

BackgroundPathologic myopia (PM) associated with myopic maculopathy (MM) is a significant cause of visual impairment, especially in East Asia, where its prevalence has surged. Early detection and accurate classification of myopia-related fundus lesions are critical for managing PM. Traditional clinical analysis of fundus images is time-consuming and dependent on specialist expertise, driving the need for automated, accurate diagnostic tools.MethodsThis study developed a deep learning-based system for classifying five types of MM using color fundus photographs. Five architectures—ResNet50, EfficientNet-B0, Vision Transformer (ViT), Contrastive Language-Image Pre-Training (CLIP), and RETFound—were utilized. An ensemble learning approach with weighted voting was employed to enhance model performance. The models were trained on a dataset of 2,159 annotated images from Shenzhen Eye Hospital, with performance evaluated using accuracy, sensitivity, specificity, F1-Score, Cohen’s Kappa, and area under the receiver operating characteristic curve (AUC).ResultsThe ensemble model achieved superior performance across all metrics, with an accuracy of 95.4% (95% CI: 93.0–97.0%), sensitivity of 95.4% (95% CI: 86.8–97.5%), specificity of 98.9% (95% CI: 97.1–99.5%), F1-Score of 95.3% (95% CI: 93.2–97.2%), Kappa value of 0.976 (95% CI: 0.957–0.989), and AUC of 0.995 (95% CI: 0.992–0.998). The voting ensemble method demonstrated robustness and high generalization ability in classifying complex lesions, outperforming individual models.ConclusionThe ensemble deep learning system significantly enhances the accuracy and reliability of MM classification. This system holds potential for assisting ophthalmologists in early detection and precise diagnosis, thereby improving patient outcomes. Future work could focus on expanding the dataset, incorporating image quality assessment, and optimizing the ensemble algorithm for better efficiency and broader applicability.

ObjectiveBased on machine learning method, four types of early postoperative frailty risk prediction model of enterostomy patients were constructed to compare the performance of each model and provide the basis for preventing early postoperative frailty of elderly patients with enterostomy.MethodsThe prospective convenience sampling method was conducted and 362 early postoperative enterostomy patients were selected in three hospitals from July 2020 to November 2023 in Shanghai, four different prediction models of Support Vector Machine (SVM), Bayes, XG Boost, and Logistic regression were used and compared the test effects of the four models (MCC, F1, AUC, and Brier index) to judge the classification performance of the four models in the data of this study.ResultsA total of 21 variables were included in this study, and the predictors mainly covered demographic information, stoma-related information, quality of life, anxiety and depression, and frailty. The validated models on the test set are XGBoost, Logistic regression, SVM prediction model, and Bayes on the MCC and F1 scores; on the AUC, XGBoost, Logistic regression, Bayes, and SVM prediction model; on the Brier scores, Bayes, Logistic regression, and XGBoost.ConclusionXGBoost based on machine learning method is better than SVM prediction model, Logistic regression model and Bayes in sensitivity and accuracy. Quality of life in the early postoperative period can help guide clinical patients to identify patients at high risk of frailty and reduce the incidence of early postoperative frailty in elderly patients with enterostomy.

ABSTRACT There are significant differences in the quantities of Camellia oleifera fruits growing within and outside the canopy distribution, meaning that a single mode of picking has drawbacks. To improve the harvesting efficiency for the inner and outer layers, this article proposes a synergistic mode of harvesting based on a vibration comb brush, and presents a design for a harvesting device based on this principle. The overall structure and working principle of the proposed device are explained, and the operational processes of the vibration and comb parts of the device are analyzed. ADAMS software is used to construct a rigid-flexible coupling model of the device and the fruiting branch, and simulation results are presented to show that the fruit drop and flower loss rates for Camellia oleifera are related to the vibration frequency, the amplitude, and the spacing between the teeth and comb plates. Finally, a three factor and three level field orthogonal experiment was conducted, and the results showed that under the conditions of vibration frequency 5.85Hz, amplitude 60.43mm, and comb spacing 45mm, the flower loss rate was the lowest and it had good picking performance. Under these conditions, the fruit drop rate is 87.32% and the flower loss rate is 8.06%, values that meet the requirements for mechanized picking of Camellia oleifera fruits.

The strength and plasticity trade-off in metal materials can be effectively addressed by Eutectic High-Entropy Alloys (EHEAs) through the realization of heterogeneous biphase layered structures at both micrometer and nanometer scales. In this work, a series of (CoCrFeNi)88NbxW(12-x) EHEAs were prepared, and the effects of the synergistic of Nb and W elements on the microstructure and mechanical properties of CoCrFeNi High-Entropy Alloys (HEAs) were investigated. With the increase of Nb content and the decrease of W content, the microstructure of the alloy underwent three changes, from Face Center Cubic (FCC) + μ biphase to FCC + μ + Laves triple phase, and finally to FCC + Laves biphase. The strength of the alloy increases, but the compression rate decreases. Among these alloys, (CoCrFeNi)88Nb10W2 alloy exhibits exceptional mechanical properties. The synergistic effect of precipitation strengthening and grain boundary strengthening makes the yield strength, fracture strength, and plastic strain of the alloy are 1568 MPa, 2516 MPa, and 32 % respectively. In addition, in the CoCrFeNi HEAs, the weighted average atomic radius ratio (rm‾/rQ) is used to further precise the phase selection law of Laves phase and μ phase. When rm‾/rQ < 1.112, HEAs forms the μ phase, when 1.112 ≤ rm‾/rQ ≤ 1.14, HEAs forms the Laves + μ biphase, when rm‾/rQ > 1.14, HEAs forms the Laves phase. The results can provide a basis for synergistic strengthening and phase selection of CoCrFeNi HEAs.

With the clinical prevalence of drug-resistant pathogenic bacteria, developing non-antibiotic strategies to treat multi-drug-resistant bacterial infections is urgent yet challenging. Ferroptosis is a non-apoptotic form of regulated cell death that can overcome drug resistance. Emerging evidence shows the potential of triggering ferroptosis-like for anti-infection therapy, but the direct delivery of iron species is inefficient and may cause detrimental effects. Herein, CuFeS2 nanozyme is revealed as a ferroptosis-like initiator to eradicate bacterial infections for effective anti-infection therapy. Upon activating by visible light irradiation or hydrogen peroxide, the as-prepared CuFeS2 nanozyme can significantly expedite reactive oxygen species generation, deplete intracellular glutathione, and interfere with respiratory metabolisms, resulting in lipid peroxidation-driven ferroptotic damage. Additionally, the CuFeS2 displays good photothermal conversion capacity under near-infrared light irradiation, further augmenting the antibacterial efficiency. Accordingly, the CuFeS2 nanozyme shows potent antibacterial activity against Gram-negative Escherichia coli and Gram-positive methicillin-resistant Staphylococcus aureus strains in vitro. Moreover, it shows excellent biocompatibility and robust anti-infection effects in MRSA-infected wounds in vivo. This ferroptosis-like antibacterial strategy may open up new insights into the treatment of drug-resistant pathogen infection.

Abstract Background Malignant melanoma is a highly heterogeneous skin cancer with the highest mortality rate among dermatological cancers. Catenins form functional networks in the nucleus to regulate gene expression and determine cell fate. Dysregulation of catenin expression correlates with the malignant characteristics of the tumor. We aimed to investigate the regulatory mechanisms of catenins in melanoma and to further define the function of catenin-related molecular signaling in the tumor microenvironment. Methods In this study, a bioinformatics approach combined with experimental validation was used to explore the potential tumor biology mechanisms of catenin-related signaling. Results Melanoma patients can be divided into two catenin clusters. Patients defined by high Junction Plakoglobin (JUP), Plakophilin 1 (PKP1), Plakophilin 3 (PKP3) levels (C2) had shorter survival time than other patients (C1). We demonstrated that JUP regulates Anterior Gradient 2 (AGR2)/LY6/PLAUR Domain Containing 3 (LYPD3) to maintain melanoma stemness and promotes glycolysis. We also found that LYPD3 was co-expressed with S100A9 and associated with immunosuppressive tumor microenvironment (TME). Conclusion The JUP/AGR2/LYPD3 signaling axis plays an important role in the malignant features of melanoma. Targeting the JUP/AGR2/LYPD3 signaling axis can help develop promising drugs.

ABSTRACT A March male Golden, weighing 7.6kg, presented with gradual weight loss, high body temperature, depression, poor appetite and thirst, and vomiting before consultation. The results showed that the erythrocytes, hematocrit, hemoglobin, and platelets were lower than the reference values. The diagnosis of mixed infection with haematocrit and eosinophilic bodies was confirmed by real-time fluorescence PCR of whole blood, which was positive for haematocrit and eosinophilic bodies. The dog was treated with doxycycline and ceftriaxone, and the dog fully recovered after 2 weeks with blood transfusion, symptomatic treatment, and supportive therapy. This indicates that the disease can be treated well by a comprehensive treatment approach.

With the development of economy, the problem of heavy metal pollution in water environment is becoming more and more serious, so it is urgent to find a kind of efficient water purification material. The current work aimed to investigate the potential power of sodium vanadate nanowire arrays (Na5V12O32) to remove cadmium (Cd2+) and chromium (Cr3+) from simulated aqueous solutions. The adsorption effects of Na5V12O32 on Cd2+ and Cr3+ under different adsorption conditions were analyzed. The products before and after adsorption were compared by XRD, SEM, TEM, FTIR and XPS. The results showed that the irregular grass-like structure of Na5V12O32 nanowire arrays provided more active sites for the ion exchange reaction, and the maximum adsorption capacity of Cd2+ and Cr3+ was 541.2 and 251.8 mg·g-1, respectively. The pseudo-second-order kinetic model was more suitable to describe the adsorption behavior by kinetic study. The research demonstrated that Na5V12O32 nanowire arrays exhibited excellent adsorption performance, which provided an effective parameter basis for the future adsorption of heavy metal ions.

Abstract Introduction Our previous study has proofed the glucose sensitive gene-thioredoxin-interacting protein (TXNIP) expression was up in the placenta of the patients with gestational diabetes mellitus (GDM), but the pathological mechanisms underlying abnormal TXNIP expression in the placenta of patients with GDM is completely unclear and additional investigations are required to explain the findings we have observed. In the present study, we simulated the high TXNIP expression via introducing the Tet-On “switch” in vitro, approximate to its expression level in the real world, to explore the following consequence of the abnormal TXNIP. Methods The expression and localization of TXNIP in the placenta of GDM patients and the health control was investigated via immunofluorescent staining, western blot and RT-qPCR. Overexpression of TXNIP was achieved through transfecting Tet-on system to the human trophoblastic cell line-HTR-8/Svneo cell. TXNIP knockout was obtained via CRISPR-Cas9 method. The cell phenotype was observed via IncuCyte Imaging System and flow cytometry. The mechanism was explored via western blot and RT-qPCR. Results The expression level of TXNIP in the GDM placenta was nearly 2–3 times higher than that in the control. The TXNIP located at trophoblastic cells of the placenta. When the expression of TXNIP was upregulated, the migration and invasion of the cells accelerated, but cell apoptosis and proliferation did not changed compared with the control group. Furthermore, the size of the TetTXNIP cells became larger, and the expression level of Vimentin and p-STAT3 increased in the TetTXNIP cells. All the changes mentioned above were opposite in the TXNIP-KO cells. Conclusions Abnormal expression of TXNIP might be related to the impairment of the GDM placental function, affecting the migration and invasion of the placental trophoblast cells through STAT3 and Vimentin related pathway; thus, TXNIP might be the potential therapeutic target for repairing the placental dysfunction deficient in GDM patients.

IntroductionPhotoreceptor degenerative diseases are characterized by the progressive death of photoreceptor cells, resulting in irreversible visual impairment. However, the role of competing endogenous RNA (ceRNA) in photoreceptor degeneration is unclear. We aimed to explore the shared ceRNA regulation network and potential molecular mechanisms between primary and secondary photoreceptor degenerations.MethodsWe established animal models for both types of photoreceptor degenerations and conducted retina RNA sequencing to identify shared differentially expressed long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs). Using ceRNA regulatory principles, we constructed a shared ceRNA network and performed function enrichment and protein–protein interaction (PPI) analyses to identify hub genes and key pathways. Immune cell infiltration and drug–gene interaction analyses were conducted, and hub gene expression was validated by quantitative real-time polymerase chain reaction (qRT-PCR).ResultsWe identified 37 shared differentially expressed lncRNAs, 34 miRNAs, and 247 mRNAs and constructed a ceRNA network consisting of 3 lncRNAs, 5 miRNAs, and 109 mRNAs. Furthermore, we examined 109 common differentially expressed genes (DEGs) through functional annotation, PPI analysis, and regulatory network analysis. We discovered that these diseases shared the complement and coagulation cascades pathway. Eight hub genes were identified and enriched in the immune system process. Immune infiltration analysis revealed increased T cells and decreased B cells in both photoreceptor degenerations. The expression of hub genes was closely associated with the quantities of immune cell types. Additionally, we identified 7 immune therapeutical drugs that target the hub genes.DiscussionOur findings provide new insights and directions for understanding the common mechanisms underlying the development of photoreceptor degeneration. The hub genes and related ceRNA networks we identified may offer new perspectives for elucidating the mechanisms and hold promise for the development of innovative treatment strategies.

A group of low-cost Fe40Ni(50-x)Cr10Mox high-entropy alloys (HEAs) without the Co element were proposed. The microstructure and properties were investigated. With the increase of Mo content, the microstructure changes from FCC single-phase to two-phase divorced eutectic, divorced eutectic + hypoeutectic, hypoeutectic, eutectic and hypereutectic, in which the two-phase is composed of FCC phase + σ phase. The yield strength of alloy increases with the increase of Mo content. Its strengthening mechanism transforms from solution strengthening to second phase strengthening and grain boundary strengthening. Mo-20 and Mo-22.5 have comprehensive mechanical properties, and their yield strength, fracture strength and plastic strain are 1103.1 MPa and 1127.9 MPa, 1924.5 MPa and 1881.7 MPa, 30.4% and 28.7% respectively. In addition, the revised equivalent Cr content (ECC) is proposed in the FeNiCrMo HEAs, ECC = at.%[Cr]+8/3 × at.%[Mo]. The eutectic composition can be precisely designed through the revised ECC and atomic content ratio (RI/F) of the intermetallic forming elements to the FCC forming elements in FeNiCrMo HEAs system. When 20 at.%≤Fe and Ni ≤ 40 at.%, and RI/F = ECC/[x × at.%Fe + y × at.%Ni] = 1.05 ± 0.3, FexNiyCrmMon is the eutectic high-entropy alloy.

Abstract Background Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism. Methods Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, β-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells. Results Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent β-catenin stabilization and nuclear translocation. Nuclear β-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells. Conclusions This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma. Video Abstract

Since the beginning of the digital music era, the number of available digital music resources has skyrocketed. The genre of music is a significant classification to use when elaborating music; the role of music tags in locating and categorizing electronic music services is essential. To categorize such a large music archive manually would be prohibitively expensive and time-consuming, rendering it obsolete. This study’s main contributions to knowledge are the following: This article will break down the music into many MIDI (music played on a digital musical instrument) movements, playing way close by analysis movement, character extraction from passages, and character sequencing from movement so that you may get a clearer picture of what you are hearing. The procedure includes the following steps: extracting the note character matrix, extracting the subject and segmentation grouping based on the note character matrix, researching and extracting beneficial characteristics based on the theme of the segments, and composing the feature sequence. It is challenging for the sorter to acquire spatial and contextual knowledge about music using traditional classification techniques due to its shallow structure. This study uses the unique pattern of input MIDI segments, which are used to probe the relationship between recurrent neural networks and attention. The approach for music classification is verified when paired with the testing precision of the same-length segment categorization; thus, gathering MIDI tracks 1920 along with genre tags from the network to construct statistics sets and perform music classification analysis.

Persistent idiopathic macular hole (PIMH), the occurrence of idiopathic macular holes that have failed to close after standard pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling, has become a global health threat to the aging population. Because postoperative anatomic closure or restoration of visual acuity is more difficult to achieve in PIMH, surgical approaches that would yield the best outcomes remain to be elucidated. On paper, extended ILM peeling combined with silicone oil (SiO) tamponade is believed to be a feasible option for excellent macular hole closure. However, no studies on this combined treatment for PIMH is compared with simple air tamponade have been conducted. Thus, in this retrospective case series, we used spectral-domain optical coherence tomography (SD-OCT) and other technologies to investigate real-world evidence for the anatomical and functional outcomes of revisional PPV with either SiO or air tamponade for failed primary idiopathic macular hole surgery. We included the records of 76 patients with PIMH who had SD-OCT examinations and best-corrected visual acuity (BCVA). Regression analysis was performed to find factors affecting PIMH fracture closure. Seventy-six participants were allocated to a SiO group (n = 21, with an extended ILM peeling and SiO tamponade) or an air group (n = 55, with extended ILM peeling and air tamponade). Anatomical success was achieved in 18 (85.7%) and 40 (72.7%) eyes in the SiO and air groups, respectively (p = 0.37). BCVA was significantly improved in both subgroups of closed PIMH (SiO group: p = 0.041; air group: p 650 μm; 88.4% vs. 52%, p = 0.002). In conclusion, we demonstrated that extended ILM peeling combined with SiO or air tamponade is effective in PIMH treatment. Moreover, though not statistically significant herein, the anatomic closure rate was better for silicone-operated eyes than for air-operated eyes. MLD is the best predictor of PIMH closure; MLD ≤ 650 μm could achieve a significantly higher closure rate.

External prestressing is widely employed in structural strengthening engineering due to its numerous advantages. However, external prestressed steel bars are prone to corrosion when exposed to the service environment. This paper is dedicated to examining the use of fiber-reinforced polymer (FRP) bars as external prestressing materials to strengthen one-way concrete slabs. Five one-way concrete slabs were strengthened with externally prestressed FRP bars with different prestress levels and different amounts of FRP bars, while one non-strengthened slab was used for comparison. The effects of strengthening on the flexural behavior, specifically the cracking load, ultimate load, stiffness and failure mode, were analyzed systematically. Moreover, the ductility and cost–benefit optimizing properties of the reinforcing design were discussed. The results show that external prestressed FRP bars significantly improve the cracking load, ultimate load and stiffness of one-way concrete slabs. The absence of a bond between the concrete and FRP bars overcomes the brittleness of the FRP bars, while the strengthened slabs exhibit satisfactory ductility and a higher post-yield stiffness and bearing capacity. Additionally, the cost/benefit ratio is optimized by increasing the prestress level, while a higher number of prestressed FRP bars is beneficial to ductility. Finally, a method for calculating the stress in prestressed FRP bars at ultimate loads was proposed. Irrespective of the prestressing material, this method is applicable to both strengthened beams and one-way slabs.

Objective To explore the feasibility of establishing a computer-aided diagnostic model of multi-stained pathological images in patients with non-inflammatory aortic medial degeneration(MD). Methods In this study, pathological sections of aortic surgical specimens for non-inflammatory lesions from patients with thoracic aortic aneurysms and dissections were retrospectively collected at the Beijing Anzhen Hospital, Capital Medical University from July to December 2018. The lesions were scanned under ×400 magnification as whole slide images(WSI) and then annotated by two pathologists. The annotated WSI images were randomly split into training and test sets in a 6:1 ratio. SE-EmbraceNet was used to train the data to construct a multi-classification model for MD of multi-stained pathology images, including intralamellar mucoid extracellular matrix accumulation (MEMA-I), translamellar mucoid extracellular matrix accumulation (MEMA-T), elastic fiber fragmentation and/or loss(EFFL) and smooth muscle cell nuclei loss (SMCNL). The classification effect of the model was evaluated based on the test set data, and the results were expressed in terms of accuracy, sensitivity, precision, and the F1 value. Results Totally 530 pathological slides of non-inflammatory aortic lesion surgical specimens from patients with aortic aneurysm and dissection were included. Extracted 5265 sets of images, each containing 5 stained pathological images of the same lesion site: HE staining, special staining (elastic fiber/VanGieson, Masson, Alcian blue/periodic acid Schiff) and smooth muscle actin staining. There were 4513 sets of training images, including 987 SMCNL, 2013 EFFL, 1337 MEMA-I, and 176 MEMA-T; and 752 test images including 166 SMCNL, 335 EFFL, 222 MEMA-I, and 29 MEMA-T. The overall performance of the model in the test set showed good results, with an accuracy of 96.54%(726/752). The model had the best classification performance for EFFL, with accuracy, sensitivity, precision, and F1 value all ≥98.51%. The model also had a great classification ability for SMCNL, with all evaluated indexes≥97.59%. Conclusion The multi-stained pathology image-based MD classification model constructed in this study has high classification accuracy and good generalization ability, which has the potential to be applied to assist in the diagnosis of the non-inflammatory aortic lesion.

SETD2 methylates histone H3K36me3 in gene bodies in mammalian cells. Here the authors show H3K36me3 is also enriched at the promoter regions, and that this methylation is carried out by SMYD5, which is recruited by RNA polymerase II. They furthermore show SMYD5 is elevated in liver cancer and is correlated with changes in gene expression.

BackgroundPatients with high myopia have an increased lifetime risk of complications. The prevalence patterns of high myopia in children and adolescents in southern China are unclear. Early identification of high-risk individuals is critical for reducing the occurrence and development of high myopia and avoiding the resulting complications. ObjectiveThis study aimed to determine the prevalence of high myopia in children and adolescents in southern China via real-world screening data and to predict its onset by studying the risk factors for high myopia based on machine learning. MethodsThis retrospective school-based study was conducted in 13 cities with different gross domestic products in southern China. Through data acquisition and filtering, we analyzed the prevalence of high myopia and its association with age, school stage, gross domestic product, and risk factors. A random forest algorithm was used to predict high myopia among schoolchildren and then assessed in an independent hold-out group. ResultsThere were 1,285,609 participants (mean age 11.80, SD 3.07, range 6-20 years), of whom 658,516 (51.2%) were male. The overall prevalence of high myopia was 4.48% (2019), 4.88% (2020), and 3.17% (2021), with an increasing trend from the age of 11 to 17 years. The rates of high myopia increased from elementary schools to high schools but decreased at all school stages from 2019 to 2021. The coastal and southern cities had a higher proportion of high myopia, with an overall prevalence between 2.60% and 5.83%. Age, uncorrected distance visual acuity, and spherical equivalents were predictive factors for high myopia onset in schoolchildren. The random forest algorithm achieved a high accuracy of 0.948. The area under the receiver operator characteristic curve (AUC) was 0.975. Both indicated sufficient model efficacy. The performance of the model was validated in an external test with high accuracy (0.971) and a high AUC (0.957). ConclusionsHigh myopia had a high incidence in Guangdong Province. Its onset in children and adolescents was well predicted with the random forest algorithm. Efficient use of real-world data can contribute to the prevention and early diagnosis of high myopia.

As it is a typical dye pollutant in water, methylene blue detection is important to health and environmental safety. A kind of methylene blue optical fiber sensor was successfully fabricated, which was highly sensitive, responded linearly, was easy to manufacture and was low cost. The sensor was composed of a capillary glass tube, single-mode fiber and calcium alginate hydrogel. The interference spectrum of the optical fiber F–P cavity successfully responded to the methylene blue solution. The response sensitivity of 2.46 nm/(mg/L) was obtained with the typical sensor with a 39.18 μm cavity length. The linearity of the experiment curve was 0.99247. Furthermore, the influence of sodium alginate concentrations on sensitivity was also investigated. The results showed that the sodium alginate concentration had an optimum value. In addition, the dynamic response characteristic was tested. A 25 s response time was obtained with testing using a typical sensor, which showed a fast response time. The sensor has the potential to be applied to online methylene blue detection.

Abstract Metastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.

A localized Wnt3a signal has been shown to induce asymmetric division of mouse embryonic stem cells. Here the authors develop SET-seq, an approach to jointly profile epigenome and transcriptome in the same single cell and use it to provide mechanistic insights into the gene regulatory programs for maintaining and resetting stem cell fate during differentiation.

Icariside II, as a favonoid compound derived from epimedium, has been proved to involed in a variety of biological and pharmacological effects such as anti-inflammatory, anti-osteoporosis, anti-oxidation, anti-aging, and anti-cancer but its mechanism is unclear, especially in terms of its effect on post-transcriptional modification of endothelial nitric oxide synthase (eNOS). Phosphorylation of eNOS plays an important role in the synthesis of nitric oxide in endothelial cells, which is closely related to erectile dysfunction, atherosclerosis, Alzheimer’s disease, and other diseases. Our study aims to investigate the effect and mechanism of Icariside II on the rapid phosphorylation of eNOS. In this study, human umbilical vein endothelial cells (HUVECs) were stimulated with Icariside II in the presence or absence of multiple inhibitors (1 µM), including LY294002 (PI3K-inhibitor), MK-2206 (AKT-inhibitor), Bisindolylmaleimide X (AMPK-inhibitor), H-89 (CaMKII-inhibitor), KN-62 (PKA-inhibitor), Dorsomorphin (PKC-inhibitor). The proliferation of HUVECs was assessed using cell counting kit-8 (CCK-8). The release of nitric oxide (NO) within HUVECs was detected via fluorescence probe (DAF-FM). Western blot was used to examine the effect of Icariside II on the expression of eNOS, phosphorylation of eNOS, and common signaling pathways proteins. In this study, Icariside II was found to promote the cell proliferation and rapid NO release in HUVECs. The phosphorylation of eNOS-Ser1177 was significantly increased after Icariside II stimulation and reached a peak at 10 min (p

Multi-modal imaging technology was used to screen the cervical microlymph nodes of patients with head and neck squamous cell carcinoma. Based on the pathological results, radiotherapy was optimized to improve the quality of life of patients. CT or magnetic resonance imaging (MRI) examination before radiotherapy was performed in 36 patients with head and neck squamous cell carcinoma. Fifty-one microlymph nodes with ≤1 cm diameter were selected. Following the ultrasonic detection of relevant indicators, ultrasound-guided puncture biopsy was performed to confirm the pathology. Based on the multi-modal evaluation results, the target area and plan of radiotherapy was confirmed. We evaluated the dose to organs at risk before and after target optimization. The difference in the detection results was compared, and the 3-year local control rate of the lymph node region of interest was observed. The Dmean and V30 of the parotid (left and right) and submandibular gland (left and right) and the V50 of the mandibular gland (left and right) had significant differences before and after optimization in the microlymph node target area of the neck (p

This article discusses how a new APRS service-learning model was implemented in a new service-learning project in the traditional Chinese medicine (TCM) orthopedics curriculums at three Hong Kong institutions. The APRS model adopting flipped learning approach consists of four cyclic stages, including Application, Practice, Reflection and Self-regulated learning. Qualitative and quantitative findings in this study reveal that TCM students gained confidence in applying discipline knowledge/skills and improved in various areas, including cross-cultural competence, communication, problem-solving and collaboration. Drawing evidence from this study, possible factors contributing to positive impacts on student learning in the APRS model are the "strong connectivity" (including clear alignment with programme, profession, institutional missions and traditional Chinese philosophy "xiushen"), "reinforced motivation" (student autonomy and buy in) and "structured organisation" (strong network among participating parties and use of a centralised electronic platform). The APRS service-learning model is a culture-based approach helping students reconnect Confucian "xiushen" to the discipline knowledge and the real-life application in the Hong Kong context. This model may also be applicable to other Asian contexts where the Confucian culture prevails.

Background: Endothelial dysfunction is commonly accompanied by a reduced capacity for nitric oxide (NO) production and decreased NO sensitivity, playing a central role in numerous vascular diseases. Saturated free fatty acids are known to reduce NO production and then induce endothelial dysfunction. Alternative splicing participates in the regulation of cellular and tissular homeostasis and is highly regulated by serine-arginine protein kinase (SRPK1). The role of SRPK1 in the biology of endothelial cells remains elusive. Icariside Ⅱ (ICA Ⅱ) has been reported to have protective effects on endothelial function. However, the specific molecular mechanisms are still unknown. The purpose of this study is to explore the role of SRPK1 in the biology of endothelial cells and the underlying mechanism of ICA Ⅱ on palmitic acid (PA) induced endothelial dysfunction.Methods: Endothelial dysfunction was induced using PA in human umbilical vein endothelial cells (HUVECs). The expression and phosphorylation of related proteins in the SRPK1-Akt-eNOS signaling pathway were detected by Western Blot. Cell Counting Kit-8 assay and Ki-67 immunofluorescence were used to estimate cell viability. Endothelial cell function was assessed by detecting NO production using DAF-FM DA. Interaction between ICA Ⅱ and SRPK1 was demonstrated by a biotinylated protein interaction pull-down assay.Results: The expressions of eNOS, Akt, and SRPK1 were down-regulated in the endothelial dysfunction stimulated by PA. SRPK1 inhibitor SPHINX31 restrained endothelial cell viability in a dose-dependent manner. Moreover, inhibition of SRPK1 using SPHINX31 and knockdown of SRPK1 by shRNA also showed a down-regulation of the proteins associated with the SRPK1-Akt-eNOS signaling pathway. Biotinylated protein interaction pull-down assay revealed that ICA Ⅱ could be directly bound with SRPK1. On the other hand, ICA Ⅱ could attenuate the PA-induced endothelial dysfunction and restore cell viability through the SRPK1-Akt-eNOS pathway.Conclusions: ICA Ⅱ, bound with SRPK1, could attenuate the endothelial dysfunction induced by the PA in HUVECs via the SRPK1-Akt-eNOS signaling pathway.

Proliferative vitreoretinopathy (PVR), an inflammatory and fibrotic blinding disease, is still a therapeutic challenge. Retinal pigment epithelial (RPE) cells dislodged in the vitreous play a central role in the PVR pathogenesis. To identify potential novel contributors to the pathogenesis of PVR, we investigated a profile of vitreous-induced changes in ARPE-19 cells by RNA sequencing. Bioinformatics analysis of the sequencing data showed that there were 258 genes up-regulated and 835 genes down-regulated in the ARPE-19 cells treated with human vitreous. Among these genes, there were three genes related to eye disease with more than threefold changes. In particular, quantitative PCR and western blot results showed that interleukin 13 receptor (IL13R)α2 that is over-expressed in a variety of cancers was up-regulated more than three times in the vitreous-treated ARPE-19 cells. Immunofluorescence analysis indicated that interleukin-13 receptor subunit α2 (IL13Rα2) was highly expressed in ARPE-19 cells within epiretinal membranes from patients with PVR. Importantly, blocking IL13Rα2 with its neutralizing antibody significantly inhibited vitreous-induced contraction of ARPE-19 cells, suggesting a novel role of IL13Rα2 in the PVR pathogenesis. These findings will improve our understanding of the molecular mechanisms by which PVR develops and provides potential targets for PVR therapeutics.

Abstract Substitution of lysine 36 with methionine in histone H3.3 (H3.3K36M) is an oncogenic mutation that inhibits SETD2-mediated histone H3K36 tri-methylation in tumors. To investigate how the oncohistone mutation affects the function of SETD2 at the nucleosome level, we determined the cryo-EM structure of human SETD2 associated with an H3.3K36M nucleosome and cofactor S-adenosylmethionine (SAM), and revealed that SETD2 is attached to the N-terminal region of histone H3 and the nucleosome DNA at superhelix location 1, accompanied with the partial unwrapping of nucleosome DNA to expose the SETD2-binding site. These structural features were also observed in the previous cryo-EM structure of the fungal Set2–nucleosome complex. By contrast with the stable association of SETD2 with the H3.3K36M nucleosome, the EM densities of SETD2 could not be observed on the wild-type nucleosome surface, suggesting that the association of SETD2 with wild-type nucleosome might be transient. The linker histone H1, which stabilizes the wrapping of nucleosome DNA at the entry/exit sites, exhibits an inhibitory effect on the activities of SETD2 and displays inversely correlated genome distributions with that of the H3K36me3 marks. Cryo-EM analysis of yeast H3K36 methyltransferase Set2 complexed with nucleosomes further revealed evolutionarily conserved structural features for nucleosome recognition in eukaryotes, and provides insights into the mechanism of activity regulation. These findings have advanced our understanding of the structural basis for the tumorigenesis mechanism of the H3.3K36M mutation and highlight the effect of nucleosome conformation on the regulation of histone modification.

Abstract Background Age-associated lung tissue degeneration is a risk factor for lung injury and exacerbated lung disease. It is also the main risk factor for chronic lung diseases (such as COPD, idiopathic pulmonary fibrosis, cancer, among others). So, it is particularly important to find new anti-aging treatments. Methods We systematically screened and evaluated elderly senile multiple organ dysfunction macaque models to determine whether BMMSCs inhibited lung tissue degeneration. Results The average alveolar area, mean linear intercept (MLI), and fibrosis area in the elderly macaque models were significantly larger than in young rhesus monkeys (p

Abstract The histone H3.3K36M mutation, identified in over 90% of chondroblastoma cases, reprograms the H3K36 methylation landscape and gene expression to promote tumorigenesis. However, it’s still unclear how the H3K36M mutation preferentially occurs in the histone H3 variant H3.3 in chondroblastomas. Here, we report that H3.3K36M-, but not H3.1K36M-, mutant cells showed increased colony formation ability and differentiation defects. H3K36 methylations and enhancers were reprogrammed to different status in H3.3K36M- and H3.1K36M-mutant cells. The reprogramming of H3K36 methylation and enhancers was depended on the specific loci at which H3.3K36M and H3.1K36M were incorporated. Moreover, targeting H3K36M-mutant proteins to the chromatin inhibited the H3K36 methylation locally. Taken together, these results highlight the roles of the chromatic localization of H3.3K36M-mutant protein in the reprogramming of the epigenome and the subsequent induction of tumorigenesis, and shed light on the molecular mechanisms by which the H3K36M mutation mainly occurs in histone H3.3 in chondroblastomas.

C19H25N5O, monoclinic, P21 (no. 4), a = 16.0600(2) Å, b = 5.3992(1) Å, c = 19.8514(2) Å, β = 94.260(1)°, V = 1716.58(4) Å3, Z = 4, Rgt (F) = 0.0350, wRref(F2) = 0.0908, T = 100.00(10) K.

PurposeTo assess the diverse cell populations of human corpus cavernosum in patients with severe erectile dysfunction (ED) at the single-cell level.MethodsPenile tissues collected from three patients were subjected to single-cell RNA sequencing using the BD Rhapsody™ platform. Common bioinformatics tools were used to analyze cellular heterogeneity and gene expression profiles from generated raw data, including the packages Seurat, Monocle, and CellPhoneDB.ResultsDisease-related heterogeneity of cell types was determined in the cavernous tissue such as endothelial cells (ECs), smooth muscle cells, fibroblasts, and immune cells. Reclustering analysis of ECs identified an arteriole ECs subcluster and another one with gene signatures of fibroblasts. The proportion of fibroblasts was higher than the other cell populations and had the most significant cellular heterogeneity, in which a distinct subcluster co-expressed endothelial markers. The transition trajectory of differentiation from smooth muscle cells into fibroblasts was depicted using the pseudotime analysis, suggesting that the expansion of corpus cavernosum is possibly compromised as a result of fibrosis. Cell-cell communications among ECs, smooth muscle cells, fibroblasts, and macrophages were robust, which indicated that inflammation may also have a crucial role in the development of ED.ConclusionsOur study has demonstrated a comprehensive single-cell atlas of cellular components in human corpus cavernosum of ED, providing in-depth insights into the pathogenesis. Future research is warranted to explore disease-specific alterations for individualized treatment of ED.

ObjectivesTo summarize the clinicopathological diagnostic features and evolutionary trends of upper tract urothelial carcinoma (UTUC) in China over the past 20 years.MethodsAll patients diagnosed with upper tract urothelial carcinoma in the Peking University First Hospital from 2001 to 2020 were retrospectively collected. Data were divided into two groups (2001-2010 and 2011-2020) according to the date of diagnosis. Statistical analysis was done with the SPSS V22.0. Chi-square analysis and t-test were adopted to analyze depending on the data type. Subgroup analysis based on 5 years was used for visualization to present trends. Both Kaplan-Meier curve and Cox regression were used for univariate and multivariate survival analysis.ResultsThe study included 2561 cases diagnosed with upper tract urothelial carcinoma in total. Compared with the first decade (2001-2010), patients of the second decades (2011-2020) had elder mean age (66.65 versus 67.59, years, p=0.025), higher male proportion (43.5% versus 49.0%, p=0.034), lower incidence of renal pelvic tumors (53.4% versus 45.8%, p

ObjectiveWhole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.MethodsIn total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.ResultsOf 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.ConclusionsWe identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.

Diabetic kidney disease (DKD) is the leading cause of both chronic kidney disease (CKD) and end-stage renal disease (ESRD). Previous studies showed that oxamate could regulate glycemic homeostasis and impacted mitochondria respiration in a hyperglycemia-dependent manner in the rat proximal tubular cells. To explore the transcriptome gene expression profiling of kidney tissues in human renal proximal epithelial tubular cell line (HK-2), we treated HK-2 cells with high D-glucose (HG) for 7 days before the addition of 40 mM oxamate for a further 24 hours in the presence of HG in this study. Afterwards, we identified 3,884 differentially expressed (DE) genes based on adjusted P-value ≤ 0.05 and investigated gene relationships based on weighted gene co-expression network analysis (WGCNA). After qRT-PCR validations, MAP1LC3A, MAP1LC3B (P-value < 0.01) and BECN1 were found to show relatively higher expression levels in the treated groups than the control groups, while PGC1α (P-value < 0.05) showed the lower expressions. Accordingly, enrichment analyses of GO terms and KEGG pathways showed that several pathways [e.g., lysosome pathway (hsa04142) and p53 signaling pathway (hsa04115)] may be involved in the response of HK-2 cells to oxamate. Moreover, via WGCNA, we identified two modules: both the turquoise and blue modules were enriched in pathways associated with lysosome. However, the p53 signaling pathway was only found using all 3,884 DE genes. Furthermore, the key hub genes IGFBP3 (adjusted P-value = 1.34×10-75 and log2(FC) = 2.64) interacted with 6 up-regulated and 12 down-regulated DE genes in the network that were enriched in the p53 signaling pathway. This is the first study reporting co-expression patterns of a gene network after lactate dehydrogenase inhibition in HK-2 cells. Our results may contribute to our understanding of the underlying molecular mechanism of in vitro reprogramming under hyperglycemic stress that orchestrates the survival and functions of HK-2 cells.

A small-spored Alternaria was found from black spots of storaged Koerle pear (Pyrus sinkiangensis), one of the economically important fruit in Xinjiang province, China. The morphology is similar to A. limoniasperae but obviously different in secondary conidiophores and conidial septa. A phylogenetic analysis using sequence datasets of ITS, GAPDH, TEF1, RPB2, Alt a1, OPA10–2, and EndoPG genes revealed that it belonged to the Alternaria alternata complex group. Pathogenicity tests illustrated that the fungus was the causal pathogen of black spot on Koerle pear fruit.

Abstract Purpose This study aims to identify predictive local recurrence risk factors and site-specific local recurrence pattern of upper tract urothelial carcinoma (UTUC) with different primary tumor locations. Methods Three hundred and eighty-nine UTUC patients with radical nephroureterectomy were included in this study. Univariate and multivariate Cox proportional hazards regressions were performed to measure the risk of local recurrence. We also mapped the position of local recurrence sites stratified by primary tumor locations. Results A total of 73 patients (18.7%) developed local recurrence within a median follow-up of 41 months (range, 3-80 months). For patients with local recurrence, the median interval of local recurrence was 9 months. Ureter tumor, multifocality, T stage, G grade, lymph node metastasis (LNM), lymph node dissection (LND), and lymph vascular invasion (LVI) were all significantly associated with increased local recurrence by univariable analyses (P < 0.05). Only multifocality, T3–4, G3, and LNM remained independent predictors of increased local recurrence by multivariable analyses. Adjuvant radiotherapy could reduce the local recurrence (HR = 0.177; 95% CI 0.064-0.493, P = 0.001). Patients with local recurrence had poorer cancer-specific survival (4-year cancer-specific survival rate 36 ± 7.5% vs 88.4 ± 2.2%, P = 0.000). We evaluated local recurrence pattern stratified by tumor locations. Para-aortic lymph node region was the most common recurrence area for all the patients. Left-sided UTUC had more than 70% recurrent lymph nodes in the left para-aortic region (LPA). For right-sided UTUC patients, recurrent para-aortic lymph nodes distributed in the LPA (33.3%), aortocaval (AC) (41.5%), and right paracaval (RPC) (25.2%) regions. Recurrence in the internal and external iliac regions was only found in the distal ureter group (P < 0.05). Renal pelvic fossa recurrence was only found in renal pelvic tumor (22.2%, P = 0.007). The ureter tumor bed recurrence rate was higher for ureter patients (P = 0.001). Conclusions Multifocality, T3–4, G3, and LNM are predictors of higher local recurrence rate of UTUC. Adjuvant radiotherapy can reduce local recurrence rate. Local recurrence patterns are different according to primary tumor locations.

Abstract Background The treatment effect of dapoxetine in real-world practice is not well established. This study was to investigate the factors influencing efficacy of dapoxetine for the treatment of Premature ejaculation (PE) in the real-world setting. Methods Altogether 154 patients were followed up between Jan 2015 and Dec 2015. The clinical global impression of change (CGIC), premature ejaculation profile (PEP), the estimated intravaginal ejaculation latency time (eIELT) and estimated number of intravaginal thrusts before ejaculation (NITBE) were collected. The clinical characteristics of patients with CGIC = 0 and CGIC≥1 were compared. Results After 4 weeks treatment, an obvious improvement compared with the baseline was found regarding mean eIELT (2.4 ± 1.6 min vs 1.0 ± 0.7 min, P

Abstract Background Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are potential biomarkers and key regulators of tumour development and progression. SOX2 overlapping transcript (SOX2OT) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancer and cancer stem cells. However, the clinical significance and molecular mechanism of SOX2OT in bladder cancer are still unknown. Methods The expression level of SOX2OT was determined by RT-qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell (BCC) lines. Bladder cancer stem cells (BCSCs) were isolated from BCCs using flow cytometry based on the stem cell markers CD44 and ALDH1. Loss-of-function experiments were performed to investigate the biological roles of SOX2OT in the stemness phenotype of BCSCs. Comprehensive transcriptional analysis, RNA FISH, dual-luciferase reporter assays and western blots were performed to explore the molecular mechanisms underlying the functions of SOX2OT. Results SOX2OT was highly expressed in bladder cancer, and increased SOX2OT expression was positively correlated with a high histological grade, advanced TNM stage and poor prognosis. Further experiments demonstrated that knockdown of SOX2OT inhibited the stemness phenotype of BCSCs. Moreover, inhibition of SOX2OT delayed xenograft tumour growth and decreased metastases in vivo. Mechanistically, we found that SOX2OT was mainly distributed in the cytoplasm and positively regulated SOX2 expression by sponging miR-200c. Furthermore, SOX2 overexpression reversed the SOX2OT silencing-induced inhibition of the BCSC stemness phenotype. Conclusion This study is the first to demonstrate that SOX2OT plays an important regulatory role in BCSCs and that SOX2OT may serve as a potential diagnostic biomarker and therapeutic target in bladder cancer.

Abstract Histone marks control many cellular processes including DNA damage repair. This review will focus primarily on the active histone mark H3K36me3 in the regulation of DNA damage repair and the maintenance of genomic stability after DNA damage. There are diverse clues showing H3K36me3 participates in DNA damage response by directly recruiting DNA repair machinery to set the chromatin at a “ready” status, leading to a quick response upon damage. Reduced H3K36me3 is associated with low DNA repair efficiency. This review will also place a main emphasis on the H3K36me3-mediated DNA damage repair in the tumorigenesis of the newly found oncohistone mutant tumors. Gaining an understanding of different aspects of H3K36me3 in DNA damage repair, especially in cancers, would share the knowledge of chromatin and DNA repair to serve to the drug discovery and patient care.

This study aimed to compare the effects of bilateral cavernous nerve crushing (BCNC) and bilateral cavernous nerve resection (BCNR) on intracavernous pressure (ICP) and cavernous pathology in rats and to explore the optimal treatment time for the BCNC and BCNR models. Seventy-two male rats aged 12 weeks were randomly divided into three equal groups: Sham (both cavernous nerves exposed only), BCNC (BCN crushed for 2 min), and BCNR (5 mm of BCN resected). Erectile function was then measured at 1 week, 3 weeks, and 5 weeks after nerve injury, and penile tissues were harvested for histological and molecular analyses by immunohistochemistry, immunofluorescence, Western blot, and cytokine array. We found that erectile function parameters including the maximum, area, and slope of ICP/mean arterial pressure (MAP) significantly decreased after BCNR and BCNC at 1 week and 3 weeks. At 5 weeks, no significant differences were observed in ICP/MAP between the BCNC and Sham groups, whereas the ICP/MAP of the BCNR group remained significantly lower than that of the Sham group. After BCNC and BCNR, the amount of neuronal-nitric oxide synthase-positive fibers, smooth muscle cells, and endothelial cells decreased, whereas the amount of collagen III content increased. These pathological changes recovered over time, especially in the BCNC group. Our findings demonstrate that BCNC leads to acute and reversible erectile dysfunction, thus treatment time should be restricted to the first 3 weeks post-BCNC. In contrast, the self-healing ability of the BCNR model is poor, making it more suitable for long-term treatment research.

Abstract Upper tract urothelial carcinomas (UTUCs) are rare entities that are usually diagnosed at advanced stages. Research on UTUC pathobiology and clinical management has been hampered by the lack of models accurately reflecting disease nature and diversity. In this study, a modified organoid culture system is used to generate a library of 25 patient‐derived UTUC organoid lines retaining the histological architectures, marker gene expressions, genomic landscapes, and gene expression profiles of their parental tumors. The study demonstrates that the responses of UTUC organoids to anticancer drugs can be identified and the model supports the exploration of novel treatment strategies. This work proposes a modified protocol for generating patient‐derived UTUC organoid lines that may help elucidate UTUC pathophysiology and assess the responses of these diseases to various drug therapies in personalized medicine.