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Abstract Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Oxidative stress-induced growth inhibitor 1 (OSGIN1), which is a tumor suppressor gene known to regulate the cellular stress response and apoptosis, is associated with ovarian cancer development. However, the underlying mechanisms involved in ferroptosis regulation have not been elucidated. Thus, this study aimed to investigate the effect and underlying regulatory mechanism of the OSGIN1 gene on ovarian cancer cells. Our results demonstrated that loss of the OSGIN1 gene promoted ovarian cancer growth and conferred resistance to drug-induced ferroptosis. Mechanistically, the loss of OSGIN1 activates AMPK signaling through ATM, leading to the upregulation of SLC2A3, which protects cells from ferroptosis and renders them insensitive to ferroptosis inducers. Notably, an SLC2A3-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on ovarian cancer patient-derived xenograft tumors. Overall, anti-SLC2A3 therapy is a promising method to improve ovarian cancer treatment by targeting ferroptosis.

Abstract Background Extracellular vesicles (EVs) are cell-secreted membrane vesicles that have become a promising, natural nanoparticle system for delivering either naturally carried or exogenously loaded therapeutic molecules. Among reported cell sources for EV manufacture, human induced pluripotent stem cells (hiPSCs) offer numerous advantages. However, hiPSC-EVs only have a moderate ability for brain delivery. Herein, we sought to develop a stable hiPSC line for producing EVs with substantially enhanced brain targeting by genetic engineering to overexpress rabies viral glycoprotein (RVG) peptide fused to the N terminus of lysosomal associated membrane protein 2B (RVG-Lamp2B) which has been shown capable of boosting the brain delivery of EVs via the nicotinic acetylcholine receptor. Methods An RVG-Lamp2B-HA expression cassette was knocked into the AAVS1 safe harbor locus of a control hiPSC line using the CRISPR/Cas9-assisted homologous recombination. Western blot was used to detect the expression of RVG-Lamp2B-HA in RVG-edited hiPSCs as well as EVs derived from RVG-edited hiPSCs. Uptake of EVs by SH-SY5Y cells in the presence of various endocytic inhibitors was analyzed using flow cytometry. Biodistribution and brain delivery of intravenously injected control and RVG-modified EVs in wild-type mice were examined using ex vivo fluorescent imaging. Results Here we report that an RVG-Lamp2B-HA expression cassette was knocked into the AAVS1 safe harbor locus of a control hiPSC line using the CRISPR/Cas9-assisted homologous recombination. The RVG-edited iPSCs have normal karyotype, express pluripotency markers, and have differentiation potential. Expression of RVG-Lamp2B-HA was detected in total cell extracts as well as EVs derived from RVG-edited (vs. control) hiPSCs. The RVG-modified EVs enter neuronal cells via distinct endocytic pathways, compared with control EVs. The biodistribution study confirmed that EVs derived from RVG-edited hiPSCs possess higher brain delivery efficiency. Conclusion Taken together, we have established stable, genetically engineered hiPSCs for producing EVs with RVG expression, offering the improved ability for brain-targeted drug delivery.

Abstract It is not clear whether different radiation methods have different effects on enamel. The purpose of this study was to compare the effects of single and fractionated radiation on enamel and caries susceptibility and to provide an experimental basis for further study of radiation‑related caries. Thirty-six caries-free human third molars were collected and randomly divided into three groups (n = 12). Group1 (control group) was not exposed to radiation. Group 2 received single radiation with a cumulative dose of 70 Gy. Group 3 underwent fractionated radiation, receiving 2 Gy/day for 5 days followed by a 2-day rest period, for a total of 7 weeks with a cumulative dose of 70 Gy. Changes in microhardness, roughness, surface morphology, bacterial adhesion and ability of acid resistance of each group were tested. Scanning electron microscope revealed that the enamel surface in both radiation groups exhibited unevenness and cracks. Compared with the control group, microhardness and acid resistance of enamel decreased, while roughness and bacterial adhesion increased in both the single radiation and fractionated radiation groups. Compared with the single radiation group, the enamel surface microhardness and acid resistance decreased in the fractionated radiation group, while roughness and bacterial adhesion increased. Both single radiation and fractionated radiation resulting in changes in the physical and biological properties of enamel, with these changes being more pronounced in the fractionated radiation group. Therefore, fractionated radiation is recommended as a more suitable method for constructing a radiation‑related caries model in vitro.

Background: Photodynamic therapy (PDT) has shown good short-term efficacy in the treatment of oral leukoplakia (OLK). However, the malignant transformation of OLK was seldom evaluated in most PDT studies. Therefore, this study evaluated the effect of PDT on the risk of malignant transformation of OLK. Methods: Kaplan-Meier survival analysis, COX regression, and sensitivity analysis were used to evaluate the effects of PDT on the risk of malignant transformation of OLK. Subgroup analyses were performed to explore the role of PDT in OLK patients with different clinical characteristics. Results: OLK patients with older age (HR=1.032, P = 0.018) and non-homogeneous lesion (HR=2.104, P = 0.044) had higher risk of malignant transformation. Patients who had finished a complete course of PDT (HR=0.305, P = 0.006) had a significant lower risk of malignant transformation, while those who hadn't finished a complete course of PDT (HR=0.692, P = 0.352) cannot be considered to have such a protective effect. In the subgroup analyses, complete PDT course showed a significant protective effect on malignant transformation of OLK in patients with female sex, no smoking or drinking habits, non-homogeneous lesions, lesions on oral mucosa outside the dangerous region, and any grade of epithelial dysplasia. Conclusions: A complete course of PDT could significantly reduce the risk of malignant transformation of OLK, especially in those patients with risk factors of malignant transformation.

Abstract Since their inception, frequency combs generated in microresonators, known as microcombs, have sparked significant scientific interests. Among the various applications leveraging microcombs, soliton microcombs are often preferred due to their inherent mode-locking capability. However, this choice introduces additional system complexity because an initialization process is required. Meanwhile, despite the theoretical understanding of the dynamics of other comb states, their practical potential, particularly in applications like sensing where simplicity is valued, remains largely untapped. Here, we demonstrate controllable generation of sub-combs that bypasses the need for accessing bistable regime. And in a graphene-sensitized microresonator, the sub-comb heterodynes produce stable, accurate microwave signals for high-precision gas detection. By exploring the formation dynamics of sub-combs, we achieved 2 MHz harmonic comb-to-comb beat notes with a signal-to-noise ratio (SNR) greater than 50 dB and phase noise as low as − 82 dBc/Hz at 1 MHz offset. The graphene sensitization on the intracavity probes results in exceptional frequency responsiveness to the adsorption of gas molecules on the graphene of microcavity surface, enabling detect limits down to the parts per billion (ppb) level. This synergy between graphene and sub-comb formation dynamics in a microcavity structure showcases the feasibility of utilizing microcombs in an incoherent state prior to soliton locking. It may mark a significant step toward the development of easy-to-operate, systemically simple, compact, and high-performance photonic sensors. Graphical Abstract

Background: The treatment of oral leukoplakia (OLK) with aminolaevulinic acid photodynamic therapy (ALA-PDT) is widespread. Nonetheless, there is variation in efficacy. Therefore, this study constructed a model for predicting the short-term efficacy and recurrence of OLK after ALA-PDT. Methods: The short-term efficacy and recurrence of ALA-PDT were calculated by statistical analysis, and the relevant influencing factors were analyzed by Logistic regression and COX regression model. Finally, prediction models for total response (TR) rate, complete response (CR) rate and recurrence in OLK patients after ALA-PDT treatment were established. Features from pathology sections were extracted using deep learning autoencoder and combined with clinical variables to improve prediction performance of the model. Results: The logistic regression analysis showed that the non-homogeneous (OR: 4.911, P: 0.023) OLK and lesions with moderate to severe epithelial dysplasia (OR: 4.288, P: 0.042) had better short-term efficacy. The area under receiver operating characteristic curve (AUC) of CR, TR and recurrence predict models after the ALA-PDT treatment of OLK patients is 0.872, 0.718, and 0.564, respectively. Feature extraction revealed an association between inflammatory cell infiltration in the lamina propria and recurrence after PDT. Combining clinical variables and deep learning improved the performance of recurrence model by more than 30 %. Conclusions: ALA-PDT has excellent short-term efficacy in the management of OLK but the recurrence rate was high. Prediction model based on clinicopathological characteristics has excellent predictive effect for short-term efficacy but limited effect for recurrence. The use of deep learning and pathology images greatly improves predictive value of the models.

Background: The evidence on the association between cobalamin (Cbl) and aging or relevant outcomes is limited and controversial. We aimed to investigate the relationships between cobalamin intake- and function-related biomarkers and biological aging. Methods: The study encompassed 22,812 participants aged 20 years and older from the National Health and Nutrition Examination Survey. A panel of biomarkers or algorithms was used to assess biological aging, including Klemera–Doubal Age Acceleration (KDMAccel), Phenotypic age acceleration (PhenoAgeAccel), telomere length, α-Klotho, and PhenoAge advancement. Weighted generalized linear regression analysis was used to assess the associations between cobalamin-intake biomarkers (serum cobalamin, cobalamin intake from food, cobalamin supplement use, serum methylmalonic acid [MMA], and homocysteine [Hcy]) and function-related biomarkers (functional cobalamin deficiency and cobalamin insensitivity index). Results: Among the 22,812 individuals, the weighted mean (SE) age was 48.3 (0.2) years and 48.0% were males. Unexpectedly, serum and dietary cobalamin as well as serum MMA and Hcy levels were positively associated with most indicators of biological aging. Cobalamin sensitivity was assessed by the combination of binary Cbllow/high and MMAlow/high or Hcylow/high (cutoff values: 400 pg/mL for cobalamin, 250 nmol/L for MMA, and 12.1 μmol/l for Hcy) and a newly constructed cobalamin insensitivity index (based on the multiplicative term of serum cobalamin and serum MMA or Hcy). The multivariable-adjusted β (95%CIs) of KDMAccel in the MMAlowCbllow, MMAlowCblhigh, MMAhighCbllow, and MMAhighCblhigh groups were reference, 0.27 (0.03 to 0.51), 0.85 (0.41 to 1.29), and 7.97 years (5.77 to 10.17) respectively, which were consistent for the combination of serum Hcy and cobalamin. Both cobalamin insensitivity indices were robustly associated with biological aging acceleration in a dose-response pattern (each p

Background Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease characterized by malformation of the bilateral great toes and progressive heterotopic ossification. The clinical features of FOP occur due to dysfunction of the bone morphogenetic protein (BMP) signaling pathway induced by the mutant activin A type I receptor/activin‐like kinase‐2 (ACVR1/ALK2) which contributes to the clinical features in FOP. Dysregulation of the BMP signaling pathway causes the development of osteochondroma. Poor awareness of the association between FOP and osteochondromas always results in misdiagnosis and unnecessary invasive operation. Case Presentation In this study, we present a case of classical FOP involving osteochondroma. An 18‐year‐old male adolescent, born with deformity of bilateral big toes, complained multiple masses on his back for 1 year. The mass initially emerged with a tough texture and did not cause pain. It was misdiagnosed as an osteochondroma. After two surgeries, the masses became hard and spread around the entire back region. Meanwhile, extensive heterotopic ossification was observed around the back, neck, hip, knee, ribs, and mandible during follow‐up. Osteochondromas were observed around the bilateral knees. No abnormalities were observed in the laboratory blood test results. Whole exome sequencing revealed missense mutation of ACVR1/ALK2 (c.617G > A; p.R206H) in the patient and confirmed the diagnosis of FOP. Conclusion In summary, classical FOP always behaves as a bilateral deformity of the big toes, as well as progressive ectopic ossification and osteochondromas in the distal femur and proximal tibia. An understanding of the association between osteochondromas and FOP aids in diagnosis and avoids unnecessary invasive management in patients.

As one of the most widely used personal protective equipment (PPE), body armors play an important role in protecting the human body from the high-velocity impact of bullets or projectiles. The body torso and critical organs of the wear may suffer severe behind-armor blunt trauma (BABT) even though the impactor is stopped by the body armor. A type of novel composite material through incorporating shear stiffening gel (STG) into ethylene-vinyl acetate (EVA) foam is developed and used as buffer layers to reduce BABT. In this paper, the protective performance of body armors composed of fabric bulletproof layers and a buffer layer made of foam material is investigated both experimentally and numerically. The effectiveness of STG-modified EVA in damage relief is verified by ballistic tests. In parallel with the experimental study, numerical simulations are conducted by LS-DYNA® to investigate the dynamic response of each component and capture the key mechanical parameters, which are hardly obtained from field tests. To fully describe the material behavior under the transient impact, the selected constitutive models take the failure and strain rate effect into consideration. A good agreement between the experimental observations and numerical results is achieved to prove the validity of the modelling method. The tests and simulations show that the impact-induced deformation on the human body is significantly reduced by using STG-modified EVA as the buffering material. The improvement of protective performance is attributed to better dynamic properties and more outstanding energy absorption capability of the composite foam.

Abstract Ice-and-snow tourism (IST) is central to the Chinese ice-and-snow economy and can help achieve the green transformation and expansion of the Chinese economy. However, IST has not been defined conclusively in China. In this study, the IST concept was analyzed, and the growth of both tourism types was described using an Event–Time–Space comprehensive analysis method. Two temporal phases with large increases were highlighted in both tourisms. The factors promoting their increases were analyzed from market demand, the Beijing 2022 Olympics Winter Games, and scientific and technological developments for ice and snow. The 2020–2021 decrease in IST was primarily attributed to the COVID-19 pandemic. In addition, IST has dual challenges related to natural and socioeconomic factors. Climate warming has a long-term adverse effect on IST, particularly on glacier tourism. Traditional outdoor skiing tourism in Northeast China (NEC) may also be affected by more competition owing to increased ski tourism in the pan-Beijing-Tianjin-Hebei region, the Xinjiang Uygur Autonomous Region (XJUAR) and Southern China, as well as by the development of indoor skiing and ice/snow entertainment. These natural and socioeconomic factors currently limit the ability of IST to promote socioeconomic development in alpine areas, particularly in western China. However, there are many opportunities for future IST growth, including warmed comfort climate at high altitudes in the NEC, XJUAR and the Qinghai-Tibet Plateau, major glacier resource potentials, and IST development driven by policies. The findings of this study provide important information for decision-makers and investors in IST and its related industries.

Spinocerebellar ataxia type 12 (SCA12) is caused by a CAG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of protein phosphatase 2A (PP2A); while normal alleles carry 4 to 31 triplets, the disease alleles carry 43 to 78 triplets. Here, by CRISPR/Cas9n genome editing, we have generated a human heterozygous SCA12 iPSC line with 73 triplets for the mutant allele. The heterozygous SCA12 iPSCs have normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

BackgroundAccurate tumor target contouring and T staging are vital for precision radiation therapy in nasopharyngeal carcinoma (NPC). Identifying T-stage and contouring the Gross tumor volume (GTV) manually is a laborious and highly time-consuming process. Previous deep learning-based studies have mainly been focused on tumor segmentation, and few studies have specifically addressed the tumor staging of NPC.ObjectivesTo bridge this gap, we aim to devise a model that can simultaneously identify T-stage and perform accurate segmentation of GTV in NPC.Materials and methodsWe have developed a transformer-based multi-task deep learning model that can perform two tasks simultaneously: delineating the tumor contour and identifying T-stage. Our retrospective study involved contrast-enhanced T1-weighted images (CE-T1WI) of 320 NPC patients (T-stage: T1-T4) collected between 2017 and 2020 at our institution, which were randomly allocated into three cohorts for three-fold cross-validations, and conducted the external validation using an independent test set. We evaluated the predictive performance using the area under the receiver operating characteristic curve (ROC-AUC) and accuracy (ACC), with a 95% confidence interval (CI), and the contouring performance using the Dice similarity coefficient (DSC) and average surface distance (ASD).ResultsOur multi-task model exhibited sound performance in GTV contouring (median DSC: 0.74; ASD: 0.97 mm) and T staging (AUC: 0.85, 95% CI: 0.82–0.87) across 320 patients. In early T category tumors, the model achieved a median DSC of 0.74 and ASD of 0.98 mm, while in advanced T category tumors, it reached a median DSC of 0.74 and ASD of 0.96 mm. The accuracy of automated T staging was 76% (126 of 166) for early stages (T1-T2) and 64% (99 of 154) for advanced stages (T3-T4). Moreover, experimental results show that our multi-task model outperformed the other single-task models.ConclusionsThis study emphasized the potential of multi-task model for simultaneously delineating the tumor contour and identifying T-stage. The multi-task model harnesses the synergy between these interrelated learning tasks, leading to improvements in the performance of both tasks. The performance demonstrates the potential of our work for delineating the tumor contour and identifying T-stage and suggests that it can be a practical tool for supporting clinical precision radiation therapy.

Introduction: Rhubarb is a frequently used and beneficial traditional Chinese medicine. Wild resources of these plants are constantly being depleted, meaning that rhubarb products have been subjected to an unparalleled level of adulteration. Consequentially, reliable technology is urgently required to verify the authenticity of rhubarb raw materials and commercial botanical drugs.Methods: In this study, the barcode-DNA high-resolution melting (Bar-HRM) method was applied to characterize 63 rhubarb samples (five Polygonaceae species: Rheum tanguticum, Rh. palmatum, Rh. officinale, Rumex japonicus and Ru. sp.) and distinguish the rhubarb contents of 24 traditional Chinese patent medicine (TCPM) samples. Three markers, namely ITS2, rbcL and psbA-trnH, were tested to assess the candidate DNA barcodes for their effectiveness in distinguishing rhubarb from its adulterants. A segment from ITS2 was selected as the most suitable mini-barcode to identify the botanical drug rhubarb in TCPMs. Then, rhubarbs and TCPM samples were subjected to HRM analysis based on the ITS2barcode.Results: Among the tested barcoding loci, ITS2 displayed abundant sites of variation and was effective in identifying Polygonaceae species and their botanical origins. HRM analysis based on the ITS2 mini-barcode region successfully distinguished the authenticity of five Polygonaceae species and eight batches of TCPMs. Of the 18 TCPM samples, 66.7 % (12 samples) were identified as containing Rh. tanguticum or Rh. officinale. However, 33.3 % were shown to consist of adulterants.Conclusions: These results demonstrated that DNA barcoding combined with HRM is a specific, suitable and powerful approach for identifying rhubarb species and TCPMs, which is crucial to guaranteeing the security of medicinal plants being traded internationally.

BackgroundAlthough epidemiological evidence implies a link between exposure to particulate matter (PM) and Alzheimer’s disease (AD), establishing causality remains a complex endeavor. In the present study, we used Mendelian randomization (MR) as a robust analytical approach to explore the potential causal relationship between PM exposure and AD risk. We also explored the potential associations between PM exposure and other neurodegenerative diseases.MethodsDrawing on extensive genome-wide association studies related to PM exposure, we identified the instrumental variables linked to individual susceptibility to PM. Using summary statistics from five distinct neurodegenerative diseases, we conducted two-sample MR analyses to gauge the causal impact of PM on the risk of developing these diseases. Sensitivity analyses were undertaken to evaluate the robustness of our findings. Additionally, we executed multivariable MR (MVMR) to validate the significant causal associations identified in the two-sample MR analyses, by adjusting for potential confounding risk factors.ResultsOur MR analysis identified a notable association between genetically predicted PM2.5 (PM with a diameter of 2.5 μm or less) exposure and an elevated risk of AD (odds ratio, 2.160; 95% confidence interval, 1.481 to 3.149; p

In recent years, the ultra-low frequency oscillation of power system caused by hydropower units has occurred frequently. It is very important to study the ultra-low frequency oscillation characteristics of hydropower stations for the stable operation of power system. It is worth further research on how to determine the system stability margin in engineering practice. Based on the established model of single machine system with load, the analysis of the characteristic equation of closed-loop transfer function of single machine system shows that the ultra-low frequency oscillation will occur when the ratio of proportional parameter to integral parameter is too small. Based on the single machine with load system model and the equivalent single machine with load model of multi machine system, the ultra-low frequency oscillation mode of the system is analyzed by eigenvalue analysis method. According to the requirements of the damping ratio index, the security domain of the system ultra-low frequency oscillation is constructed, and the risk and stability margin of the system ultra-low frequency oscillation are evaluated by the characteristic values of the system ultra-low frequency oscillation mode.

In order to accurately predict the primary frequency modulation capability of power system when frequency deviation occurs, a method for predicting primary frequency modulation performance of power system based on improved neural network with thought evolution algorithm (MEA) is presented. Nine-dimensional parameters, such as frequency deviation before and after disturbance, system backup capacity, load level, mechanical power and electrical power, are selected as input eigenvalues, and the output is the system power change curve. This paper takes CEPRI36v8 system as an example of simulation, obtains the primary frequency modulation curve of the system by setting the shear load disturbance with PSASP, uses the disturbance data and the primary frequency modulation response data as training set, test set and validation set data, trains the prediction model of primary frequency modulation capability based on MEA-BP, and finds the prediction error is about 0.5% compared with the actual data, which proves that the proposed method can accurately and quickly predict the primary frequency modulation capability after the frequency deviation of the power network. This method can assist power dispatcher to analyze the primary frequency modulation response of power grid after power disturbance.

Rhubarb is a significant medicinal herb in China. Its adulteration or fabrication is common in the market. Consequently, it is necessary to establish a comprehensive identification method to accurately identify genuine rhubarb and its adulterants. In this study, the sequences of chloroplast genes rps3-rpl22 and rpl16 from three genuine rhubarbs (Rheum tanguticum, Rh. palmatum and Rh. officinale) and their adulterants (Rumex japonicus and Rumex spp.) were amplified, sequenced and subjected to genetic analyses. The genetic distances for rps3-rpl22 and rpl16 between genuine rhubarbs and their adulterants showed that there was an evident barcoding gap, which allowed the adulterants to be distinguished from the genuine rhubarbs, as demonstrated by a neighbor joining tree. Additionally, Rh. officinale could be distinguished from the other two genuine rhubarbs. The anthraquinone, sennoside, polysaccharide and protein contents were analyzed in seven rhubarbs using high-performance liquid chromatography and ultraviolet spectrophotometry. Cluster and principal component analyses results showed that Rh. tanguticum and Rh. palmatum could be effectively distinguished. The study suggests that DNA barcoding based on rps3-rpl22 and rpl16 sequences coupled with multiple-indicator quantification can be successfully applied to identify rhubarb species and distinguish among the three genuine rhubarbs, and this can provide a scientific foundation for rhubarb quality assurance.

Aptamers are nucleic acid sequences that specifically bind with target molecules and are vital to applications such as biosensing, drug development, disease diagnostics, etc. The traditional selection procedure of aptamers is based on the Systematic Evolution of Ligands by an Exponential Enrichment (SELEX) process, which relies on repeating cycles of screening and amplification. With the rapid development of aptamer applications, RNA and XNA aptamers draw more attention than before. But their selection is troublesome due to the necessary reverse transcription and transcription process (RNA) or low efficiency and accuracy of enzymes for amplification (XNA). In light of this, we review the recent advances in aptamer selection methods and give an outlook on future development in a non-SELEX approach, which simplifies the procedure and reduces the experimental costs. We first provide an overview of the traditional SELEX methods mostly designed for screening DNA aptamers to introduce the common tools and methods. Then a section on the current screening methods for RNA and XNA is prepared to demonstrate the efforts put into screening these aptamers and the current difficulties. We further predict that the future trend of aptamer selection lies in non-SELEX methods that do not require nucleic acid amplification. We divide non-SELEX methods into an immobilized format and non-immobilized format and discuss how high-resolution partitioning methods could facilitate the further improvement of selection efficiency and accuracy.

Endometriosis (EMs) is a prevalent gynecological disorder characterized by the growth of uterine tissue outside the uterine cavity, causing debilitating symptoms and infertility. Despite its prevalence, the exact mechanisms behind EMs development remain incompletely understood. This article presents a comprehensive overview of the relationship between gut microbiota imbalance and EMs pathogenesis. Recent research indicates that gut microbiota plays a pivotal role in various aspects of EMs, including immune regulation, generation of inflammatory factors, angiopoietin release, hormonal regulation, and endotoxin production. Dysbiosis of gut microbiota can disrupt immune responses, leading to inflammation and impaired immune clearance of endometrial fragments, resulting in the development of endometriotic lesions. The dysregulated microbiota can contribute to the release of lipopolysaccharide (LPS), triggering chronic inflammation and promoting ectopic endometrial adhesion, invasion, and angiogenesis. Furthermore, gut microbiota involvement in estrogen metabolism affects estrogen levels, which are directly related to EMs development. The review also highlights the potential of gut microbiota as a diagnostic tool and therapeutic target for EMs. Interventions such as fecal microbiota transplantation (FMT) and the use of gut microbiota preparations have demonstrated promising effects in reducing EMs symptoms. Despite the progress made, further research is needed to unravel the intricate interactions between gut microbiota and EMs, paving the way for more effective prevention and treatment strategies for this challenging condition.

Abstract Objective The purpose of this retrospective study was to investigate and compare the clinical, radiographic, pathological, pathogenesis, and therapeutic features of simple bone cysts (SBCs) and aneurysmal bone cysts (ABCs) of the jaw. Methods 35 patients with SBCs and 6 patients with ABCs who received treatment at the Department of Oral and Maxillofacial Surgery, Zhejiang University School of Medicine from 2017 to 2022 were followed up and reviewed retrospectively. Results The study included 41 patients, accounting for 2.14% of all jaw pathologies, with 35 patients having SBCs and 6 patients having ABCs; their average ages were 26.63 ± 13.62 years and 17.83 ± 7.88 years, respectively. The prevalence of SBC and ABC did not differ significantly by sex. The mandible was the most vulnerable area to be involved. Only 5.71% (2/35) of patients with SBCs and 16.7% (1/6) of patients with ABCs reported histories of previous trauma in the same region of the pseudocysts. A total of 42.86% (15/35) of SBC cases and 66.67% (4/6) of ABC cases had malocclusions. The radiographic features of pseudocysts varied in shape, were associated with the root, and unilocular or multilocular. All patients had curettage with or without bone graft or substitute implantation, and recurrences did not occur in 94.29% (33/35) of SBC patients and 100% (6/6) of ABC patients after a mean follow-up time of 26.23 ± 15.47 months and 21.67 ± 19.75 months, respectively. Conclusions Pseudocysts, including SBCs and ABCs, are benign osteolytic lesions without an epithelial lining that occur occasionally in the jaw, mostly in adolescents and young adults, and their incidence did not significantly differ by sex. The most vulnerable site of involvement is the mandible, and they are generally not overtly aggressive. Trauma has a less significant role in pseudocysts, but minor trauma, such as malocclusion, has the potential to influence pseudocyst development. The clinical presentation of pseudocysts lacks specificity, and most patients are asymptomatic and found incidentally during radiographs. Dental panoramic radiographs and CBCT cannot accurately distinguish between SBC and ABC, and the final diagnosis depends on pathological diagnosis. Curettage combined with bone grafting is currently the best treatment for both, with a 5.71% (2/35) recurrence rate for SBC and no recurrence found for ABC.

Abstract Regional facial image synthesis conditioned on a semantic mask has achieved great attention in the field of computational visual media. However, the appearances of different regions may be inconsistent with each other after performing regional editing. In this paper, we focus on harmonized regional style transfer for facial images. A multi-scale encoder is proposed for accurate style code extraction. The key part of our work is a multi-region style attention module. It adapts multiple regional style embeddings from a reference image to a target image, to generate a harmonious result. We also propose style mapping networks for multi-modal style synthesis. We further employ an invertible flow model which can serve as mapping network to fine-tune the style code by inverting the code to latent space. Experiments on three widely used face datasets were used to evaluate our model by transferring regional facial appearance between datasets. The results show that our model can reliably perform style transfer and multi-modal manipulation, generating output comparable to the state of the art.

Abstract Recently, the major challenge in treating osteosarcoma patients is the metastatic disease, most commonly in the lungs. However, the underlying mechanism of recurrence and metastasis of osteosarcoma after surgical resection of primary tumor remains unclear. This study aims to investigate whether the pulmonary metastases characteristic of osteosarcoma is associated with surgical treatment and whether surgery contributes to the formation of pre‐metastatic niche in the distant lung tissue. In the current study, the authors observe the presence of circulating tumor cells in patients undergoing surgical resection of osteosarcoma which is correlated to tumor recurrence. The pulmonary infiltrations of neutrophils and Gr‐1+ myeloid cells are characterized to form a pre‐metastatic niche upon the exposure of circulating tumor cells after surgical resection. It is found that mitochondrial damage‐associated molecular patterns released from surgical resection contribute to the formation of pre‐metastatic niche in lung through IL‐1β secretion. This study reveals that surgical management for osteosarcoma, irrespective of the primary tumor, might promote the formation of postoperative pre‐metastatic niche in lung which is with important implications for developing rational therapies during peri‐operative period.

This study presents a unified algebraic model based on the multi-layer mixing length to quantify the mean velocity of the transitional and fully turbulent boundary layer. Mean velocity profiles from direct numerical simulations of the zero-pressure-gradient boundary layer are being investigated. By using the gradient descent method, three parameters in the multi-layer mixing length are optimized and determined at each streamwise location. It turns out that the multi-layer mixing length model describes mean velocity profiles well, and the corresponding relative deviation is around 2%. This value is not less than, or even better than, the compared Nickels’ model [Nickels, J. Fluid Mech. 521, 217–239 (2004)]. Moreover, the variation of the three optimal parameters with Rex is similar to the streamwise development of the friction coefficient. This similarity offers a supplementary way to comprehend the transition process. The results confirm that the multi-layer length function is suitable for modeling transitional boundary layers.

Abstract The transforming growth factor beta (TGF-β) is a crucial cytokine that get increasing concern in recent years to treat human diseases. This signal controls multiple cellular responses during embryonic development and tissue homeostasis through canonical and/or noncanonical signaling pathways. Dysregulated TGF-β signal plays an essential role in contributing to fibrosis via promoting the extracellular matrix deposition, and tumor progression via inducing the epithelial-to-mesenchymal transition, immunosuppression, and neovascularization at the advanced stage of cancer. Besides, the dysregulation of TGF-beta signal also involves in other human diseases including anemia, inflammatory disease, wound healing and cardiovascular disease et al. Therefore, this signal is proposed to be a promising therapeutic target in these diseases. Recently, multiple strategies targeting TGF-β signals including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors targeting ligand–receptor signaling pathways, antisense oligonucleotides to disrupt the production of TGF-β at the transcriptional level, and vaccine are under evaluation of safety and efficacy for the forementioned diseases in clinical trials. Here, in this review, we firstly summarized the biology and function of TGF-β in physiological and pathological conditions, elaborated TGF-β associated signal transduction. And then, we analyzed the current advances in preclinical studies and clinical strategies targeting TGF-β signal transduction to treat diseases.

Objective: The main reasons for the poor prognoses of pancreatic adenocarcinoma (PA) patients are rapid early-stage progression, advanced stage metastasis, and chemotherapy resistance. Identification of novel diagnostic and prognostic biomarkers of PA is therefore urgently needed. Methods: Three mRNA microarray datasets were obtained from the Gene Expression Omnibus database to select differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for hub genes were performed using DAVID. Correlations between expression levels of hub genes and cancer-infiltrating immune cells were investigated by TIMER. Cox proportional hazard regression analyses were also performed. Serum hub genes were screened using the HPA platform and verified for diagnostic value using ELISAs. Results: We identified 59 hub genes among 752 DEGs. GO analysis indicated that these 59 hub genes were mainly involved in the defense response to viruses and the type I interferon signaling pathway. We also discovered that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment. Additionally, DLGAP5 mRNA might be used as an independent risk factor for the prognoses of PA patients. Furthermore, the protein encoded by ISG15, which exists in peripheral blood, was validated as a potential diagnostic biomarker that distinguished PA patients from healthy controls (area under the curve: 0.902, 95% confidence interval: 0.819–0.961). Conclusions: Our study suggested that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment, while DLGAP5 mRNA expression might be an independent risk factor for the survival prognoses of PA patients. Moreover, ELISAs indicated that serum ISG15 could be a potential novel diagnostic biomarker for PA.

In the attitude control of quadrotor drones, it is necessary to cope with matched and unmatched disturbances caused by nonlinear couplings, model uncertainties, and external disturbances, as well as to consider the effects caused by actuator dynamics. Aiming to accurately track desired trajectories under the above factors, a novel control strategy is proposed by combining a state feedback control with a high-order sliding mode disturbance observer (HOSMDO). The HOSMDO is motivated by the higher-order sliding mode (HOSM) differentiator and extended state observer (ESO) technique, allowing for the exact robust estimation of disturbances and their arbitrary order derivatives in finite time. Unlike the control schemes based on back-stepping methods, the proposed controller is designed with a holistic mindset. Specifically, a baseline feedback framework is constructed firstly, and the disturbances and relevant derivatives required for the baseline framework are then generated by the HOSMDOs to obtain the overall control scheme. The stability conditions of the controllers designed with and without considering the actuator dynamics are analyzed separately. In the latter case, the actuator dynamics imposed additional constraints on the control parameters. Numerical simulations validate the effectiveness of the proposed control strategy.

Abstract Immunotherapies like the adoptive transfer of gene-engineered T cells and immune checkpoint inhibitors are novel therapeutic modalities for advanced cancers. However, some patients are refractory or resistant to these therapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. Immunosuppressive cells such as myeloid-derived suppressive cells, tumor-associated macrophages, tumor-associated neutrophils, regulatory T cells (Tregs), and tumor-associated dendritic cells are critical factors correlated with immune resistance. In addition, cytokines and factors secreted by tumor cells or these immunosuppressive cells also mediate the tumor progression and immune escape of cancers. Thus, targeting these immunosuppressive cells and the related signals is the promising therapy to improve the efficacy of immunotherapies and reverse the immune resistance. However, even with certain success in preclinical studies or in some specific types of cancer, large perspectives are unknown for these immunosuppressive cells, and the related therapies have undesirable outcomes for clinical patients. In this review, we comprehensively summarized the phenotype, function, and potential therapeutic targets of these immunosuppressive cells in the tumor microenvironment.

Abstract The development of social networking services (SNSs) revealed a surge in image sharing. The sharing mode of multi-page photo collage (MPC), which posts several image collages at a time, can often be observed on many social network platforms, which enables uploading images and arrangement in a logical order. This study focuses on the construction of MPC for an image collection and its formulation as an issue of joint optimization, which involves not only the arrangement in a single collage but also the arrangement among different collages. Novel balance-aware measurements, which merge graphic features and psychological achievements, are introduced. Non-dominated sorting genetic algorithm is adopted to optimize the MPC guided by the measurements. Experiments demonstrate that the proposed method can lead to diverse, visually pleasant, and logically clear MPC results, which are comparable to manually designed MPC results.

Abstract Transformers, the dominant architecture for natural language processing, have also recently attracted much attention from computational visual media researchers due to their capacity for long-range representation and high performance. Transformers are sequence-to-sequence models, which use a self-attention mechanism rather than the RNN sequential structure. Thus, such models can be trained in parallel and can represent global information. This study comprehensively surveys recent visual transformer works. We categorize them according to task scenario: backbone design, high-level vision, low-level vision and generation, and multimodal learning. Their key ideas are also analyzed. Differing from previous surveys, we mainly focus on visual transformer methods in low-level vision and generation. The latest works on backbone design are also reviewed in detail. For ease of understanding, we precisely describe the main contributions of the latest works in the form of tables. As well as giving quantitative comparisons, we also present image results for low-level vision and generation tasks. Computational costs and source code links for various important works are also given in this survey to assist further development.

BackgroundOsteosarcoma commonly develops during childhood and adolescence. Only one-third of osteosarcoma patients have been clinically detected over the age of 40 years, and the survivorship of those patients is quite dismal. Apatinib, a novel multitarget angiogenesis inhibitor, has shown a short-term efficacy in advanced or metastatic osteosarcoma. However, the data for apatinib in the older patients with osteosarcoma are limited. We aim to evaluate the efficacy and safety of apatinib combined with chemotherapy versus apatinib monotherapy in the treatment of patients over 40 years old with metastatic or unresectable osteosarcoma.MethodsWe retrospectively analyzed the patients with metastatic osteosarcoma who were treated with apatinib monotherapy or apatinib combined with chemotherapy between May 2015 and December 2018 in the Department of Orthopedics at West China Hospital. Apatinib was initially administered with a dose of 500 mg daily, and the dose was adjusted according to toxicity. The objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were investigated. The treatment-related adverse events and the safety of apatinib were also documented.ResultsA total of 45 patients (28 men, 17 women) with metastatic or unresectable osteosarcoma were finally included, and 41 patients received at least one cycle of treatment and were evaluable for efficacy. Of 41 patients, 24 who were intolerant to intensive chemotherapy or have failed standard chemotherapy received apatinib monotherapy, and 17 patients were treated with apatinib plus chemotherapy. The median PFS and median OS were longer in the group treated with apatinib combined with chemotherapy than those of the apatinib monotherapy group (5.6 months vs. 2.6 months; 15.1 months vs. 9.7 months). Moreover, the median DOR was significantly prolonged in the group treated with apatinib combined with chemotherapy compared with that in the monotherapy group.ConclusionApatinib demonstrated promising activity in patients over 40 years old with metastatic or unresectable osteosarcoma. The combination of apatinib and chemotherapy conferred a durable response compared with apatinib monotherapy, which might be an alternative therapeutic strategy for the management of osteosarcoma in older patients.

Purpose: Osteosarcoma is the most common primary malignancy of bone with a dismal prognosis for patients with pulmonary metastases. Evaluation of osteosarcoma prognosis would facilitate the prognosis consultation as well as the development of personalized treatment decisions. However, there is limited effective prognostic predictor at present. Lung Immune Prognostic Index (LIPI) is a novel prognostic factor in pulmonary cancers, whereas, the prognostic significance of LIPI in osteosarcoma has not yet been well clarified. In this study, we firstly explore the prognostic role of LIPI and further modify this predictive model in osteosarcoma.Patients and methods: A retrospectively study was conducted at Musculoskeletal Tumor Center of West China Hospital between January 2016 and January 2021. Hematological factors and clinical features of osteosarcoma patients were collected and analyzed. The area under curve (AUC) and optimal cuff-off of each single hematological factor was calculated.Results: In this study, lactate dehydrogenase (LDH), derived neurtrophil to lymphocyte ratio (dNLR), and Hydroxybutyrate dehydrogenase (HBDH) have higher AUC values. LIPI was composed of LDH and dNLR and was further modified by combing the HBDH, forming the osteosarcoma immune prognostic index (OIPI). OIPI divided 223 osteosarcoma patients divided into four groups, none, light, moderate, and severe (p < 0.0001). OIPI has a higher AUC value than LIPI and other hematological indexes in t-ROC curve. According to the univariate and multivariate analysis, pathological fracture, metastasis, NLR, platelet–lymphocyte ratio (PLR), and OIPI were associated with the prognosis; and metastasis and OIPI were independent prognostic factors of osteosarcoma patients. An OIPI-based nomogram was also established and could predict the 3-year and 5-year overall survival. In addition, OIPI was also revealed correlated with metastasis and pathological fracture in osteosarcoma.Conclusion: This study first explore the prognostic significance of LIPI in osteosarcoma patients. In addition, we developed a modified LIPI, the OIPI, for osteosarcoma patients. Both the LIPI and OIPI could predict the overall survival of osteosarcoma patients well, while OIPI may be more suitable for osteosarcoma patients. In particular, OIPI may have the ability to identify some high-risk patients from clinically low-risk patients.

Stylish fonts are widely utilized in social networks, driving research interest in stylish Chinese font generation. Most existing methods for generating Chinese characters rely on GAN-based deep learning approaches. However, persistent issues of mode collapse and missing structure in CycleGAN-generated results make font generation a formidable task. This paper introduces a unique semi-supervised model specifically designed for generating stylish Chinese fonts. By incorporating a small amount of paired data and stroke encoding as information into CycleGAN, our model effectively captures both the global structural features and local characteristics of Chinese characters. Additionally, an attention module has been added and refined to improve the connection between strokes and character structures. To enhance the model’s understanding of the global structure of Chinese characters and stroke encoding reconstruction, two loss functions are included. The integration of these components successfully alleviates mode collapse and structural errors. To assess the effectiveness of our approach, comprehensive visual and quantitative assessments are conducted, comparing our method with benchmark approaches on six diverse datasets. The results clearly demonstrate the superior performance of our method in generating stylish Chinese fonts.

Abstract The two‐dimensional (2D) ultrathin titanium dioxide (TiO2) nanosheets with large specific surface area and fast electron transfer are successfully fabricated by using P123 as a soft template during a conventional hydrothermal process. Ultrathin structure improves the lifetime of the photogenerated electron and hole. The bandgap of the 2D materials is reduced with the calcination treatment. The TiO2 nanosheets calcined at 300°C exhibit higher photocatalytic activity in degradation of methylene blue and rhodamine B under visible light irradiation, and excellent photoelectrochemical performance allow them a wide use in energy and environmental applications.

BackgroundSingle nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibility loci and highlight potential risk factors.MethodsCAD-associated RNAm-SNPs were identified in the CARDIoGRAMplusC4D and UK Biobank genome-wide association studies. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Cell experiments and Mendelian randomization (MR) methods were applied to test whether the gene expression levels were associated with CAD.ResultsWe identified 81 RNAm-SNPs that were associated with CAD or acute myocardial infarction (AMI), including m6A-, m1A-, m5C-, A-to-I- and m7G-related SNPs. The m6A-SNPs rs3739998 in JCAD, rs148172130 in RPL14 and rs12190287 in TCF21 and the m7G-SNP rs186643756 in PVT1 were genome-wide significant. The RNAm-SNPs were associated with gene expression (e.g., MRAS, DHX36, TCF21, JCAD and SH2B3), and the expression levels were associated with CAD. Differential m6A methylation and differential expression in FTO-overexpressing human aorta smooth muscle cells and peripheral blood mononuclear cells of CAD patients and controls were detected. The RNAm-SNPs were associated with circulating levels of proteins with specific biological functions, such as blood coagulation, and the proteins (e.g., cardiotrophin-1) were confirmed to be associated with CAD and AMI in MR analyses.ConclusionThe present study identified RNAm-SNPs in CAD susceptibility genes, gene expression and circulating proteins as risk factors for CAD and suggested that RNA modification may play a role in the pathogenesis of CAD.

Endometriosis (EMs) is defined as the presence of tissue somewhat resembling endometrial glands and stroma outside the uterus; the retrograded endometrium grows in the peritoneal cavity and elicits fibrosis. Ferroptosis is a recently discovered form of programmed cell death, which is iron-dependent. The induction of ferroptosis has been found to participate in fibrosis. However, the relationship between EMs fibrosis and ferroptosis remains unknown. In this study, we confirmed that the iron content in ectopic stromal tissue in ovarian EMs is significantly increased. We explored the role of iron-induced ferroptosis in the pathogenesis of ovarian EMs fibrosis for the first time. We found that ferroptosis in ectopic tissues was significantly enhanced than that in eutopic tissues. Furthermore, we performed in vivo drug screening and found that ferroptosis induced by ferric ammonium citrate (FAC) could aggravate fibrosis. To clarify the mechanism of this process, the stromal composition of human uterine endometrium and endometrial tissue was characterized. Fibroblast-specific protein-1 was used for fibroblasts, smooth muscle actin alpha for myofibroblasts, and platelet-derived growth factor receptor beta (CD140b) for mesenchymal stromal cells (MSCs). The results demonstrated that the percentage of myofibroblasts was higher and the portion of MSCs was lower in ectopic endometrial stroma than those in eutopic endometrium. Moreover, the proportion of MSCs decreased significantly and the percentage of myofibroblasts increased considerably after FAC treatment in vitro. However, disruption of intracellular iron levels or ferroptosis via chelation of intracellular iron deferoxamine mesylate or ferroptosis inhibitor ferrostatin-1 could reverse this process, indicating that iron-induced ferroptosis plays a vital role in ovarian EMs fibrosis. Considering that iron accumulation can feed the Fenton reaction to generate unquenchable amounts of free radicals, causing ferroptosis and tissue damage and thereby contributing to fibrosis, we validated the underlying mechanism that excess iron can facilitate fibrotic responses. Collectively, these data provide evidence that supernumerary iron is a key regulator in promoting MSCs ferroptosis and inducing ovarian EMs fibrosis.

ObjectiveWe reported the long-term outcomes of transcatheter chemoembolization (TACE) for patients with late-stage or recurrent oral carcinoma.MethodsThis retrospective study enrolled 18 patients with late-stage or recurrent oral carcinoma between December 2015 and April 2021. The tumor-feeding artery was catheterized, and cisplatin/oxaliplatin and 5-FU/raltitrexed were infused with embolization using polyvinyl alcohol or gelatin sponge. Computed tomography was performed at about 1, 3, and 6 months after the procedure, and every 6 months after that. During the procedure and follow-up, procedure outcomes, complications, treatment efficacy, and overall survival were analyzed.ResultsA total of 31 sessions of TACE were performed, with a technical success rate of 100%. Of 12 patients combined with oral hemorrhage, two patients showed rebleeding 35 and 37 days later, with a clinical efficiency of hemostasis of 88.9%. Mild complications were observed in 11 patients (61.1%). Severe complications or procedure-related deaths were not observed during or after the procedure. The objective response rate and disease control rate were 20.0% and 86.7%, 38.5% and 61.5%, and 25.0% and 50.0% at 1, 3, and 6 months later, respectively. Seventeen patients (94.4%) were followed up, with a median duration of 37.8 months (IQR 22.3–56.8). Nine patients died of tumor progression, one died of massive rebleeding, and one died of severe lung infection. The median overall survival was 23.8 months.ConclusionTACE is a safe and effective procedure with minimal invasiveness for treating late-stage or recurrent oral carcinoma. TACE can be recommended as a palliative treatment, particularly for patients with oral hemorrhage.

Abstract Background Uncemented allograft prosthesis composite (APC) has been applied for tumorous bone defect reconstruction in the proximal femur. However, the long-term results are rarely reported. This study aimed to evaluate long-term outcomes of uncemented APC. Methods Eighteen patients who received uncemented APC reconstruction in the proximal femur after tumor resections were retrospectively reviewed. Results The average resection length was 110 mm (80–154) and the average follow-up was 106.7 months (65–141). Bone union achieved in all patients with an average duration of 7.6 months (5–10). The average HHS, MSTS score and gluteus medius strength at one-year follow-up were 88.0 (80–94), 25.2 (22–28) and 4 (3–5), respectively. While at the last follow-up, the HHS, MSTS score and gluteus medius strength were 83.0 (48–100), 24.0 (10–30) and 4 (2–5), respectively. Five intraoperative fractures were fixed with cerclage wires. Two postoperative periprosthetic and prosthetic fractures received a revision. Three local recurrent patients received a secondary surgery. One of these three lung metastatic patients underwent lung metastatic tumor resection. Another two patients were diagnosed with both bone and lung metastases, only one of them underwent amputation. Two greater trochanteric fractures received no treatment. There were10 severe, 3 moderate and 5 mild allograft resorptions without treatment. Conclusion Uncemented APC is a reliable reconstruction for neoplastic bone defect of the proximal femur, especially for the young patient who expected long-life expectancy and good function. Though allograft resorption and trochanteric fracture are the common complications, they seem no effect on the function.

We previously found that inhibition of p66Shc confers protection against hepatic stellate cell (HSC) activation during liver fibrosis. However, the effect of p66Shc on HSC proliferation, as well as the mechanism by which p66Shc is modulated, remains unknown. Here, we elucidated the effect of p66Shc on HSC proliferation and evaluated microRNA (miRNA)-p66Shc-mediated reactive oxidative species (ROS) generation in liver fibrosis. An in vivo model of carbon tetrachloride (CCl4)-induced liver fibrosis in rats and an LX-2 cell model were developed. p66Shc expression was significantly upregulated in rats with CCl4-induced liver fibrosis and in human fibrotic livers. Additionally, p66Shc knockdown in vitro attenuated mitochondrial ROS generation and HSC proliferation. Interestingly, p66Shc promoted HSC proliferation via β-catenin dephosphorylation in vitro. MicroRNA (miR)-203a-3p, which was identified by microarray and bioinformatics analyses, directly inhibited p66Shc translation and attenuated HSC proliferation in vitro. Importantly, p66Shc was found to play an indispensable role in the protective effect of miR-203a-3p. Furthermore, carnosic acid (CA), the major antioxidant compound extracted from rosemary leaves, protected against CCl4-induced liver fibrosis through the miR-203a-3p/p66Shc axis. Collectively, these results suggest that p66Shc, which is directly suppressed by miR-203a-3p, is a key regulator of liver fibrosis. This finding may lead to the development of therapeutic targets for liver fibrosis.

Quadrotor drone attitude tracking is inevitably affected by the combination of model uncertainties, external disturbances, and non-ideal actuator dynamics during stable flight and complex maneuvers. In order to achieve precise attitude control in these situations, a cascade-structured dynamic surface control (DSC) strategy is proposed based on an uncertainty and disturbance estimator (UDE), considering the actuator dynamics as represented by a first-order plus time-delay model. The DSC scheme is used to transform the original attitude dynamics system into a set of interconnected subsystems. On the one hand, the mismatched disturbances in the attitude kinematics and dynamics loops are converted into matched disturbances to accommodate the structural constraints of the UDE so that these disturbances, as well as the non-ideality caused by the actuator time delay, are estimated and compensated for by the approach. On the other hand, the “complexity explosion” problem is addressed by the first-order filter employed by DSC. The ultimate boundedness of the closed-loop system is proven while the parameter design constraints are provided. MATLAB Simulink simulations are conducted to demonstrate the desirability of considering actuator dynamics and to verify that the proposed control strategy can relax the constraints of the control parameters and enable a higher accuracy.

The vast majority of drug-induced liver injury is mainly attributed to acetaminophen (APAP) overdose. Salvianolic acid A (Sal A), a powerful water-soluble compound obtained from Salvia miltiorrhiza, has been confirmed to exert hepatoprotective effects. However, the beneficial effects and the exact mechanisms of Sal A on APAP-induced hepatotoxicity remain unclear. In this study, APAP-induced liver injury with or without Sal A treatment was examined in vitro and in vivo. The results showed that Sal A could alleviate oxidative stress and inflammation by regulating Sirtuin 1 (SIRT1). Furthermore, miR-485-3p could target SIRT1 after APAP hepatotoxicity and was regulated by Sal A. Importantly, inhibiting miR-485-3p had a hepatoprotective effect similar to that of Sal A on APAP-exposed AML12 cells. These findings suggest that regulating the miR-485-3p/SIRT1 pathway can alleviate oxidative stress and inflammation induced by APAP in the context of Sal A treatment.

Osteosarcoma (OS) is rare cancer with bimodal age distribution with peaks observed in children and young adults. Typically, OS is treated with pre-surgery neoadjuvant therapy, surgical excision, and post-surgery chemotherapy. However, the efficacy of treatment on disease prognosis and objective response is not currently optimal, often resulting in drug resistance; in turn, highlighting the need to understand mechanisms driving resistance to therapy in OS patients. Using Doxycycline (Dox)-sensitive and resistant variants of OS cells lines KHOS and U2OS, we found that the resistant variants KHOS-DR and U2OS-DR have significantly higher in vitro proliferation. Treating the Dox-sensitive KHOS/U2OS cells with exosomes isolated from KHOS-DR/U2OS-DR made them resistant to treatment with Dox in vitro and in vivo and enhanced tumor growth and progression, while decreasing overall survival. Expression of the long non-coding RNA (lncRNA) ANCR was significantly higher in the KHOS-DR and U2OS-DR variants. SiRNA-mediated knockdown of ANCR decreased in vitro proliferation, while increasing sensitivity to Dox treatment in the KHOS-DR/U2OS-DR cells. Expression of the exosomal lncRNA ANCR was critical for drug resistance and OS tumor progression in xenografts and was correlated to resistance to Adriamycin and overall survival is patients with OS. These results establish lncRNA ANCR as a critical mediator of resistance to therapy in OS patients, highlighting it as a potential therapeutic target in OS patients.

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS), with limited therapies available for metastatic disease. Here, we describe a case of a 30-year-old male with ES of the left knee and underwent surgery and radiation therapy for the primary disease. After 2 years, he had local recurrence and underwent extensive resection surgery; however, adjuvant chemotherapies were delayed due to recurrent wound infection. Nine months after the second surgery, progressive disease was confirmed after detection of metastases to the lungs and inguinal lymph nodes. Amputation was performed for the local recurrence, followed by inguinal lymph nodes dissection. Pazopanib was transiently administered but discontinued as a result of wound dehiscence. The tumour specimens were detected with unexpected high level of PD-L1 expression and tumoural infiltrating lymphocytes. Subsequently, he received camrelizumab 2.0 mg/kg every 21 days for 18 cycles with rapid remission of the pulmonary metastases. This promising response to camrelizumab indicates that immunotherapies may be an alternative choice for patients with metastatic ES in lung based on analysing the tumour immune microenvironment.

Abstract Surgical resection remains the mainstay treatment for solid cancers, especially for localized disease. However, the postoperative immunosuppression provides a window for cancer cell proliferation and awakening dormant cancer cells, leading to rapid recurrences or metastases. This immunosuppressive status after surgery is associated with the severity of surgical trauma since immunosuppression induced by minimally invasive surgery is less than that of an extensive open surgery. The systemic response to tissue damages caused by surgical operations and the subsequent wound healing induced a cascade alteration in cellular immunity. After surgery, patients have a high level of circulating damage‐associated molecular patterns (DAMPs), triggering a local and systemic inflammation. The inflammatory metrics in the immediate postoperative period was associated with the prognosis of cancer patients. Neutrophils provide the first response to surgical trauma, and the production of neutrophil extracellular traps (NETs) promotes cancer progression. Activated macrophage during wound healing presents a tumor‐associated phenotype that cancers can exploit for their survival advantage. In addition, the amplification and activation of myeloid‐derived suppressor cells (MDSCs), regulatory T cells (Tregs) or the elevated programmed death ligand‐1 and vascular endothelial growth factor expression under surgical trauma, exacerbate the immunosuppression and favor of the formation of the premetastatic niche. Therapeutic strategies to reduce the cellular immunity impairment after surgery include anti‐DAMPs, anti‐postoperative inflammation or inflammatory/pyroptosis signal, combined immunotherapy with surgery, antiangiogenesis and targeted therapies for neutrophils, macrophages, MDSCs, and Tregs. Further, the application of enhanced recovery after surgery also has a feasible outcome for postoperative immunity restoration. Overall, current therapies to improve the cellular immunity under the special condition after surgery are relatively lacking. Further understanding the underlying mechanisms of surgical trauma‐related immunity dysfunction, phenotyping the immunosuppressive cells, and developing the related therapeutic intervention should be explored.

Abstract Background En bloc excision has been increasingly used for the management of giant cell tumors (GCTs) in the distal radius. An osteoarticular allograft has been used extensively for decades, and custom-made prosthesis reconstruction has been more recently applied. We aimed to compare the clinical outcomes of the two procedures. Methods We retrospectively analyzed 30 patients with Campanacci III or recurrent GCTs of the distal radius for follow-up at a mean of 33.2 months. In total, 15 underwent osteoarticular allograft reconstruction (allograft group) and 15 received cementless three-dimensional (3D)-printed prosthesis reconstruction (prosthesis group) between March 18, 2013, and May 20, 2018. All patients underwent by clinical and radiological examinations, including pre- and postoperative active range of motion (ROM) of the wrist, VAS score, grip strength, degenerative change of wrist, Mayo wrist score and Musculoskeletal Tumor Society (MSTS) score. Complications were evaluated using the Henderson classification. Results Both groups showed significantly increased ROM, grip strength, Mayo score and MSTS score postoperatively. Furthermore, the extension, flexion, MSTS, and Mayo score were significantly higher in the prosthesis group. There was no significant difference in grip strength and VAS between the groups. In allograft group, one patient had a late infection one had resorption of allograft without allograft bone fracture. and four had wrist subluxation. All patients had degenerative changes (mean 9 months). In the prosthesis group, three patients developed wrist subluxation, three had separation of the distal radioulnar joint, and none of the patients developed wrist degeneration. Conclusions Our study compared the objective functional outcomes and complications of two reconstructive methods for Campanacci III or recurrent GCT in the distal radius. 3D-printed prosthesis replacement can partially preserve wrist function better than allograft reconstruction in the short-term. During the design of 3D-printed prosthesis, preoperative morphological assessment of the affected proximal row carpal is helpful to control postoperative dislocation. After allograft reconstruction, wrist degeneration, which has been demonstrated in all patients, severely influence their wrist function. Therefore, compared to allograft reconstruction, 3D-printed prosthesis reconstruction has irreplaceable advantages at early-stage application, especially in wrist function, however, further studied with a larger number of cases and longer follow-up.

Summary: The generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in humans is poorly understood. Here, we applied a rostrocaudal patterning system from hESCs to dissect global transcriptional networks controlling early neural regionalization. We found that SOX21 is required for rostral forebrain fate specification. SOX21 knockout led to activation of Wnt signaling, resulting in caudalization of regional identity of rostral forebrain neural progenitor cells. Moreover, we identified WNT8B as a SOX21 direct target. Deletion of WNT8B or inhibition of Wnt signaling in SOX21 knockout neural progenitor cells restored rostral forebrain identity. Furthermore, SOX21 interacted with β-catenin, interfering with the binding of TCF4/β-catenin complex to the WNT8B enhancer. Collectively, these results unveil the unknown role of SOX21 and shed light on how a transcriptional factor modulates early neural regionalization through crosstalk with a key component of Wnt signaling. : Jin and colleagues identify SOX21 as a key player in neural regionalization from human embryonic stem cells. SOX21 ensures the rostral forebrain identity of neural progenitors by repressing WNT8B expression. Key words: SOX21, forebrain, human embryonic stem cells, neural regionalization, Wnt signaling, WNT8B

Abstract Background Gorham-Stout disease, also known as vanishing bone disease, idiopathic massive osteolysis, is a rare entity of unknown etiopathology. This disease is characterized by destruction of osseous matrix and proliferation of lymphatic vascular structures and associated with massive regional osteolysis. It has a variable clinical presentation and is commonly considered as a benign disease with a progressive tendency and an unpredictable prognosis. The diagnosis is made by exclusion and based on combination with histological, radiological, and clinical features. Despite that several therapeutic options have shown certain efficacy, the effective treatment still remains controversial and there is no standard treatment to be recommended. Case presentation A previously healthy 40-year-old man presented with right lateral malleolus pain after an ankle sprain and was referred to our hospital. The radiographs indicated rapid massive bone destruction in the distal right lateral malleolus with an unclear margin. Based on the combination with histological, radiological, and clinical features, the diagnosis of Gorham-Stout disease was made. Considering that the residual function of malleolus had to be protected, prior bisphosphonate was used to control the progression of lesion, followed by surgical resection and biological reconstruction with autologous fibular bone grafting. The patient was followed up 8 years after surgery, he presented without progression and recurrence. Conclusions We depict a case of Gorham-Stout disease at the right lateral malleolus and was successfully controlled by medication and surgical intervention. Based on the prior effective medical treatment, resection with biological reconstruction is a useful approach to treat Graham-Stout disease in bone.

Objective To investigate the neuroprotective effect of bone marrow mesenchymal stem cell (BMMSC) transplantation on collagenase-induced intracerebral hemorrhage (ICH) adult sprague-Dawley (SD) rat model. Methods The collagenase-induced ICH models were constructed by injection of collagenase type Ⅶ into the striatum on the right side stereotaxically. Forty-five healthy male SD rats were selected and then randomly divided into 3 groups of fifteen each, control group, ICH rat model group (model group), BMMSC transplanted ICH group (transplantation group). In transplantation group, BMMSC were transplanted into the perilesional sites 2 h after ICH injury. Modified Neurological Severity Score (mNSS), brain-derived neurotrophic factor (BDNF) immunohistochemical expression, and TUNEL test (cell apoptosis) were assessed at the 1, 3, 7, 14 and 28 d after model-made/transplanted treatment of BMMSC. Results The mNSS score (P = 0.000) and apoptotic cell number (P = 0.000) of rats in different treatment groups at each observation time point showed statistically significant differences. Compared with the control group and the model group, the mNSS score of the transplantation group was lower 28 d after treatment (P < 0.05), showing a decreasing timeliness. The mNSS scores 7, 14 and 28 d after treatment was lower than that 1and 3 d after treatment (P < 0.05). On 1, 3, 7, 14 and 28 d after transplantation, the number of apoptotic cells in the model group and the transplantation group increased (P < 0.05) and reached the peak on 7 d after treatment (all P < 0.05). The number of apoptotic cells on 14 and 28 d was reduced but still higher than that on 1 and 3 d (all P < 0.05). In the transplantation group the expression of BDNF protein was significantly increased, and very few GFP + GFAP and GFP + NeuN positive cells were found in the brain tissue. These results indicated that the transplanted BMMSC had survived in the host brain tissue and with neuronal and glial differentiation. Conclusions Rat ICH model induced by collagenase type Ⅶ is stable for experimental study. The transplanted BMMSC can significantly provide better neuroprotection by increasing BDNF expression and reduce apoptosis. DOI:10.3969/j.issn.1672-6731.2019.09.007

Abstract Background In order to treat proximal femur fibrous dysplasia (FD) patients combined with hip joint osteoarthritis (OA), the three-dimensional (3D) designing osteotomy and implantation of femoral component was firstly used for deformity correction and total hip arthroplasty (THA). The purpose is to present the detailed design, perioperative management and evaluate short-term clinical outcomes of this novel therapeutic method. Method A retrospective study was performed in twelve FD patients combined with hip joint OA who were treated in our hospital between July 2013 and April 2015. Seven patients received 3D designing combined osteotomy and THA, and the other five patients underwent 3D designing THA only. Results All patients were followed-up with an average duration of 47 months (range, 35–56 months). There was no infection, dislocation, postoperative wound problems or mechanical failures. For the seven patients receiving 3D designing corrective osteotomy, the mean extremity lengthening was 2.8 (range, 1.5–4) cm. The average duration of bone union was 4.2 months. The average Harris Hip Score was improved from 46.08 (range, 13–67) points preoperatively to 93.72 (range, 83–100) points at the last follow-up. The average modified criteria of Guille was improved from 3.2 (range, 1–7) points preoperatively to 8.6 (range, 6–10) points at the last follow-up. Conclusions The 3D designing THA with long uncemented stem, including 3D designing corrective osteotomy and implantation of long prosthesis stem, seems to be a reliable method for FD patients combined with hip joint OA. Through preoperative 3D design, corrective osteotomy and implantation of long prosthesis stem can be precise to re-store alignment, uttermost preserve host bone, obtain primary stem stability and provide necessary condition for long-term stem survival, finally leading to better limb function. Besides, perioperative management should be abided strictly for late stability. Nevertheless, the outcomes of long-term follow-up and larger cases are still required.

Ice and snow tourism has yielded considerable socioeconomic benefits, especially for the countries and regions that are rich in ice and snow resources. Boosted by the Beijing Winter Olympics, China’s ice and snow tourism economy is likely to usher in a period of high-quality development. This study utilized Hailuogou Glacier Forest Park, a relatively well-developed glacier tourism area in China, as the study area. We used data on the regional GDP of Ganzi Prefecture and the comprehensive tourism revenue of Hailuogou scenic area from the period of 1990–2021 to quantitatively analyze the reciprocal feedback relationships between the regional economic growth of Ganzi Prefecture and the development of Hailuogou glacier tourism. The analyses were performed through the construction of a VAR model and through conducting robustness tests using the instrumental variable method. The results show that there is a long-term equilibrium cointegration relationship between regional economic growth in Ganzi Prefecture and tourism development in the Hailuogou scenic area, with each 1% increase in the former driving a corresponding growth of 2.01% in the latter. There is an asymmetric reciprocal feedback relationship between the economic growth of Ganzi Prefecture and the development of tourism in the Hailuogou scenic area. Economic growth in Ganzi Prefecture significantly contributes to the development of glacier tourism in Hailuogou over a longer period of time, with a contribution rate of 49%; meanwhile, the development of tourism in the Hailuogou scenic area has a limited effect on the quality and acceleration of economic development in Ganzi Prefecture, with a contribution rate of 16%. Based on the above results, relevant policy recommendations are proposed to provide a theoretical basis and decision-making reference for the high-quality development of the Hailuogou scenic area in the post-COVID-19 and post-Winter Olympics era.