Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC-MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.

Objective:To analyze the clinical characteristics, treatment course and prognosis of children with intermediate-high risk pulmonary embolism.Methods:The clinical data of 48 children with pulmonary embolism treated in Beijing Children′s Hospital, Capital Medical University from January 2017 to December 2021 were analyzed retrospectively.Including 12 intermediate-high risk cases and 36 low-risk cases.The clinical manifestations, laboratory results, treatment and prognosis were compared between groups by the t-test, rank sum test and Chi- square test with the yates continuity correlation or Fisher′ s exact test. Results:There were no significant differences in the sex and age between the intermediate-high risk group and the low-risk group.The proportions of patients with shortness of breath, dyspnea, cyanosis or hypoxemia were higher in the intermediate-high risk group than those of in low-risk group.Twelve children in the low-risk group did not have specific symptoms of pulmonary embolism.There were no significant differences in the D-dimer level, and the distribution of pulmonary embolism between the two groups (all P>0.05). However, the proportion of children with other thromboembolism in the intermediate-high risk group was significantly higher than that of the low-risk group, among which heart thrombosis was the most common (7 cases). There were no significant differences in the underlying diseases and thrombophilia between the two groups (all P>0.05). The treatment of the intermediate-high risk group was more active: 6/12(50.00%) patients in the intermediate-high risk group received reperfusion treatment, including 3 cases of systemic thrombolysis, 1 case of catheter thrombolysis, and 2 cases of thrombectomy.In the low-risk group, only 1 case was treated with systematic thrombolysis.Unfavorable outcomes were reported in 3/48 (6.25%) patients, including 1 death of massive bleeding after catheter-directed thrombolysis in the acute phase, 1 case of recurrent pulmonary embolism after self-decided withdrawal and 1 case of progression of pulmonary embolism that was managed by surgical thrombectomy, all of whom were in the intermediate-high risk group. Conclusions:Shortness of breath, dyspnea, cyanosis or hypoxemia and co-existed venous thromboembolism were more common in intermediate-high risk cases.The treatment regimen of was more aggressive, but the incidence of unfavorable outcomes was higher in intermediate-high risk group; further research is needed to determine the risk factors for intermediate-high risk pulmonary embolism in children.

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK^6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK^6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK^6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK^6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK^6/7 in cells. These results suggested that FAK^6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.
Female ; Humans ; Alternative Splicing ; Breast Neoplasms/metabolism* ; Carcinoma, Pancreatic Ductal/pathology* ; Focal Adhesion Protein-Tyrosine Kinases/therapeutic use* ; Nerve Tissue Proteins/genetics* ; Neuroendocrine Tumors/genetics* ; Oncogenes ; Pancreatic Neoplasms/metabolism*

The unique professionalism of the medical industry,the complexity of diseases,and the lag of medical insurance supervision and other factors bring challenges to the supervision of medical insurance funds.Taking the practice of a tertiary public hospital in Weifang City,Shandong Province in the construction of a full-process,multi-dimensional and three-dimensional medical insurance intelligent monitoring system as an example,it retrospectively analyzed the construction and operation of the hospital's medical insurance intelligent monitoring system since 2020,summarized the achievements,and put forward constructive suggestions on further improving the medical insurance intelligent monitoring system.

Due to good mechanical properties and biocompatibility, tissue engineering scaffolds have become the vital method for repairing and regenerating articular cartilage defects. With the continuous development of tissue engineering technology, many scaffolds preparation and formation methods have been developed and tested in the past decade, however, the preparation of ideal regenerative scaffolds remain controversial. As load-bearing tissue inside the body joints, the matrix structure and cell composition of articular cartilage are hierarchical, and there are several smooth natural gradients from the cartilage surface to the subchondral bone layer, including cell phenotype and number, specific growth factors, matrix composition, fiber arrangement, mechanical properties, nutrient and oxygen consumption. Therefore, in the design of regenerative scaffolds, it is necessary to achieve these gradients to regenerate articular cartilage in situ. In recent studies, many new biomimetic gradient scaffolds have been used to simulate the natural gradient of articular cartilage. These scaffolds show different mechanical, physicochemical or biological gradients in the structure, and have achieved good repair effects. The related articles on tissue engineering for the treatment of articular cartilage defects were retrieved by searching databases with key wordsarticular cartilage injury, cartilage repair and gradient scaffolds. In this work,the structural, biochemical, biomechanical and nutrient metabolism gradients of natural articular cartilage were studied and summarized firstly. Then, the latest design and construction of articular cartilage gradient scaffolds were classified. Besides that, the material composition (such as hydrogels, nanomaterials, etc.) and the preparation process (such as electrospinning, 3D printing, etc.) of grandient scaffolds were further enhanced. Finally, the prospect and challenge of biomimetic gradient scaffolds in cartilage engineering are discussed, which provides a theoretical basis for the successful application of gradient scaffolds in clinical transformation.

OBJECTIVE: Bufalin is an effective drug for the treatment of liver cancer. But its high toxicity, poor water-solubility, fast metabolism and short elimination half-life limit its use in tumor treatment. How to make the drug accumulate in the tumor and reduce side effects while maintaining its efficacy are urgent problems to be solved. The goal of this study is to solve these problems. METHODS: A copolymer with tunable poly-N-isopropylacrylamide and polylactic acid was designed and synthesized. The corresponding dual targeting immunomicelles (DTIs) loaded with bufalin (DTIs-BF) were synthesized by copolymer self-assembly in an aqueous solution. The size and structure of DTIs-BF were determined by ZetaSizer Nano-ZS and transmission electron microscopy. Then, its temperature sensitivity, serum stability, critical micelle concentration (CMC), entrapment efficiency (EE), drug release and non-cytotoxicity of blank block copolymer micelles (BCMs) were evaluated. Next, the effects of DTIs-BF on cellular uptake, cytotoxicity, and tumor cell inhibition were evaluated. Finally, the accumulation of DTIs-fluorescein isothiocyanate (FITC) and the in vivo anti-tumor effect were observed using an interactive video information system. RESULTS: DTIs-BF had a small size, spherical shape, good temperature sensitivity, high serum stability, low CMC, high EE, and slow drug release. The blank BCMs had very low cytotoxicity. Compared with free bufalin, the in vitro cellular internalization and cytotoxicity of DTIs-BF against SMMC-7721 cells were significantly enhanced, and the effects were obviously better at 40 °C than 37 °C. In addition, the therapeutic effect on SMMC-7721 cells was further enhanced by the programmed cell death specifically caused by bufalin. When DTIs-FITC were injected intravenously in BALB/c nude mice bearing liver cancer, the accumulation of FITC was significantly increased in tumors. CONCLUSION DTIs-BF is a potentially effective nano-formulation and has broad prospects in the clinical treatment of liver cancer.
Animals ; Antineoplastic Agents/pharmacology* ; Bufanolides ; Cell Line, Tumor ; Liver Neoplasms/drug therapy* ; Mice ; Mice, Inbred BALB C ; Mice, Nude

Objective:To investigate the strategy of balanoplasty in penile reconstruction with free forearm flap.Methods:From October 2010 to October 2015, 20 patients (19-41 years old) underwent penile reconstruction with free forearm skin flap in Xijing Hospital of Air Force Military Medical University, including 14 cases of transexuals (female to male), 3 cases of hermaphroditism, 2 cases of congenital penile dysplasia and 1 case of penile defect after trauma. According to the tissue quantity of forearm flap and the development of glans, three methods were adopted to reconstruct the glans: free forearm skin flap + E-shaped cartilage framework, free dorsalis pedis flap + E-shaped cartilage framework or free glans transplantation. The patients were followed up for a long time postoperation to observe the morphological changes of the glans after different method of balanoplasty.Results:Among the 20 patients, 18 cases were treated with distal part of free forearm flap and E-shaped cartilage framework for glans reconstruction, 1 case of transexuals used free dorsalis pedis flap and E-shaped cartilage framework for glans reconstruction, and 1 case of hermaphroditism used free glans transplantation to reconstruct glans. After 10-36 months of follow-up, all reconstructed penises survived. The shape of glans reconstructed by dorsalis pedis flap was the most plump and natural with clear coronal sulcus; the amount of glans tissue reconstructed by forearm skin flap was slightly insufficient, and the coronal sulcus was slightly flat, while the overall shape was satisfactory. The reconstructive glans with free glans transplantation was not plump, but they retained the shape of glans, which was lifelike.Conclusions:If the tissue quantity of forearm skin flap is sufficient, the distal part of free forearm flap and E-shaped cartilage framework is used; if the tissue quantity of forearm is seriously insufficient, the free dorsalis pedis flap and E-shaped cartilage framework is used. For hermaphroditism patients with well-developed glans, autologous glans free transplantation is used.Individualized strategy of balanoplasty according to different conditions of patients is conducive to obtaining satisfactory appearance of the glans.

Since it was introduced in the 1970s, skin and soft tissue expansion has been widely used in the field of plastic and reconstructive surgery, and has achieved good results. In the field of ear reconstruction, there are many related studies and reports available. The author reviewed and summarized the history and current progress of skin and soft tissue expansion and its application in auricular reconstruction, and offered author’s personal opinion on the classification and naming of ear reconstruction based on expansion technique.

Objective:To investigate the strategy of balanoplasty in penile reconstruction with free forearm flap.Methods:From October 2010 to October 2015, 20 patients (19-41 years old) underwent penile reconstruction with free forearm skin flap in Xijing Hospital of Air Force Military Medical University, including 14 cases of transexuals (female to male), 3 cases of hermaphroditism, 2 cases of congenital penile dysplasia and 1 case of penile defect after trauma. According to the tissue quantity of forearm flap and the development of glans, three methods were adopted to reconstruct the glans: free forearm skin flap + E-shaped cartilage framework, free dorsalis pedis flap + E-shaped cartilage framework or free glans transplantation. The patients were followed up for a long time postoperation to observe the morphological changes of the glans after different method of balanoplasty.Results:Among the 20 patients, 18 cases were treated with distal part of free forearm flap and E-shaped cartilage framework for glans reconstruction, 1 case of transexuals used free dorsalis pedis flap and E-shaped cartilage framework for glans reconstruction, and 1 case of hermaphroditism used free glans transplantation to reconstruct glans. After 10-36 months of follow-up, all reconstructed penises survived. The shape of glans reconstructed by dorsalis pedis flap was the most plump and natural with clear coronal sulcus; the amount of glans tissue reconstructed by forearm skin flap was slightly insufficient, and the coronal sulcus was slightly flat, while the overall shape was satisfactory. The reconstructive glans with free glans transplantation was not plump, but they retained the shape of glans, which was lifelike.Conclusions:If the tissue quantity of forearm skin flap is sufficient, the distal part of free forearm flap and E-shaped cartilage framework is used; if the tissue quantity of forearm is seriously insufficient, the free dorsalis pedis flap and E-shaped cartilage framework is used. For hermaphroditism patients with well-developed glans, autologous glans free transplantation is used.Individualized strategy of balanoplasty according to different conditions of patients is conducive to obtaining satisfactory appearance of the glans.

Since it was introduced in the 1970s, skin and soft tissue expansion has been widely used in the field of plastic and reconstructive surgery, and has achieved good results. In the field of ear reconstruction, there are many related studies and reports available. The author reviewed and summarized the history and current progress of skin and soft tissue expansion and its application in auricular reconstruction, and offered author’s personal opinion on the classification and naming of ear reconstruction based on expansion technique.