To establish and identify induced pluripotent stem cells (iPSCs) derived from patients with Aicardi-Goutières syndrome (AGS) with TREX1 gene 667G>A mutation, and obtain a specific induced pluripotent stem cell model for Aicardi-Goutières syndrome (AGS-iPSCs). A 3-year-old male child with Aicardi-Goutieres syndrome was admitted to Zhongshan People's Hospital in December 2020. After obtaining the informed consent of the patient's family members, 5 ml peripheral blood samples from the patient were collected, and mononuclear cells were isolated. Then,the peripheral blood mononuclear cells(PBMCs) were transduced with OCT3/4, SOX2, c-Myc and Klf4 by using Sendai virus, and PBMCs were reprogrammed into iPSCs. The pluripotency and differentiation ability of the cells were identified by cellular morphological analysis, real-time PCR, alkaline phosphatase staining (AP), immunofluorescence, teratoma formation experiments in mice. The results showed that the induced pluripotent stem cell line of Aicardi-Goutieres syndrome was successfully constructed and showed typical embryonic stem-like morphology after stable passage, RT-PCR showed mRNA expression of stem cell markers, AP staining was positive, OCT4, SOX2, NANOG, SSEA4, TRA-1-81 and TRA-1-60 pluripotency marker proteins were strongly expressed. In vivo teratoma formation experiments showed that iPSCs differentiate into the ectoderm (neural tube like tissue), mesoderm (vascular wall tissue) and endoderm (glandular tissue). Karyotype analysis also confirmed that iPSCs still maintained the original karyotype (46, XY). In conclusion, induced pluripotent stem cell line for Aicardi-Goutières syndrome was successfully established using Sendai virus, which provided an important model platform for studying the pathogenesis of the disease and for drug screening.
Animals ; Male ; Mice ; Cell Differentiation ; Induced Pluripotent Stem Cells/pathology* ; Leukocytes, Mononuclear ; Teratoma/pathology* ; Child, Preschool

This project was aimed to investigate the role and the underlying mechanism of microglia polarization on blood-brain barrier (BBB) during cerebral ischemia-reperfusion. After construction of the mouse model of cerebral ischemia-reperfusion, upregulated IL-6 and TNF-α in peripheral blood and increased IL-6 and iNOS in ischemia tissues were confirmed. The supernatant expression of TNF-α and IL-6, as well as IL-6, iNOS and CD86 mRNA, was significantly increased in the of Bv-2 cells after oxygen-glucose deprivation/reoxygenation (OGD/R) model was constructed in vitro. For further understanding the expression pattern of RNAs, the next-generation RNA sequencing was performed and upregulation of Robo4 (roundabout guidance receptor 4) was found both in M1-polarized and OGD/R treated Bv-2 cells, which was also confirmed by RT-qPCR. Extracellular soluble Robo4 (sRobo4) protein also increased in the supernatant of M1-polarized and OGD/R treated Bv-2 cells. Treating bEND3 cells with the Robo4 recombinant protein, M1-polarized Bv-2 cell supernatant or OGD/R Bv-2 cell supernatant decreased trans-endothelial electrical resistance (TEER), suggesting the injury of BBB. In addition, Robo4 was also highly expressed in the serum of patients who experienced acute ischemia stroke and mechanical thrombectomy operation. All the results suggest that increased secretion of Robo4 by M1-polarized-microglia during cerebral ischemia-reperfusion is most likely one of the causes of BBB injury, and Robo4 may be one of the therapeutic targets for BBB functional protection.
Animals ; Blood-Brain Barrier/metabolism* ; Brain Ischemia/drug therapy* ; Glucose/metabolism* ; Interleukin-6/metabolism* ; Mice ; Microglia/metabolism* ; Oxygen/metabolism* ; Receptors, Cell Surface/metabolism* ; Reperfusion ; Reperfusion Injury/drug therapy* ; Tumor Necrosis Factor-alpha/metabolism*

Nonalcoholic fatty liver disease (NAFLD) is the manifestation of metabolic syndrome in the liver and is closely associated with glucose and lipid metabolism disorders, and they interact as both cause and effect of each other, with insulin resistance as the common pathogenesis. About three quarters of patients with obesity and type 2 diabetes mellitus have NAFLD, and current guidelines recommend reducing metabolic risk factors and treating metabolic syndrome as the primary treatment goals for patients with NAFLD. Although there are no approved drugs for the treatment of NASH at present, the hypoglycemic drugs on the market can bring varying degrees of benefits to NAFLD patients while lowering blood glucose. This article reviews the prospects of three types of hypoglycemic drugs on the market (thiazolidinediones, GLP-1 receptor agonists, and SGLT-2 inhibitors) in the treatment of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease involving metabolic disorder and is more common in patients with obesity and type 2 diabetes mellitus (T2DM), with similar adverse outcomes to these two comorbidities. For a long time, NAFLD has emphasized liver lesions and outcomes of liver diseases, and when treating T2DM according to the current clinical guidelines for diabetes, endocrinologists often neglect the screening, diagnosis, and treatment of liver lesions. Therefore, in clinical practice, NAFLD renamed as metabolic-associated fatty liver disease has important practical significance. Strategies for T2DM prevention and treatment aiming at reducing liver lipid content require multidisciplinary cooperation, and prevention and treatment of obesity, fatty liver disease, and diabetes with the same concepts can help to implement the prevention and treatment of the most common chronic diseases.

Although nonalcoholic fatty liver disease (NAFLD) is a liver disease, it has attracted more and more attention among endocrinologists. There are complex interactions between the metabolic status of diabetes and the pathology of NAFLD, and they promote the development of each other. In the population with type 2 diabetes mellitus (T2DM), the incidence rate of NAFLD is as high as 57%-80%, and NAFLD patients with diabetes are more likely to develop progressive liver diseases such as nonalcoholic steatohepatitis (NASH) and liver fibrosis. NAFLD also leads to the deterioration of glucose and lipid metabolism disorder in diabetes patients, as well as the development and progression of chronic macrovascular and microvascular complications in diabetes. The above evidence supports the view that NASH should be considered a complication of T2DM. Once a definite diagnosis of T2DM is made in clinical practice, the risk of NASH or progressive fibrosis should be evaluated and intervention should be given as early as possible.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Though surgical resection is the only radical treatment, postoperative recurrence and metastasis often occur. The first-line therapy for the treatment of recurrent, metastatic and unresectable GIST is imatinib. More than 80% of patients can benefit from imatinib treatment, but half of patients will still have recurrence or metastasis within 2 years after treatment initiation, and secondary drug resistance is a major cause of disease progression. Therefore, adeep understanding of the mechanisms of secondary drug resistance will guide us to develop personalized therapeutic schedule in the future. This article describes the mechanism of IM secondary resistance from the aspects of gene alteration, abnormal activation of signal transduction pathway, autophagy, apoptosis and drug concentration. It is found that single drug therapy has certain limitations in patients with secondary resistance to IM. Using IM combined with downstream signaling molecule inhibitors, autophagy inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, heat shock protein 90 (HSP90) inhibitors, cytotoxic T lymphocyte - associated antigen - 4 (CTLA - 4) antibodies and mitochondrial inhibitors provide us new therapeutic ideas. However, these combination treatments are still in the research phase, and further trials are needed to confirm the safety and efficacy. With the gradual deepening of research on drug resistance mechanisms, it will provide more solutions to the current serious drug resistance problem.

Iron is an important nutrient element which is involved in a variety of physiological processes. The potential toxicity of excess iron requires that cells should evolve a robust, tightly regulated mechanism for maintaining iron homeostasis. At the same time, iron plays an indispensable role in the process of tumorigenesis and progression. The mechanism involved in iron homeostasis can make changes to adapt to its metabolic level and to maintain the activity of the tumor cells. This paper reviews iron metabolism and its role in the maintaining of iron homeostasis, as well as the importance of iron metabolism in solid cancers.

Hepatocellular carcinoma (HCC), a highly prevalent malignancy and one of the leading cause of cancer death in China, remains a major public health problem in the next decades. Owing to the tremendous achievements in early diagnosis, precision liver surgery, molecular targeted therapy and immunotherapy, we have witnessed significant improvements in the long-time survival of HCC patients, if properly treated. However, HCC is a highly heterogeneous disease. Even for patients within the same clinical stage, their clinical outcome and treatment efficacy vary significantly. Great efforts to improve the molecular classification of HCC patients are needed to foster precision medicine, paving the way for novel therapeutic strategies. Advances in multi-omics, single-cell analysis, molecular imaging and artificial intelligence will lead to better understanding of the molecular classification and refine precision treatment in HCC, ultimately excluding this neoplasm from the risk list of our Healthy China.

Female ; Humans ; Infant, Newborn ; Infant, Premature ; Infant, Premature, Diseases ; etiology ; Male ; Premature Birth ; Risk Factors

OBJECTIVETo evaluate clinical effect of micro-modified Fulkerson osteotomy under arthroscope in treating habituation patellar dislocation.

METHODSTwenty patients of habituation patellar dislocation (25 knees) were treated by the medial retinaculum plication, lateral retinaculum releasing and modified Fulkerson osteotomy (tibial tubercle anteromedial transfer) under arthroscope. There were 5 males and 15 females with the age from 16- to 28-years-old (average of 21 years). The subjective symptoms and the joint function were evaluated according to Lysholm and Tegner scoring system.

RESULTSAll the patients were followed up from 12 to 36 months with an average of 24 months. No found redislocation in the patients. The Lysholm score was 54.4 +/- 12.1 and 87.7 +/- 9.6 (t=2.33, P<0.05) before and after surgery respectively. The Tegner score was 2.8 +/- 0.8 and 5.1 +/- 1.3 (t=4.36, P<0.01) before and after surgery respectively.

CONCLUSIONMicro-modified Fulkerson osteotomy under arthroscope for the treatment of habituation patellar dislocation is a rescheduled in extend knee equipment, its advantages including affirmative effect, minor damage, quick rehabilitation, fewer complications and lower rate of recurrence after operation.

Adolescent ; Adult ; Female ; Humans ; Male ; Osteotomy ; methods ; Patella ; injuries ; surgery ; Patellar Dislocation ; surgery ; Young Adult