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    Research progress in immune cells regulating drug resistance of tumor cells in tumor microenvironment
    ZHANG Yesheng, YANG Yijing, HUANG Yiwen, SHI Longyu, WANG Manyuan, CHEN Sisi
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 830-838.   DOI: 10.3969/j.issn.1674-8115.2024.07.004
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    Tumor microenvironment (TME) is a complex cellular environment where tumor cells reside, along with various types of cells and extracellular components surrounding the tumor cells. Immune cells are key components of TME, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), lymphocytes, regulatory T cells (Tregs), natural killer cells (NK cells), dendritic cells (DCs), and many others. It is worth noting that drug resistance is currently a major factor limiting the efficacy of cancer treatment methods such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and a leading cause of treatment failure. Research has found that the development of drug resistance in tumor cells is the result of interactions between tumor cells and TME. Consequently, overcoming drug resistance in tumors caused by TME is considered a significant challenge in cancer treatment. In recent years, with in-depth research into immune cells within TME, significant progress has been made in understanding the specific mechanisms by which immune cells regulate drug resistance in tumor cells. Furthermore, therapeutic strategies that target these immune cells, signaling pathways, or cytokines have been shown to effectively combat tumor drug resistance and enhance the therapeutic outcomes of cancer treatment. This article reviews the research advancements regarding the roles of TAMs, MDSCs, Tregs, and NK cells in tumor drug resistance within TME and discusses the development of targeting strategies to overcome this resistance. Additionally, we explore the relationship of tumor-associated neutrophils (TANs) and B regulatory cells (Bregs) with tumor drug resistance. It is hoped that this review will offer insights and serve as reference for reducing tumor drug resistance and improving the efficacy of anti-tumor therapies.

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    Comparative study on methods for colon polyp endoscopic image segmentation and classification based on deep learning
    CHEN Jian, WANG Zhenni, XIA Kaijian, WANG Ganhong, LIU Luojie, XU Xiaodan
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (6): 762-772.   DOI: 10.3969/j.issn.1674-8115.2024.06.012
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    Objective ·To compare the performance of various deep learning methods in the segmentation and classification of colorectal polyp endoscopic images, and identify the most effective approach. Methods ·Four colorectal polyp datasets were collected from three hospitals, encompassing 1 534 static images and 15 videos. All samples were pathologically validated and categorized into two types: serrated lesions and adenomatous polyps. Polygonal annotations were performed by using the LabelMe tool, and the annotated results were converted into integer mask formats. These data were utilized to train various architectures of deep neural networks, including convolutional neural network (CNN), Transformers, and their fusion, aiming to develop an effective semantic segmentation model. Multiple performance indicators for automatic diagnosis of colon polyps by different architecture models were compared, including mIoU, aAcc, mAcc, mDice, mFscore, mPrecision and mRecall. Results ·Four different architectures of semantic segmentation models were developed, including two deep CNN architectures (Fast-SCNN and DeepLabV3plus), one Transformer architecture (Segformer), and one hybrid architecture (KNet). In a comprehensive performance evaluation of 291 test images, KNet achieved the highest mIoU of 84.59%, significantly surpassing Fast-SCNN (75.32%), DeepLabV3plus (78.63%), and Segformer (80.17%). Across the categories of “background”, “serrated lesions” and “adenomatous polyps” , KNet's intersection over union (IoU) were 98.91%, 74.12%, and 80.73%, respectively, all exceeding other models. Additionally, KNet performed excellently in key performance metrics, with aAcc, mAcc, mDice, mFscore, and mRecall reaching 98.59%, 91.24%, 91.31%, 91.31%, and 91.24%, respectively, all superior to other models. Although its mPrecision of 91.46% was not the most outstanding, KNet's overall performance remained leading. In inference testing on 80 external test images, KNet maintained an mIoU of 81.53%, demonstrating strong generalization capabilities. Conclusion ·The semantic segmentation model of colorectal polyp endoscopic images constructed by deep neural network based on KNet hybrid architecture, exhibits superior predictive performance, demonstrating its potential as an efficient tool for detecting colorectal polyps.

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    Advances in drug therapy of diabetic retinopathy
    CHEN Minghao, LIU Peiyu, WANG Xuan, WU Yixiang, JIANG Yujin, ZHANG Chaoyang, ZHANG Jingfa
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 822-829.   DOI: 10.3969/j.issn.1674-8115.2024.07.003
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    Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and has become one of the leading causes of blindness and visual impairment in diabetes patients. The pathogenesis of DR is multifaceted, involving inflammation, oxidative stress, neurovascular abnormalities, and other factors that present potential targets for disease management interventions. Currently, anti-vascular endothelial growth factor (VEGF) drugs serve as the primary treatment for advanced stages of DR when irreversible neurovascular damage and visual impairment have occurred. Additionally, some patients show poor or no response to anti-VEGF treatment. There is a lack of early intervention options for the initial phases of the disease. Therefore, there is an urgent need to develop novel local or systemic therapies based on the underlying mechanisms of DR to enable early prevention and treatment with the aim of preserving patients′ vision. Medications targeting various pathways including anti-inflammatory agents (corticosteroids and nonsteroidal anti-inflammatory drugs), neurotrophic and neuroprotective drugs, drugs modulating biochemical pathways, antioxidant phytochemicals, and gene therapy can complement each other in terms of therapeutic effects to benefit a larger number of individuals affected by DR. This article reviews previous research reports on the pathogenesis, drug treatment methods, and potential therapeutic targets associated with DR in order to provide guidance for clinical practice.

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    Observation on the effect of hydrogel probiotics colonized in inflammatory sites in the treatment of inflammatory bowel disease
    XU Wei, LI Meng, WANG Haoze, CUI Kai, XIAO Zeyu
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 883-890.   DOI: 10.3969/j.issn.1674-8115.2024.07.009
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    Objective ·To construct a probiotic ( Escherichia coli Nissle1917,EcN) system (EcN@PVA-ALG) loaded on polyvinyl alcohol (PVA) / alginate (ALG) hydrogel (PVA-ALG) rich in negative hydroxyl groups, and to explore its colonization in the inflammatory site of colon and its therapeutic effect on dextran sulfate sodium salt (DSS)-induced inflammatory bowel disease (IBD). Methods ·EcN suspension was added to the PVA-ALG hydrogel, and then EcN@PVA-ALG hydrogel probiotic complex was obtained after screening and centrifugation. The synthesis of PVA-ALG hydrogel was verified by rheometer. The surface charge of EcN@PVA-ALG was detected by potentiometer and the load of EcN on PVA-ALG was observed by fluorescence microscope. The absorbance of EcN@PVA-ALG at 600 nm was detected by enzyme labeling instrument. Meanwhile, the bacterial plate count of EcN@PVA-ALG complex suspension was taken to study the growth activity of EcN in EcN@PVA-ALG. The CCK-8 kit was used to assess the inhibitory ability of EcN@PVA-ALG on HEK cell proliferation. In vivo imaging system (IVIS) was used to firstly analyze the enrichment of PVA-ALG on inflammatory colon to study its inflammatory targeting property; then EcN was loaded on PVA-ALG, and IVIS was used to observe the enrichment of EcN@PVA-ALG on inflammatory colon to study its ability to colonize the inflammatory site. To establish the model of IBD mice induced by DSS, EcN@PVA-ALG group ( n=5) was given 1×10 8CFU EcN@PVA-ALG every day for 5 d, and PVA-ALG group, EcN group, PBS group and healthy control group with 5 mice were set up. During the treatment, the body mass of the mice was recorded every day. After treatment, the colonic tissue was taken, and the length of colon was measured. The disease activity index (DAI) score was graded. The levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10 and transforming growth factor-β (TGF-β) were detected, and the pathological evaluation of colonic tissue was made by H-E staining. Results ·Both PVA-ALG and EcN@PVA-ALG were negatively charged. EcN was successfully loaded onto PVA-ALG and PVA-ALG did not affect the growth viability of EcN, which contributed to the subsequent colonization of inflammatory colons. PVA-ALG had a favorable safety profile on normal cells. Compared with healthy controls, PVA-ALG had more than 2-fold enrichment effect on inflammatory colon tissue. In vitro and in vivo experiments revealed that EcN@PVA-ALG complex loaded with EcN had 8 times higher enrichment effect on inflammatory tissue than EcN without any modification. After EcN@PVA-ALG treatment, the body weight of mice recovered rapidly. The increase of DAI was significantly inhibited. The length of colon was similar to that of healthy mice. The levels of TNF- α and IL-6 decreased, while the levels of IL-10 and TGF- β increased. The crypt structure of colon tissue recovered. Conclusion ·Compared to unmodified EcN, EcN@PVA-ALG promotes the colonization of EcN at inflammatory sites of colon and allows it to exert better efficacy on treating DSS-induced IBD.

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    Progress in cumulative risk assessment of human health from combined exposure to environmental pollutants
    CHENG Xiaomeng, ZHANG Yan, GAO Yu, TIAN Ying
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 1037-1043.   DOI: 10.3969/j.issn.1674-8115.2024.08.013
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    The combined exposure to environmental pollutants can result in unanticipated adverse effects on human health, and how to compare and assess these effects has always been a matter of great concern for the international community. Currently, several prevalent methods for assessing combined exposure risks in the field of human health risk assessment primarily encompass the hazard index (HI) method, the point of departure index (PODI) method, the margin of exposure (MOE) method, and the relative potency factor (RPF) method. The review summarizes the application of these methods to the cumulative risk assessment of combined exposure to the same class of chemicals with the same toxic mechanism, primarily focusing on pesticides such as organophosphorus pesticides, pyrethroids, carbamates, and neonicotinoids, as well as typical compounds intimately related to human production and life, including organophosphorus flame retardants, per- and poly-fluoroalkyl substances, and bisphenols. Furthermore, progress in the application of physiologically based pharmacokinetics models to human health risk assessment has been introduced, which might provide more options for risk assessment of combined exposure to multiple chemicals, and help to provide insights for further exploration and establishment of more systematic and scientific approaches to human health risk assessment.

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    Progress in translational research on immunotherapy for osteosarcoma
    HU Fei, CAI Xiaohan, CHENG Rui, JI Shiyu, MIAO Jiaxin, ZHU Yan, FAN Guangjian
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 814-821.   DOI: 10.3969/j.issn.1674-8115.2024.07.002
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    Osteosarcoma is a common primary malignant bone tumor in adolescents and children, characterized by a high recurrence rate and metastasis, making its treatment extremely challenging. Traditional treatment modalities, including surgery, radiation therapy, and chemotherapy, can alleviate symptoms to some extent, but improving long-term survival rates remains a pressing issue. With the continuous development of immunotherapy, breakthroughs have been made in the research of tumor immune microenvironment and the application of immunotherapy in recent years, providing new perspectives and strategies for osteosarcoma treatment. Currently, immunotherapy strategies include tumor vaccines, targeted cytokines, immune checkpoint inhibition, adoptive cell therapy, combination therapy, etc., significantly enhancing patient immune responses from the aspects of boosting immunity, overcoming immune tolerance, and preventing immune evasion, thereby effectively improving the patients′ survival rates and prognosis. This review aims to systematically introduce the immune microenvironment of osteosarcoma and discuss the latest advances in immunotherapy in clinical translational research of osteosarcoma. By deeply understanding the immune characteristics of osteosarcoma and corresponding treatment methods, it is hopeful to provide more effective strategies for personalized treatment, contributing to the improvement of the patients′ survival rates and prognosis.

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    Research progress in Menin-MLL interaction and its inhibitors in MLL-rearranged leukemia
    FANG Xinyue, SHI Lan, XIA Siyi, WANG Jiaxuan, WU Yingli, HE Kejun
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (10): 1287-1298.   DOI: 10.3969/j.issn.1674-8115.2024.10.011
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    Acute leukemias caused by mixed lineage leukemia (MLL) gene rearrangements (MLL-r) are characterized by high invasiveness and a poor prognosis, with few specific treatment options available. MLL protein is essential in embryonic development and hematopoiesis. It exhibits histone methyltransferase activity and can interact with various proteins through its functional domains, thus regulating downstream target gene expression through epigenetic modifications. MLL-r leads to the formation of MLL fusion proteins (MLL-FPs), in which the C-terminal is replaced by fusion partner proteins; over 100 such partner proteins have been identified to date. In numerous studies of the molecular mechanism, Menin serves as an important cofacter in the leukemogenesis of MLL-FPs and participates in forming the key complex when interacting with the N terminal of MLL protein, resulting in the disregulation of certain targeted genes, which makes the development of Menin-MLL inhibitors theoretically possible. To date, several small molecules have been identified that inhibit Menin-MLL interaction, including thienopyrimidine derivatives, piperidine derivatives, pyrimidine derivatives, and macrocyclic mimic peptides. Based on these prototypes, at least seven drugs are currently undergoing clinical evaluation, with some promising preliminary data regarding safety, tolerability, and efficacy. This review summarizes the structure and function of MLL, the mechanism of the occurrence of MLL-r leukemia, and current Menin-MLL inhibitors tested in MLL-r leukemia.

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    Progress in the regulatory mechanisms of mandibular condylar development and deformity
    LIU Jingyi, XU Hongyuan, DAI Qinggang, JIANG Lingyong
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 951-958.   DOI: 10.3969/j.issn.1674-8115.2024.08.003
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    The temporomandibular joint is the only joint structure within the craniofacial skeletal system, responsible for performing functions related to opening and closing mouth movements, such as chewing, speaking, and facial expression in daily life. The condyle of the mandible, as a vital component of the temporomandibular joint, originates from the mandibular process formed by the first gill arch and is the key growth center at the end of the mandibular ramus. Condyle is composed of a layer of cartilage as its surface and subchondral bone below, exhibiting unique biological processes during its growth and development. In the articular fossa, the functional movement of the condyle depends on its normal physiological and anatomical structure, which plays a crucial role in establishing occlusion and shaping facial features. Abnormal growth and development can lead to the occurrence of condylar deformities, which affect the vertical height of the patient's maxillofacial region and ultimately lead to secondary skeletal class Ⅱ or Ⅲ craniofacial deformities. During the process of growth and development, the condyle is subject to complex signal regulation. In recent years, with in-depth research on the temporomandibular joint, researchers have begun to discuss the regulatory mechanisms of condyle growth and development from the perspectives of gene expression and molecular level, in order to explain the causes of temporomandibular joint diseases and condylar deformities. This article provides a review on the growth process and structure of condyle, classification and pathological manifestations of condylar deformities, and related regulatory mechanisms of the growth and development of condyle, as well as pathogenesis of condylar deformities. The aim of this article is to provide research ideas for temporomandibular joint diseases and craniofacial malformations caused by abnormal development of the mandibular condyle in clinical practice.

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    Clinical validation and application value exploration of multi-modal pulmonary nodule diagnosis model
    XU Wanxing, WANG Lin, GUO Qiaomei, WANG Xueqing, LOU Jiatao
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 1030-1036.   DOI: 10.3969/j.issn.1674-8115.2024.08.012
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    Objective ·To verify the performance and explore the clinical application value of a multi-modal pulmonary nodule diagnosis model combined with metabolic fingerprints, protein biomarker CEA and Image-AI via random forest (MPI-RF). Methods ·This study enrolled 289 patients with pulmonary nodules who were admitted to the Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine and were detected by low-dose helical computed tomography (LDCT). The patients were divided into malignant nodule group ( n=197) and benign nodule group ( n=92) based on postoperative pathological results, and the basic information of the two groups was collected and compared. Electrochemiluminescence was used to detect the preoperative serum CEA levels of the patients in the two groups, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was used to detect the serum metabolic fingerprints, and the CT image artificial intelligence model Image-AI was used to calculate the image scores. CEA data, serum metabolic fingerprints data and image scores were integrated and input into MPI-RF to calculate the malignant probability score of each patient. The receiver operator characteristic curve (ROC curve) and area under the curve (AUC) were used to evaluate the performance of different models, and the DeLong test was used for comparative analysis, including the diagnostic performance of MPI-RF in different types (solid nodule, pure ground-glass nodule and part-solid nodule) and sizes (diameter<8 mm and diameter≥8 mm) of pulmonary nodules, the diagnostic performance comparison of MPI-RF with Mayo Clinic model, veterans administration (VA) model and Brock model, and the diagnostic performance comparison of MPI-RF with lung imaging reporting and data system (Lung-RADS) in benign and malignant nodules. Results ·MPI-RF had good diagnostic performance in the differentiation of benign and malignant pulmonary nodules (AUC=0.887, 95% CI 0.848?0.925, sensitivity 81.22%, specificity 83.70%). Among them, the AUC of MPI-RF for solid nodules was 0.877 (95% CI 0.820?0.934), for part-solid nodules was 0.858 (95% CI 0.771?0.946), and for pure ground-glass nodules was 0.978 (95% CI 0.923?1.000). The AUC of MPI-RF was 0.840 (95% CI 0.716?0.963) for nodules within 8 mm diameter and 0.891 (95% CI 0.849?0.933) for nodules larger than 8 mm diameter. Compared with the existing models, the diagnostic performance of MPI-RF was better than that of Mayo Clinic model, VA model and Brock model (all P=0.000). Compared with Lung-RADS, MPI-RF had better diagnostic performance in the total samples and different types of nodules (all P=0.000). Conclusion ·MPI-RF is a model for the differential diagnosis of benign and malignant pulmonary nodules with excellent performance, and has potential clinical application value.

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    Research progress in the role of SIRT6 in aging and metabolism
    LIU Yonghui, TANG Li, LIANG Taigang, ZHANG Jian, FENG Li
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (11): 1439-1446.   DOI: 10.3969/j.issn.1674-8115.2024.11.011
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    SIRT6, a member of the sirtuin family of histone deacetylases, belongs to the class Ⅲ longevity proteins and exhibits NAD+-dependent deacetylase and mono-ADP-ribosyltransferase activities. SIRT6 is primarily located in the cell nucleus and plays a pivotal role in regulating genomic stability and relative gene expression, participating in the control of key processes such as energy metabolism and aging. Given its crucial role in maintaining cellular homeostasis and organismal health, SIRT6 has emerged as a potential therapeutic target, sparking significant research interest in the development of targeted modulators. Activating the longevity protein with drugs may provide therapeutic strategies for age-associated diseases, including aging, metabolic syndrome, inflammation, and reproductive health issues. The review elaborates the structural characteristics, enzymatic activities, and biological functions of SIRT6, as well as the mechanisms of action, pharmacological activities, and clinical applications of various SIRT6 activators.

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    Research progress of the role of intestinal microbiota-mediated bile acids in inflammatory bowel disease
    XIA Xixi, DING Keke, ZHANG Huiheng, PENG Xufei, SUN Yimin, TANG Yajun, TANG Xiaofang
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 839-846.   DOI: 10.3969/j.issn.1674-8115.2024.07.005
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    It is estimated that approximately seven million people worldwide are affected by inflammatory bowel disease (IBD), causing a huge burden on healthcare systems and society. In the occurrence, progression, and treatment of IBD, the intestinal microbiota and its key metabolic product, bile acids, play a crucial role. The intestinal microbiota not only participates in the biotransformation of bile acids, enriching the diversity of bile acids, but also regulates their synthesis and transport through the farnesoid X receptor (FXR). Meanwhile, bile acids contribute to regulating the structure and function of the intestinal microbiota by supporting microbial diversity, exerting direct toxicity, participating in indirect antimicrobial pathways, and influencing microbial metabolic capabilities. Furthermore, under normal physiological conditions, intestinal microbiota-derived bile acids facilitate the repair process of the intestinal epithelial barrier. They also promote the balance of the immune system by modulating the functions of various immune cells including helper T (Th) cells 17, regulatory T (Treg) cells, CD8+ T cells and natural killer T(NKT) cells, thereby slowing down the development of IBD. This article focuses on exploring the role of intestinal microbiota and bile acids in the onset and progression of IBD, and investigating new effective treatment strategies by targeting intestinal microbiota and bile acids, such as bile acid receptor modulators, probiotics, prebiotics, fecal microbiota transplantation (FMT), and phage therapy.

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    Progress in mechanisms and treatment of sunitinib resistance in renal cell carcinoma
    CHEN Zixuan, LIU Min
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (10): 1307-1315.   DOI: 10.3969/j.issn.1674-8115.2024.10.013
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    Renal cell carcinoma (RCC) originates from the epithelial cells of renal tubules and is the most common type of renal cancer, as well as the urological tumor with the highest mortality rate. Over the past half-century, the morbidity and mortality of RCC have been increasing, posing a significant threat to human health. Although surgical treatment offers the possibility of a cure for most RCC patients, tumor recurrence or metastasis leads to the failure of traditional treatment options to achieve the desired results. The advent of targeted drugs, such as receptor tyrosine kinase inhibitors and immune checkpoint inhibitors, has brought new hope for the treatment of RCC. Targeted therapy has become the mainstay of treatment for advanced RCC. Sunitinib is a receptor tyrosine kinase inhibitor that plays a pivotal role in the treatment of RCC. It inhibits the activity of various receptor tyrosine kinases, including epidermal growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor. This, in turn, inhibits tumor angiogenesis and cellular proliferation, effectively controlling tumor progression. However, a considerable number of RCC patients develop resistance to sunitinib within 15 months of initiating treatment, presenting new challenges for the treatment of RCC. Therefore, this paper summarizes the mechanism of sunitinib resistance in RCC and reviews the treatment of sunitinib resistance in RCC, in order to provide ideas for overcoming the resistance of RCC to sunitinib, and developing a more effective treatment plan for patients with advanced RCC.

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    Advances in molecular mechanisms of iodine-131 therapy resistance in thyroid carcinoma
    LIU Shiqi, WANG Hui, FENG Fang
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 915-921.   DOI: 10.3969/j.issn.1674-8115.2024.07.013
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    Thyroid cancer is the most common malignant tumor of the endocrine system, with differentiated thyroid carcinoma (DTC) accounting for over 90%. Most DTC patients have a good prognosis after systematic treatment, but a few develop dedifferentiation of primary tumor site or metastases, progressing to radioiodine-refractory DTC (RAIR-DTC), leading to significantly worse prognosis, which is a major cause of thyroid carcinoma-related mortality. Dysregulation of sodium iodide symporter (NIS) expression and function is the main reason for iodine-131 therapy resistance in thyroid carcinoma, influenced by genetic changes, epigenetic changes, tumor microenvironment, autophagy, and other factors. Genetic alterations such as the BRAFV600E mutation and RET/PTC chromosomal rearrangements activate oncogenic signaling pathways, directly or indirectly affecting NIS expression and its normal localization on the cell membrane. Epigenetic regulation modulates specific gene expression patterns, regulating NIS gene expression levels, thereby affecting the radioiodine uptake function of thyroid cells. Components in the tumor microenvironment, including immune cells, cytokines, and extracellular matrix, may also disrupt iodine uptake by reducing the expression levels of NIS and/or disrupting its normal function on the cell membrane. Additionally, autophagy, as an intracellular metabolic regulatory mechanism, can also modulate NIS expression and its intracellular distribution, thus impacting the radioiodine uptake and the sensitivity to iodine-131 therapy. Reviewing the roles of these factors in thyroid carcinoma dedifferentiation comprehensively can provide a more thorough understanding of the occurrence and progression of RAIR-DTC, aiding in the exploration of new therapeutic targets, improving prognosis, and providing more effective personalized treatment strategies for patients.

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    Impact of folic acid and active folate supplementation on red blood cell folate levels in patients with unexplained recurrent pregnancy loss and MTHFR 677TT genotype
    LU Yongjie, HOU Shuchen, CHANG Liang, LIU Ping
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (6): 741-745.   DOI: 10.3969/j.issn.1674-8115.2024.06.009
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    Objective ·To study the effects of folic acid and active folate supplementation on red blood cell folate levels in patients with unexplained recurrent pregnancy loss (URPL) and methylenetetrahydrofolate reductase (MTHFR) 677TT genotype. Methods ·A total of 45 patients with MTHFR 677TT genotype and URPL in the Center for Reproductive Medicine of Peking University Third Hospital from January to December 2021 were selected. They were divided into three groups according to folic acid supplementation, including 16 cases in Group A (who had not received any form of folic acid supplementation before the study began, but received active folic acid supplementation after the study began),15 cases in Group B (who had received ordinary folic acid supplementation before the study began, and active folic acid supplementation after the study began),and 14 cases in Group C (ordinary folic acid was supplemented before the start of the study, and after the start of the study, ordinary folic acid and active folic acid were supplemented together). The concentration of 5-methyltetrahydrofolate (5-MTHF) in red blood cells was measured and compared at the time of enrollment (first measurement) and after supplementation (second measurement). Results ·There was no statistically significant difference in the first measurement of 5-MTHF concentrations in red blood cells between any two groups of patients in the three groups. Compared with the first measurement of 5-MTHF concentrations in red blood cells, the second increased (all P=0.000); the increase in 5-MTHF concentrations in red blood cells in Group B was higher than that in Group A (all P=0.000); the increasing 5-MTHF concentration in Group B was higher than that in Group A (t=2.373, P=0.049), but there was no significant difference between Group B and Group C. Conclusion ·Compared with folic acid supplementation, active folate supplementation can better improve red blood cell folate levels in patients with MTHFR 677TT genotype and URPL in a short period.

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    Targeting folate cycle enhances effects of cancer immunotherapy by modulating myeloid-derived suppressor cells
    HE Rui, YAN Kepeng, WANG Jing
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 1011-1022.   DOI: 10.3969/j.issn.1674-8115.2024.08.010
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    Objective ·To explore the regulatory mechanism of folate cycle metabolism in the immunosuppressive effect of myeloid derived suppressor cells (MDSCs). Methods ·Bone marrow cells were isolated from C57BL/6 mice and cultured in RPMI 1640 medium supplemented with GM-CSF, G-CSF, and IL-6 to induce MDSCs in vitro. PD-L1 expression level and ROS production level of induced MDSCs were detected by flow cytometry. CD8+ T cells were enriched from the spleen by MACS with anti-CD8a-conjugated microbeads, labeled with Celltrace violet, and then co-cultured with MDSCs. After 72 h, proliferation was assessed by flow cytometry. Folate cycle-related metabolic enzymes in MDSCs were detected by real-time quantitative PCR. MDSCs were treated with folate cycle metabolic enzyme MTHFD2 inhibitor DS18561882 (DS18) and folic acid antagonist Pemetrexed. ROS and mitoROS production in MDSCs were assessed by flow cytometry. CD8+ T cells were enriched from the spleen by MACS with anti-CD8a-conjugated microbeads, labeled with Celltrace violet, and then co-cultured with Pemetrexed or DS18-treated MDSCs. After 72 h, proliferation was assessed by flow cytometry. Transcript levels of folate cycle-related metabolic enzymes in pemetrexed or DS18-treated MDSCs were detected by RNAseq. A subcutaneous tumor mouse model of colon cancer was established. From the tenth day post-implantation, tumor-bearing mice were intraperitoneally injected with Pemetrexed (200 mg/kg) and tumor size was recorded for tumor growth curve. On the fourteenth day, mice were sacrificed, and tumors were harvested. MC38 tumor-bearing mice were treated with isotype antibody, anti-CD8 monoclonal antibody (1 mg/kg, deplete CD8+ T cells), Pemetrexed (200 mg/kg), and combination of Pemetrexed with anti-CD8 antibody. MC38 tumor-bearing mice were treated with isotype antibody, anti-Gr1 monoclonal antibody (1.25 mg/kg, clearing MDSCs), combination of Pemetrexed with anti-Gr1 antibody. On the tenth day after implantation, tumor-bearing mice were treated with Pemetrexed (50 mg/kg), anti-PD-1 monoclonal antibody (250 μg/kg), Pemetrexed, and combination of Pemetrexed with anti-PD-1 antibody. Results ·Flow cytometry data showed that PD-L1 level and ROS production were increased in induced MDSCs, and CD8+ T cell proliferation was also suppressed significantly. qPCR data revealed the expression of folate cycle-related metabolic enzymes MTHFD2 and others was increased in MDSCs. The accumulation of MDSCs was affected by DS18 or Pemetrexed, ROS production in MDSCs was reduced, and the immunosuppression of CD8+ T cells was relieved. RNA-seq results showed that genes related to MDSCs differentiation, such as S100 calc-binding protein A8, and genes related to MDSCs inhibition, such as cytochrome b-245β chain, which is related to ROS production, were also down-regulated after treatment with two folic acid cycling inhibitors. Tumor growth was suppressed by Pemetrexed. Tumor progression was promoted by combination of Pemetrexed with anti-CD8 antibody, compared with Pemetrexed monotherapy. However, tumor growth delay was inhibited by combination of Pemetrexed and anti-CD8, compared with anti-CD8 monotherapy. Tumor growth delay was caused by MDSCs depletion. But tumor growth was promoted by combination of pemetrexed and anti-Gr1, compared with pemetrexed monotherapy. Tumor growth was restricted by combination of pemetrexed and anti-PD-1 antibody, compared with anti-PD-1 monotherapy. Conclusion ·Pemetrexed relies on CD8+ T cells for anti-tumor effects and further retards tumor growth by reprogramming MDSCs to an anti-tumor phenotype. Modulating MDSCs by targeting folate cycle could impair their immunosuppressive ability and enhance the efficacy of immune checkpoint blockade in cancer treatment.

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    Study on the developmental function of CT14 using the model organism Caenorhabditis elegans
    YANG Shuwen, CHEN Juan, YANG Qin, LEI Ming, HUANG Chenhui
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 871-882.   DOI: 10.3969/j.issn.1674-8115.2024.07.008
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    Objective ·To investigate the effects of the cancer-testis antigen 14 (CT14) on embryonic and larval development in nematodes by using the model organism Caenorhabditis elegans (C. elegans), aiming to uncover its potential functions and mechanisms during development. Methods ·Transgenic C. elegans strains were constructed by using microinjection for the inducible expression of human CT14 (HsCT14), a truncated mutant of CT14 (HsCT14?CIR) lacking CT14-specific intermediate region (CIR), and a green fluorescent protein (GFP) control. The impacts of full-length and truncated mutant CT14 on nematode embryonic and larval development were analyzed and compared. Additionally, transgenic C. elegans strains with inducible expression of CT14 from various primates, including the crab-eating macaque (Macaca fascicularis) and mouse lemur (Microcebus murinus), were also constructed to assess the effects on egg hatching and larval-to-adult transformation rates. The differential gene expression in nematode embryos induced by CT14 was analyzed by Smart-seq transcriptome sequencing, with further insights gained through KEGG (Kyoto Encyclopedia of Genes and Genomes) and GSEA (Gene Set Enrichment Analysis), to explore the involved biological processes and pathways. Results ·The induced expression of HsCT14 and its truncated mutant HsCT14?CIR significantly reduced the hatching rate of nematode eggs, with a more pronounced effect observed in HsCT14-expressing strains. Differential interference contrast (DIC) microscopy imaging revealed significant morphological abnormalities in embryos expressing HsCT14 during the comma stage. Nematodes expressing HsCT14 or HsCT14?CIR exhibited developmental arrest in larvae and substantially lower larval-to-adult transformation rates compared to the GFP control. The impact was more pronounced in nematodes expressing HsCT14 than those with HsCT14?CIR. The expression of Macaca fascicularis CT14 (MfCT14) exhibited significant effects on the hatching rate and adult transformation rate, similar to that of HsCT14, while the expression of Microcebus murinus CT14 (MmCT14) displayed significantly reduced impact compared to HsCT14 and MfCT14. Smart-seq results indicated that CT14 expression affected various biological processes in nematode embryos, related to ATP-dependent chromatin remodeling and DNA replication. Conclusion ·Ectopic expression of the cancer-testis antigen CT14 significantly disrupts both embryonic and larval developments in C. elegans, with the CIR sequence substantially enhancing this effect. It suggests that CT14 may play an important regulatory role in biological development by affecting gene expression in multiple pathways, including chromatin remodeling.

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    Comparison of human-induced pluripotent stem cell-derived macrophages with peripheral blood-derived macrophages using single-cell genomics
    ZHANG Yutong, HOU Guojun, SHEN Nan
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (12): 1477-1489.   DOI: 10.3969/j.issn.1674-8115.2024.12.001
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    Objective ·To explore the heterogeneity in single-cell genomics between human-induced pluripotent stem cell (iPSC)-derived macrophages (IPSDM) and human peripheral blood-derived macrophages (PBDM). Methods ·iPSCs were differentiated into IPSDMs in vitro using a feeder-free and serum-free protocol. The expression of cluster of differentiation antigen 14 (CD14) and monocyte-macrophage marker genes in IPSDMs was analyzed using flow cytometry and real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. Single-cell sequencing was then performed on IPSDMs. Simultaneously, the single-cell sequencing dataset GSE126085 was downloaded from the Gene Expression Omnibus database as a reference dataset for PBDMs. Sequencing data for both IPSDMs and PBDMs were processed and analyzed using the seurat package in R software, with PBDMs annotated using the singleR package. A reference dataset was constructed with highly variable genes from PBDMs, and the highly variable genes of IPSDMs were projected onto the PBDM dataset using the scmap package to infer IPSDMs cell identities based on variable gene similarity. IPSDMs were annotated using cell-type annotation tools and referenced against relevant studies. The expression distribution of macrophage marker genes was compared between IPSDMs and PBDMs. Differentially expressed genes (DEGs) between IPSDMs and PBDMs were identified using the seurat package, and their potential biological functions were explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Results ·Suspended IPSDMs were obtained after 29 d of in vitro differentiation. Flow cytometry and RT-qPCR confirmed that approximately 23.1% of IPSDMs expressed CD14, and IPSDMs exhibited higher expression of monocyte-macrophage marker genes compared to the U-937 cell line. All cells in the PBDM dataset were annotated as macrophages. After constructing a scmap reference dataset using PBDMs, 59.8% of IPSDMs were annotated as macrophages through mapping their highly variable genes to the PBDM dataset. The remaining 40.2% of IPSDM cells could not be matched to the variable genes of PBDMs. Further manual annotation of IPSDMs revealed a composition of 97.15% macrophages, 2.71% hematopoietic precursor cell-like cells, and 0.14% dendritic cells. When comparing the expression of macrophage markers, both IPSDMs and PBDMs highly expressed the classical macrophage marker CD68 gene, while IPSDMs exhibited higher expression of markers associated with tissue-resident macrophages. GO analysis of DEGs showed enrichment in the molecular functions such as ubiquitin-like protein ligase binding, cellular components such as the nuclear speck and nuclear envelope, and biological processes such as the regulation of translation. KEGG pathway enrichment indicated that the DEGs between IPSDMs and PBDMs might be related to various intracellular pathogen infections. Conclusion ·Human IPSDMs and PBDMs exhibit certain similarities and heterogeneity at the single-cell transcriptional level. Transcriptomic analysis indicates that IPSDMs display more characteristics of tissue-resident macrophages. The DEGs between IPSDMs and PBDMs are potentially associated with intracellular infection immunity.

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    GPR87 promotes invasion and migration through the RHO/ROCK pathway in non-small cell lung cancer
    LIU Chenxi, HAN Lin, YANG Yi, ZHOU Han, LIU Yayun, SHENG Deqiao
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (12): 1514-1525.   DOI: 10.3969/j.issn.1674-8115.2024.12.004
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    Objective ·To explore the role and molecular mechanism of GPR87 in regulating the invasion and migration of non-small cell lung cancer (NSCLC). Methods ·Bioinformatics methods, including GEO, UALCAN, KM Plotter and other public database analysis platforms, were used to screen candidate genes related to NSCLC invasion and predict their clinical relevance to NSCLC. Eighty NSCLC clinical patient samples and corresponding clinical pathological data were collected from Yichang Central People's Hospital from January 2018 to August 2020. Immunohistochemistry was used to analyze the expression of GPR87 in tumor tissues and the clinical relevance of GPR87 was analyzed. siRNA-GPR87 and pCMV-GPR87-his were transfected into the human lung adenocarcinoma cell line A549 and the human lung squamous cell carcinoma cell line SK-MES-1, to construct cell lines with low and high expression of GPR87. Transwell assay was used to investigate the effect of GPR87 expression on the migration and invasion ability of NSCLC cells. ELISA was used to detect the secretion of MMP7 in the culture supernatant. RT-qPCR was used to detect the mRNA expression levels of GPR87, MMP2, MMP7, MMP9, E-cadherin,N-cadherin, vimentin,snail,twist, RHOA, RHOC, and ROCK1. ELISA was used to detect the secreted protein MMP7. Western blotting was used to detect the protein expression levels ofGPR87, MMP9, E-cadherin, vimentin, RHOA, and ROCK1. Results ·Bioinformatics analysis of clinical sample data showed that GPR87 was highly expressed in NSCLC. Patients with higher expression of GPR87 had worse clinical stage and were more prone to lymph node metastasis, suggesting that GPR87 might be a key gene for the high invasiveness of NSCLC. Downregulation of GPR87 expression significantly reduced the invasion and migration ability of A549 and SK-MES-1 cells, while overexpression of GPR87 enhanced the invasion and migration ability of A549 and SK-MES-1 cells. Further detection revealed that downregulation of GPR87 led to decreased mRNA expression levels of MMP2, MMP7, MMP9, RHOA, RHOC, and ROCK1, as well as a reduction in the secretion of MMP7 and the protein expression levels of MMP9, RHOA, and ROCK1 in A549 and SK-MES-1 cells. Overexpression of GPR87 increased the mRNA expression levels of MMP2, MMP7, MMP9, RHOA, RHOC, and ROCK1, as well as the secretion of MMP7 and the protein expression levels of MMP9, RHOA, and ROCK1. Regardless of GPR87 knockdown or overexpression, the expression of genes and proteins related to epithelial-mesenchymal transition (EMT) in the cells did not change significantly. Conclusion ·High expression of GPR87 is closely related to the high invasiveness of NSCLC. In SK-MES-1 and A549 cells, GPR87 can activate the RHOA/ROCK1 signaling pathway, promote the expression of MMPs, and ultimately promote the invasion and migration of NSCLC.

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    Research progress in food preferences mechanisms and their impact on obesity
    KANG Piao, ZHANG Ying, LI Huating
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (9): 1190-1196.   DOI: 10.3969/j.issn.1674-8115.2024.09.014
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    In recent years, the global prevalence of obesity has continued to rise, with a preference for high-sugar and high-fat foods being one of the primary contributors to this condition. Food preference refers to the degree of individual liking for specific foods, and its formation is closely related to the physiological effects such as satiety, satisfaction and reward that occur after food digestion in the gastrointestinal tract. With the continuous advancement of technologies such as neuroimaging and chemogenetics, the underlying neural and physiological mechanisms of food preference behavior are gradually being elucidated. Studies have shown that the digestion and absorption of food in the gastrointestinal tract can release chemical or electrical signals, which are transmitted to the central nervous system via neural pathways, humoral pathways and the gut-brain axis mediated by gut microbiota. Subsequently, these signals regulate feeding behavior by activating or inhibiting neurons in the nucleus of the solitary tract, the dopaminergic reward pathways and relevant neural circuits in the hypothalamus. Based on this, the article introduces the definition, evaluation methods and mechanisms of food preference, and reviews the pathways of food information transmission within the gut-brain axis, the reward circuits that modulate food preference and the application of food preference behavior to the treatment of obesity, in order to provide reference for research in the field of food preference and obesity treatment.

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    Optimizing arch expansion with clear aligners in the mixed dentition based on finite element analysis
    LÜ Qinyi, GAO Ziqi, FENG Qingchen, MEI Hongxiang, LI Juan
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 935-943.   DOI: 10.3969/j.issn.1674-8115.2024.08.001
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    Objective ·To reveal the direction, efficiency, and mechanical load of single tooth displacement with clear aligners for expansion treatment during the transitional dentition period with the aid of finite element analysis. Additionally, overcorrection and torque compensation systems were designed to address insufficient expansion efficiency and buccal inclination of posterior teeth. Methods ·One volunteer in mixed dentition period was included to construct a three dimentional cranio-maxillary complex model and an invisible orthodontic system, simulating the buccal displacement (load 1?4: 0.200, 0.275, 0.300, 0.325 mm, respectively) and root buccal torque (load 1: buccal displacement load 0.200 mm, root buccal torque 0°; load 5: buccal displacement load 0.275 mm, root buccal torque 1.0°; load 6: buccal displacement load 0.300 mm, root buccal torque 1.3° and load 7: buccal displacement load 0.325mm, root buccal torque 1.8°) on the maxillary deciduous teeth to the first permanent molar with a non bracket invisible orthodontic appliance. Through finite element analysis, the tooth displacement and equivalent stress distribution of the periodontal membrane can be calculated. Results ·Expansion treatment with clear aligners in the transitional dentition phase primarily revealed the effect of buccal expansion of teeth; different teeth achieved different levels of expansion rate. At a set expansion amount of 0.200 mm per side, expansion efficiency in the maxillary first permanent molar was 51.86%, second primary molar 68.76%, first primary molar 73.48%, and primary cuspid 84.17%. By designing over-correction (0.275, 0.300, 0.325 mm), the results showed significant enhancement in expansion effect. When overcorrection length reached 150% (0.300 mm), expansion efficiency at the maxillary first permanent molar, second primary molar, first primary molar, and primary cuspid were 75.16%, 99.96%, 107.35%, and 122.37%, respectively. The expansion efficiency of maxillary second primary molar, first primary molar, and primary cuspid was close to 100.00%. The overcorrection design exacerbated the dental effects of expansion, intensifying the tendency for teeth to tilt toward the cheek side, leading to side effects such as buccal inclination and drooping of the palatal cusps. When the overcorrection amount for expansion reached 150%, the crown-root displacement in the upper first permanent molar, second primary molar, first primary molar, and primary cuspid were -0.109, -0.134, -0.132, and -0.298 mm, respectively. Applying specific torque compensation for different tooth positions can combat the buccal inclination of posterior teeth. At an overcorrection length of 150% (0.300 mm) with an added 1.3° root buccal torque, expansion efficiency was 56.15%, 73.88%, 79.49%, and 87.80%, respectively. While the crown-root displacement differences reduced to -0.081, -0.097, -0.095, and -0.208 mm. Conclusion ·When using clear aligners for expansion treatment during a transitional dentition period, side effects such as buccal inclination of posterior teeth exist. Furthermore, various teeth realize differing levels of expansion efficiency, necessitating the design of unique adjustment strategies according to different tooth positions. Overcorrection can improve expansion efficiency but needs to be coordinated with root buccal torque for the whole tooth to move buccally.

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