Journal of Shanghai Jiao Tong University (Medical Science)

Status and advances in the mechanism research on dento-maxillofacial skeletal abnormalities

JIANG Lingyong

2024, 44 (6): 663-675.
doi: 10.3969/j.issn.1674-8115.2024.06.001

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Dento-maxillofacial skeletal abnormalities exhibit high incidence rate, complex etiology, severe symptoms, difficult diagnosis and treatment, and lack of early intervention strategies, which is mainly due to insufficient exploration of mechanism research. These diseases are characterized by abnormal morphology, disordered mutual location and impaired function of bones and teeth, including skeletal abnormalities and malocclusion. Among them, maxillofacial bone and dento-periodontal complex are the two core structures, which respectively determine facial aesthetics and occlusal function. As for maxillofacial skeletal abnormalities, mechanism studies on skeletal development and pathogenesis are required for precise prevention and treatment. As for malocclusion, mechanism studies on homeostasis and stress remodeling are required from the perspective of orthodontics. Both mechanism studies can provide basic support for the diagnosis and treatment of dento-maxillofacial skeletal deformities. In this regard, previous studies usually focused on the expression maps of mutated genes and differential factors. In recent years, the development of conditional gene editing techniques, such as Cre-LoxP system, has enabled researchers to intuitively evaluate the function of key genes in a single cell lineage in vivo, helping to advance research on dento-maxillofacial skeletal abnormalities from phenotype level to molecular mechanism level. This review summarizes recent domestic and foreign researches on dento-maxillofacial skeletal abnormalities, as well as recent achievements of the author's team, and systematically proposes a research mode concluded as “One Centre, Two Motives”. The centre is dento-maxillofacial skeletal abnormalities. One motive is the development and pathogenic mechanisms of maxillofacial bone, and the other is the homeostasis and remodeling mechanisms of dento-periodontal complex. The research mode aims at systematical study of the pathogenesis and prognosis of diseases to explore potential therapies. Many advanced technologies have contributed to the exploration of “One Centre” through “Two Motives”: on the one hand, conditional gene editing models have provided a new strategy for studying the function of key factors in key cells in vivo; on the other hand, inducible conditional gene editing models have supported the precise control of the timeline for interventions after birth. Furthermore, with the help of single-cell sequencing and lineage tracing techniques, researchers have been focusing on tissue-specific stem cells, due to their in situ and characteristic functions. This situation is highly in line with the “One Centre, Two Motives” mode, and is benefit to shed a new insight on the theoretical researches and clinical applications of dento-maxillofacial skeletal abnormalities. The article reviews the “One Centre, Two Motives” mechanism research mode of dento-maxillofacial skeletal abnormalities.

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Generation and validation of the conditional osteoblast-specific retinoic acid signaling inhibition mouse model

SUN Siyuan, LIU Yuanqi, CUI Yiwen, HUANG Zihan, MEI Li, DAI Qinggang, JIANG Lingyong

2024, 44 (6): 676-686.
doi: 10.3969/j.issn.1674-8115.2024.06.002

Abstract ( 203 )

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Objective ·To construct and verify the mouse model that can mimic the vitamin A deficiency (VAD)-like craniofacial skeletal deformity and do not cause embryonic death. Methods ·Based on the Cre-LoxP system, the Osx^Cre;Rosa26^dn/dn mice expressing osteoblast-specific dominant-negative retinoid acid receptor α (dnRARα) mutation were obtained by hybridization through Osx^Cre and Rosa26^{dnRARα/dnRARα} mice, to achieve the conditional inhibition of retinoic acid signaling to simulate VAD disease. Femur bone mesenchymal stem cells (BMSCs) and parietal bone cells of Osx^Cre;Rosa26^dn/dn mice and their control littermates were isolated and underwent osteogenic induction, to assess the expression of retinoid acid receptor α (RARα) protein through Western blotting. Osteoblasts induced from parietal bone cells of Osx^Cre;Rosa26^dn/dn mice and their control littermates were isolated and the effect of retinoic acid signaling inhibition was verified through dual luciferase gene reporter assay. Meanwhile, Ad-eGFP or Ad-Cre adenovirus-infected femur BMSCs and parietal bone cells of Rosa26^dn/dn mice underwent osteogenic induction to assess the expression of dominant-negative mutant protein and the inhibition of the retinoic acid signaling pathway in vitro by Western blotting and dual luciferase gene reporter assay. Moreover, the skulls of 6-week-old Osx^Cre;Rosa26^dn/dn mice were collected, and Micro-CT scanning and three-dimensional (3D) reconstruction were performed to verify the craniofacial skeletal deformities of the mouse model. Results ·Western blotting results demonstrated that the level of RARα protein increased in the femur and parietal osteoblasts of Osx^Cre;Rosa26^dn/dn mice compared to that of their control littermates, and also increased in the Ad-Cre-infected femur and parietal osteoblasts of Rosa26^dn/dn mice compared to that in the Ad-eGFP-infected group (P<0.05). Dual luciferase gene reporter assay results indicated that the activity of retinoid acid response element (RARE) was inhibited in the osteoblasts of Osx^Cre;Rosa26^dn/dn mice compared to their control littermates, and was also inhibited in the Ad-Cre-infected group compared to the Ad-eGFP-infected group (P<0.05). Micro-CT and 3D reconstruction suggested that the skull of 6-week-old Osx^Cre;Rosa26^dn/dn mice exhibited VAD-like craniofacial skeletal deformities, including smaller size of the skull and osteogenesis imperfecta compared to their control littermates. Conclusion ·An osteoblast-specific dnRARα expressing mouse model that can mimic VAD-like craniofacial skeletal deformity is successfully constructed, therefore providing a new model for exploring the pathogenesis and therapeutic targets of VAD-like craniofacial skeletal deformity in the future.

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Dentofacial phenotype of non-syndromic tooth agenesis patients with PAX9 mutation

DOU Jiaqi, GAO Jie, BIAN Xiaoling, WANG Feng, DAI Qinggang, WU Yiqun

2024, 44 (6): 687-693.
doi: 10.3969/j.issn.1674-8115.2024.06.003

Abstract ( 156 )

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Objective ·To evaluate the dentofacial phenotype in non-syndromic tooth agenesis (NSTA) patients with paired box gene 9 (PAX9) mutation. Methods ·Patients with NSTA who visited the Department of Second Dental Center of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, between January 2016 and December 2023 received whole-exome sequencing to screen PAX9 mutation. The location and number of missing teeth were evaluated by oral pantomography, and dentofacial deformities were evaluated by X-ray cephalometrics. Results ·Seven patients with PAX9 mutation were included in the study, including 3 males (42.9%) and 4 females (57.1%). The patients were 7?31 years old at first visit, with a mean age of (19.7±8.0) years old. All the 7 patients were PAX9 heterozygotes, of which 4 were missense and 3 were frameshift. The average number of missing teeth was 15.9±2.9. The number of missing teeth in maxilla (9.6±2.6) was slightly higher than that in mandible (6.3±2.4) (P=0.030). Maxillary second molar (100.0%), maxillary canine (85.7%) and mandibular second premolar (85.7%) were the three most common missing teeth, while mandibular lateral incisor (14.3%) and mandibular canine (14.3%) were the two least missing teeth. Patients with frameshift mutation had more missing teeth (18.3±2.1) than those with missense mutation (14.0±1.8) (P=0.032). X-ray cephalometrics analysis results showed that the angle sella-nasion-subspinale (SNA), angle nasion-subspinale-subspinale-porion (NA-Apo) and sella-nasion (S-N) in adult patients with PAX9 mutation were significantly lower than the normal reference values, suggesting a shorter anterior cranial base and maxillary length. The frankfort horizontal plane-nasion-porion (FH-NPo) was higher than the reference value, and the Y-axis was lower than the reference value, indicating a more prognathic mandible. The angle subspinale-nasion-supramental (ANB) was lower than the reference value, indicating a skeletal angle Ⅲ malocclusion. The angle upper central incisor-nasion-subspinale (angle U1-NA) was higher than the reference value, indicating a lip inclination of maxillary central incisor. The angle lower central incisor-mandibular plane (IMPA) and lower central incisor-nasion-supramental (L1-NB) were lower than the reference values, indicating a retroclination of the mandibular central incisor, and crossbite in the maxillary and mandibular anterior teeth. Conclusion ·The dentofacial phenotype of PAX9-mutated patients with NSTA is reported comprehensively. It is helpful to improve the understanding of the role of PAX9 in human maxillofacial development.

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Congenital tooth agenesis-related EDAR variants and pedigree analysis of HED patients with two variants

LAN Rong, DAI Qinggang, YU Kang, BIAN Xiaoling, YE Lijuan, WU Yiqun, WANG Feng

2024, 44 (6): 694-701.
doi: 10.3969/j.issn.1674-8115.2024.06.004

Abstract ( 180 )

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Objective ·To explore EDAR (ectodysplasin A receptor) gene variants that lead to congenital tooth agenesis, and preliminarily analyze the reasons why variants in EDAR can cause both syndromic and non-syndromic tooth agenesis. Methods ·Patients with congenital tooth agenesis admitted to the Department of 2nd Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine and their family members were included, and genomic DNA from their peripheral blood was extracted for whole exome sequencing (WES). After preliminary screening, PolyPhen-2, Mutation Taster, and Provean were used to predict the harmfulness of potential variants. The screened variants in patients and their families were verified by Sanger sequencing. Conservation analysis of variants was performed, and Swiss-Model was used to analyze the changes in the three-dimensional structure of EDAR. The teeth and syndromic phenotype of the patients and their family members were investigated. Results ·Among the included congenital tooth agenesis patients, five patients with EDAR mutations were found, one with EDAR frameshift mutation c.368_369insC(p.L123fs) and the other four with EDAR missense mutations. Two of these four patients were diagnosed as non-syndromic tooth agenesis (NSTA), resulted from c.77C>A(p.A26E) homozygous mutation and c.380C>T(p.P127L) heterozygous mutation, respectively. The other two patients with two variants were diagnosed as hypohidrotic ectodermal dysplasia (HED). One compound heterozygous missense mutation patient carried EDAR c.77C>T(p.A26V) from her father and EDAR c.1281G>C (p.L427F) from her mother; the other patient with both EDAR and EDA mutations carried EDAR c.1138A>C(p.S380R) heterozygous mutation and EDA c.1013C>T(p.T338M) hemizygous mutation. Both variants were from his mother and were reported to be related with NSTA. Two of these missense mutations, EDAR c.1281G>C(p.L427F) and EDAR c.77C>A (p.A26E), had not been reported before. The missense mutations affected the protein's spatial conformation by altering the polarity, charge, or volume of the amino acid residues. The frameshift mutation caused a non-triplet base addition, which probably led to protein truncation or degradation. Conclusion ·Two new EDAR missense mutations are discovered. An NSTA patients with EDAR homozygous mutations and an HED patient with both EDA and EDAR mutations are reported. It expands the understanding of pathogenic mechanisms of EDAR mutations causing HED and NSTA.

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Function and mechanism study of hypoxia-induced long non-coding RNA 68 in hepatocellular carcinoma

TAN Lu, SHEN Shaoming, HE Ping

2024, 44 (6): 702-712.
doi: 10.3969/j.issn.1674-8115.2024.06.005

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Objective ·To investigate the biological roles and associated mechanisms of the hypoxia-induced long non-coding RNA 68 (HILRNA68) in hepatocellular carcinoma (HCC) cell lines. Methods ·Long non-coding RNA (lncRNA) microarray analysis was conducted to study the differential expression of lncRNAs in the HCC cell lines cultured under hypoxia treatment and normoxia treatment separately for 12 h, and DEseq2 R package was used for the analysis of differentially expressed lncRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the differential lncRNAs. Short hairpin RNAs (shRNAs) were used to knock down hypoxia-inducible factors (HIFs) to investigate whether HILRNA68 transcription was regulated by HIFs under hypoxia. Nucleus-cytoplasmic isolation combined with qRT-PCR and RNA fluorescence in situ hybridization (RNA-FISH) experiments were used to investigate the subcellular localization of HILRNA68. HILRNA68 was knocked down in SMMC-7721 and MHCC-97H cells by small interfering RNA (siRNA) to investigate its cellular function under hypoxia. The impact of HILRNA68 on the cell proliferation and invasion capabilities of HCC cells under hypoxia was examined by cell counting and Transwell assays. Dual-luciferase reporter assay was employed to identify how HILRNA68 regulated the transcriptional activity of HIFs under hypoxia. Results ·By differential expression analysis of lncRNAs, a total of 247 and 17 significantly (defined as fold change≥4, FDR≤0.05) up- and down-regulated lncRNAs, respectively, were identified. Among these differentially expressed genes, lncRNA HILRNA68 was up-regulated about 10-fold in multiple HCC cell lines when cultured under hypoxia for 12 h. Knockdown of HIF1α, HIF2α, and HIF1β significantly suppressed (all P<0.05) the upregulation of HILRNA68 under hypoxia. Luciferase reporter assay suggested that the transcription of HILRNA68 was regulated by HIFs. Subcellular localization studies revealed that HILRNA68 was mainly localized in the nucleus. Biological function experiments showed that silencing of HILRNA68 significantly inhibited the proliferation and invasion of HCC cells under hypoxia (all P<0.05). Mechanistic studies demonstrated that knock-down of HILRNA68 significantly suppressed the transcriptional activity of HIF1α under hypoxia (P<0.05) and the up-regulation of these canonical HIFs targets under hypoxia was also significantly inhibited after HILRNA68 knockdown (P<0.05). Conclusion ·The current study identifies a series of differential hypoxia-regulated lncRNAs and functionally annotates the upregulated HILRNA68. HILRNA68 is directly up-regulated by HIFs which promotes cell proliferation and invasion under hypoxia. Mechanistically, the upregulation of HILRNA68 under hypoxia enhances the transcriptional activity of HIF1α.

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Phenotype and function of NK cell in colorectal cancer

FENG Xujiao, LIU Jianyue, QI Yangyang, SUN Jing, SHEN Lei

2024, 44 (6): 713-722.
doi: 10.3969/j.issn.1674-8115.2024.06.006

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Objective ·To investigate the composition of immune cells in tumor microenvironment of colorectal cancer (CRC), and examine the proportion, phenotype and effector function of natural killer (NK) cells in CRC. Methods ·Fresh tumor tissues, paired normal tissues adjacent to tumor, and peripheral blood samples in the same cohort were collected from CRC patients. Tissues were digested and prepared into single cell suspension. The major immune cell lineages were detected by flow cytometry. t-Distributed stochastic neighbor embedding (t-SNE) and statistical analysis were used to analyze the composition of immune cells in tumor microenvironment of CRC. To analyze the phenotype of NK cells, the expression levels of activation markers, including CD16, CD27, CD69, human leukocyte antigen-DR (HLA-DR), and T cell immunoglobulin domain and mucin domain-3 (TIM-3), were detected by flow cytometry. NK cell subsets: CD38^lowNK cells and CD38^highNK cells were also examined by flow cytometry. To assess the effector function of NK cells, they were stimulated with cell stimulation cocktail and the expression levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured by flow cytometry. Results ·Twenty-five pairs of fresh tumor tissues and normal tissues adjacent to tumor, and 15 peripheral blood samples in the same cohort were collected from CRC patients. The tumor microenvironment of CRC included diverse immune cell types, including T cells, B cells, NK cells and myeloid cells. The proportions of T cells (P=0.000) and myeloid cells (P=0.026) in tumor tissues were significantly higher than those in normal tissues. By contrast, the proportion of NK cells (P=0.007) in tumor was significantly reduced. The proportion of B cells was comparable between tumor and normal tissues. Compared to normal tissues, NK cells in tumor tissues expressed significantly lower CD27 (P=0.000) and CD69 (P=0.001), while the expression levels of CD16 (P=0.008), HLA-DR (P=0.000) and TIM-3 (P=0.024) were significantly elevated. The results indicated that NK cells in CRC tumor exhibited a phenotype of late activation and exhaustion. According to the expression level of CD38, NK cells could be divided into two subsets, CD38^highNK cells and CD38^lowNK cells. The proportion of CD38^highNK cells (P=0.003) in tumor tissues was significantly lower than that in normal tissues, while the proportion of CD38^lowNK cells was unaffected. Compared to CD38^lowNK cells, CD38^highNK cells expressed higher CD27, meanwhile significantly less CD16, NKp46, CD57, CD94, HLA-DR and CD158a (P=0.000). These results suggested that CD38^highNK cells were at early differentiation state. The secretion of cytokines IFN-γ (P=0.032), TNF-α (P=0.042), and GM-CSF (P=0.019) by tumor-infiltrated NK cells was significantly decreased compared to that in normal tissues. The results showed that the function of tumor-infiltrated NK cells was impaired. Conclusion ·Together, these data suggest that NK cell compartment is disrupted in tumor tissues of CRC, leading to the impaired anti-tumor immunity mediated by NK cells.

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Atp2b2 Oblivion heterozygous mutation causes progressive vestibular dysfunction in mice

LIU Yiqing, JIN Chenxi, FENG Baoyi, CHENG Zhenzhe, SUN Yilin, ZHENG Xiaofei, DONG Tingting, WU Hao, TAO Yong

2024, 44 (6): 723-732.
doi: 10.3969/j.issn.1674-8115.2024.06.007

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Objective ·To study the alterations in vestibular hair cell morphology and function of ATPase plasma membrane Ca²⁺ transporting 2 oblivion (Atp2b2 Oblivion) heterozygous mice at different ages. Methods ·Atp2b2 Oblivion heterozygous male mice aged 2 months and 8 months were selected with ten in each kind and C57BL/6J wild-type mice with the same gender, age and number were selected as the control group. Expression patterns of ATP2B2 in vestibular hair cells and numbers of hair cells in the striola zone and the extra striola zone in the two groups of mice at different ages were observed and calculated respectively through immunofluorescence assay. Hair bundle structures were detected by scanning electron microscopy (SEM), and mitochondria and ribbon synapse structures were observed by transmission electron microscopy (TEM). Vestibular evoked potential (VsEP), vestibular evoked myogenic potential (VEMP), rotarod rod test, and balance beam test were adopted for the evaluation of vestibular functions. Results ·ATP2B2 was mainly expressed in the hair bundle of vestibular hair cells in the two groups of mice. Hair cell numbers in the striola zone and the extra-striola zone did not exhibit any differences between Atp2b2 Oblivion heterozygous mutant mice and wild-type mice of 2-month-old and 8-month-old. No visible structural abnormality in the hair bundle could be seen through SEM. TEM results implied no morphological abnormality in mitochondria or ribbon synapses in the 2-month-old heterozygous mutant mice, while vacuolar degeneration was discovered in the mitochondria under the cuticular plate in the 8-month-old heterozygous mutant mice with the normal ribbon synapses and the normal mitochondria near the innervation site. VsEP and VEMP thresholds of 2-month-old and 8-month-old Atp2b2 Oblivion heterozygous mutant mice were significantly elevated compared with the wild-type mice. Analysis of VsEP waveform manifested prolonged P1 latency and declined P1N1 amplitude in heterozygous mutant mice (P<0.05). Results of rotarod rod test and balance beam test acquired from 2-month-old Atp2b2 Oblivion heterozygous mutant mice were not significantly different from the wild-type mice, while the ability of the mutant mice to accomplish the tests descended significantly at 8 months of age compared with the wild-type mice (P<0.05). Conclusion ·Atp2b2 Oblivion heterozygous mutant mice showed defective vestibular electrophysiological function at 2 months old, and abnormalities in vestibule-related behaviors can be detected at 8 months old. The vestibular function of Atp2b2 Oblivion heterozygous mutant mice deteriorate progressively.

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Early symptom network analysis of patients after transfer from intensive care unit

DONG Ran, YU Qian, TAI Rui, YANG Fu, FANG Fang

2024, 44 (6): 733-740.
doi: 10.3969/j.issn.1674-8115.2024.06.008

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Objective ·To establish the early symptom network of adult intensive care unit (ICU) patients after transfer (post-ICU patients), identify the core symptoms and bridge symptoms, compare the symptom networks of two subgroups, i.e. mixed ICU and coronary care unit (CCU), and analyze the occurrence of symptoms. Methods ·From December 2022 to August 2023, a total of 328 adult patients transferred to wards from mixed ICU and CCU of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine were selected by convenience sampling. The general situation and clinical data questionnaire, and symptom questionnaires (including Hospital Anxiety and Depression Scale, Fatigue Severity Scale, Richards-Campbell Sleep Questionnaire, and Pain Numeric Rating Scale) were used. Based on Spearman correlation analysis and GLASSO algorithm, contemporaneous symptom network was built, and centrality indices and differences between subgroup symptom networks were computed. The edge accuracy and the stability of centrality indices of the network were tested. Results ·A total of 302 valid questionnaires were collected, and the effective rate was 92.1%. The results of the centrality indices computations showed that in the early symptom network of post-ICU patients, the highest strength was “feel cheerful” (r_S=1.145), the highest closeness was “enjoy something” (r_C=1.851×10^-3), and the highest expected influence was “（fatigue） interferes with physical function” (r_E=1.143). The top three highest bridge strengths of symptoms were “worrying thoughts” (r_b=10.392), “enjoy something” (r_b=10.359), and pain (r_b=10.221). There were no significant differences in network structure (M=0.289) and overall connection strength (GS_{mixed ICU}=13.876, GS_CCU=13.838; S=0.039) of the early symptom networks between mixed ICU and CCU patients after being transferred to wards. When comparing the centrality indices, apart from the strength and expected influence of five symptoms showing statistically significant differences (all P<0.05), other indices were not significantly different. The edge accuracy and the stability of centrality indices in the early symptom network of post-ICU patients were fine. Conclusion ·Anxiety and depression are the core symptoms of adult post-ICU patients, and pain is one of the bridge symptoms. There is no significant difference in the incidence of early symptoms between mixed ICU and CCU patients after being transferred out. Medical care personnel should pay attention to the discomfort symptoms of post-ICU patients, and carry out targeted interventions to improve patients' comfort and promote the rehabilitation process.

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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

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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Heterogeneity and related factors of dyadic coping in infertility couples

XI Huiqin, TIAN Meimei, XIE Lei, XU Yurui, HUANG Xin, XU Ying, ZHANG Yaqing

2024, 44 (6): 746-754.
doi: 10.3969/j.issn.1674-8115.2024.06.010

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Objective ·To analyze infertility couples, dyadic coping level by using latent profile analysis (LPA), and explore the heterogeneity and related factors of different profiles. Methods ·From September to November 2023, 257 newly diagnosed infertility couples in pre-infertility treatment with assisted reproductive technology (ART) were recruited from Reproductive Medicine Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine. All couples were evaluated by using general information questionnaire, Fertility Problem Inventory (FPI), Dyadic Coping Inventory (DCI), and Fertility Quality of Life (FertiQoL) Tool. LPA was used to explore the dyadic coping profiles of the couples before ART treatment, and general information, FPI scores and FertiQoL scores were compared among the profiles. Multinomial Logistic regression analysis was used to explore the related factors of different profiles. Results ·A total of 257 couples with infertility were included, with an average age of (30.15±3.07) years for females, (31.82±3.82) years for males, (3.75±2.16) years for marriage, and (2.90±1.92) years for infertility; there were 118 couples caused by male infertility, 109 couples caused by female infertility, and 30 couples caused by both infertility; the average DCI score for males was (128.25±19.15) points, while for females it was (129.91±18.32) points. According to the dyadic coping levels, the infertile couples were divided into four profiles: common positive coping group (153 couples, 59.5%), common negative coping group (85 couples, 33.1%), male positive coping group (12 couples, 4.7%), and male negative coping group (7 couples, 2.7%). There were statistically significant differences in the infertile couples' age, FPI score, FertiQoL score, and remarriage rate among the four profiles (P<0.05). Multinomial Logistic regression analysis results showed that, with the common positive coping group as the reference, the common negative coping group had older men (OR=1.122, 95%CI 1.004?1.254, P=0.036), higher FPI scores for both males and females (male: OR=1.019, 95%CI 1.003?1.035, P=0.018; female: OR=1.020, 95%CI 1.004?1.036, P=0.015), and lower FertiQol scores for males (OR=0.966, 95%CI 0.937?0.996, P=0.029). Conclusion ·There are four types of dyadic coping profiles in infertile couples before ART treatment. Compared with the common positive coping couples, higher reproductive pressure, elder age, and lower perceived fertility quality of life of males, and higher reproductive pressure of females are all risk factors for common negative coping couples.

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Analysis of impact of type 1 diabetes on colorectal cancer by using two-sample Mendelian randomization

YU Yang, MENG Dan, QIU Yiwen, YUAN Jian, ZHU Yingjie

2024, 44 (6): 755-761.
doi: 10.3969/j.issn.1674-8115.2024.06.011

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Objective ·To investigate the potential causal relationship between type 1 diabetes and colorectal cancer by using Mendelian randomization (MR). Methods ·Two-sample bidirectional MR was used to investigate the causal relationship between type 1 diabetes and colorectal cancer. All research data were collected from the IEU Open GWAS Project database. The dataset of type 1 diabetes included 9 266 cases and 15 574 controls, with correlation analysis in 12 783 129 single nucleotide polymorphisms (SNPs); the dataset of colorectal cancer included 5 657 cases and 372 016 controls, with correlation analysis in 29 999 696 SNPs. The instrumental variables SNPs were screened. The results derived from the inverse-variance weighted (IVW) method were used as the main indicator of effect. The results derived from other four methods, namely MR-Egger regression, weighted median, simple mode, and weighted mode, were used as reference. Sensitivity was analyzed with the leave-one-out method. Heterogeneity was analyzed with Cochran's Q test by using both IVW and MR-Egger methods. Pleiotropy was analyzed with MR-pleiotropy function, and Steiger test was used for directional research. The colocation analysis was used to find out whether the causal relationship between type 1 diabetes and colorectal cancer was caused by the same SNP. The genetic correlation between 2 diseases was analyzed by using the linkage disequilibrium score regression (LDSC). All tests were analyzed by using R language software (version 4.3.1). Results ·After being screened, a total of 33 instrumental variables (SNPs) were used. The heterogeneity test results showed that there was heterogeneity among the SNPs (IVW and MR-Egger: P<0.05), so the effect evaluation was based on the results of the random effect model. MR analysis showed that type 1 diabetes had a significant causal effect on colorectal cancer (P<0.05) by using IVW, MR-Egger, weighted median and weighted mode. Sensitivity analysis showed that the results were stable. Pleiotropy was not detected in pleiotropy test (P>0.05). Steiger test showed that the effect of type 1 diabetes on colorectal cancer was not interfered with by the reverse effect. Reverse MR analysis showed no causal effect of colorectal cancer on type 1 diabetes (P>0.05). The results of colocalization analysis showed that the probability of H₄ hypothesis was 45.7%, and the causal relationship between the 2 diseases was not caused by the same SNP in the gene sequences. LDSC analysis demonstrated that there was no genetic correlation between the two diseases. Conclusion ·Type 1 diabetes may promote colorectal cancer, but colorectal cancer has no effect on type 1 diabetes.

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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

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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Research progress in the artificial intelligence-assisted measurement of myocardial strain

LI Xinxin, BIAN Yize, ZHAO Hang, JIANG Meng

2024, 44 (6): 773-778.
doi: 10.3969/j.issn.1674-8115.2024.06.013

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Myocardial strain is a dimensionless parameter reflecting the degree of deformation of the whole or local myocardium under stress, which can quantitatively detect myocardial injury and guide the early diagnosis, intervention and prognostic assessment of cardiac diseases. Cardiac ultrasound, cardiac CT and cardiac magnetic resonance can all be used for strain imaging and analysis, with two-dimensional speckle-tracking echocardiography being the most widely used means of myocardial strain detection today. However, due to inter-observer variations in manual analysis of myocardial strain and differences in the imaging systems and analysis software, the consistency and reproducibility of measured strain values among vendors are poor, limiting the clinical application of myocardial strain. Artificial intelligence (AI) can overcome the defects of strain measurement to a certain extent through automatic strain calculation and image quality assessment, which has a broad developmental prospect. This review focuses on the progress of AI-assisted measurement of myocardial strain in ultrasound, magnetic resonance, and other imaging modalities, as well as its application to disease diagnosis and patient prognosis assessment. This will improve the efficiency and consistency of strain measurement and promote the routine application of myocardial strain to clinical practice, which will play an incremental role in assessing myocardial injury and cardiac function. However, most of the current studies involve small sample sizes and lack external validation, and the reliability of their results needs to be further verified.

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Prospect of naturally derived polysaccharides in intervention in neurodevelopmental disorders

ZENG Dejie, CHEN Zenghui, DING Qiankun, SUN Xiaqing, SUN Qi, ZHAO Shibing

2024, 44 (6): 779-787.
doi: 10.3969/j.issn.1674-8115.2024.06.014

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Neurodevelopmental disorders (NDDs) are chronic developmental brain disorders that can affect cognition, motor, social adaptation, behavior and so on due to multiple genetic or acquired causes. Natural polysaccharides are synthesized by living organisms, located in the cell wall, inside and between cells, and outside the cells, and are essential components of life activities. Previous studies have found that natural polysaccharides play an important role in neurological diseases, which mainly ameliorate the behavioral abnormalities and clinical symptoms caused by anti-oxidative stress, anti-neuronal apoptosis, anti-neuroinflammation, anti-excitatory amino acid toxicity, and regulation of the brain-gut axis. This review summarizes the intervention role of 17 bioactive polysaccharides from plants and fungi in neurological diseases, aiming to provide new ideas for the research and treatment of NDDs.

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Research status of receptor-interacting protein kinase 1 in regulating cancer progression and immune response

ZHANG Yong, LI Weihong, CHENG Zhipeng, WANG bin, WANG Siheng, WANG Yubin

2024, 44 (6): 788-794.
doi: 10.3969/j.issn.1674-8115.2024.06.015

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Receptor-interacting protein kinase 1 (RIPK1) is a multi-domain serine/threonine protein kinase that causes downstream signal transduction and biological effects by phosphorylating specific proteins. In recent years, with the in-depth study of RIPK1, scholars have found that it is of great significance in autoimmune diseases, neurodegenerative diseases, and a variety of solid tumors and hematological tumors. On the one hand, RIPK1 promotes cell survival and inflammatory responses by activating specific pathways such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK). On the other hand, RIPK1 promotes apoptosis by interacting with cysteinyl aspartate specific proteinase-8 (caspase-8), or promotes necroptosis by interacting with RIPK3 and mixed lineage kinase domain-like protein (MLKL). As an upstream signal, RIPK1 has different expression levels in patients with different tumors. Its scaffold function and kinase activity can regulate cancer progression, initiate adaptive immunity, inhibit tumor progression, and generate an immunosuppressive tumor microenvironment to promote tumor development. Its dual role has been demonstrated in regulating the occurrence and development of tumors and the body's immune response, and can be used as a new therapeutic target to control cancer progression. This paper starts with the structure of RIPK1 to further explore its function in regulating cancer progression and immune response, and to provide new ideas for the development of cancer-targeted drugs.

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Two cases of primary Sjögren's syndrome with neurological impairment as initial symptom

YAO Li, TIAN Wotu, CAO Li

2024, 44 (6): 795-800.
doi: 10.3969/j.issn.1674-8115.2024.06.016

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Objective ·To study the clinical features of two primary Sj?gren's syndrome (pSS) patients with neurological symptoms as initial manifestations and review the related literature. Methods ·The clinical data, response to treatment as well as prognosis of 2 cases were analyzed and followed up. Results ·Case 1, female, initially presented progressive gait instability and distal sensory impairment at the age of 50. Clinical manifestations included spastic gait, sensory ataxia, conduction fascicular sensory impairment, as well as urination and defecation dysfunction. At the age of 58, this patient was unable to walk independently. The laboratory findings revealed a positive result for anti-nuclear antibody with a titer of 1∶1 000, anti-Sj?gren's syndrome A (SSA)/Ro-52, anti-SSA/Ro-60, and anti-centromere antibodies. Labial salivary gland biopsy showed lymphocytes and plasma cells infiltration into the glandular tissues, interstitium, and lobules, with 2 foci/4 mm² (lymphocytes >50). The cranial magnetic resonance imaging exhibited bilateral symmetric hyperintensity in the brainstem, characterized by the "snake-eye sign". Electromyography examination revealed axonal impairment of the right peroneal nerve. The patient was treated with high-dose corticosteroid therapy in combination with immunosuppressants. She experienced remarkable improvement. After three months, she was able to walk with aids and take care of herself in daily life. Case 2, female, presented spasmodic torticollis since the age of 81 with unknown reason. She had a history of mild mucosal dryness of mouth and eyes, and painful knee for one year. Laboratory findings revealed positive results for anti-SSA/Ro-52 and anti-SSA/Ro-60 antibodies, as well as hemoglobin of 86 g/L. Labial salivary gland biopsy demonstrated partial atrophy of the acini and the presence of 2 foci/4 mm²of lymphocytes and plasma cells infiltration into the stroma (lymphocytes>50). Electromyography examination showed reduced conduction velocity in the right median nerve. She got a significant relief after the treatment of immunosuppressants, antispasmodics, and muscle relaxants. Conclusion ·Patients presenting initial symptoms such as complex forms of spastic paraplegia and cervical dystonia expand the clinical spectrum of pSS. In clinical practice, it is important to distinguish neurological involvement secondary to pSS from other primary neurological disorders. For patients with neurological impairments but without apparent etiology, it is crucial to screen relevant series of autoimmune antibodies.

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