Welcome to JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCE EDITION)

2021 Vol. 52, No. 1

坚守初心 砥砺前行
2021, 52(1): 1-1.
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2021 年 1 期目录
2021, (1): 1-4.
Abstract(102) HTML (46)
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Metastasis is a multistep and low-efficiency biological process driven by acquisition of genetic and/or epigenetic alterations within tumor cells. These evolutionary alterations enable tumor cells to thrive in the inhospitable microenvironment they encounter in the process of metastasis and eventually lead to macroscopic metastases in distant organs. The unfolded protein response (UPR) induced by endoplasmic reticulum (ER) stress is one of the most important mechanisms regulating cellular adaptation to an adverse microenvironment. UPR is involved in all stages of metastasis, playing an important role in tumor cell growth, survival, and differentiation and the process of maintaining protein hemostasis. Sustained activation of ER stress sensors endows tumor cells with better epithelial–mesenchymal transition (EMT), survival, immune escape, angiogenesis, cellular adhesion, dormancy-to reactivation capacity in the process of metastasis. Here, we discussed the role of UPR in regulating the above-mentioned abilities of tumor cells during metastasis, providing a reference for development of new targets for the treatment of tumor metastasis.UPR in regulating the above-mentioned characteristics and mechanisms of tumor cells during metastasis, providing a reference for development of new targets for the treatment of tumor metastasis.
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In the early stage of infection in severe burn patients, the killing function of the natural immune cells is continuously low, which causes the immune system to continuously and compensatorily secrete a large amount of cytokines to improve the ability to resist bacterial infection. Once the cytokine secretion is out of control, a cytokine storm will form. In the late stage of severe burn infection, the bone marrow mobilization caused by continuous acute myelodysplasia will be exhausted, the level of immune response will be low, and the secretion of anti-inflammatory factors promoting repair will be increased, which will lead to immune suppression. Cytokine storm after burn infection is caused by excessive proinflammatory stimulation, inadequate inflammatory regulation, or a combination of the two. From the perspective of immunology, this review will briefly summarize the changing process of immune response against pathogenic bacteria after severe burn infection, cytokine storm in the early stage of severe burn infection and the mechanism of occurrence and transformation of immunosuppression in the late stage of severe burn infection. We suggest that future research direction from the following aspects: Mechanism of low bacterial killing function of innate immune cells after severe burns; The mechanism by which acute myeloid hyperplasia leads to myeloid inhibitory cells (MDSC) and nucleated erythrocytosis during the development of cytokine storms; The key regulatory mechanism between macrophage phagocytic dysfunction and cytokine hyperactivity; The role and key regulatory mechanism of destruction of the dynamic balance of M1/M2 macrophages and effector/regulatory T cells in triggering immune suppression.
Abstract:
Stress can improve an individual’s ability to adapt to environmental changes. However, excessive stress can induce stress-related mental disorders, including anxiety disorder, depression disorder and post-traumatic stress disorder (PTSD). Stress can regulate the level of hormones and immune inflammation in the body through the brain network, neural circuits, hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, thereby causing the occurrence of mental disorders. In addition, stress can mediate the occurrence of mental disorders by regulating molecular changes in the level of genes, transcription, protein and metabolism, etc. Studies have shown that the brain-gut axis also plays an important role in the pathogenesis of stress-related mental disorders. However, the pathophysiological mechanism of stress-related mental disorders remains unclear. Besides, studies have also shown that the onset of stress-related mental disorders is closely associated with the individual's physiological and psychological qualities,which has a cross-talk with other mental and physical diseases as well. Therefore, it is important to study individual premorbid diathesis clinical, and to conduct clinical medical, basic medical, and psychological studies of the different stages of the disease, so as to obtain further understanding of the pathogenesis of stress-related mental disorders.
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Post-traumatic stress disorder (PTSD) is characterized by intrusive emotional memory, alertness and avoidance after individuals suffer from one or more traumatic events. With the exception of manifestations, sleep disturbances are also considered to be the core symptoms of PTSD. This article mainly discussed insomnia, nightmares, obstructive sleep apnea (OSA), and periodic limb movement during sleep (PLMS) in patients with PTSD. Existing evidence suggested that insomnia is a predictor of the development of PTSD. Cognitive behavioral therapy for insomnia is an important research direction for treating insomnia in PTSD patients. Nightmares are also the core symptom of PTSD. Prazosin and image rehearsal therapy are effective therapies to treat post-traumatic nightmares. The co-occurrence of obstructive sleep apnea (OSA) is over 40% in patients with PTSD. Preliminary studies have shown that continuous positive airway pressure therapy can improve PTSD symptoms in patients with PTSD comorbid OSA. In the process of diagnosis and treatment of PTSD patients, it is important to firstly evaluate whether PTSD patient comorbid OSA or insomnia, and then clinicians could further develop an appropriate treatment plan for these patients.
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Purinergic signaling is involved in multiple physiological and pathological processes. Psychological stress, as an inharmonious state in response to stressors, is closely related to the function or dysfunction of purinergic signaling. Abnormal expression of ATP interceptors caused by stress leads to psychological stress-related diseases, such as anxiety, depression, post-traumatic stress disorder and schizophrenia. Recent studies demonstrate that a complex network of purinergic signaling (such as ATP, adenosine and P2X2R, P2X3R, P2X4R, P2X7R, A1R, A2AR) plays a key role in psychological stress, but the specific mechanism remains to be further studied. And few studies focus on the application of ATP real-time detecting to psychological stress animal models, so the specific biological role of ATP in the process of stress is still unknown. This review will summarize the relationship between purinergic signaling and psychological stress and propose to apply the duplicate ATP real-time detection technology and purinergic compounds on psychological stress research in order to provide novel potential targets for the treatment of stress-related diseases.
Abstract:
Chronic stress activates the typical neuroendocrine system, hypothalamus pituitary adrenal axis and sympathetic nervous system, and leads to a sustained non-specific adaptive response. It has been proved that chronic stress can promote tumor initiation and induce tumor evolution, especially in immune function and remodeling of tumor microenvironment. However, due to the complex mechanism of chronic stress and the great difference in individual tolerance, the research evidence of chronic stress in tumor genesis and progression is still unclear. Therefore, in this paper, we review the research on the relationship between chronic stress and tumor initiation and evolution, focusing on the molecular mechanism of chronic stress promoting tumor occurrence and development, inhibiting immune response and remodeling tumor immune microenvironment, and exploring the stress management program of healthy people and cancer patients, so as to provide clues for exploring new strategies of cancer prevention and treatment. In our opinion, targeting the cAMP/PKA/CREB signaling pathway to reverse tumor treatment strategy, the relationship between the tumor and stress, inflammation, immunity, the suppressor activity of β receptor antagonist and its mechanism as well as associated with different treatment options, still need to be further explored. A healthy lifestyle, positive life attitudes and professional stress management guidance are essential for the prevention and treatment of cancer.
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Tumor associated macrophages (TAMs) are one of the most common types of stromal cells in solid tumors. They are closely related to the immunosuppressive status of tumor microenvironment and potentiate the malignant progress of tumors. Studies have shown that metabolism in tumor associated macrophages has been reprogrammed and involved in the regulation of their own polarization and corresponding functions and phenotypes. Metabolic reprogramming refers to the alteration of key enzymes activity, substrate and its associated metabolites’ concentration in a certain metabolic pathway, which accounts for the disorder of original metabolic states. In this paper, we mainly concentrated on the lipid metabolic reprogramming of TAMs, including triglycerides, fatty acids and their derivatives, cholesterol, phospholipids, and their regulations on tumor progression. However, the metabolism of tumor and tumor microenvironment cells is highly heterogeneous. It is worthy of further exploration on the similarities and differences of lipid metabolism reprogramming between stromal cells and tumor cells, and the mechanism of how reprogramming modulates cell activity. It will be a new strategy for immunotherapy of tumor with metabolic intervention to accurately target the lipid metabolism reprogramming of TAMs, so as to promote the polarization of TAMs to M1 like macrophages, when synthetically considering the diverse types of tumors and different stages of development.
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Historically, the Cambrian explosion was a major life evolution event caused by changes of natural environmental oxygen concentration. The use of oxygen was part of the basic survival instinct of higher life, which evolved a complex regulation system in response to variant levels of oxygen concentration. Hypoxia is one of the typical environmental characteristics in plateau areas. After long-term natural selection in hypoxic conditions, numerous species living in plateau areas have evolved unique mechanisms adapted to hypoxia. Recent studies have found that there are some similarities in adaptation to hypoxia between the animals in highland and different types of human solid tumor cells. Herein, we will summarize recent findings about the hypoxia adaptation evolution in high-altitude animals and the characteristics of hypoxic solid tumors, especially the reactive oxygen species responses in hypoxic solid tumors. We believe that deciphering the underlying molecular mechanisms involved in hypoxia adaptation in highland will facilitate the identification of new genes or biomarkers critical for research on hypoxic solid tumors in the future.
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Metabolic aberrance is one of the hallmarks of cancer. The metabolic patterns in cancer cells are well reprogrammed to provide building blocks and energy for their sustained growth. During tumor metabolic reprogramming, reactive oxygen species (ROS) are generated and the antioxidant systems are activated. High levels of ROS lead to oxidative damage and even cell death, whereas ROS at low levels act as second messenger to regulate many signaling pathways. Recently, with the revisiting of oxidative stress, it has been found that ROS can directly mediate the redox modifications of proteins, resulting in protein conformational and functional alterations. However, only a very small portion of metabolic enzymes, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and PKM2, etc., has been reported to undergo redox modifications. Whether other metabolic enzymes are regulated by redox modifications and thus exhibit critical functions remain largely unknown. Moreover, the specific spatio-temporal targeting of redox modifications of metabolic enzymes, as well as overcoming the existed redox and metabolic adaptation, are key points to be solved. Here, we will review the reported redox modification patterns of metabolic enzymes, the involved regulatory mechanisms and their roles in tumorigenesis and tumor progress. In addition, we will discuss the future therapeutic strategies targeting redox modifications of metabolic enzymes for tumor treatment.
Abstract:
Stress response is an adaptive process of the organism to confront environmental perturbation. Moderate stress response induces the organism to establish effective adaptive strategies for survival, while excessive stress response results in stress injury, which is a major cause of a variety of physical or psychological diseases, including diabetes mellitus. Diabetes mellitus is a typical stress-related disease, with numerous evidence indicating that the development and progression of diabetes mellitus are closely related to stress response, such as metabolic stress, oxidative stress and endoplasmic reticulum stress. However, the detailed mechanisms of stress response mediated regulation of diabetes mellitus and how to prevent or treat diabetes mellitus via modification of stress response remain to be further investigated. Here, we will introduce the definition and regulatory mechanisms of stress response, as well as discuss the biological functions and mechanisms of various stress responses during the pathogenesis of diabetes mellitus. This review highlights recent advances of stress medicine associated with diabetes mellitus, in order to provide theoretical basis and reference for prevention and treatment of diabetes mellitus. Future studies should focus on elucidating the clinical application potential of the key factors of stress response that mediate the pathogenesis of diabetes mellitus, as well as boosting the related translational medicine studies.
Abstract:
  Objective  In order to better understand the role of mechanical stress in early tooth development, we examined the spatiotemporal expression patterns of mechanical-stress related regulatory protein (actin filament, or F-actin), non-muscle myosin ⅡB (NMⅡB) and vinculin at different stages of tooth development in mice.  Methods  Mouse first mandible molars were used as the research model. Immunofluorescence staining was performed to detect the expression patterns of F-actin, NMⅡB and Vinculin, the key molecules constituting the chemical mechanical system, at bud, cap, early bell and late bell stages of tooth.  Results  F-actin, NMⅡB and vinculin were all expressed in the tooth epithelium in an extensive or a limited way at different stages of tooth development, while F-actin was also expressed steadily in the mesenchymal cells. The quantitative analysis of fluorescence intensity showed that F-actin and NMⅡB exhibited significantly increase in the early stage of tooth development, but then dropped to their basal levels at the end of the late bell stage and the early bell stage respectively, with the differences of expression changes between successive developmental stages showing statistically significance (P<0.05). Vinculin expression, however, remained at a relatively constant level except for the late bell stage when vinculin expression was slightly elevated compared to that of the early bell stage (P<0.05).  Conclusions  The findings suggest that mechanical stress is involved in early tooth development. F-actin may have an important role in dispersing and transmitting mechanical stress while NMⅡB may participate in tooth epithelial invagination and cusps formation. The findings also suggest that vinculin can respond to the mechanical stimuli and its interaction with cell adhesion molecules may play a role in tooth development. The mechanism of how actomyosin and cell adhesion interact with each other in regulating tooth development still needs further investigation.
Abstract:
  Objective  To understand the level of job satisfaction and work engagement of physicians in public hospitals, to analyze the interaction between job satisfaction and work engagement, and to discuss how each dimension of job satisfaction affects work engagement so as to provide information and reference for improving the level of work engagement of physicians in public hospitals.  Methods  Covering 6 public hospitals in Sichuan (3 tertiary-level hospitals and 3 secondary-level hospitals), 638 questionnaires were obtained from physicians through convenient sampling for data description and analysis. Pearson correlation method was used to analyze the correlation between job satisfaction and work engagement, and multiple linear stepwise regression method was used to analyze work engagement and the influencing factors of each dimension.  Results  With regard to job satisfaction, physicians showed high levels of satisfaction in personal safety (3.77±0.87), leadership identification and support (3.59±0.77), and job pressure (3.51±0.81). The mean points of work engagement and each dimension were as follows: total mean points of work engagement (4.02±0.99), dedication (4.21±1.13), absorption (4.19±1.08) and vigor (3.63±1.04). In job satisfaction, salary and benefits, work environment, social recognition, organizational management, leadership identification and support are positively correlated to work engagement and all dimensions. In job satisfaction, 5 dimensions, including social recognition, leadership recognition and support, work achievement, personal safety and organizational management, had a significant influence on work engagement and all dimensions.  Conclusion  Emphasis on the high-level needs for recognition and self-actualization of doctors, doctor-patient communication, and personal development of doctors may improve doctors' job satisfaction and work engagement.
Abstract:
  Objective  R6G-ddATP was used as a dideoxy fluorescence substrate to establish the single base end extension (SNaPShot)-gel fluorescence method for the rapid detection of the genotypes of three high-risk human papillomaviruses (HR-HPV) (HPV18, HPV33 and HPV35) genotypes.  Methods  HPV quality control products were used as as samples, and R6G-ddATP dideoxy fluorescence reagent was used as substrate. Firstly, HPV was amplified by using universal primers to obtain the first round of amplified products, which were purified and used as templates for subsequent SNaPShot reactions. Then, specific one-step extension primers were used to perform SNaPShot reaction to generate R6G-fluorescence-labeled DNA extension products. The product was subjected to agarose gel electrophoresis, the results of which were observed under a Gel Imager, and the HPV genotyping was done with different one-step extension primers. Each sample was tested three times and the results were compared with DNA sequencing results.  Results  The preferred annealing temperature for SNaPShot reaction is 55 ℃. Three HPV genotypes were examined by R6G-ddATP/SNaPShot gel fluorescence assay under optimal conditions, and the results were consistent with DNA sequencing results.  Conclusion  The R6G-ddATP/SNaPShot-gel fluorescence method for the micro-detection methods of three HR-HPV genotypes was successfully established and can be used for rapid detection of HPV genotypes.
Abstract:
  Objective  To investigate the characteristics of aortic remodeling after thoracic endovascular aortic repair using two-stent graft implantation (TEVAR-TSI) for Stanford B aortic dissection.  Methods  The clinical and imaging data of 128 patients who underwent TEVAR-TSI for Stanford B aortic dissection in the First Affiliated Hospital of Hebei North University from January 2013 through May 2019 were retrospectively collected. CT images were obtained before (T0) TEVAR-TSI and, 1 week (T1), 3 months (T2), 6 months (T3), 1 year (T4) after TEVAR-TSI. The maximum diameter of the true lumen and false lumen in the short axis view was accessed at five levels: L1: the level of primary tear entry, L2: the level of the bronchial bifurcation, L3: the level of the distal of the first stent-graft, L4: the level of the celiac trunk, L5: the level of the lowest renal arteries. The false lumen thrombosis in the thoracic aorta and abdominal aorta were assessed at different times, the false lumen and true lumen changes in diameter were evaluated between the preoperative and postoperative CT scan.  Results  The stented segment of the descending thoracic aorta was evaluated (L1-L3): The true lumen diameter showed an increasing trend and the false lumen diameter showed an decreasing trend at levels L1, L2, and L3, the change of true lumen diameter was positively correlated with the follow-up time (r=0.721, 0.827, 0.893, P<0.05), and the change rate of true lumen diameter was positively correlated with the follow-up time (r=0.763, 0.818, 0.902, P<0.05), and the change of false lumen diameter was negatively correlated with the follow-up time (r=−0.750, −0.927, −0.934, P<0.05), and the change rate of false lumen diameter was negatively correlated with the follow-up time (−0.774, −0.935, −0.952, P<0.05). When the unstented segment of the abdominal aorta was evaluated (L4-L5), the average true lumen diameter at the level of celiac trunk increased significantly at 1 year by 13.7% (P=0.007), however, the average false lumen diameter did not change over time (P=0.406). The average true lumen diameter and false lumen diameter at the level of the lowest renal arteries increased over time as well, the average true lumen increased by 10.1%, and the average false lumen increased by 13.6% (P=0.048, 0.017). Besides, the complete false lumen thrombosis rate of the stented segment of the descending thoracic aorta was higher than that of the unstented segment of the abdominal aorta.e complete false lumen thrombosis rate of the stented segment of the descending thoracic aorta was higher than that of the unstented segment of the abdominal aorta.  Conclusion  After receiving TEVAR-TSI, Stanford type B aortic dissection patients had high thrombosis absorption rate in the thoracic aortic segment covered by stent, and the aortic remodeling was more ideal. The aortic remodeling effect in the abdominal aortic segment not covered was not ideal, and the inner diameter of the abdominal aorta tended to increase. Therefore, close follow-up monitoring should be conducted.
Abstract:
  Objective  To evaluate the clinical application of array-based comparative genomic hybridization (a-CGH) in the prenatal diagnosis of fetal chromosomal aberrations in gravidas with advanced maternal age (AMA).  Methods  A total of 3 677 amniotic fluid samples from pregnant women who underwent amniocentesis for prenatal diagnosis solely due to AMA were selected. Array-CGH was performed on the Agilent CGXTM (8X60K) platform and the data were analyzed by the Genoglyphix software.  Results  The overall detection rate of chromosomal aberration was 2.04% (75/3677), with 53.33% (40/75) being aneuploidies, including 22 cases of trisomy-21, 5 cases of trisomy-18, 8 cases with XXY, 3 cases of XYY and 2 cases of mosaic monosomy X, 32.00% (24/75) being pathogenic copy number variations (pCNVs), including 19 cases of microdeletion and 5 cases of microduplication, with the fragment size ranging from 323 kb to 26 780 kb, and 14.67% (11/75) being likely pathogenic CNVs (lpCNVs), including 7 cases of microdeletion and 7 cases of microduplication, with the fragment size ranging from 358 kb to 16 873 kb. Besides, the detection rate of CNVs of unknown clinical significance (VUS) was 0.84% (31/3 677). The detection rate of aneuploidies increased significantly with increased maternal age (P<0.05). However, there were no significant differences in the detection rate of p/lpCNVs among different maternal age groups (P>0.05).  Conclusion  Our findings suggest that, compared with traditional karyotype analysis, a-CGH not only detects aneuploidies, but also detect pathogenic CNVs, including microdeletion/microduplication syndromes. The detection rate of fetal aneuploidies was closely correlated to maternal age. However, no correlation was found between the detection rate of p/lpCNVs and maternal age.
Abstract:
  Objective  To explore the significance of the resistance to polymyxin resistance of the extensively drug resistant Acinetobacter baumannii (XDRAB) lipopolysaccharide (LPS) lpx A, lpx C, lpx D and to screen appropriate combination therapy.  Methods  In the past two years, 72 XDRAB in the secretions of our patients were selected as the research object. According to the minimum inhibitory concentration (MIC) of the XDRAB strain on polymyxin, they were included in the drug resistance group and the sensitive group. The gene sequences of strains lpx A, lpx C, lpx D were compared with the standard strains to analyze gene mutations and compared the mutation rates in the drug resistant group and the sensitive group. The efficacy of the combination drugs was evaluated by microcheckerboard dilution method, including polymyxin+imipenem group, polymyxin+meropenem group, polymyxin+cefoperazone/sulbactam group, polymyxin+levofloxacin group, and polymyxin+fosfomycin group. Calculated the fractional inhibitory concentration (FIC) index of the combined medication regimen and compared the percentage of strains that exhibited synergistic, additive, irrelevant, and antagonistic effects.  Results  Tentyone were in the drug resistant group, accounting for 21 (29.17%,) and 51 were in the sensitive group, accounting for 70.83%. Some strains had mutations in lpx A, lpx C, lpx D genes. The mutation rate in the drug resistant group was 90.48%, which was significantly higher than 11.76% in the sensitive group, the difference was statistically significant (P<0.05). The combined drug sensitivity test showed, compared with the polymyxin+fosfomycin group, the mycotin+fosfomycin group had a higher percentage of strains with synergistic FIC index in the polymyxin+imipenem group, the difference was statistically significant (P<0.01).  Conclusion  XDRAB is resistant to polymyxin, which is related to mutations in LPS lipid A biosynthesis genes lpx A, lpx C, lpx D. Clinical treatment should adopt a combination of polymyxin+imipenem/meropenem and other drug combination to reduce the secondary infection of drug resistant bacteria.
Abstract:
  Objective  To study the effect of cytochrome P-4504F2 (CYP4F2) gene polymorphism on the initial dose of warfarin in patients after mechanical heart valve replacement.  Methods  We collected 350 patients receiving warfarin after mechanical heart valve replacement from January 2013 to December 2015 in our hospital. According to the international standardized ratio (INR) ≥2 at the initial stage after surgery, the patients were divided into two groups: INR≥2 group and INR<2 group. We selected the blood samples of all the 350 patients with testing the CYP4F2 gene type of each patient, and analyzed the effect of CYP4F2 gene polymorphism on the initial dose of warfarin after mechanical heart valve replacement (the average daily dose during hospitalization of patients 5-10 days after mechanical heart valve replacement).  Results  There was no statistical significance in the initial dose of warfarin among patients with different CYP4F2 genotypes. However, warfarin dose was higher in CYP4F2 TT genotype than in CYP4F2 CC carriers ((3.37±0.68) mg vs. (2.94±0.74) mg, P<0.05) in INR≥2 group; In patients with the same genotype, the initial dose of warfarin in the CYP4F2 CC ((4.02±0.58) mg vs. (2.94±0.74) mg) and CYP4F2 CT genotypes ((4.15±0.88) mg vs. (3.18±0.82) mg) of INR<2 group was higher than that in INR≥2 group (P<0.05). Gender, age, body mass index (BMI), comorbidities (hypertension, diabetes mellitus, coronary heart disease, atrial fibrillation), cytopigment P-450 2C9 (CYP2C9), CYP4F2 and vitamin K peroxide-reductase complex 1 (VKORC1) gene polymorphism and INR compliance were included in multiple linear regression analysis. The regression equation was as follows: warfarin initial dose (mg) =−8.634+0.352×BMI (kg/m2) +1.102×CYP4F2 genotype (CC or CT values 1, TT values 2) +2.147×VKORC1 (AA or AG values 1, GG values 2) +1.325×INR ( INR≥2 values 0, INR<2 values 1). The coefficient of determination (R2) of regression equation was 0.431 (P<0.05).   Conclusion   CYP4F2 gene polymorphism may affect the initial dose of warfarin in patients after heart valve replacement, and this effect is also affected by body characteristics and other factors.
Abstract:
  Objective  To investigate the diagnostic value of different captopril challenge test (CCT) diagnostic criteria for diagnosing primary aldosteronism (PA).  Methods  We collected the clinical data of 184 patients with hypertension retrospectively in West China Hospital of Sichuan University. Receiver operating characteristic (ROC) curves were used to analyze the post-CCT efficacy of aldosterone renin activity ratio (ARR), plasma aldosterone concentration (PAC), plasma renin activity (PRA) and PAC suppression rate for PA diagnosis.  Results  This study included 125 cases of primary aldehyde (PA group) and 59 cases of essential hypertension (EH group), and there were 38 normal renin primary hypertension (NREH group) and 21 low renin primary hypertension (LREH group) in EH group. The post-CCT PAC suppression rate (median (P25, P75)) of EH and PA group were 0.190 (0.083, 0.351) and 0.125 (0.024, 0.237), respectively. Compared with the NREH group, the basic and post-CCT PRA of LREH group were lower (P<0.001), and there were no significant differences compared with the PA group (P>0.05). We found significant overlap of post-CCT PRA and ARR between PA group and LREH group, while the overlap of post-CCT PAC between the two groups was small. In differential diagnosis of PA and EH, the areas under ROC curve of the post-CCT ARR, PAC, PRA and PAC suppression rate were 0.860 (95% confidence interval (CI): 0.800-0.907), 0.881 (95%CI: 0.825-0.924), 0.771 (95%CI: 0.703-0.831) and 0.632 (95%CI: 0.558-0.701), respectively. There was no significant difference between the first two indexes (Z=0.443, P=0.658), and both of them were higher than the latter two (P<0.05). The optimal post-CCT cut-off values for ARR and PAC in differential diagnosis of PA and EH were 19.24 ng·dL−1 with a sensitivity of 78.4% and a specificity of 88.1%, and 32.47 (ng·dL−1)/(ng·mL−1·h−1) with a sensitivity of 84.17% and a specificity of 72.41%.  Conclusion  Both ARR and PAC have higher diagnostic value than the post-CCT PAC suppression rate, post-CCT PAC is especially suitable as a confirmatory testing criterion of PA.
Abstract:
  Objective  To explore the clinical diagnostic application of invasive cardiopulmonary exercise test (iCPET) in patients with unexplained dyspnea.  Methods  A retrospective analysis was conducted, covering patients with a chief complaint of exertional dyspnea between May 5, 2017 and October 1, 2020. Right cardiac catheterization examination was performed on patients whose cause had not been identified through routine examination, and further iCPET was performed on patients if no clear etiology was identified through right cardiac catheterization. According to the results and the diagnostic criteria of iCPET, patients showing no obvious abnormalities in the right cardiac catheterization examination were divided into four subgroups: exercise-induced pulmonary arterial hypertension (eiPAH), exercise-induced heart failure with preserved ejection fraction (eiHFpEF), preload failure, and oxidative myopathy. By comparing the lab test, echocardiography, right heart catheter and iCPET peak exercise data of the subgroups, the disease distribution and exercise hemodynamic characteristics of patients with unexplained dyspnea examined by iCPET were described.  Results  Of the 1 046 patients with exertional dyspnea, 771 were diagnosed with routine examination, while among the remaining 275 patients, 131 (47.6%) were diagnosed with right cardiac catheterization and 144 (52.4%) showed no clear etiology after routine examination and right cardiac catheterization. Of these 144 patients, 49 (34.0%) received iCPET with a median exercise time of 375 s. A total of 47 patients completed the examination, with a male-to-female ratio of 0.27∶1 and an average age of (47.9±14.4) years old. Among the 47 patients, 76.6% (36/47) aged between 20 and 59 and 78.7% (36/47) lived in urban areas. The preload failure group (n=27) showed low right atrium pressure at peak exercise intensity. The eiHFpEF group (n=9) showed high wedge pressure of pulmonary capillaries at peak of exercise intensity. The eiPAH group (n=8) showed high average pulmonary artery pressure at peak exercise intensity. The oxidative myopathy group (n=3) was characterized by impairment of tissue uptake and/or utilization of oxygen during exercise. According to the comparison among the three subgroups of the preload failure, eiHFpEF and eiPAH, the eiPAH group had the highest blood K+ level in routine examination, while the preload failure group had the lowest blood K+ level (P=0.014). The iCPET of the three subgroups showed statistically significant (P=0.001) difference in right atrial pressure increase during exercise. Among the three, the eiHFpEF group had the highest increase and the preload failure group had the lowest increase. Conclusion  In unexplained dyspnea patients showing no abnormal results in right cardiac catheterization examination, the main cause was preload failure, which manifested as low right atrial pressure at peak exercise intensity. The study showed that iCPET was of important value for dyspnea cases when the cause of the condition was not revealed with right cardiac catheterization.
Abstract:
  Objective  This study investigated the clinicopathological traits and ultrasound features of female reproductive system extraosseous Ewing's sarcoma (EES) and explored the diagnostic value of ultrasonography for this condition.  Methods  Cases of female pelvic EES diagnosed and treated at our hospital between June 2009 and June 2019 were included in this study. Pathology data and ultrasound manifestations were assessed retrospectively to summarize the clinical traits and ultrasound features of female reproductive system EES. Based on the results, recommendations for the ultrasonography-based diagnosis of this disease were proposed.  Results  During the 10-year study period, 13 female patients were diagnosed with EES in the pelvic cavity based on the results of postoperative pathology tests. The age of the patients ranged from 8 mouth to 40 years, and no patients demonstrated specific clinical symptoms. However, an examination of tumor biomarkers revealed that certain patients had elevated levels of CA125. In the 13 patients, 19 lesions were identified, including 16 that involved the reproductive system. The primary ultrasound manifestation was uneven, low-echo solidity or cystic solidity, exhibiting large size, irregular shape, and unclear boundary. A few patients had concurrent ascites. Although some lesions lacked blood supply, the blood supply of most lesions was medium to abundant, and the blood flow was mostly characterized by low resistant. Almost none of the lesions were definitively diagnosed preoperatively.  Conclusions  Preoperative definitive diagnosis of EES in the female reproductive system remains a great clinical challenge. Although certain clinical traits and ultrasound features are associated with this disease, and color Doppler ultrasonography might provide vital information indicating the presence of EES, the final diagnosis still depends on the pathological test results of the patients.
Special Editorial
Abstract:
Stress is an nonspecific adaptive response to endogenous or exogenous stimuli, which is commonly applied by organisms to maintain their internal homeostasis and normal physiological functions. When the extent of stress response surpasses the threshold that the organism can adjust to, a variety of physiological or psychological diseases can be induced by stress response. Stress medicine focuses on investigating the mechanisms underlying the development and progression of the diseases induced by stress response, aiming to find ways to prevent and treat stress-related diseases. Here, we will start with an introduction of stress response, then review the recent advances of stress medicine by discussing the latest research advances in the regulatory mechanisms and biological functions of stress response under various physiological or pathological conditions.
Review
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most notorious malignancies with a 5-year survival rate of less than 8%. Therefore, it is crucial to investigate the molecular mechanism underlining PDAC initiation, promotion, and progression for efficient treatment of PDAC. In order to adapt and survive in an extremely adverse microenvironment of hypoxia and insufficiency of nutrients and energy, PDAC cells undergo extensive metabolic modification triggered by intrinsic signalings which are activated by different genetic events, including mutations occurred at KRAS, TP53, and DPC4/SMAD4, collaboratively promoting PDAC development. Notably, PDCA cells have extensive crosstalk in the form of reciprocal metabolic flux with its surrounding microenvironment to facilitate tumor advancement and therapy resistance. We herein summarize recent findings of PDAC metabolism and discuss metabolic rewiring-based therapeutic strategies.
Medical Education
Abstract:
Personnel training is the core and cornerstone of stomatology education. This paper introduces the background and connotation of “New Medicine Department”, and discusses the influence of new medicine on the development of stomatology from the aspects of precision medicine, transformation medicine and intelligent medicine, the new requirements of stomatology education in the new medical department construction under the health China strategy were analyzed, this paper puts forward some thoughts on how to promote the development of stomatology education in new medical disciplines from aspects of promoting the cross-integration of disciplines, consolidating the basis of talents training, promoting the training mode of general education, integrating moral education into the whole teaching process, promoting the coordination of Medical Education and education in all aspects, cultivating different types of stomatology talents, and building up a contingent of teachers in all dimensions, in order to provide reference for the reform and development of stomatology education in China.
Original Articles
Abstract:
  Objective  To explore the differences in transcriptional levels between mutant strains of csn2 gene of CRISPR-Cas9 system of Streptococcus mutans (S. mutans) and wild-type strains.  Methods  The S. mutans UA159, csn2-gene-deleted strains (Δcsn2) and csn2-gene-covering strains (Δcsn2/pDL278-csn2) of S. mutans were cultivated. Total RNA was extracted, and high-throughput sequencing technology was used for transcriptome sequencing. Based on the GO analysis and the KEGG analysis of the differentially expressed genes, the biological processes involved were thoroughly examined. The qRT-PCR method was used to verify the transcriptome sequencing results.  Results  The transcriptome results showed that, compared with UA159, there were 176 genes in Δcsn2 whose gene expression changed more than one fold (P<0.05), of which 72 were up-regulated and 104 were down-regulated. The GO enrichment analysis and the KEGG enrichment analysis revealed that both the up-regulated and down-regulated differentially expressed genes (DEG) were involved in amino acid transport and metabolism. In addition, the biological processes that up-regulated DEGs participated in were mainly related to carbohydrate metabolism, energy production and conversion, and transcription; down-regulated DEGs were mainly related to lipid metabolism, DNA replication, recombination and repair, signal transduction mechanisms, nucleotide transport and metabolism. The functions of some DEGs were still unclear. Results of qRT-PCR verified that the expressions of leuA, leuC and leuD (genes related to the formation of branched-chain amino acids) were significantly down-regulated in Δcsn2 when compared with UA159 and Δcsn2/pDL278-csn2.  Conclusion  Through transcriptome sequencing and qRT-PCR verification, it was found that the expression of genes related to branched-chain amino acid synthesis and cell membrane permeability in Δcsn2 changed significantly.
New Technology and Methods
Abstract:
  Objective  To evaluate the diagnostic value of 3.0T time-of-flight MR angiography with sparse undersampling and iterative reconstruction (TOFu-MRA) for unruptured intracranial aneurysms (UIAs) on the basis of using digital subtraction angiography (DSA) as the reference standard.  Methods  A total of 65 patients with suspected UIAs were prospectively enrolled and all patients underwent TOFu-MRA and DSA. Relying on DSA as the reference standard, the sensitivity (SEN), specificity (SPE), positive predictive value (PPV) and negative predictive value (NPV) of using TOFu-MRA in UIA diagnosis were calculated, and the inter-observer agreement between two doctors was determined. Comparison of maximum intensity projection (MIP) and volume rendering (VR) image datasets was made to evaluate the agreement between DSA results and TOFu-MRA in the measurement of UIA morphological parameters, including the neck width (Dneck), height (H) , and width (Dwidth) of UIAs.   Results  The study covered 55 UIAs from 46 patients. The SEN, SPE, PPV and NPV of the two doctors using TOFu-MRA in UIA diagnosis were as follows: (95.7%, 95.7%), (94.7%, 94.7%), (97.8%, 97.8%) and (90.0%, 90.0%), respectively for patient-based assessment; (96.4%, 94.5%), (94.7%, 94.7%), (98.1%, 98.1%) and (90.0%, 85.7%), respectively, for aneurysm-based assessment. There is a strong inter-observer agreement (Kappa=0.93 for patient-based assessment and 0.96 for aneurysm-based assessment) between the two doctors. Moreover, Bland-Altman analysis showed that more than 95% points fell within the limits of agreement (LoA), suggesting strong agreement between the two examination methods for the measurement of UIAs morphological parameters.   Conclusion  TOFu-MRA showed good diagnostic efficacy for UIAs and the results were in good agreement with those of DSA, the reference standard, for assessing UIA morphological parameter. TOFu-MRA can be used as a first choice for noninvasive diagnostic evaluation of UIAs.
Clinical Research
Abstract:
  Objective  To investigate A1 pulley thickness of flexor tendon in healthy volunteers and to analyze its influence factors.  Methods  The study included 90 healthy volunteers and the A1 pulley thickness at bilateral fingers was measured using high frequency ultrasound. The following parameters were recorded for each participant: age, gender, weight, height, body mass index (BMI).  Results  High-frequency ultrasound can clearly show A1 pulley. There was no significant difference in A1 pulley thickness between the bilateral fingers (P>0.05). A1 pulley thickness was significantly different in different fingers (P<0.05). Further comparison showed that A1 pulley thickness could be divided into two subsets: thumb and little finger ((0.196±0.051) mm), index, middle and ring fingers ((0.230±0.055) mm). A1 pulley thickness was positively correlated with age (r=0.468, P<0.001). The normal reference ranges for thumb and little finger were 0.09-0.23 mm, 0.12-0.30 mm and 0.12-0.32 mm, respectively. The normal reference ranges for index, middle and ring fingers were 0.11-0.27 mm, 0.15-0.35 mm and 0.17-0.35 mm in volunteers aged 3-19 yr., 20-49 yr., and ≥50 yr., respectively. Gender and BMI had negligible impact on A1 pulley thickness (P>0.05).  Conclusion  High-frequency ultrasound can clearly show and measure A1 pulley. Site and age should be taken into account when determining the reference range of normal A1 pulley thickness. High-frequency ultrasound can be a quantitative evaluation method for A1 pulley lesions.