Objective:To explore the changes of dynamic cerebral autoregulation ability in pilots exposed to acute positive acceleration(+ Gz) by transcranial Doppler combined with beat-to-beat blood pressure.Methods:A total of 26 pilots enrolled in the + 8Gz manned centrifuge trial at the Air Force Medical Center, Air Force Medical University from June to October 2022 were prospectively included. Blood pressure and heart rate were monitored in the resting state before the trial and within 5 min after centrifugation. Transcranial Doppler combined with noninvasive continuous beat-to-beat blood pressure monitor were used to detect bilateral middle cerebral artery blood flow velocity and beat-to-beat pulse pressure respectively. The transfer function analysis was applied to derive the parameters of cerebral blood flow autoregulation in each frequency band from 0.02 to 0.50 Hz, and the phase, gain and coherence were calculated. The above parameters were compared between resting state and after acute + 8Gz positive acceleration exposure.Results:Compared with the resting state, in all of the 26 pilots after acute + 8Gz positive acceleration exposure, the systolic and diastolic blood pressure and heart rate increased significantly ( P<0.001), the phase significantly increased and the gain significantly decreased in the ultra-low frequency band (0.02-0.07 Hz) ( P<0.05); whereas there were no statistical differences of gain and phase in the low frequency band (0.07-0.20 Hz) and the high frequency band (0.20-0.50 Hz) (all P>0.05). Conclusions:Transcranial Doppler combined with beat-to-beat pulse pressure can be used for the assessment of changes in immediate dynamic cerebral autoregulation after acute + Gz exposure, and transfer function analysis of ultra-low frequency band parameters is suitable for this type of evaluation.

OBJECTIVE To study the effects of bergapten in the treatment of liver fibrosis and its mechanism based on serum metabolomics. METHODS Forty mice were divided into normal control group （0.5% carboxymethyl cellulose sodium solution）， model group （0.5% carboxymethyl cellulose sodium solution）， and BP low-dose and high-dose groups （50， 100 mg/kg）， with 10 mice in each group. Except for the normal control group， the other three groups were all treated with carbon tetrachloride to induce liver fibrosis model； they were given relevant medicine/solution intragastrically， once a day， for consecutive 8 weeks. After the last medication， the levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in serum were detected， and liver pathological changes were observed； the expressions of α-smooth muscle actin （α-SMA） and Collagen Ⅰ were detected in liver tissue； the serum of the mice was collected for metabolomics analysis. RESULTS Compared with the model group， serum levels of ALT and AST and protein expressions of α-SMA and Collagen Ⅰ in liver tissue were decreased significantly in BP high-dose and low-dose groups （P＜0.05）， while liver fibrosis was improved significantly. Meanwhile， metabolomics analyses showed that there were a total of 175 serum differential metabolites in the BP high-dose group and model group， of which 18 substances were upregulated and 157 substances were downregulated； the main metabolic pathways involved in bergapten intervention were pyrimidine metabolism， butanoate metabolism， fatty acid synthesis， tyrosine metabolism， β-alanine metabolism， nicotinic acid and nicotinamide metabolism， glutathione metabolism， etc. CONCLUSIONS BP is effective in the treatment of liver fibrosis by regulating pyrimidine metabolism， butanoate metabolism， glutathione metabolism and so on in rats with liver fibrosis.

Objective:To compare the antiplatelet effects of vicagrel and clopidogrel in patients with different cytochrome P450 (CYP) 2C19 genotypes.Methods:This is a post-hoc analysis of a phase Ⅱ clinical trial of vicagrel, which included patients with coronary heart disease who underwent percutaneous coronary intervention from August 2018 to June 2019 in 18 centers. Patients were categorized based on the presence of CYP 2C19 *2 or *3 loss-of-function (LOF) alleles into LOF carrier group ( n=111) and non-LOF carrier group ( n=90). Each group included patients received vicagrel 5 mg, 6 mg, 7.5 mg, or clopidogrel 75 mg for 28 days per study protocol. P2Y 12 reaction units (PRU) were measured using VerifyNow at baseline, 6 to 8 hours after loading dose, 7 to 10 days after randomization, and 28 days after randomization and the percentage inhibition of platelet aggregation (%IPA) was calculated. The primary endpoint was %IPA on day 28. Within the patients from the General Hospital of Northern Theater Command, 8 to 12 patients in each study arms were enrolled in a prespecified pharmacokinetic sub-study, measuring the time to reach maximum plasma concentration (T max), peak plasma concentration (C max), and area under the plasma concentration-time curve (AUC). Results:Among 201 patients, the age was (58.8±8.5) years, and 139 (69.2%) were male. In non-LOF carriers, there was no significant differences in PRU values and %IPA between the vicagrel 5 mg, 6 mg, 7 mg, and clopidogrel groups at all time points (all P>0.05). In LOF carriers, %IPA was significantly higher in the vicagrel-treated groups than in the clopidogrel group at 6-8 hours after loading dose (22.9 (14.2, 31.5)% vs. 19.8 (11.0, 28.6)% vs. 29.5 (20.9, 38.0)% vs. 12.9 (3.9, 21.9)%, P=0.038) and 7-10 days after randomization (22.4 (14.2, 30.5)% vs. 34.4 (26.1, 42.6)% vs. 39.8 (31.8, 47.9)% vs. 24.7 (16.3, 33.2)%, P=0.001), with a trend towards higher %IPA in the vicagrel-treated groups at day 28 (30.4 (21.3, 39.6)% vs. 36.5 (27.2, 45.7)% vs. 40.8 (31.8, 49.8)% vs. 30.7(21.2, 40.2)%, P=0.056). Pharmacokinetic results of 35 patients showed that the C max and AUC of the active metabolite M15-2 of vicagrel was similar to that of clopidogrel in non-LOF carriers, but AUC between vicagrel 5 mg, 6 mg, 7 mg and clopidogrel were significantly different in LOF carriers ((5.6±0.6) h·μg -1·L -1 vs. (6.8±2.7) h·μg -1·L -1 vs. (9.2±3.3) h·μg -1·L -1 vs. (4.2±1.9) h·μg -1·ml -1, P=0.020). Conclusion:Vicagrel and clopidogrel have similar antiplatelet effects in non-LOF carriers, but vicagrel exhibits superior antiplatelet effects in LOF carriers.

Objective To analyze the clinical application value of cinematic rendering(CR)reconstruction technology in acute aortic dissection(AAD),and to compare the imaging quality between CR and volume rendering(VR)reconstruction.Methods Patients with suspected A AD who underwent aortic computed tomography angiography(CTA)were analyzed retrospectively.All images were uploaded to Siemens Syngo.via post-processing workstation for VR and CR three-dimensional reconstruction,respectively.The optimized view angle,staining and transparency were selected and segmented by a radiologist to display the lesion to the full extent.All subjective evaluations of post-processing images were randomly evaluated on Siemens Syngo.via post-processing workstation by two radiologists.The two radiologists reached a consensus after consultation,and the results without consensus were evaluated by another senior radiologist.The 3-point scale was used in the subjective evaluation of post-processing images.The scores of rupture,endometrium,and true and false cavity were recorded.The diagnostic confidence was also recorded.Results A total of 21 ADD patients were enrolled,11 patients(52.3％)were Debakey Ⅲ type.The scores of rupture in CR and VR reconstruction were 2.952 points and 2.619 points,respectively,which had significant difference(P=0.016).For the endometrium of AAD,the score of all 21 patients in the CR reconstruction was 3 points,while only 7 patients(33.3％)in the VR reconstruction had 3 points,which showed significant difference between the both(P＜0.001).For the true and false cavity of AAD,only 1 patient(4.8％)in the VR reconstruction was 3 points,while all 21 patients in the CR reconstruction had 3 points(P＜0.001).The scores of CR reconstruction on the diagnostic confidence were significantly higher than those of VR reconstruction(P＜0.001).Conclusion CR reconstruction can provide photorealistic anatomical post-processing images,and can improve the display and evaluation of AAD.

Objective:To assess the predictive value of dosiomics in predicting the occurrence of bone marrow suppression (BMS) in patients with pelvic tumors during radiotherapy.Methods:A retrospective analysis was conducted on the clinical data and radiotherapy planning documents of 129 patients with pelvic region tumors who underwent radiotherapy at the First Affiliated Hospital of Nanjing Medical University from January 2019 to January 2023. The region of interest (ROI) was outlined for bone marrow in the pelvic region by Accu Contour software in planning CT, and the ROI was exported together with the dose distribution file. According to a stratified randomization grouping method, the patients were divided into the training set and test set in an 8 vs. 2 ratio. The dosiomic features were extracted from the ROI, and the two independent samples t-test and the least absolute shrinkage and selection operator (LASSO) algorithm was employed to identify the best predictive characteristics. Subsequently, the dosiomic scores were calculated. Clinical predictors were identified through both univariant and multivariate logistic regression analyses. Predictive models were constructed by using clinical predictors alone and combining clinical predictors and dosiomic scores. The efficacy of predictive model was assessed by plotting the receiver operating characteristic (ROC) curve and evaluating its performance through the area under the ROC curve (AUC), the calibration curve, and decision curve analysis (DCA). Results:Fourteen dosiomic features that showed a strong correlation with the occurrence of BMS were screened and utilized to calculate the dosiomic scores. Based on both univariant and multivariate logistic regression analyses, chemotherapy, planning target volume (PTV) and V 5 Gy were identified as clinical predictors. According to the combined model, the AUC values for the training set and test set were 0.911 and 0.868, surpassing those of the clinical model (AUC=0.878 and 0.824). Furthermore, the analysis of both the calibration curve and DCA suggested that the combined model had higher calibration and net clinical benefit. Conclusion:The combined model has a high diagnostic value for predicting BMS in patients with pelvic tumors during radiotherapy.

Objective:To explore the differences in clinicopathological features, survival status and prognostic influencing factors of breast cancer patients with different molecular subtypes, and to provide bases for the prevention and treatment of breast cancer.Methods:The clinicopathological data of new-onset female breast cancer patients hospitalized in Shanxi Province Cancer Hospital from January 2015 to December 2016 were retrospectively analyzed, and patients were followed up. The clinicopathological features of patients with different molecular subtypes were compared. The follow-up was performed until June 30, 2021. Kaplan-Meier method was used to analyze the survival of patients, and Cox proportional hazards model was used to analyze the factors affecting overall survival (OS) of patients with different molecular subtypes.Results:There were 272 (14.9%), 1 005 (55.2%), 277 (15.2%) and 268 (14.7%) patients with subtypes of Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2) overexpression and triple-negative breast cancer (TNBC), respectively. The differences in the distribution of patients with age at diagnosis, age at menarche, menopausal status, age at menopause, pathological type, longest tumor diameter, T staging, N staging, histological grading, and TNM staging were statistically significant among the four groups (all P < 0.05). At a median follow-up of 60 months, the 5-year OS rates of Luminal A, Luminal B, HER2 overexpression and TNBC subtypes were 93.8%, 89.2%, 77.6% and 78.0%, respectively, and the difference was statistically significant ( χ2 = 58.76, P < 0.001). M staging was an independent influencing factor for OS in patients with Luminal A breast cancer ( HR = 16.789, 95% CI 4.972-56.690, P < 0.001); T staging ( HR = 2.721, 95% CI 1.715-4.319), N staging ( HR = 4.460, 95% CI 2.399-8.291) and M staging ( HR = 3.364, 95% CI 1.988-6.670) were independent influencing factors for OS in patients with Luminal B breast cancer (all P < 0.001); N staging ( HR = 4.428, 95% CI 1.836-10.677) and M staging ( HR = 13.489, 95% CI 6.043-30.107) were independent influencing factors for OS of patients with HER2 overexpression breast cancer (both P < 0.01); T staging ( HR = 3.052, 95% CI 1.575-5.915), N staging ( HR = 2.492, 95% CI 1.298-4.785) and M staging ( HR = 33.012, 95% CI 8.606-126.637) were independent influencing factors for OS of patients with TNBC (all P < 0.01). Conclusions:The clinicopathological features and prognostic influencing factors of breast cancer patients with different molecular subtypes are different, and the prognosis of HER2 overexpression and TNBC patients is poor. Clinicians should provide individualized treatment and follow-up programs for patients with different molecular subtypes of breast cancer.

Aristolochic acid (AA), extracted from Aristolochiaceae plants, plays an essential role in traditional herbal medicines and is used for different diseases. However, AA has been found to be nephrotoxic and is known to cause aristolochic acid nephropathy (AAN).AA-induced acute kidney injury (AKI) is a syndrome in AAN with a high morbidity that manifests mitochondrial damage as a key part of its pathological progression. Melatonin primarily serves as a mitochondria-targeted antioxidant. However, its mitochondrial protective role in AA-induced AKI is barely reported. In this study, mice were administrated 2.5 mg/kg AA to induce AKI. Melatonin reduced the increase in Upro and Scr and attenuated the necrosis and atrophy of renal proximal tubules in mice exposed to AA. Melatonin suppressed ROS generation, MDA levels and iNOS expression and increased SOD activities in vivo and in vitro. Intriguingly, the in vivo study revealed that melatonin decreased mitochondrial fragmentation in renal proximal tubular cells and increased ATP levels in kidney tissues in response to AA. In vitro, melatonin restored the mitochondrial membrane potential (MMP) in NRK-52E and HK-2 cells and led to an elevation in ATP levels. Confocal immunofluorescence data showed that puncta containing Mito-tracker and GFP-LC3A/B were reduced, thereby impeding the mitophagy of tubular epithelial cells. Furthermore, melatonin decreased LC3A/B-II expression and increased p62 expression. The apoptosis of tubular epithelial cells induced by AA was decreased. Therefore, our findings revealed that melatonin could prevent AA-induced AKI by attenuating mitochondrial damage, which may provide a potential therapeutic method for renal AA toxicity.

Objective:To investigate the genomic manifestation and pathogenesis of osteosarcoma with different relapse pattens, which were respectively initially presented with bone metastasis or pulmonary metastasis.Methods:From May 1, 2021 to October 1, 2021, 38 fresh tumor specimens and some paraffin-embedded specimens of high-grade osteosarcoma were collected in Peking University People's Hospital, including 29 males and 9 females, aged 19.6±2.2 years (range, 6-61 years). Among the 38 cases, 12 cases had initial bone metastasis (group A) and 26 cases had initial lung metastasis (group B), of which 15 cases (40%, 15/38) had paired specimens of primary and metastatic lesions. Based on Illumina NovaSeq 6000, we analyzed whole-exome sequencing (WES) as well as transcriptome for osteosarcoma with paired samples in different relapse patterns. During all their treatment courses, we also collected their paired samples to reveal these tumors' evolution. We sought to redefine disease subclassifications for osteosarcoma based on genetic alterations and correlate these genetic profiles with clinical treatment courses to elucidate potential evolving cladograms.Results:We found that osteosarcoma in group A mainly carried single-nucleotide variations (83%, 10/12), displaying higher tumor mutation burden [4.9 (2.8, 12.0) & 2.4 (1.4, 4.5), P=0.010] and neoantigen load [743.0 (316.5, 1,034.5) & 128.5 (49.0, 200.5), P=0.003], while those in group B mainly exhibit structural variants (58%, 15/26). The mutation spectrum showed that there was a significant difference in age-related gene imprinting 1 between the bone metastasis group and the lung metastasis group ( P=0.005). Samples were randomly selected from group A (3 patients) to investigate immunologic landscape by multiplex immunohistochemistry, from which we noticed tertiary lymphatic structure from one patient from group A. High conservation of reported genetic sequencing over time was found in their evolving cladograms. Conclusion:Osteosarcoma with mainly single-nucleotide variations other than structural variants might exhibit biological behavior predisposing toward bone metastases with older in age as well as better immunogenicity in tumor microenvironment.

Objective:To explore the clinicopathological characteristics and factors influencing the survival of young breast cancer patients with diagnostic age below 35 years, and to provide the basis for the prevention and treatment of young breast cancer patients.Methods:Epidemiological and clinicopathological data of young female patients with newly diagnosed breast cancer from Shanxi Province Cancer Hospital between January 2015 and December 2016 were retrospectively analyzed. The data included age at diagnosis, reproductive history, history of abortion, menopausal status, and immunohistochemical results. Univariate and multivariate analysis were performed by using Cox regression model.Results:A total of 118 young breast cancer patients were collected, and the median age was 31 years old. Among them, the vast majority of 118 young breast cancer patients were invasive cancer (113 cases, accounting for 95.8%); there were 65 cases (55.1%) with tumor diameter ≤ 20 mm, 61 cases (51.7%) at N 0 stage, and 112 cases (94.9%) at M 0 stage. The positive rates of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) were 73.7% (87/118), 69.5% (82/118) and 28.8% (34/118), respectively. Luminal B breast cancer was the predominant molecular subtype, accounting for 55.1% (65/118). By the end of follow-up (median follow-up period of 60 months), the overall survival rate of young breast cancer patients was 78.8%. Multivariate analysis showed that TNM staging was an independent factor affecting overall survival in young breast cancer patients ( HR = 7.858, 95% CI 2.924-21.120, P < 0.001). Conclusions:Young breast cancer patients have unique clinicopathological features and TNM staging is an independent factor affecting the prognosis. Individualized treatment helps to improve the quality of life and prolong the survival time of patients.

Objective:To investigate the association between breast cancer and thyroid diseases, and to provide evidence for the prevention and treatment of thyroid diseases in breast cancer patients.Methods:A total of 511 newly diagnosed breast cancer patients were recruited between March 2018 and August 2019 from Shanxi Province Cancer Hospital, and 303 age-matched newly diagnosed breast benign disease patients and 341 age-matched healthy controls were recruited during the same time-frame. Thyroid B-ultrasound and thyroid function test were performed in the three groups. By reviewing the medical records, the general and clinicopathological data of the patients were collected, and the differences in the prevalence of thyroid diseases among the three groups were compared. The changes of thyroid function in breast cancer patients before treatment, in the middle stage of chemotherapy and at the end of chemotherapy were compared.Results:Among breast cancer group, breast benign disease group and healthy control group, the differences in the prevalence rates of hypothyroidism [32.5% (166/511), 25.7% (78/303) and 21.7% (74/341)], thyroid nodules [50.7% (259/511), 43.2% (131/303) and 41.6% (142/341)] and Thyroid Imaging Reports and Data System(TI-RADS) grade 4 and above thyroid nodules [15.4% (40/259), 14.5% (19/131) and 4.9% (7/142)] were statistically significant (all P < 0.05). The abnormal rates of thyroid stimulating hormone (TSH) and free thyroxine (fT4) in breast cancer group were higher than those in breast benign disease group and healthy control group [34.1% (174/511) vs. 26.1% (79/303), 23.5% (80/341); 24.9% (127/511) vs. 8.6% (26/303), 3.2% (11/341)], and the differences were statistically significant (both P < 0.05). The levels of fT4, free three iodide thyroxine (fT3), thyroid immunoglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) in breast cancer patients before treatment, in the middle stage of chemotherapy and at the end of chemotherapy were statistically different (all P < 0.05). The abnormal rates of fT4, TgAb and TPOAb in the last chemotherapy cycle were lower than those before chemotherapy [11.5% (59/511) vs. 24.9% (127/511), 5.1% (26/511) vs. 17.4% (89/511), 11.9% (61/511) vs. 20.4% (104/511)] in breast cancer patients, and the differences were statistically significant (all P < 0.001). Conclusions:The breast cancer is associated with thyroid diseases. Clinicians should pay more attention to the changes of thyroid diseases and thyroid function during the treatment and in the follow-up process of breast cancer patients, so as to detect the thyroid diseases early and carry out standardized treatment.