Objective To investigate the setup error in patients with spinal bone metastasis who underwent radiotherapy under the guidance of kilovoltage cone-beam CT (KV-CBCT). Methods A total of 118 patients with spinal metastasis who underwent radiotherapy, including 17 cases of cervical spine, 62 cases of thoracic spine, and 39 cases of lumbar spine, were collected. KV-CBCT scans were performed using the linear accelerators from Elekta and Varian’s EDGE system. CBCT images were registered with reference CT images in the bone window mode. A total of 973 data were collected, and 3D linear errors were recorded. Results The patients with spinal bone metastasis were grouped by site, height, weight, and BMI. The P value of the patients grouped only by site was P<0.05, which was statistically significant. Conclusion When grouped by site in the 3D direction, the positioning effect of cervical spine is better than that of thoracic and lumbar spine. The positioning effect of the thoracic spine is better in the head and foot direction but worse in the left and right direction compared with that of the lumbar spine. Instead of extending or narrowing the margin according to the BMI of patients with spinal metastasis, the margin must be changed according to the site of spinal bone metastasis.

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

OBJECTIVES: To investigate the antioxidative mechanism of snake venom-derived protein C activator (PCA) in mitigating vascular endothelial cell injury. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in DMEM containing 1.0 g/L D-glucose and exposed to hypoxia (1% O₂) for 6 h followed by reoxygenation for 2 h to establish a cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The cell model was treated with 2 μg/mL PCA alone or in combination with 2-ME2 (a HIF-1α inhibitor) or DMOG (a HIF-1α stabilizer), and intracellular production of reactive oxygen species (ROS) and protein expression levels of HIF-1α, BNIP3, and Beclin-1 were detected using DCFH-DA fluorescence probe, flow cytometry, and Western blotting. The OGD/R cell model was transfected with a BNIP3-specific siRNA or a scrambled control sequence prior to PCA treatment, and the changes in protein expressions of HIF-1α, BNIP3 and Beclin-1 and intracellular ROS production were examined. RESULTS: In the OGD/R cell model, PCA treatment significantly upregulated HIF-1α, BNIP3 and Beclin-1 expressions and reduced ROS production. The effects of PCA were obviously attenuated by co-treatment with 2-ME2 but augmented by treatment with DMOG (a HIF-1α stabilizer). In the cell model with BNIP3 knockdown, PCA treatment increased BNIP3 expression and decreased ROS production without causing significant changes in HIF-1α expression. Compared with HUVECs with PCA treatment only, the cells with BNIP3 knockdown prior to PCA treatment showed significantly lower Beclin-1 expression and higher ROS levels. CONCLUSIONS Snake venom PCA alleviates OGD/R-induced endothelial cell injury by upregulating HIF-1α/BNIP3 signaling to suppress ROS generation, suggesting its potential as a therapeutic agent against oxidative stress in vascular pathologies.
Humans ; Reactive Oxygen Species/metabolism* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Human Umbilical Vein Endothelial Cells/drug effects* ; Membrane Proteins/metabolism* ; Proto-Oncogene Proteins/metabolism* ; Up-Regulation ; Cell Hypoxia ; Cells, Cultured ; Snake Venoms/chemistry* ; Beclin-1

Objective:To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) .Methods:A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results:Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype ( P=0.02, OR=0.39, 95% CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation ( P=0.02, OR=0.22, 95% CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95% CI 21.14-30.19) months. HMA response ( P=0.036, HR=0.47, 95% CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype ( P=0.024, HR=2.14, 95% CI 1.10-4.15) , leukemia transformation ( P<0.001, HR=2.839, 95% CI 1.64-4.92) , and TP53 mutation ( P=0.012, HR=2.19, 95% CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion:Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Constructing a multi-tiered healthcare security system can meet the diverse and individualized healthcare service demand of the general public.Public hospitals,as the main providers of healthcare services in China,effectively integrate with commercial health insurance,which can accelerate the implementation of high-quality healthcare services,promote innovative development,and optimize product coverage and operational efficiency for commercial health insurance,achieving a win-win situation.Taking Shanghai as the research object,it analyzes the supply and demand status of multi-tiered healthcare security in Shanghai based on population characteristics,economic level,healthcare resources,and policy environment.It identifies the difficulties in the current collaboration between public hospitals and commercial insurance.Finally,it proposes exploring the expansion of independent development space for specialized services,improving the level of coordination between commercial insurance institutions and public hospitals in health management services,promoting the management and sharing of data,strengthening the protection of innovative medicines and devices by commercial insurance,in order to promote the coordinated development of commercial insurance and public hospitals.

Objective:To compare the efficacy of amide proton transfer-weighted (APTw) imaging with time-dependent diffusion MRI (td-dMRI) in the diagnosis of malignant breast lesions.Methods:This study was a cross-sectional study. The clinical, pathological and imaging data of patients with breast lesions admitted to the First Affiliated Hospital of Zhengzhou University from March to August 2023 were prospectively analyzed. All patients firstly underwent T 2WI, diffusion-weighted imaging, followed by dynamic contrast-enhanced MRI (DCE-MRI), and finally APTw imaging and td-dMRI were performed for breast lesions using DCE-MRI as reference. Reconstructed images from APTw imaging measured lesions with a frequency shift of 3.5 ppm asymmetric magnetic susceptibility MTR asym(+3.5 ppm). The apparent diffusion coefficient (ADC) values at different oscillating frequency gradients (ADC PGSE, ADC 17 Hz, ADC 33 Hz values) were measured using reconstructed td-dMRI images. Independent sample t-test was used to compare APTw imaging, td-dMRI parameter differences between benign and malignant breast tumors, breast malignant tumors with different molecular types [estrogen receptor (ER) negative and positive, progesterone receptor (PR) negative and positive, human epidermal growth factor receptor (HER-2) negative and positive, proliferation index (Ki-67) low and high expression] and different histological grades (grade Ⅱ and Ⅲ). Receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the efficacy of APTw imaging and td-dMRI parameters in differentiating benign and malignant breast tumors, molecular classification and histological grading of malignant breast lesions. Results:There were 171 lesions in 171 patients, including 103 malignant lesions and 68 benign lesions. Histological grades were grade Ⅱ in 51 cases and grade Ⅲ in 38 cases of 89 cases of invasive carcinoma. Totally 98 cases of malignant lesions were included in molecular typing analysis, 36 cases were ER negative and 62 cases were ER positive. PR was negative in 51 cases and positive in 47 cases. There were 33 negative HER-2 patients, 65 positive HER-2 patients. There were 50 cases of low Ki-67 expression and 48 cases of high Ki-67 expression. The MTR asym(+3.5 ppm) value of malignant breast lesions was higher than that of benign lesions ( t=5.76, P<0.001), and the ADC PGSE, ADC 17 Hz and ADC 33 Hz values were lower than those of benign breast lesions ( t was 4.84, 4.62, 4.01, respectively, all P<0.001). MTR asym(+3.5 ppm) had the highest AUC value (0.83) and the highest specificity (90.38%), and ADC PGSE had the highest sensitivity (85.86%). There were no significant differences in MTR asym(+3.5 ppm), ADC PGSE, ADC 17 Hz and ADC 33 Hz between grade Ⅱ and grade Ⅲ histological grades of malignant breast lesions (all P>0.05). The ADC PGSE value of ER negative was higher than that of ER positive ( t=2.34, P=0.018), and the AUC for distinguishing ER positive from negative was 0.64. The ADC PGSE and ADC 17 Hz values of PR negative were higher than those of PR positive ( t=2.87, 2.81, P=0.004, 0.006, respectively), and their AUCs for identifying PR positive versus negative breast malignant lesions were 0.68 and 0.67, respectively. The ADC 33 Hz value of negative HER-2 was lower than that of positive HER-2 ( t=3.00, P=0.003), and the AUC for distinguishing positive and negative HER-2 was 0.67. There were no significant differences in other parameters among different subtypes of breast malignant lesions (all P>0.05). Conclusion:Compared with td-dMRI, APTw imaging is more effective in differentiating benign and malignant lesions of breast tumors, and ADC values at different gradient oscillation frequencies obtained by td-dMRI show better diagnostic efficacy in differentiating different molecular types of breast malignant lesions.

Constructing a multi-tiered healthcare security system can meet the diverse and individualized healthcare service demand of the general public.Public hospitals,as the main providers of healthcare services in China,effectively integrate with commercial health insurance,which can accelerate the implementation of high-quality healthcare services,promote innovative development,and optimize product coverage and operational efficiency for commercial health insurance,achieving a win-win situation.Taking Shanghai as the research object,it analyzes the supply and demand status of multi-tiered healthcare security in Shanghai based on population characteristics,economic level,healthcare resources,and policy environment.It identifies the difficulties in the current collaboration between public hospitals and commercial insurance.Finally,it proposes exploring the expansion of independent development space for specialized services,improving the level of coordination between commercial insurance institutions and public hospitals in health management services,promoting the management and sharing of data,strengthening the protection of innovative medicines and devices by commercial insurance,in order to promote the coordinated development of commercial insurance and public hospitals.

Objective To investigate the efficacy and safety of camrelizumab monoclonal antibody combined with molecular-targeted therapy in elderly patients with unresectable or advanced hepatocellular carcinoma(HCC).Methods A retrospective analysis was performed for the patients with unresectable/advanced HCC who attended six hospitals from January 1,2019 to March 31,2021,and all patients received camrelizumab monoclonal antibody treatment,among whom 84.8%also received targeted therapy.According to the age of the patients,they were divided into elderly group(≥65 years)and non-elderly group(＜65 years).The two groups were assessed in terms of overall survival(OS),progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and immune-related adverse events(irAE).The chi-square test or the Fisher's exact test was used for comparison of categorical data between groups;the independent samples t-test was used for comparison of normally distributed continuous data,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups.The Kaplan-Meier method was used for survival analysis,and the log-rank test was used for comparison of survival curves.Univariate and multivariate Cox proportional hazards regression analyses were used to determine the independent influencing factors for PFS and DCR at 6 months.Results A total of 99 HCC patients were enrolled,with 27 in the elderly group and 72 in the non-elderly group.The elderly group had an OS rate of 67.8%,an ORR of 44.4%,and a DCR of 74.1%at 12 months and a median PFS of 6.4(95%confidence interval[CI]:3.0-12.4)months,with no significant differences compared with the non-elderly group(all P＞0.05).The median OS was unavailable for the elderly group,while the non-elderly group had an OS of 18.9(95%CI:13.0-24.8)months;there was no significant difference between the two groups(P=0.485).The univariate and multivariate Cox regression analyses showed that major vascular invasion(MVI)was an independent risk factor for PFS(hazard ratio[HR]=2.603,95%CI:1.136-5.964,P=0.024)and DCR(HR=3.963,95%CI:1.671-9.397,P=0.002)at 6 months,while age,sex,etiology of HBV infection,presence of extrahepatic metastasis,Child-Pugh class B,and alpha-fetoprotein＞400 ng/mL were not associated with PFS or DCR at 6 months.For the elderly group,the incidence rates of any irAE and grade 3/4 irAE were 51.9%and 25.9%,respectively,with no significant differences compared with the non-elderly group(P＞0.05),and skin disease was the most common irAE in both groups(39.4%).Conclusion Camrelizumab monoclonal antibody combined with molecular-targeted therapy has similar efficacy and safety in patients with unresectable/advanced HCC aged≥65 years and those aged＜65 years.MVI is associated with suboptimal response to immunotherapy and poor prognosis.

Objective:To explore the clinical characteristics and genetic variant of a patient with desminopathy manifesting with atypical symptoms.Methods:A patient who was admitted to the Department of Neurology of Jing′an District Central Hospital on February 24, 2021 was selected as the study subject. Clinical data, laboratory tests, muscle pathology, muscle magnetic resonance imaging (MRI) and genetic testing of the patient were retrospectively analyzed.Results:The patient had developed myalgia after lower limb activity, and gradually developed asymmetrical muscle weakness and atrophy of the lower limbs. Cardiac examination revealed atrioventricular block and decreased left ventricular diastolic function. Muscle MRI showed that semitendinosus, sartorius, gracilis, fibula, gastronemius and supinator muscles were selectively involved at the early stage. Muscle biopsy confirmed pathological changes of desmin positive myofibrils. Genetic testing revealed that the patient has harbored a c. 1024A>G (p.n342d) missense variant in exon 6 of the DES gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PS4_moderate+ PM2_supporting+ PP3_moderate+ PP1). Conclusion:Desmin disease has a great clinical heterogeneity. Postexercise myalgia of lower limbs is a rare clinical phenotype. For patients harboring the c. 1024A>G (p.n342d) variant of the DES gene, in addition to semitendinosus and fibula, Cardiac involvement is relatively insidious and easy to be ignored in clinic. Timely muscle MRI, muscle biopsy and gene detection will help the early diagnosis of the disease.