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.

OBJECTIVE To compare the metabolomic characteristics of stage T1 papillary thyroid carcinoma(PTC)and nodular goiter(NG),and the relationship between metabolites and lymph node metastasis of PTC.METHODS Serum samples were collected from 60 patients with stage T1 PTC and 30 patients with NG who underwent thyroidectomy at the Department of Otolaryngology Head and Neck Surgery,Civil Aviation General Hospital between September 2021 and April 2022.The PTC group was divided into the N+ group with lymph node metastasis and the N-group without lymph node metastasis according to the presence or absence of lymph node metastasis.The serum metabolites of the N+ and N-groups and the PTC and NG groups were compared and analyzed using an ultra-performance liquid chromatography-mass spectrometry(UPLC-Q-Exactive-MS)coupled platform,and principal component analysis(PCA),partial least squares discriminant analysis(PLS-DA),and orthogonal partial least squares discriminant analysis(OPLS-DA)was performed using SIMCA-P 14.1 software.OPLS-DA modeling,combined with FDR-corrected Mann-Whitney-Wilcoxon test results and metabolite difference multiples in the two groups undergoing comparison,etc.to screen for potential small molecule metabolic markers,and to establish a joint diagnostic model by binary logistic regression analysis.RESULTS There were no significant differential metabolites between the N+ group with lymph node metastasis and the N-group without lymph node metastasis.Seven differential metabolites were found between PCA patients and NG patients,and the five relevant metabolic pathways were the pentose phosphate pathway,pentose and glucuronide interconversion,glycolysis/gluconeogenesis,fructose,and mannose metabolism,and fatty acid biosynthesis.The differential metabolite with an area under the ROC curve>0.9 was D-glyceraldehyde 3-phosphate,and another N-undecanoylglycine,uronic acid,and the area under the ROC curve for three metabolites,N-undecanoylglycine,uric acid,and triiodothyronine glucuronide,was>0.8.CONCLUSION PTC patients differed from NG patients mainly in glucose metabolism and lipid metabolism,and D-glyceraldehyde 3-phosphate could be distinguished from NG patients with the aid of N-undecanoylglycine,uric acid,and triiodothyronine glucuronide,combined with imaging findings.Also,no significant differences in serum metabolites were found in the N+ group compared with the N-group,and the presence or absence of lymph node metastases did not affect serum metabolites in patients with stage T1 PTC.

Objective To explore the CT and MRI characteristic manifestations of nodular fasciitis(NF).Methods A retrospec-tive analysis was conducted on the imaging data of 27 cases pathologically confirmed NF,and their special CT and MRI signs were analyzed.Among them,21 cases underwent MRI examination,14 cases underwent CT examination,and another 8 cases underwent both CT and MRI examinations.Results Among the 27 cases of NF,16 cases were subcutaneous type,4 cases were intramuscular type,and 7 cases were intermuscular(fascial)type.Eleven cases were located in the head and neck,8 cases in the trunk,6 cases in the upper limbs,and 2 cases in the lower limbs.Fourteen cases underwent CT plain scan,and all lesions showed slightly low density,while 1 case showed mild enhancement on CT enhanced scan.On T1 WI,19 cases showed iso-or slightly hypointense signals,and 2 cases showed slightly hyperintense signals.On T2WI,16 cases showed inhomogeneous hyperintense signals and 5 cases showed homoge-neous hyperintense signals.Fifteen cases showed mixed hyperintense signals on diffusion weighted imaging(DWI).Among the 7 cases with MRI enhancement,5 cases showed significant inhomogeneous enhancement,and 2 cases showed rim enhancement."Fascial tail sign"was observed in 25 cases of NF;"double low signal sign"was seen in 16 cases of NF;"reverse target sign"was observed in 6 cases of NF lesions;peritumoral edema was seen in 9 cases;and small cystic degeneration and necrotic foci were found in 3 cases.Conclusion The imaging manifestations of NF have certain characteristics.When the tumor course is short and the tumor size is small and manifesta-tions such as"fascial tail sign""double low signal sign"and"reverse target sign"are present,the possibility of NF should be considered.

Objective:To investigate the efficacy and safety of combining venetoclax (VEN) with hypomethylated drugs (HMA) in the treatment of higher-risk (IPSS-R score >3.5) myelodysplastic syndromes (MDS) .Methods:From March 2021 to December 2022, forty-five MDS patients with intermediate and high risk were treated with VEN in combination with HMAs. Clinical data were collected and analyzed retrospectively, including gender, age, MDS subtype, IPSS-R score, treatment regimen, and efficacy, etc. Kaplan-Meier method and Cox regression model were used to analyze univariate and multivariate of survival prognosis.Results:①Forty-five patients with MDS, including ninety-one percent were classified as high or very high risk. According to the 2023 consensus proposal for revised International Working Group response criteria for higher-risk MDS, the overall response rate (ORR) was 62.2% (28/45), with the complete response rate (CR) was 33.3% (15/45). For twenty-five na?ve MDS, the ORR was 68% (17/25) and the CR rate was 32% (8/25). In nonfirst-line patients, the ORR and CR were 55% (11/20) and 35% (7/20) respectively. The median cycle to best response was 1 (1-4). ②With a median followup of 189 days, the median overall survival (OS) time was 499 (95% confidence interval, 287-711) days, and most patients died from disease progression. Responders had a significantly better median OS time than nonresponders (499 days vs 228 days, P<0.001). Multifactor analysis revealed that IPSS-R score and response to treatment were independent prognostic factors for OS; the presence of SETBP1 gene mutations was associated with a longer hospital stay (51.5 days vs 27 days, P=0.017) . Conclusions:There is clinical benefit of venetoclax in combination with hypomethylated agents in patients with higher-risk MDS, but adverse events such as severe hypocytopenia during treatment should be avoided.

Objective:To analyze the clinical characteristics and prognosis of patients with myelodysplastic syndrome (MDS) with a bone marrow nucleated erythroid cell proportion of greater than or equal to 50% (MDS-E) .Methods:The clinical characteristics and prognostic factors of patients with MDS-E were retrospectively analyzed by collecting the case data of 1 436 newly treated patients with MDS diagnosed in the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences from May 2014 to June 2023.Results:A total of 1 436 newly diagnosed patients with complete data were included in the study, of which 337 (23.5%) patients with MDS-E had a younger age of onset and lower neutrophil and platelet counts compared with those in patients with an erythroid cell proportion of less than 50% (MDS-NE) (all P<0.05). The proportion of MDS cases with ring sideroblasts (MDS-RS) was higher in the MDS-E group than in the MDS-NE group, and multi-hit TP53 mutations were more enriched in the MDS-E group than in the MDS-NE group (all P<0.05). Among patients with MDS-RS, the frequency of complex karyotypes and the TP53 mutation rate were significantly lower in the MDS-E group than in the MDS-NE group (0 vs 11.9%, P=0.048 and 2.4% vs 15.1%, P=0.053, respectively). Among patients with TP53 mutations, the frequencies of complex karyotypes and multi-hit TP53 mutations were significantly higher in the MDS-E group than in the MDS-NE group (87.5% vs 64.6%, P=0.003 and 84.0% vs 54.2%, P<0.001, respectively). Survival analysis of patients with MDS-RS found that the overall survival (OS) in the MDS-E group was better than that in the MDS-NE group [not reached vs 63 (95% CI 53.3-72.7) months, P=0.029]. Among patients with TP53 mutations and excess blasts, the OS in the MDS-E group was worse than that in the MDS-NE group [6 (95% CI 2.2-9.8) months vs 12 (95% CI 8.9-15.1) months, P=0.022]. Multivariate analysis showed that age of ≥65 years ( HR=2.47, 95% CI 1.43-4.26, P=0.001), mean corpuscular volume (MCV) of ≤100 fl ( HR=2.62, 95% CI 1.54-4.47, P<0.001), and TP53 mutation ( HR=2.31, 95% CI 1.29-4.12, P=0.005) were poor prognostic factors independent of the Revised International Prognostic Scoring System (IPSS-R) prognosis stratification in patients with MDS-E. Conclusion:Among patients with MDS-RS, MDS-E was strongly associated with a lower proportion of complex karyotypes and TP53 mutations, and the OS in the MDS-E group was longer than that in the MDS-NE group. Among patients with TP53 mutations, MDS-E was strongly associated with complex karyotypes and multi-hit TP53 mutations, and among TP53-mutated patients with excess blasts, the OS in the MDS-E group was shorter than that in the MDS-NE group. Age of ≥65 years, MCV of ≤100 fl, and TP53 mutation were independent adverse prognostic factors affecting OS in patients with MDS-E.

Objective:To explore the risk factors in leukemia transformation (LT) in those with myelodysplastic syndromes (MDS) .Methods:From January 2012 to December 2020,data on 320 patients with newly diagnosed primary MDS were gathered from the MDS center. The clinical features and molecular characteristics are explored. Additionally, a retrospective analysis of risk factors for the development of acute leukemia from MDS was done.Results:The median follow-up was13.6 (0.4-107.3) months. 23.4% (75/320) of the MDS patients had LT group. Significant differences between the LT group and non-LT group can be seen in age ( P<0.001) , bone marrow blast percentage ( P<0.001) , bone marrow fibrosis ( P=0.046) , WHO classification ( P<0.001) , IPSS-R ( P<0.001) and IPSS-R karyotype group ( P=0.001) . The median number of mutation of LT group was 1 (1, 3) , that in non-LT group was 1 (0, 2) ,which had a statistical difference ( P=0.003) .At the time of the initial diagnosis of MDS, the LT group had higher rates of the TP53 mutation ( P=0.034) , DNMT3A mutation ( P=0.026) , NRAS mutation ( P=0.027) and NPM1 mutation ( P=0.017) . Compared with the mutations at first diagnosis and LT of six patients, the number of mutations increased and the variant allele frequencies (VAF) increased significantly in LT patients. Higher bone marrow blast percentage (Refer to <5% , 5% -10% : HR=4.587, 95% CI 2.214 to 9.504, P<0.001, >10% : HR=9.352, 95% CI 4.049 to 21.600, P<0.001) , IPSS-R cytogenetic risk groups ( HR=2.603, 95% CI 1.229-5.511, P=0.012) , DNMT3A mutation ( HR=4.507, 95% CI 1.889-10.753, P=0.001) , and NPM1 mutation ( HR=3.341, 95% CI 1.164-9.591, P=0.025) were all independently associated with LT in MDS patients, according to results of multivariate Cox regression. Conclusion:Bone marrow blast percentage, IPSS-R cytogenetic risk groups, DNMT3A mutation, and NPM1 mutation are independent risk factors in LT for MDS patients.

With the continuous development of precision targeting medicine, antiangiogenic drugs have achieved good therapeutic effects in the treatment of advanced cancer, but renal injury and other adverse reactions often occur during the use, which reduce the quality of life of patients. This article reviews the mechanism of renal injury induced by antiangiogenic drugs and the potential relation between renal injury and prognosis.

Objective:To study the effect of psoralen on the proliferation, invasion and migration of HTB-47 and CRL-1932 renal cancer cells cultured in vitro, and to further explore the internal mechanism of psoralen inhibiting renal cancer.Methods:The experimental group was HTB-47 and CRL-1932 renal cancer cells treated with dimethyl sulfoxide solution containing 30 μg/ml psoralen, and the control group was renal cancer cells treated with dimethyl sulfoxide. Scratch test, CCK8, Transwell, and Western blot were used to detect the effect of psoralen on renal cancer cells.Results:Compared with the control group, the proliferation, invasion and migration of renal cancer cells treated with psoralen in the experimental group were significantly inhibited. In the renal cancer cells treated with psoralen, the protein expression levels of MKI67, PCNA, MMP2 and MMP9 were significantly decreased (all P<0.05). Conclusions:Psoralen can significantly inhibit the proliferation, invasion and migration of HTB-47 and CRL-1932 renal cancer cells in vitro. The mechanism may be to inhibit the progression of renal cancer by regulating MKI67, PCNA, MMP2 and MMP9.

Objective:To investigate the application value of magnetic resonance dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) combined with microRNA-21 (miR-21) and miR-92a in the benign and malignant differentiation of bone tumors and the evaluation of their efficacy.Methods:A total of 120 patients with bone tumors were selected retrospectively from June 2018 to June 2019 in Panyu Hospital of Chinese Medicine, including 52 cases in the benign group and 68 cases in the malignant group. The DCE-MRI dynamic enhancement parameters and tumor tissue miR-21, miR-92a levels were compared between the two groups. The diagnostic value of DCE-MRI, miR-21, miR-92a levels of cancer tissue and their correlation were analyzed. Patients with bone malignant tumors were given comprehensive treatment. Six months after operation, according to the criteria of solid tumor curative effect, they were divided into good curative effect group and poor curative effect group. The DCE-MRI dynamic enhancement parameters [signal enhancement amplitude (SEE), early dynamic enhancement slope value (Slope), centripetal enhancement rate (DER)], miR-21, miR-92a levels of patients with different curative effects were compared.Results:The levels of SEE, Slope, DER and miR-21 a nd miR-92a in the malignant group were higher than those in the benign group ( P<0.05); The area under curve (AUC) of DCE-MRI, miR-21, miR-92a combined in the diagnosis of benign and malignant bone tumors (0.885)>Slope(0.808)>SEE(0.788)>miR-21(0.785)>miR-92a (0.740)>DER(0.660), with sensitivity 80.88%, specificity 88.46%, respectively; the DCE-MRI dynamic enhancement parameters SEE, Slope, DER were positively correlated with miR-21 and miR-92a ( P<0.05); the DCE-MRI dynamic enhancement parameters SEE, Slope, DER and miR-21, miR-92a of patients with good curative effect were lower than those with poor curative effect ( P<0.05). Conclusions:DCE-MRI dynamic enhancement parameters, miR-21, miR-92a levels are abnormally high expression in patients with bone malignant tumors, and combined detection is expected to become an important means to identify benign and malignant bone tumors and evaluate the efficacy.

Objective:To assess the prognostic value of modified Charlson comorbidity index (mCCI) combined with serum albumin for long-term prognosis in peritoneal dialysis (PD) patients.Methods:From January 1, 2007 to June 30, 2015, patients who started PD in Nanjing Drum Tower Hospital were enrolled in this retrospective cohort study. Clinical data including gender, age, underlying diseases, laboratory examination and prognosis were collected. The mCCI at the beginning of PD was calculated. Whether the duration of PD exceeded 5 years was used as an indicator to evaluate the prognosis. The patients were divided into≥5 years group and<5 years group according to the duration of PD, and the data were compared between the two groups. Cox regression model was constructed to analyze the influencing factors of all-cause death in PD patients. Multivariate logistic regression model and receiver operating characteristic (ROC) curve were used to analyze the predictive value of mCCI and serum albumin levels on whether patients could maintain long-term PD.Results:Of the 183 patients included [males 106(57.9%), females 77(42.1%); (53.35±16.50) years old; 162 cases (88.5%) with hypertension, 55 cases (30.1%) with diabetes], 97 cases had PD duration for ≥5 years and 86 cases less than 5 years. The overall 5-year technical survival rate was 65.1%. At the beginning of PD, compared with the dialysis age≥5 years group, the patients in the dialysis age less than 5 years group had older age, higher mCCI, lower serum albumin level, and higher C-reactive protein (CRP) level (all P<0.05), but there were no significant differences in gender, education level, electrolyte, mean arterial pressure, high densitv lipoprotein (HDL), low-density lipoprotein (LDL) and PD adequacy index between the two groups (all P>0.05). Multivariate logistic regression analysis showed that increased age ( OR=1.022, 95% CI 1.000-1.043, P=0.046), increased mCCI ( OR=1.620, 95% CI 1.300-2.018, P<0.001) and decreased serum albumin ( OR=0.807, 95% CI 0.730-0.893, P<0.001) were independent predictors for the duration of PD<5 years. ROC curve analysis showed that the area under ROC curves ( AUC) of mCCI, serum albumin level and combined prediction probability of the two for the duration of PD<5 years were 0.647(95% CI 0.568-0.727), 0.655(95% CI 0.577-0.734), and 0.767(95% CI 0.700-0.835), respectively, indicating that the accuracy of combined parameters to predict survival outcome was higher than that of any single parameter. Multivariate Cox analysis showed that increased age ( HR=1.073, 95% CI 1.046-1.100, P<0.001), increased mCCI ( HR=1.198, 95% CI 1.044-1.375, P=0.010) and decreased serum albumin ( HR=0.904, 95% CI 0.843-0.969, P=0.004) were independent influencing factors for all-cause death in PD patients. Conclusions:Old age, high mCCI and low serum albumin level are influencing factors for dialysis age<5 years and all-cause death in PD patients. mCCI combined with serum albumin level can improve the accuracy of predicting the long-term dialysis in PD patients.