BACKGROUND:Ursolic acid can promote the directed differentiation of bone marrow mesenchymal stem cells into osteoblasts.However,there are few reports on whether ursolic acid has osteogenic effect on human periodontal ligament stem cells. OBJECTIVE:To investigate the effect of ursolic acid on proliferation and osteogenic differentiation of human periodontal ligament stem cells. METHODS:The human periodontal ligament stem cells were isolated and cultured.Passage 3 cells were selected and treated with ordinary medium containing different concentrations(0,1,2,4,6,8 μmol/L)of ursolic acid.After intervention for 1,3,5,7 days,the cell proliferation was detected by CCK-8 assay and the appropriate intervention concentration was screened.Passage 3 human periodontal ligament stem cells were treated with osteogenic induction solution containing 0,1,2,4 μmol/L ursolic acid,respectively.After 7 days of intervention,the mRNA expressions of alkaline phosphatase,Runx2,and osteocalcin were detected by qRT-PCR.After 14 days of intervention,the formation of mineralized nodules was observed by alizarin red staining.Passage 3 human periodontal ligament stem cells were taken and the control group was added with osteogenic induction solution;the ursolic acid group and the antagonist group were added with osteogenic induction solution containing ursolic acid(2 μmol/L)and the bone morphogenetic protein signaling pathway antagonist Noggin,respectively.The ursolic acid+antagonist group was added with osteogenic induction solution containing ursolic acid(2 μmol/L)and Noggin,the inhibitor of bone morphogenetic protein signaling pathway,and cultured for 7 days.qRT-PCR and western blot assay were used to detect the mRNA and protein expressions of bone morphogenetic protein 2,Smad1,osteopontin,and Runx2. RESULTS AND CONCLUSION:(1)1,2,4 μmol/L ursolic acid could promote the proliferation of human periodontal ligament stem cells.6,8 μmol/L ursolic acid could inhibit the proliferation of human periodontal ligament stem cells,and 1,2,4 μmol/L ursolic acid was selected to intervene in subsequent experiments.(2)Compared with 0 μmol/L,1,2,4 μmol/L ursolic acid could promote the expression of alkaline phosphatase,Runx2,and osteocalcin mRNA and the formation of mineralized nodules(P<0.05),and the effect of 2 μmol/L ursolic acid was the most significant.(3)Compared with the control group,the mRNA and protein expressions of bone morphogenetic protein 2,Smad1,osteopontin,and Runx2 in the ursolic acid group were increased(P<0.05),while mRNA and protein expressions of the above indexes were decreased in the antagonist group(P<0.05).Compared with the ursolic acid group,mRNA and protein expressions of above indexes were decreased in ursolic acid+antagonist group(P<0.05).(4)The results indicate that ursolic acid promotes osteogenic differentiation of human periodontal ligament stem cells through bone morphogenetic protein signaling pathway.

Objective:To summarize the human aging assessment scales, so as to provide reference for clinical healthcare professionals to carry out related research.Methods:In accordance with the framework of the scoping review methodology, Chinese and English databases such as China National Knowledge Infrastructure, Wanfang Data, China Biology Medicine disc, Embase, CINAHL, Web of Science, and PubMed were systematically searched. The search period was from database establishment to December 25, 2024. The included literature was summarized and analyzed.Results:A total of 27 papers covering 18 human aging assessment scales were included. The assessment dimensions mainly covered physical, psychological and social aspects, and the assessment methods were categorized into self-assessment, assessment by others and a combination of both. Assessment scales were tested for reliability or (and) validity, and some of them were validated in empirical studies and applied for dissemination.Conclusions:Human aging assessment scales are heterogeneous in terms of assessment dimensions, content and methods, with overall good reliability and validity. It is recommended that future research should take a multidimensional approach when developing new assessment scales and conduct empirical and multicenter applied research to improve the accuracy and applicability of the scales.

Objectives:To explore the predictive value of residual Murray's law-based quantitative flow ratio(μQFR)on long-term vessel-oriented composite endpoints(VoCE).Methods:This retrospective study included 3 510 patients from the FAVOR Ⅲ China trial.Offline residual μQFR analysis was performed on all vessels(diameter≥2.5 mm)with 50%-90%stenotic lesions.Patients were stratified into high-,intermediate-,and low-risk groups based on residual μQFR tertiles.The primary endpoint was 3-year VoCE,defined as a composite of cardiac death related to the target vessel,target vessel-related spontaneous myocardial infarction,and ischemia-driven target vessel revascularization.Results:Offline analysis was performed on 5 256 vessels from 3 510 patients.The mean residual μQFR was 0.92±0.75.The high-risk group(residual μQFR≤0.91)with 1 554 patients(1 958 vessels);the intermediate-risk group(residual μQFR 0.92-0.96)with 1 211 patients(1 906 vessels);and the low-risk group(residual μQFR>0.96)with 745 patients(1 392 vessels).Over 3-year follow-up,VoCE occurred in 227 vessels(4.3%).The 3-year VoCE incidence was significantly higher in the high-risk group compared to the intermediate-and low-risk groups(6.2%vs.4.1%vs.2.5%,log-rank P<0.001),primarily driven by ischemia-driven target vessel revascularization(5.0%vs.3.0%vs.1.6%,log-rank P<0.001).Hypertension(OR=0.83,95%CI:0.72-0.96),hypercholesterolemia(OR=0.84,95%CI:0.73-0.97),bifurcation lesions(OR=0.72,95%CI:0.63-0.83),moderate/severe calcification(OR=0.70,95%CI:0.57-0.84),and tandem lesions(OR=0.59,95%CI:0.47-0.75)were independent predictors of lower residual μQFR values.Conclusions:Lower residual μQFR is significantly associated with increased VoCE risk during the 3-year follow up period.

Objective:To elucidate the genomic characteristics of the immunoglobulin (IG) heavy-chain variable region and light-chain variable region, the expression of subclones, and the prognostic significance in patients with CLL.Methods:Blood and/or bone marrow specimens were gathered from a cohort of 36 patients with CLL diagnosed at Jiangsu Province Hospital from December 2018 to May 2023, including 12 cases of B cell receptor (BCR) stereotyped patients. IG heavy-chain (IGH) and light-chain (IG Kappa [IGK] and IG lambda [IGL]) gene rearrangements were performed using next-generation sequencing (NGS) technology to analyze the characteristics and prognostic value in CLL.Results:NGS detection of IG variable region (IGHV) demonstrated a significant correlation and superior consistency with Sanger sequencing ( r=0.957, P < 0.001). Among the 36 patients, the IGH variant (IGHV) was observed in 9 (25.0%) but not in 27 (75.0%) participants. The incidence of the MYD88 mutation was higher among patients with mutated IGHV [1/27 (3.7%) vs 4/9 (44.4%), P=0.00]. A high incidence of trisomy 12 was observed in the IGHV #8/#8B subset [4/11 (36.4%) vs 1/25 (4.0%), P=0.023], which were more likely to develop Richter transformation [8/11 (72.7%) vs 4/25 (16.0%), P=0.002]. In the patient cohort, 36 individuals (36/36, 100.0%) used the IGK variable, whereas 15 individuals (15/36, 41.7%) employed the IGL variable (IGLV). IGLV3 - 21 reported the highest utilization rate in IGLV (5/15, 33.3%). Remarkably, patients with CLL with IGLV3-21 fragments were exclusively observed in the Binet C stage and Rai Phase Ⅲ-Ⅳ, with an incidence of del (13) (q14) at 60.0% (3/5). The median time to first treatment (TTFT) of patients with or without IGLV3 - 21 fragments was 5.2 (1.1 - 41.5) and 9.9 (0.1 - 94.4) months, respectively. Using the total reads threshold of 2.5%, 4 (4/36, 11.1%) samples were detected to have two IGHV productive clones. The median TTFT and overall survival (OS) time were 2.8 (0.9-72.7) and 12.8 months in patients with one mutated clone and 57.5 (32.0-120.7) and 51.8 months in those with two mutated clones, respectively. The median TTFT and OS time were 10.9 (0.3-94.4) and 6.3 (0.1 - 12.5) months in patients with one unmutated clone and 49.9 (22.2 - 211.1) and 30.0 (9.6 - 50.3) months in those with multiple unmutated clones, respectively ( P>0.05) . Conclusions:Detection of IG gene rearrangements using NGS technology not only facilitates the analysis of the IGHV mutation status, dominant clones, and prognostic value but also contributes to the exploration of IGK/IGL gene rearrangement fragments and the utilization of subclones. Further, it provides information about the poor prognosis of IGLV3 - 21 CLL. The shortened survival of the two unmutated clone groups in the IGHV unmutated group may indicate a poor prognosis.

Objective:To investigate the clinicopathological features, diagnosis, and prognosis of aggressive natural killer-cell leukemia (ANKL).Methods:A retrospective analysis was conducted on 27 ANKL patients treated at the First Affiliated Hospital of Nanjing Medical University from 2014 to 2024. Their clinical data, histomorphology, and immunophenotype were reviewed. Kaplan-Meier analysis was used to evaluate the overall survival (OS), and COX regression analysis was performed to identify prognostic factors affecting OS.Results:Among the 27 patients, 18 were male and 9 were female, with a male-to-female ratio of 2∶1. The age ranged from 15-75 years, with a median age of 42.0 (28.5, 54.5) years. Fever and splenomegaly were the most common signs and symptoms. Most patients presented with pancytopenia, coagulation abnormalities, and liver dysfunction; and all patients had elevated EBV loads. Microscopically, 16 cases showed marked to hypercellular bone marrow proliferation, with predominant interstitial infiltration (15 cases, 55.6%), followed by sinusoidal infiltration (3 cases), diffuse infiltration (6 cases, 22.2%), mixed infiltration (interstitial and focal, 3 cases, 11.1%), focal infiltration (2 cases, 7.4%), and nodular infiltration (1 case, 3.7%). The proportion of tumor cells among nucleated cells ranged from 2% to 80%, with a median of 30%. The tumor cells displayed variable morphology. Hemophagocytosis was observed in 23 cases. Immunohistochemistry revealed that all cases expressed CD56, with mostly expressing cytotoxic molecules (granzyme B, TIA-1). The Ki-67 proliferative index ranged from 50% to 90%. CD56-EBER dual staining showed that NK cells were the primary targets of the virus. Reticulin staining showed increased fibrosis. By flow cytometry, all cases were positive for CD2 but negative for surface CD3 (sCD3), CD4, CD5 and CD57. Among them, 21 cases (95.5%) exhibited a typical phenotype of strong CD56 expression (CD56str+) with CD16 negativity (CD16-), while only one case (4.5%) showed CD16 positivity (CD16+) with dim CD56 expression (CD56dim). In killer-cell immunoglobulin-like receptor (KIR) analysis, 6 out of 17 patients (6/17) demonstrated monoclonal expression, including CD158a (4/6), CD158i (1/6), and CD158e (1/6); the remaining 11 cases (11/17) showed complete absence of KIR expression. All tested cases (17/17) were negative for T-cell receptor (TCR) protein expression. Follow-up period was from 257 days, 1 patient was lost to follow-up, and the remaining 26 patients died. Kaplan-Meier analysis revealed that OS was significantly longer in patients who received chemotherapy compared to those who did not ( P<0.05). Univariate Cox proportional hazards model analysis indicated that age, bone marrow proliferation, proportion of tumor cells among nucleated cells, absolute neutrophil count, platelet count, and triglycerides and bilirubin levels significantly affected OS ( P<0.05). Multivariate COX regression analysis identified triglycerides and bilirubin levels as independent prognostic factors for OS. Conclusion:Aggressive natural killer-cell leukemia is a rare lymphoid malignancy with very poor prognosis. Tumor cells exhibit significant morphological variation, and bone marrow infiltration patterns are diverse. Accurate recognition, early diagnosis, and timely chemotherapy are critical to improving the prognosis of patients with ANKL.

Objective:To evaluate the efficacy and long-term outcomes of fludarabine, cyclophosphamide, and rituximab (FCR) in treatment-na?ve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) .Methods:Clinical data from 68 CLL/SLL patients treated with FCR at Jiangsu Province Hospital (August 2008–May 2021) were retrospectively analyzed to assess efficacy, safety, and survival outcomes.Results:Among 68 patients [46 males, 22 females; median age 55 (47, 60) years], 13.1% (8/61) had a complex karyotype, 32.3% (20/62) had immunoglobulin heavy variable region mutated (IGHV-M) type, 6.6% (4/61) had del (17p), and 14.8% (8/54) had del (11q). Patients received a median of 6 (4, 6) FCR cycles. The overall response rate was 88.2% (60/68), including 47.0% (32/68) complete remissions. Over a median follow-up of 82 (59, 98) months, 66.2% (45/68) experienced disease progression. Median progression-free survival was 56 (21, 123) months, while median overall survival was not reached. The 5- and 10-year PFS rates were 42.6% (95% CI: 31.9–56.8% ) and 28.7% (95% CI: 19.0–43.4% ), respectively. Poor PFS was associated with del (17p) ( HR=5.04, 95% CI: 1.72–14.74, P=0.003), del (11q) ( HR=5.27, 95% CI: 2.11–13.15, P<0.001), IGHV unmutated (IGHV-UM) ( HR=4.11, 95% CI: 1.72–9.79, P=0.001), complex karyotype (CK) ( HR=3.53, 95% CI: 1.58–7.85, P=0.002), β 2-microglobulin >3.5 mg/L ( HR=2.87, 95% CI: 1.37–6.01, P=0.005). In multivariate analysis, IGHV-UM remained an independent predictor of PFS ( HR=8.63, 95% CI: 1.09–68.40, P=0.042). Sixteen patients with IGHV-M and lacking del (17p) or CK had a median PFS of 123 (58,123) months and a 5-year PFS rate of 70.7% (95% CI: 49.7–99.1% ), reaching a plateau after 5 years with no recurrences by 10 years. Common grade 3–4 adverse events included hematologic toxicity (44.1%, 30/68), infection (36.7%, 25/68), and liver dysfunction (4.4%, 3/68). Among 25 patients receiving single-agent BTK inhibitors after FCR progression, median follow-up was 45 (26, 64) months; 36% (9/25) experienced disease progression, with a median PFS time of 55 (27, 55) months. Conclusion:First-line FCR provides durable long-term benefits for patients with IGHV-M CLL without del (17p) or CK.

Objective:To assess the impact of induction chemotherapy sensitivity on the prognosis and larynx preservation rates in patients with locally advanced hypopharyngeal cancer and to identify risk factors influencing induction chemotherapy sensitivity.Methods:This study included patients with locally advanced (stage III-IV) hypopharyngeal cancer who received induction chemotherapy as initial treatment at the Eye & ENT Hospital of Fudan University between August 2017 and September 2022. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, enrolled patients were classified into the sensitive group and the resistant group according to their response to induction chemotherapy. Chi-square tests and Log-rank tests were used to compare the objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and laryngeal preservation rate (LPR) between groups. Propensity score matching (PSM) was employed to accurately evaluate the impact of induction chemotherapy sensitivity on prognosis in real-world settings. Univariate and multivariate logistic regression analyses were performed to identify risk factors for induction chemotherapy resistance in locally advanced hypopharyngeal cancer.Results:A total of 197 patients with locally advanced hypopharyngeal cancer who received induction chemotherapy as initial treatment were included in, comprising 195 males and 2 females, with ages ranging from 36 to 74 years. Among them, 155 patients (78.68%) were classified into the sensitive group and 42 patients (21.32%) into the resistant group. The overall response rate (ORR) of induction chemotherapy in this cohort was 78.68%, with a five-year OS rate of 63.7%. The sensitive group had significantly better OS (mOS 6.32 vs. 5.05 year), PFS (mPFS 5.71 vs. 3.09 year) and a significantly higher LPR (91.6% vs. 69.0%) ( P<0.05). After propensity score matching, all covariates were balanced between the two groups, and the sensitive group showed significant improvement in OS ( P<0.05), while, no significant difference was observed in PFS and LPR between the two groups. Logistic regression analysis revealed that risk factors for induction chemotherapy failure in locally advanced hypopharyngeal cancer included: smoking status ( OR [95% CI]=4.751 [1.887-11.961]), tumor location in the posterior pharyngeal wall ( OR [95% CI]=2.988 [1.264-7.063]), and cN2-3 stage ( OR [95% CI]=3.641 [1.109-11.954]) ( P<0.05). Conclusions:Induction chemotherapy sensitivity significantly affects the prognosis of locally advanced hypopharyngeal cancer, which is influenced by various risk factors, including smoking status, tumor sublocation, and clinical N stage.

Brain imaging abnormalities are present in schizophrenia (SZ) and bipolar disorder (BD), demonstrating disease-specific changes, yet they also share similarities in certain brain regions or functional characteristics, with SZ potentially exhibiting more extensive brain damage compared to BD. Structural magnetic resonance imaging (MRI) studies demonstrated widespread gray matter reductions in SZ, particularly in the prefrontal and temporal lobes. In BD, gray matter thickening was observed in the prefrontal lobes during manic episodes, while a reduction in gray matter was noted in the amygdala and hippocampus during depressive episodes. Both SZ and BD exhibited increased ventricular volume and reduced overall brain volume. Functional MRI studies revealed reduced functional connectivity in the prefrontal and temporal lobes in SZ, with decreased global and local efficiency in brain regions such as the hippocampus and cingulate gyrus. BD showed enhanced connectivity in the anterior cingulate gyrus and the default mode network (DMN). Both SZ and BD demonstrated altered functional connectivity in areas such as the striatum, salience network, central executive network and DMN. Diffusion tensor imaging studies showed decreased fractional anisotropy (FA) in the corpus callosum of SZ, with a decrease in FA in the left fronto-occipital fasciculus in BD. Both SZ and BD exhibited reduced FA in the uncinate fasciculus and corpus callosum. Magnetic resonance spectroscopy revealed decreased concentrations of glutathione, N-acetylaspartate (NAA) and inositol in the anterior cingulate gyrus of SZ. In BD, glutathione and inositol concentrations were elevated in the anterior cingulate gyrus, while NAA levels decreased during depressive episodes and increased during remission. Both SZ and BD showed increased levels of glutamate and gamma-aminobutyric acid in the prefrontal cortex. This article provides a review of the current evidence on the differences and similarities in multimodal magnetic resonance brain imaging between SZ and BD, aiming to offer a reference for future exploration of neuroimaging biomarkers and the neurobiological mechanisms of SZ and BD.

Objective:To elucidate the genomic characteristics of the immunoglobulin (IG) heavy-chain variable region and light-chain variable region, the expression of subclones, and the prognostic significance in patients with CLL.Methods:Blood and/or bone marrow specimens were gathered from a cohort of 36 patients with CLL diagnosed at Jiangsu Province Hospital from December 2018 to May 2023, including 12 cases of B cell receptor (BCR) stereotyped patients. IG heavy-chain (IGH) and light-chain (IG Kappa [IGK] and IG lambda [IGL]) gene rearrangements were performed using next-generation sequencing (NGS) technology to analyze the characteristics and prognostic value in CLL.Results:NGS detection of IG variable region (IGHV) demonstrated a significant correlation and superior consistency with Sanger sequencing ( r=0.957, P < 0.001). Among the 36 patients, the IGH variant (IGHV) was observed in 9 (25.0%) but not in 27 (75.0%) participants. The incidence of the MYD88 mutation was higher among patients with mutated IGHV [1/27 (3.7%) vs 4/9 (44.4%), P=0.00]. A high incidence of trisomy 12 was observed in the IGHV #8/#8B subset [4/11 (36.4%) vs 1/25 (4.0%), P=0.023], which were more likely to develop Richter transformation [8/11 (72.7%) vs 4/25 (16.0%), P=0.002]. In the patient cohort, 36 individuals (36/36, 100.0%) used the IGK variable, whereas 15 individuals (15/36, 41.7%) employed the IGL variable (IGLV). IGLV3 - 21 reported the highest utilization rate in IGLV (5/15, 33.3%). Remarkably, patients with CLL with IGLV3-21 fragments were exclusively observed in the Binet C stage and Rai Phase Ⅲ-Ⅳ, with an incidence of del (13) (q14) at 60.0% (3/5). The median time to first treatment (TTFT) of patients with or without IGLV3 - 21 fragments was 5.2 (1.1 - 41.5) and 9.9 (0.1 - 94.4) months, respectively. Using the total reads threshold of 2.5%, 4 (4/36, 11.1%) samples were detected to have two IGHV productive clones. The median TTFT and overall survival (OS) time were 2.8 (0.9-72.7) and 12.8 months in patients with one mutated clone and 57.5 (32.0-120.7) and 51.8 months in those with two mutated clones, respectively. The median TTFT and OS time were 10.9 (0.3-94.4) and 6.3 (0.1 - 12.5) months in patients with one unmutated clone and 49.9 (22.2 - 211.1) and 30.0 (9.6 - 50.3) months in those with multiple unmutated clones, respectively ( P>0.05) . Conclusions:Detection of IG gene rearrangements using NGS technology not only facilitates the analysis of the IGHV mutation status, dominant clones, and prognostic value but also contributes to the exploration of IGK/IGL gene rearrangement fragments and the utilization of subclones. Further, it provides information about the poor prognosis of IGLV3 - 21 CLL. The shortened survival of the two unmutated clone groups in the IGHV unmutated group may indicate a poor prognosis.

Brain imaging abnormalities are present in schizophrenia (SZ) and bipolar disorder (BD), demonstrating disease-specific changes, yet they also share similarities in certain brain regions or functional characteristics, with SZ potentially exhibiting more extensive brain damage compared to BD. Structural magnetic resonance imaging (MRI) studies demonstrated widespread gray matter reductions in SZ, particularly in the prefrontal and temporal lobes. In BD, gray matter thickening was observed in the prefrontal lobes during manic episodes, while a reduction in gray matter was noted in the amygdala and hippocampus during depressive episodes. Both SZ and BD exhibited increased ventricular volume and reduced overall brain volume. Functional MRI studies revealed reduced functional connectivity in the prefrontal and temporal lobes in SZ, with decreased global and local efficiency in brain regions such as the hippocampus and cingulate gyrus. BD showed enhanced connectivity in the anterior cingulate gyrus and the default mode network (DMN). Both SZ and BD demonstrated altered functional connectivity in areas such as the striatum, salience network, central executive network and DMN. Diffusion tensor imaging studies showed decreased fractional anisotropy (FA) in the corpus callosum of SZ, with a decrease in FA in the left fronto-occipital fasciculus in BD. Both SZ and BD exhibited reduced FA in the uncinate fasciculus and corpus callosum. Magnetic resonance spectroscopy revealed decreased concentrations of glutathione, N-acetylaspartate (NAA) and inositol in the anterior cingulate gyrus of SZ. In BD, glutathione and inositol concentrations were elevated in the anterior cingulate gyrus, while NAA levels decreased during depressive episodes and increased during remission. Both SZ and BD showed increased levels of glutamate and gamma-aminobutyric acid in the prefrontal cortex. This article provides a review of the current evidence on the differences and similarities in multimodal magnetic resonance brain imaging between SZ and BD, aiming to offer a reference for future exploration of neuroimaging biomarkers and the neurobiological mechanisms of SZ and BD.