Objective:To investigate the value of CT radiomic model based on analysis of primary gastric cancer and the adipose tissue outside the gastric wall beside cancer in differentiating stage T1-2 from stage T3-4 gastric cancer.Methods:This study was a case-control study. Totally 465 patients with gastric cancer treated in Affiliated People′s Hospital of Jiangsu University from December 2011 to December 2019 were retrospectively collected. According to postoperative pathology, they were divided into 2 groups, one with 150 cases of T1-2 tumors and another with 315 cases of T3-4 tumors. The cases were divided into a training set (326 cases) and a test set (139 cases) by stratified sampling method at 7∶3. There were 104 cases of T1-2 stage and 222 cases of T3-4 stage in the training set, 46 cases of T1-2 stage and 93 cases of T3-4 stage in the test set. The axial CT images in the venous phase during one week before surgery were selected to delineate the region of interest (ROI) at the primary lesion and the extramural gastric adipose tissue adjacent to the cancer areas. The radiomic features of the ROIs were extracted by Pyradiomics software. The least absolute shrinkage and selection operator was used to screen features related to T stage to establish the radiomic models of primary gastric cancer and the adipose tissue outside the gastric wall beside cancer. Independent sample t test or χ2 test were used to compare the differences in clinical features between T1-2 and T3-4 patients in the training set, and the features with statistical significance were combined to establish a clinical model. Two radiomic signatures and clinical features were combined to construct a clinical-radiomics model and generate a nomogram. The area under the receiver operating characteristic curve (AUC) was used to evaluate the efficacy of each model in differentiating stage T1-2 from stage T3-4 gastric cancer. The calibration curve was used to evaluate the consistency between the T stage predicted by the nomogram and the actual T stage of gastric cancer. And the decision curve analysis was used to evaluate the clinical net benefit of treatment guided by the nomogram and by the clinical model. Results:There were significant differences in CT-T stage and CT-N stage between T1-2 and T3-4 patients in the training set ( χ2=10.59, 15.92, P=0.014, 0.001) and the clinical model was established. After screening and dimensionality reduction, the 5 features from primary gastric cancer and the 6 features from the adipose tissue outside the gastric wall beside cancer established the radiomic models respectively. In the training set and the test set, the AUC values of the primary gastric cancer radiomic model were 0.864 (95% CI 0.820-0.908) and 0.836 (95% CI 0.762-0.910), and the adipose tissue outside the gastric wall beside cancer radiomic model were 0.782 (95% CI 0.731-0.833) and 0.784 (95% CI 0.702-0.866). The AUC values of the clinical model were 0.761 (95% CI 0.705-0.817) and 0.758 (95% CI 0.671-0.845), and the nomogram were 0.876 (95% CI 0.835-0.917) and 0.851 (95% CI 0.781-0.921). The calibration curve reflected that there was a high consistency between the T stage predicted by the nomogram and the actual T stage in the training set ( χ2=1.70, P=0.989). And the decision curve showed that at the risk threshold 0.01-0.74, a higher clinical net benefit could be obtained by using a nomogram to guide treatment. Conclusions:The CT radiomics features of primary gastric cancer lesions and the adipose tissue outside the gastric wall beside cancer can effectively distinguish T1-2 from T3-4 gastric cancer, and the combination of CT radiomic features and clinical features can further improve the prediction accuracy.

Objective To investigate the mechanism of metformin for regulating tumor-stromal cell cross-talk in breast cancer.Methods Tumor associated fibroblasts(CAFs)co-cultured with breast cancer cells were treated with metformin,and the changes in expressions of hypoxia-inducible factor-1α(HIF-1α),p-AMPK,stroma-derived factor-1(SDF-1)and interleukin-8(IL-8)in the CAFs were detected using ELISA,RT-qPCR or Western blotting;Transwell assay was used to evaluate the invasiveness of the tumor cells and its changes following treatment with exogenous SDF-1,IL-8 and TGF-β1.The effects of HIF-1α shRNA or overexpression plasmid,AMPK shRNA,and treatment with OG(a proline hydroxylase inhibitor)or 2-OXO(a proline hydroxylase activator)were examined on p-AMPK,HIF-1α,SDF-1 and IL-8 expressions and invasiveness of the CAFs.Results Metformin treatment significantly increased the expression levels of p-AMPK,SDF-1 and IL-8(P<0.05)and decreased HIF-1α expression(P<0.05)without affecting AMPK expression level(P>0.05)in the CAFs.The invasion ability of metformin-treated breast cancer cells was significantly decreased(P<0.05).Exogenous SDF-1 and IL-8,HIF-1α overexpression,and OG-induced upregulation of HIF-1α all significantly attenuated the inhibitory effects of metformin on breast cancer cell invasion(P<0.05)and HIF-1α,SDF-1 and IL-8 expressions in CAFs(P<0.05).Transfection with HIF-1α shRNA or treatment with 2-OXO significantly decreased the invasiveness of breast cancer cells(P<0.05).P-AMPK knockdown significantly suppressed the inhibitory effect of metformin on HIF-1α expression in CAFs and on invasion of breast cancer cells(P<0.05).Treatment with TGF-β1 partially decreased the inhibitory effect of metformin on HIF-1α expression in CAFs and invasiveness of the breast cancer cells(P<0.05).Conclusion Metformin suppresses HIF-1α expression in CAFs to block tumor-stromal cross talk in breast cancer.

Objective To investigate the mechanism of metformin for regulating tumor-stromal cell cross-talk in breast cancer.Methods Tumor associated fibroblasts(CAFs)co-cultured with breast cancer cells were treated with metformin,and the changes in expressions of hypoxia-inducible factor-1α(HIF-1α),p-AMPK,stroma-derived factor-1(SDF-1)and interleukin-8(IL-8)in the CAFs were detected using ELISA,RT-qPCR or Western blotting;Transwell assay was used to evaluate the invasiveness of the tumor cells and its changes following treatment with exogenous SDF-1,IL-8 and TGF-β1.The effects of HIF-1α shRNA or overexpression plasmid,AMPK shRNA,and treatment with OG(a proline hydroxylase inhibitor)or 2-OXO(a proline hydroxylase activator)were examined on p-AMPK,HIF-1α,SDF-1 and IL-8 expressions and invasiveness of the CAFs.Results Metformin treatment significantly increased the expression levels of p-AMPK,SDF-1 and IL-8(P<0.05)and decreased HIF-1α expression(P<0.05)without affecting AMPK expression level(P>0.05)in the CAFs.The invasion ability of metformin-treated breast cancer cells was significantly decreased(P<0.05).Exogenous SDF-1 and IL-8,HIF-1α overexpression,and OG-induced upregulation of HIF-1α all significantly attenuated the inhibitory effects of metformin on breast cancer cell invasion(P<0.05)and HIF-1α,SDF-1 and IL-8 expressions in CAFs(P<0.05).Transfection with HIF-1α shRNA or treatment with 2-OXO significantly decreased the invasiveness of breast cancer cells(P<0.05).P-AMPK knockdown significantly suppressed the inhibitory effect of metformin on HIF-1α expression in CAFs and on invasion of breast cancer cells(P<0.05).Treatment with TGF-β1 partially decreased the inhibitory effect of metformin on HIF-1α expression in CAFs and invasiveness of the breast cancer cells(P<0.05).Conclusion Metformin suppresses HIF-1α expression in CAFs to block tumor-stromal cross talk in breast cancer.

The disorder of group 3 innate lymphoid cells(ILC3)subgroup,such as the predominance of NCR-ILC3 but the deple-tion of NCR+ILC3,is unfavorable to damaged intestinal barrier repair,which leads to the prolongations and obstinacy of ulcerative colitis(UC).Our previous studies had shown that luteolin promoted NCRILC3 differentitating into NCR+ILC3 to improving the de-pletion of NCR+ILC3 in UC mice,while the mechanism is unclear.This article aimed to explore the underlying mechanism of luteolin enhancing the proportion NCR+ILC3.UC mice model was established with 2％DSS and Notch signaling was blocked,then luteolin was used to intervene.The results showed that the effect of luteolin on ameliorating disease symptoms in UC mice,including inhibit-ing the weight loss,reducing the pathological damage of colon mucosa,etc.,was diminished with blocking Notch signaling pathway.In addition,luteolin increased the proportion of NCR+ILC3,NCR+MNK3 and IL-22+ILC3,decreased intestinal permeability,pro-moted mucin secretion,and promoted ZO-1 and Occludin expression,the above effect of luteolin was neutralized by Notch inhibitor LY-411575.Luteolin activated the abnormally blocked Notch signaling pathway in UC mice.And molecular docking predicted the af-finity of luteolin for RBPJ to be-7.5 kcal·mol-1 in mouse,respectively;the affinity of luteolin for Notchl and RBPJ was respectively scored to be-6.4 kcal·mol-1 and-7.7 kcal·mol-1 homo sapiens.These results proved that luteolin is positive for enhancing the propor-tion of NCR+ILC3 via Notch signaling,and it provides a basis for targeting NCR+ILC3 for restoring intestinal barrier function to alle-viating ulcerative colitis.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.
Animals ; Rabbits ; Atrial Fibrillation/metabolism* ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Signal Transduction ; NF-E2-Related Factor 2/pharmacology* ; Molecular Docking Simulation ; Oxidative Stress ; Energy Metabolism ; Mitochondria/metabolism* ; Inflammation/metabolism* ; Heme Oxygenase-1

Objective To evaluate the effect of hypothermic machine perfusion (HMP) on the expression levels of inflammatory cytokines in rat kidney. Methods Thirty male rats were randomly divided into the control (Control group), static cold storage group (SCS group) and HMP group, with 10 rats in each group. The velocity, intrarenal resistance and pH value of perfusion effluent were recorded during HMP. The expression levels of CXC chemokine ligand (CXCL)1, CXCL2, interferon (IFN)-β1, IFN-α4, CC chemokine ligand (CCL)2, CCL20, interleukin (IL)-17α, IL-17C and tumor necrosis factor (TNF)-α messenger RNA (mRNA) in renal tissues were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Pathological changes of the kidney were observed by hematoxylin-eosin (HE) staining. Results During HMP, the velocity and intrarenal resistance remained stable, and the pH value of perfusion effluent was decreased slowly. RT-PCR showed that the relative expression levels of CXCL1, CXCL2, CCL2, CCL20, IL-17α, IL-17C and TNF-α mRNA in the SCS and HMP groups were higher compared with those in the Control group. Compared with the SCS group, the relative expression levels of CXCL1, CXCL2, CCL2, CCL20, IL-17α and TNF-α mRNA were up-regulated in the HMP group (all P<0.05). HE staining revealed that the morphology of renal cells was normal in the Control group, whereas evident epithelial necrosis, cytoplasmic vacuolation, brush border loss and epithelial shedding were observed in the SCS group. Compared with the SCS group, pathological changes in the HMP group were alleviated. Conclusions HMP may activate renal inflammation, and inhibiting the activation of inflammation during HMP is expected to further improve the effect of allograft preservation.

Objective:To evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection in the treatment of peripheral T-cell lymphoma (PTCL) in a real-world setting.Methods:This was a real-world ambispective cohort study (MOMENT study) (Chinese clinical trial registry number: ChiCTR2200062067). Clinical data were collected from 198 patients who received mitoxantrone hydrochloride liposome injection as monotherapy or combination therapy at 37 hospitals from January 2022 to January 2023, including 166 patients in the retrospective cohort and 32 patients in the prospective cohort; 10 patients in the treatment-na?ve group and 188 patients in the relapsed/refractory group. Clinical characteristics, efficacy and adverse events were summarized, and the overall survival (OS) and progression-free survival (PFS) were analyzed.Results:All 198 patients were treated with mitoxantrone hydrochloride liposome injection for a median of 3 cycles (range 1-7 cycles); 28 cases were treated with mitoxantrone hydrochloride liposome injection as monotherapy, and 170 cases were treated with the combination regimen. Among 188 relapsed/refractory patients, 45 cases (23.9%) were in complete remission (CR), 82 cases (43.6%) were in partial remission (PR), and 28 cases (14.9%) were in disease stabilization (SD), and 33 cases (17.6%) were in disease progression (PD), with an objective remission rate (ORR) of 67.6% (127/188). Among 10 treatment-na?ve patients, 4 cases (40.0%) were in CR, 5 cases (50.0%) were in PR, and 1 case (10.0%) was in PD, with an ORR of 90.0% (9/10). The median follow-up time was 2.9 months (95% CI 2.4-3.7 months), and the median PFS and OS of patients in relapsed/refractory and treatment-na?ve groups were not reached. In relapsed/refractory patients, the difference in ORR between patients with different number of treatment lines of mitoxantrone hydrochloride liposome injection [ORR of the second-line, the third-line and ≥the forth-line treatment was 74.4% (67/90), 73.9% (34/46) and 50.0% (26/52)] was statistically significant ( P = 0.008). Of the 198 PTCL patients, 182 cases (91.9%) experienced at least 1 time of treatment-related adverse events, and the incidence rate of ≥grade 3 adverse events was 66.7% (132/198), which was mainly characterized by hematologic adverse events. The ≥ grade 3 hematologic adverse events mainly included decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and anemia; non-hematologic adverse events were mostly grade 1-2, mainly including pigmentation disorders and upper respiratory tract infection. Conclusions:The use of mitoxantrone hydrochloride liposome injection-containing regimen in the treatment of PTCL has definite efficacy and is well tolerated, and it is a new therapeutic option for PTCL patients.

Tooth root development involves intricate spatiotemporal cellular dynamics and molecular regulation. The initiation of Hertwig's epithelial root sheath (HERS) induces odontoblast differentiation and the subsequent radicular dentin deposition. Precisely controlled signaling pathways modulate the behaviors of HERS and the fates of dental mesenchymal stem cells (DMSCs). Disruptions in these pathways lead to defects in root development, such as shortened roots and furcation abnormalities. Advances in dental stem cells, biomaterials, and bioprinting show immense promise for bioengineered tooth root regeneration. However, replicating the developmental intricacies of odontogenesis has not been resolved in clinical treatment and remains a major challenge in this field. Ongoing research focusing on the mechanisms of root development, advanced biomaterials, and manufacturing techniques will enable next-generation biological root regeneration that restores the physiological structure and function of the tooth root. This review summarizes recent discoveries in the underlying mechanisms governing root ontogeny and discusses some recent key findings in developing of new biologically based dental therapies.
Female ; Humans ; Tooth Root/metabolism* ; Odontogenesis ; Epithelial Cells ; Cell Differentiation ; Biocompatible Materials/metabolism*

Objective:To compare the growth speed of pulmonary artery and left ventricle after the repair of tetralogy of Fallot(TOF) with valve-sparing and transannular patch.Methods:The clinical data of children with tetralogy of Fallot admitted to our hospital from January 2015 to October 2020 were reviewed. According to the way of relieving right ventricular outflow tract stenosis, they were divided into two groups: valve-sparing and transannular patch. Independent sample t test or non- parametric test was used to compare the pulmonary artery and left ventricular growth indexes before operation and at the last follow-up between the two groups. The paired t test was used to compare preoperative and postoperative indexes. Results:A total of 104 children with tetralogy of Fallot, including 58 males and 46 females, had surgery at a median age and weight of 6.7(4.1, 10.3) months and 7.0(5.8, 8.4) kg, respectively. The preoperative Nakata index, McGoon ratio, pulmonary artery Z-score, left ventricular end diastolic volume(LVEDV) index and Z-score in valve-sparing were higher than those in transannular patch( P=0.001, 0.000, 0.003, 0.000, 0.000). At the last follow-up, the Z-scores of pulmonary arteries in both groups were greater than those before operation( P=0.016, 0.000), the LVEDV Z-score in transannular patch was greater than that before surgery( P=0.000), while the LVEDV Z-score of valve-sparing was not significantly different from that before operation( P=0.581), there was no significant difference in pulmonary artery Z-score and LVEDV Z-score between two groups( P=0.468, 0.884). The difference between the last follow-up and preoperative of pulmonary artery Z-score and LVEDV Z-score in valve-sparing was smaller than that in transannular patch( P=0.000, 0.000). Conclusion:Compared with valve-sparing, the pulmonary artery and left ventricle grow faster in transannular patch during the early stage after TOF repair.

Objective:To explore risk factors for relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-ALL).Methods:A retrospective analysis was performed for 65 adult Ph-ALL patients undergoing initial allo-HSCT from 2016 to 2018. The effect of baseline level and treatment pre-transplantation for relapse after allo-HSCT was analyzed.Results:There were 37 males and 28 females with a median age of 25(14-58) years during allo-HSCT. And the median follow-up period was 27 months post-HSCT. The 2-year overall survival (OS) was 78.8%(95%CI 67.8%-89.8%) and the 2-year relapse-free survival (RFS) 70.7% (95%CI 58.2%-83.2%). Pre-transplant chemotherapy was offered for 3 to 7 courses and the median dose of polyethylene glycol-conjugated asparaginase (PEG-ASP) was 3 doses (2 000 IU/m 2 per dose). Multiariate analysis revealed that the regimen included more than 4 doses of PEG-ASP pre-HSCT (HR=4.067, P=0.046) was a protective factor for post-transplant relapse (HR=0.193, P=0.009). High-risk chromosome karyotype was a risk factor for relapse (HR=0.193, P=0.009). The 2-year RFS rate was 90.0%(95%CI 79.2%-100.0%) for intensive PEG-ASP group and 56.9%(95%CI 39.1%-74.7%) for control group ( P=0.01). No significant inter-group difference existed in overall survival (OS)( P=0.079). The 2-year OS was 90.6% (95%CI 80.4%-100.0%) in intensive PEG-ASP group and 72.1% (95%CI 56.6%-87.6%) in control group. Conclusions:For adult ph-ALL patients, a higher dose of PEG-ASP in pretransplant chemotherapy regimens may improve post-transplant RFS and achieve a better outcome.