Antitumor activity and safety of the PD-1 inhibitor retifanlimab in patients with recurrent microsatellite instability-high or deficient mismatch repair endometrial cancer: Final safety and efficacy results from cohort H of the POD1UM-101 phase I study.

OBJECTIVE: Retifanlimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1 being investigated in several solid tumor types. We report final results from patients with recurrent microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer treated with retifanlimab in a POD1UM-101 expansion cohort. METHODS: Eligible patients (≥18 years; histologically proven/unresectable/recurrent, MSI-H/dMMR endometrial cancer; checkpoint inhibitor naive) received retifanlimab 500 mg intravenously every 4 weeks for ≤2 years. Primary endpoint was safety/tolerability. RESULTS: At data cutoff (May 17, 2023), 76 patients had received at least one retifanlimab dose. Median (range) age was 67 (49-88) years; 88.2% of patients had recurrent metastatic disease and 80.3% had visceral metastases. Seventy-five patients (98.7%) had received at least one prior systemic therapy. Median retifanlimab exposure was 10.0 (0.03-25.9) months; 23 patients completed treatment. 38 patients (50.0%) had grade ≥3 treatment-emergent adverse events (TEAEs), most commonly anemia (n = 10 [13.2%]). 63 patients (82.9%) had treatment-related AEs (TRAEs; grade ≥3, n = 14 [18.4%]); most common was fatigue (n = 14 [18.4%]). Two patients had TEAEs that led to death; no TRAEs were fatal. 39 patients had objective responses (51.3%; 95% CI, 39.6-63.0%); 19 patients (25.0%) had complete response and 20 (26.3%) had partial response. Median progression-free survival was 12.2 months; 30 patients (76.9%) had duration of response (DOR) ≥12 months. Median DOR was not reached after median follow-up time of 26.0 months. CONCLUSIONS: Retifanlimab was generally well tolerated and demonstrated encouraging anti-tumor activity in patients with pre-treated recurrent MSI-H/dMMR endometrial cancer.

Whole-transcriptome profiling reveals potential biomarkers for the reversal of thymic epithelial cell senescence by umbilical cord mesenchymal stem cells.

BACKGROUND: Reduced numbers and dysfunction of thymic epithelial cells (TECs) are important factors of thymic degeneration. Previous studies have found that umbilical cord mesenchymal stem cells (UCMSCs) reverse the structure and function of the senescent thymus in vivo. However, the transcriptomic regulation mechanism is unclear. METHODS: TECs were cultured with H2O2 for 72 hours to induce senescence. UCMSCs were cocultured with senescent TECs for 48 hours to detect SA-ß-gal, P16 and Ki67. The cocultured TECs were collected for lncRNA, mRNA and miRNA sequencing to establish a competitive endogenous regulatory network (ceRNA). And RT-qPCR, immunofluorescence staining, and western blot were used to identified key genes. RESULTS: Our results showed that H2O2 induced TEC aging and that UCMSCs reversed these changes. Compared with those in aged TECs, 2260 DE mRNAs, 1033 DE lncRNAs and 67 DE miRNAs were differentially expressed, and these changes were reversed by coculturing the cells with UCMSCs. Differential mRNA enrichment analysis of ceRNA regulation revealed that the PI3K-AKT pathway was a significant signaling pathway. UCMSC coculture upregulated VEGFA, which is the upstream factor of the PI3K-AKT signaling pathway, and the expression of the key proteins PI3K and AKT. Thus, the expression of the cell cycle suppressor P27, which is downstream of the PI3K-AKT signaling pathway, was downregulated, while the expression of the cell cycle regulators CDK2 and CCNE was upregulated. CONCLUSION: UCMSC coculture upregulated the expression of VEGFA, activated the PI3K-AKT signaling pathway, increased the expression of CDK2 and CCNE, decreased the expression of P27, and promoted the proliferation of TECs.

Anticancer activities of natural abietic acid.

Cancer is the main cause of death in the world. There are several therapies that are in practice for cancer cure including radiotherapy, chemotherapy, and surgery. Among the chemotherapies, natural products are considered comparable safe, easily available and cost effective. Approximately 60% of cancer approved FDA drugs are natural products including vinblastine, doxorubicin, and paclitaxel. These natural products have complex structures due to which they work against cancer through different molecular pathways, STAT3, NF-kB, PI3K/AKT/mTOR, cell cycle arrest, mitochondrial dependent pathway, extrinsic apoptosis pathway, autophagy, mitophagy and ferroptosis. AA is a natural abietane diterpenoid compound from Pinus palustris and Pimenta racemose var. grissea with different pharmacological activities including anti-inflammatory, anti-convulsant, anti-obesity and anti-allergic. Recently it has been reported with its anticancer activities through different molecular mechanisms including NF-kB, PI3K/AKT, call cycle arrest at G0/G1 phase, mitochondrial dependent pathway, extrinsic apoptosis pathway, AMPK pathway and ferroptosis pathways. The literature survey reveals that there is no review on AA anticancer molecular mechanisms, therefore in current review, we summarize the anticancer molecular mechanisms of AA.

Systemic loss of CD36 aggravates NAFLD-related HCC through MEK1/2-ERK1/2 signaling pathway.

BACKGROUND & AIMS: CD36, a membrane protein widely present in various tissues, is crucial role in regulating energy metabolism. The rise of HCC as a notable outcome of NAFLD is becoming more apparent. Patients with hereditary CD36 deficiency are at increased risk of NAFLD. However, the impact of CD36 deficiency on NAFLD-HCC remains unclear. METHODS: Global CD36 knockout mice (CD36KO) and wild type mice (WT) were induced to establish NAFLD-HCC model by N-nitrosodiethylamine (DEN) plus high fat diet (HFD). Transcriptomics was employed to examine genes that were expressed differentially. RESULTS: Compared to WT mice, CD36KO mice showed more severe HFD-induced liver issues and increased tumor malignancy. The MEK1/2-ERK1/2 pathway activation was detected in the liver tissues of CD36KO mice using RNA sequencing and Western blot analysis. CONCLUSION: Systemic loss of CD36 leaded to the advancement of NAFLD to HCC by causing lipid disorders and metabolic inflammation, a process that involves the activation of MAPK signaling pathway. We found that CD36 contributes significantly to the maintenance of metabolic homeostasis in NAFLD-HCC.

Celecoxib and cisplatin dual-loaded microspheres synergistically enhance transarterial chemoembolization effect of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is a first-line treatment for intermediate to advanced-stage liver cancer, with drug-eluting microspheres commonly used as embolic agents. However, currently available drug-eluting microspheres suffer from low drug-loading capacity and limited drug options. In this work, we developed polydopamine-modified polyvinyl alcohol dual-drug-loaded microspheres encapsulating celecoxib and cisplatin (referred to as PCDMS). Physicochemical characterization revealed that the surface of the microspheres displayed increased roughness after polydopamine modification, and celecoxib and cisplatin were successfully loaded onto the microsphere surface. In vitro cell experiments demonstrated that the PCDMS significantly inhibited the proliferation and migration of highly metastatic human liver cancer cells (MHCC-97H) and human liver cancer cells (SMMC-7721). Furthermore, the dual-loaded microspheres exhibited remarkable tumor growth inhibition and reshaped the tumor microenvironment in both subcutaneous H22 liver cancer model in Balb/c mice and intrahepatic VX2 tumor model in New Zealand rabbits, demonstrating a synergistic antitumor effect where 1 + 1>2. This work provides a potential therapeutic approach for the treatment of refractory liver cancer and holds significant translational potential.

Nanotechnology for brain tumor imaging and therapy based on π-conjugated materials: state-of-the-art advances and prospects.

In contemporary biomedical research, the development of nanotechnology has brought forth numerous possibilities for brain tumor imaging and therapy. Among these, π-conjugated materials have garnered significant attention as a special class of nanomaterials in brain tumor-related studies. With their excellent optical and electronic properties, π-conjugated materials can be tailored in structure and nature to facilitate applications in multimodal imaging, nano-drug delivery, photothermal therapy, and other related fields. This review focuses on presenting the cutting-edge advances and application prospects of π-conjugated materials in brain tumor imaging and therapeutic nanotechnology.

Hematopoietic aging: cellular, molecular, and related mechanisms.

ABSTRACT: Aging is accompanied by significant inhibition of hematopoietic and immune system function and disruption of bone marrow structure. Aging-related alterations in the inflammatory response, immunity, and stem cell niches are at the root of hematopoietic aging. Understanding the molecular mechanisms underlying hematopoietic and bone marrow aging can aid the clinical treatment of aging-related diseases. In particular, it is unknown how the niche reprograms hematopoietic stem cells (HSCs) in an age-dependent manner to maintain normal hematopoiesis in elderly individuals. Recently, specific inhibitors and blood exchange methods have been shown to reshape the hematopoietic niche and reverse hematopoietic aging. Here, we present the latest scientific discoveries related to hematopoietic aging and hematopoietic system rejuvenation, discuss the relationships between hematopoietic niche aging and HSC aging, and describe related studies on stem cell-mediated regulation of hematopoietic aging, aiming to provide new ideas for further study.

[Clinical Characteristics and Risk Factors in Children with Acute Leukemia Complicated with Multiple Drug Resistant Bacterial Septicemia].

OBJECTIVE: To investigate the clinical characteristics and risk factors of acute leukemia complicated with multi-drug resistant bacterial septicemia in children. METHODS: The clinical data of children with acute leukemia complicated with septicemia admitted to the Affiliated Hospital of Guangdong Medical University from January 2013 to May 2021 were retrospectively analyzed. Their flora composition and drug resistance were also analyzed. The children were divided into multi-drug resistant bacteria (MDRB) group and non-multi-drug resistant bacteria (non-MDRB) group according to the drug sensitivity results, and the differences in clinical data between the two group were compared. RESULTS: A total of 108 children had drug sensitivity results, 47 cases in the MDRB group, including 26 strians of Gram-positive bacteria (G+), the most common multi-drug resistant G+ bacteria were coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, and the most common multi-drug resistant Gram-negative bacteria G- bacteria were Escherichia coli and Klebsiella pneumoniae subspecies pneumoniae. Compared with non-MDRB group, children in MDRB group had higher C-reactive protein (CRP) level and mortality rate (P <0.001, P =0.009), lower initial empirical anti-infection efficiency (P <0.001), and were more likely to have septic shock (P =0.003). Logistic analysis showed that the risk factors of acute leukemia complicated with MDRB septicemia in children were previous MDRB infection (OR =6.763, 95% CI: 1.141-40.092, P =0.035), duration of agranulocytosis before infection≥7 days (OR =3.071, 95% CI: 1.139-8.282, P =0.027), and previous use of antimicrobial drugs within 90 days before infection (OR =7.675, 95% CI: 1.581-37.261, P =0.011). CONCLUSIONS: The clinical features of acute leukemia complicated with MDRB septicemia in children include a heavy inflammatory response, significantly elevated CRP, susceptibility to secondary septic shock, low efficiency of initial empirical anti-infective therapy, and high mortality rate. Previous MDRB infection, duration of agranulocytosis before infection≥7 days, and previous use of antimicrobial drugs within 90 days before infection are risk factors of acute leukemia complicated with MDRB septicemia in children.

Potential Biomarker of Acute Anthracycline-induced Cardiotoxicity Among Children With Acute Lymphoblastic Leukemia: Cardiac Adriamycin-responsive Protein.

ABSTRACT: This study aimed to investigate whether serum cardiac adriamycin-responsive protein (CARP) can serve as a sensitive and specific biomarker of anthracyclines (ANT)-induced cardiotoxicity. Fifty-five children with acute lymphoblastic leukemia were recruited. Before and after the administration of ANT, serum levels of CARP, high-sensitivity troponin T, creatine kinase-MB, and electrocardiogram were measured. Postchemotherapeutic clinical manifestations of cardiotoxicity were also investigated. Adverse cardiac events (ACEs) were graded according to the Common Terminology Criteria for Adverse Events 4.0. Then, the CARP expression was statistically analyzed among different groups. The receiver operating characteristic curve was used to evaluate the efficacy of CARP in predicting acute ANT-induced cardiotoxicity. After ANT chemotherapy, the serum CARP concentration increased in the non-ACEs group but decreased in the ACEs group ( P < 0.05). In addition, not only the serum CARP levels (△CARP) was negatively correlated with the grade of ACEs (R=-0.754, P < 0.0001) but also the extent of QT interval corrected (QTc) prolongation (△QTc; R=-0.5592, P < 0.01). The area under the receiver operating characteristic curve of CARP was 90.94% ( P < 0.0001), and the sensitivity and specificity were 88.64% and 91.67%, respectively, all of which are superior to △high-sensitivity troponin T, △creatine kinase-MB, and △QTc. In conclusion, serum CARP could serve as a novel sensitive and specific biomarker of acute ANT-induced cardiotoxicity, which is negatively associated with ACE grade.

An analysis of the relationship between donor and recipient biomarkers and kidney graft function, dysfunction, and rejection.

BACKGROUND: The study aimed to find predictive biomarkers to evaluate donor kidney function to predict graft dysfunction as well as to assess an early signs of acute graft rejection. METHOD: Twenty-seven deceased donors and 54 recipients who underwent a successful kidney transplantation were enrolled in the study. An assessment was made in serum and urine from donors and recipients to measure the following biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase 2 (TIMP-2) and urinary N-acetyl-b-D-glucosaminidase (uNAG). These biomarkers were used to establish a model for predicting a reduced graft function (RGF) classified as either a delayed or slow graft function. RESULT: Our analysis suggest that out of four tested biomarkers, the serum TIMP-2 and uNAG levels of the donors had a predictive value for RGF; the area under the receiver operating characteristic curves (AUROC) of serum TIMP-2 and uNAG were 0.714 and 0.779, respectively. The combined best fitting prediction model of serum TIMP-2, uNAG, and creatinine levels was better in predicting RGF than the serum creatinine level alone. In addition, the recipient serum TIMP-2 level on the third day post-transplantation (D3) was associated with the estimated glomerular filtration rate (eGFR) on the seventh day post-transplantation (D7; OR 1.119, 95% CI 1.016-1.233, p = 0.022). Furthermore, the ROC curve value revealed that the AUROC of TIMP-2 on D3 was 0.99 (95% CI 0.97-1, p < 0.001), and this was the best predictive value of the renal function on D7. CONCLUSIONS: Donor serum TIMP-2 and uNAG levels are useful predictive biomarkers because they can provide the donor-based prediction for RGF.

All-in-one properties of an anticancer-covered airway stent for the prevention of malignant central airway obstruction.

Malignant central airway obstruction (MCAO) resulting from tumor metastasis and compression severely impairs respiration, posing life-threatening risks. To address this, we employed a synergistic modification strategy, combining cisplatin (CIS) and silver nanoparticles (AgNPs). Polycaprolactone (PCL) served as a drug carrier, enabling the preparation of a functional CIS@AgNPs@PCL fiber membrane-covered airway stent via electrospinning. This approach aimed to enhance the patency rate of MCAO. Characterization via ATR-FTIR, scanning electron microscope-energy-dispersive spectroscopy, and transmission electron microscope confirmed successful immobilization of CIS and AgNPs onto the stent surface. CIS@AgNPs@PCL substantially suppressed non-small cell lung cancer cells (A549), causing DNA damage, ultrastructural disruption, and over 50% apoptosis in 48 h. It also displayed potent antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans biofilms. A mouse subcutaneous tumor recurrence model assessed anti-cancer efficacy. CIS@AgNPs@PCL fiber-covered stents significantly inhibited lung cancer tissue and enhanced anti-cancer effects by up-regulating caspase-3 and Bax, while down-regulating Bcl-2. This study's functional airway stent provides a proof-of-concept for an integrated anti-cancer and antibacterial strategy. It promptly restores the lumen, inhibits biofilm formation, prevents tumor progression, and improves postoperative MCAO patency.

"One-stop" synergistic strategy for hepatocellular carcinoma postoperative recurrence.

Residual tumor recurrence after surgical resection of hepatocellular carcinoma (HCC) remains a considerable challenge that imperils the prognosis of patients. Notably, intraoperative bleeding and postoperative infection are potential risk factors for tumor recurrence. However, the biomaterial strategy for the above problems has rarely been reported. Herein, a series of cryogels (coded as SQ-n) based on sodium alginate (SA) and quaternized chitosan (QC) were synthesized and selected for optimal ratios. The in vitro assays showed that SQ-50 possessed superior hemostasis, excellent antibacterial property, and great cytocompatibility. Subsequently, SQAP was constructed by loading black phosphorus nanosheets (BPNSs) and anlotinib hydrochloride (AL3818) based on SQ-50. Physicochemical experiments confirmed that near-infrared (NIR)-assisted SQAP could control the release of AL3818 in photothermal response, significantly inhibiting the proliferation and survival of HUVECs and H22 cells. Furthermore, in vivo studies indicated that the NIR-assisted SQAP prevented local recurrence of ectopic HCC after surgical resection, achieved through the synergistic effect of mPTT and molecular targeted therapy. Thus, the multifunctional SQAP provides a "one-stop" synergistic strategy for HCC postoperative recurrence, showing great potential for clinical application.

Intra-luminal iodine-125 brachytherapy in patients with esophageal carcinoma and 3/4 dysphagia score: A feasibility study.

Purpose: To evaluate the clinical results of nasal feeding nutritional tube (NFNT)-loaded iodine-125 (125I) seeds in intra-luminal brachytherapy (ILBT) for esophageal carcinoma (EC) patients with a 3/4 dysphagia score. Material and methods: From January 2019 to January 2020, 26 patients (female/male: 17/9, mean age: 75.3 years, dysphagia score 3/4: 6/20, mean Karnofsky score: 58.4) with EC underwent NFNT-loaded 125I seed placement for both nutrition and brachytherapy. Technical and clinical success, D90 (radiation dose received by 90% of tumor volume) and organ at risk (OAR) dose, complications, dysphagia-free time (DFT), and overall survival (OS) time were documented. Local tumor diameter, Karnofsky score, dysphagia score, and quality of life (QoL) were compared before and 6 weeks after tube placement. Results: Technical and clinical success rates were 100% and 76.9%, respectively. The D90 and OAR doses were 39.7 Gy and 2.3 Gy, respectively. Eight cases (30.8%) experienced mild complications, but no seed loss, fistula, and massive bleeding were observed. Median DFT and OS were 3.1 months and 13.7 months, respectively. Tumor diameter and dysphagia score significantly decreased (p < 0.05), Karnofsky score significantly improved (p < 0.05), and QoL scores related to physical function, physical functioning, general health, vitality, and emotional functioning improved (p < 0.05). Conclusions: NFNT-loaded 125I brachytherapy for ILBT is technically a safe and effective strategy for EC patients with low Karnofsky scores, and can be a bridging therapy for advanced anti-cancer treatment.

Silencing LCN2 enhances RSL3-induced ferroptosis in T cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a life-threatening malignancy and therapeutic toxicity remains a huge challenge for survival rates. A novel iron-dependent form of cell death, ferroptosis, shows potentials in cancer therapy. This study aimed to identify ferroptosis-associated hub genes within a proteinprotein interaction (PPI) network. METHODS: We screened differential expressed genes (DEGs) in GSE46170 dataset and obtained ferroptosis-related genes from FerrDb database. Through overlapping between DEGs and ferroptosis-related genes, ferroptosis-associated DEGs were identified for further PPI network construction. Molecular complex detection (MCODE) algorithm in Cytoscape was employed to determine tightly connected protein clusters. Chord diagram of Gene Ontology (GO) was generated to reveal the potential biological process of hub genes. Through transfection with siRNA of lipocalin 2 (LCN2) into TALL cells, the regulatory role of LCN2 in ferroptosis was investigated. RESULTS: Venn diagram identified a total of 37 ferroptosis-associated DEGs between GSE46170 and ferroptosis-associated genes, which were mainly enriched in ferroptosis and necroptosis. Based on PPI network analysis, 5 hub genes (LCN2, LTF, HP, SLC40A1 and TFRC) were found. These hub genes were involved in iron ion transport and could distinguish T-ALL from normal individuals. Further experimental studies demonstrated that LCN2 was highly expressed in T-ALL, while silencing LCN2 promoted RSL3-induced ferroptotic cell death in T-ALL cells. CONCLUSION: This study identified novel ferroptosis-associated hub genes, which shed new insights into the underlying mechanism of ferroptosis in T-ALL and also provide promising therapeutic targets for T-ALL.

All-in-one bioactive properties of photothermal nanofibers for accelerating diabetic wound healing.

Diabetic wound healing has attracted widespread attention in biomedical engineering. However, the harsh hypoxic microenvironment (HME) comprising high glucose levels, local bleeding, and bacterial infection often leads to the formation of hyperplastic scars, increasing the clinical demand for wound dressings. Here, we report a comprehensive strategy using near-infrared NIR-assisted oxygen delivery combined with the bioactive nature of biopolymers for remodeling the HME. Black phosphorus (BP) nanosheets and hemoglobin (Hb) were self-assembled layerwise onto electrospun poly-l-lactide (PLLA) nanofibers using charged quaternized chitosan (QCS) and hyaluronic acid. BP converts NIR radiation into heat and stimulates Hb to release oxygen in situ. QCS is a hemostatic and broad-spectrum antibacterial material. Moderate BP-derived photothermal therapy can increase the sensitivity of bacteria to QCS. A series of composite wound dressings (coded as PQBH-n) with different numbers of layers were fabricated, and the in vivo diabetic wound healing potentials were tested. The molecular mechanism can be partly attributed to the cytokine-cytokine receptor interaction. Notably, this comprehensive strategy based on NIR-assisted oxygen delivery combined with the bioactive properties of biopolymers is not only applicable for fabricating multifunctional wound dressings but also has a great potential in expanding biomedical engineering fields.

Identification of Ultrasound-Sensitive Prognostic Markers of LAML and Construction of Prognostic Risk Model Based on WGCNA.

Background: Acute myeloid leukemia (LAML) is the most widely known acute leukemia in adults. Chemotherapy is the main treatment method, but eventually many individuals who have achieved remission relapse, the disease will ultimately transform into refractory leukemia. Therefore, for the improvement of the clinical outcome of patients, it is crucial to identify novel prognostic markers. Methods: The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were utilized to retrieve RNA-Seq information and clinical follow-up details for patients with acute myeloid leukemia, respectively, whereas samples that received or did not receive ultrasound treatment were analyzed using differential expression analysis. For consistent clustering analysis, the ConsensusClusterPlus package was utilized, while by utilizing weighted correlation network analysis (WGCNA), important modules were found and the generation of the coexpression network of hub gene was generated using Cytoscape. CIBERSORT, ESTIMATE, and xCell algorithms of the "IOBR" R package were employed for the calculation of the relative quantity of immune infiltrating cells, whereas the mutation frequency of cells was estimated by means of the "maftools" R package. The pathway enrichment score was calculated using the single sample Gene Set Enrichment Analysis (ssGSEA) algorithm of the "Gene Set Variation Analysis (GSVA)" R package. The IC50 value of the drug was predicted by utilizing the "pRRophetic." The indications linked with prognosis were selected by means of the least absolute shrinkage and selection operator (Lasso) Cox analysis. Results: Two categories of samples were created as follows: Cluster 1 and Cluster 2 depending on the differential gene consistent clustering of ultrasound treatment. The prognosis of patients in Cluster 2 was better than that in Cluster 1, and a considerable variation was observed in the immune microenvironment of Cluster 1 and Cluster 2. Lasso analysis finally obtained an 8-gene risk model (GASK1A, LPO, LTK, PRRT4, UGT3A2, BLOCK1S1, G6PD, and UNC93B1). The model acted as an independent risk factor for the patients' prognosis, and it showed good robustness in different datasets. Considerable variations were observed in the abundance of immune cell infiltration, genome mutation, pathway enrichment score, and chemotherapeutic drug resistance between the low and high-risk groups in accordance with the risk score (RS). Additionally, model-based RSs in the immunotherapy cohort were significantly different between complete remission (CR) and other response groups. Conclusion: The prognosis of people with LAML can be predicted using the 8-gene signature.

Bone Marrow Mesenchymal Stem Cells Reversed Ovarian Aging-related m6A RNA Methylation Modification Profile in Aged Granulosa Cells.

BACKGROUND: Ovarian ageing causes endocrine disturbances and the degeneration of systemic tissue and organ functions to seriously affect women's physical and mental health, and effective treatment methods are urgently needed. Based on our previous studies using juvenile rhesus monkey bone marrow mesenchymal stem cells (BMMSCs) to treat ovarian ageing in rhesus monkey, we found that BMMSCs improved ovarian structure and function. This study continues to explore the mechanism by which BMMSCs reversed granulosa cell (GC) ageing. METHODS: A GC ageing model and coculture system of BMMSCs were established, changes in the level of the N6-methyladenosine (m6A) methylation modification were detected, m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq) were performed, correlations between m6A peaks and mRNA expression were determined, and the expression of hub genes was identified using Q-PCR, immunofluorescence staining, and western blot. RESULTS: Our results showed that H2O2 successfully induced GC ageing and that BMMSCs reversed measures of GC ageing. BMMSCs increased the expression of the FTO protein and reduced the overall level of m6A. We identified 797 m6A peaks (348 hypomethylated and 449 hypermethylated peaks) and 817 differentially expressed genes (DEGs) (412 upregulated and 405 downregulated) after aged GCs were cocultured with BMMSCs, which significantly associated with ovarian function and epigenetic modification. The epigenetic repressive mark and important cell cycle regulator lysine demethylase 8 (KDM8) was downregulated at both the mRNA and protein levels, histone H3 was upregulated in aged GCs after BMMSC coculture, and KDM8 was upregulated after FTO was inhibited through FB23. CONCLUSIONS: Our study revealed an essential role for m6A in BMMSCs in reversing GC ageing, and FTO regulated KDM8 mediates histone H3 changes may as a novel regulatory mechanism in BMMSCs to reverse GC ageing.

Surgical treatment patterns and clinical outcomes of type B aortic dissection involving the aortic arch.

OBJECTIVE: In the present report, we have described the outcomes of endovascular repair, hybrid arch repair, and open surgical repair for type B dissection involving the aortic arch (B1-2, D). METHODS: Cases of endovascular repair, hybrid arch repair, and open surgical repair performed between January 2015 and December 2019 for aortic dissection designated as B1-2, D by the Society for Vascular Surgery/Society of Thoracic Surgeons classification were retrospectively analyzed. The primary end point was all-cause mortality at follow-up. The secondary end points included early mortality, early morbidities, and aortic-related late events. Kaplan-Meier curves were created to analyze survival from all-cause mortality and freedom from aortic-related late events in the endovascular, hybrid, and open groups. Propensity score matching and stratification (stratified by proximal dissection extension: B1, D and B2, D) were performed as sensitivity analyses to compare the outcomes among the three treatment patterns after controlling for major confounders. RESULTS: The present study included 151 patients (men, 79.5%; mean age, 47.3 ± 10.5 years), with 72 (47.7%) in the endovascular group, 46 (30.5%) in the hybrid group, and 33 (21.8%) in the open group. No significant difference was noted in early mortality between the endovascular, hybrid, and open groups (1.4% vs 2.2% vs 3.0%; P = .791). The incidence of early endoleak was significantly greater (33.3% vs 13.0% vs 6.1%; P = .002) and the incidence of renal function deterioration was less (4.2% vs 26.1% vs 24.2%; P = .001) after endovascular repair vs hybrid arch repair and open surgery. After a median follow-up of 40.0 months (range, 0-84.0 months), no significant differences were found in all-cause mortality (5.6% vs 4.3% vs 3.0%; P = 1.0), aortic-related late events (16.7% vs 15.2% vs 12.1%; P = .834), or late endoleak (9.7% vs 4.3% vs 6.1%; P = .630) after endovascular, hybrid, and open surgery. The propensity score matching and stratification analyses displayed consistent outcomes for early mortality, all-cause mortality, and aortic-related late events among the three groups. CONCLUSIONS: The mid- to long-term outcomes after endovascular repair, hybrid arch repair, and open surgical repair for type B dissection involving the aortic arch (B1-2, D) were favorable and comparable in selected patients. Extensive experience and multidisciplinary teamwork are prerequisites for individualized strategies for repair of B1-2, D.