Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

ObjectiveThe nucleolar protein PES1 (Pescadillo homolog 1) plays critical roles in ribosome biogenesis and cell cycle regulation, yet its involvement in cellular senescence remains poorly understood. This study aimed to comprehensively investigate the functional consequences of PES1 suppression in cellular senescence and elucidate the molecular mechanisms underlying its regulatory role. MethodsInitially, we assessed PES1 expression patterns in two distinct senescence models: replicative senescent mouse embryonic fibroblasts (MEFs) and doxorubicin-induced senescent human hepatocellular carcinoma HepG2 cells. Subsequently, PES1 expression was specifically downregulated using siRNA-mediated knockdown in these cell lines as well as additional relevant cell types. Cellular proliferation and senescence were assessed by EdU incorporation and SA-β-gal staining assays, respectively. The expression of senescence-associated proteins (p53, p21, and Rb) and SASP factors (IL-6, IL-1β, and IL-8) were analyzed by Western blot or qPCR. Furthermore, Northern blot and immunofluorescence were employed to evaluate pre-rRNA processing and nucleolar morphology. ResultsPES1 expression was significantly downregulated in senescent MEFs and HepG2 cells. PES1 knockdown resulted in decreased EdU-positive cells and increased SA‑β‑gal-positive cells, indicating proliferation inhibition and senescence induction. Mechanistically, PES1 suppression activated the p53-p21 pathway without affecting Rb expression, while upregulating IL-6, IL-1β, and IL-8 production. Notably, PES1 depletion impaired pre-rRNA maturation and induced nucleolar stress, as evidenced by aberrant nucleolar morphology. ConclusionOur findings demonstrate that PES1 deficiency triggers nucleolar stress and promotes p53-dependent (but Rb-independent) cellular senescence, highlighting its crucial role in maintaining nucleolar homeostasis and regulating senescence-associated pathways.

Eleven compounds were isolated from the ethyl acetate fraction of the 95% aqueous ethanol extract of the roots of Sophora tonkinensis by silica gel, ODS, Sephadex LH-20 column chromatography, and semi-preparative RP-HPLC. Their structures were identified as 7-hydroxy-8-isopentenylchromone (1), furo[2,3-f]-1,3-benzodioxole-7-carboxylic acid (2), 6-[3-(2′,4′-dihydroxyphenyl)acryloyl]-7-hydroxy-2,2-dimethyl-8-(3-methyl-2-butenyl)-2H-benzopyran (3), flemichapparin B (4), tectorigenin (5), genistein (6), 6-hydroxy-1,3-benzodioxole-5-carboxylic acid (7), vanillic acid (8), protocatechuic acid (9), 2,4-dihydroxybenzoic acid (10), and p-hydroxybenzoic acid (11) through extensive spectroscopic data (IR, UV, HR-ESI-MS, and NMR spectra). Among them, compounds 1 and 2 were new compounds. In addition, compound 3 showed significant α-glucosidase and protein tyrosine phosphatase-1B (PTP1B) inhibitory activities with IC₅₀ values of 5.595 and 0.320 μmol·L^-1, respectively.

Objective: To explore the clinical effects of island posterior femoral composite tissue flaps in the repair of sinus cavity pressure ulcers in the areas of ischial tuberosity and greater trochanter. Methods: The retrospective observational study was conducted. From December 2018 to December 2021, 23 patients with sinus cavity pressure ulcers in the areas of ischial tuberosity and greater trochanter who met the inclusion criteria were admitted to Ganzhou People's Hospital, including 16 males and 7 females, aged 45 to 86 years. The size of pressure ulcers in ischial tuberosity ranged from 1.5 cm×1.0 cm to 8.0 cm×5.0 cm, and the size of pressure ulcers in greater trochanter ranged from 4.0 cm×3.0 cm to 20.0 cm×10.0 cm before debridement. After treatment of underlying diseases, debridement and vacuum sealing drainage for 5 to 14 days were performed. All the wounds were repaired by island posterior femoral composite tissue flaps, with area of 4.5 cm×3.0 cm-24.0 cm×12.0 cm, pedicle width of 3-5 cm, pedicle length of 5-8 cm, and rotation radius of 30-40 cm. Most of the donor site wounds were sutured directly, and only 4 donor site wounds were repaired by intermediate thickness skin graft from the contralateral thigh. The survival of composite tissue flaps, wound healing of the donor and recipient sites and the complications were observed. The recurrence of pressure ulcers, and the appearance and texture of flaps were observed during follow-up. Results: A total of 32 wounds in 23 patients were repaired by island posterior femoral composite tissue flaps (including 3 fascio subcutaneous flaps, 24 fascial flaps+fascio subcutaneous flaps, 2 fascial flaps+fascial dermal flaps, 2 fascial flaps+fascio subcutaneous flaps+femoral biceps flaps, and one fascial flap+fascio subcutaneous flap+gracilis muscle flap). Among them, 31 composite tissue flaps survived well, and a small portion of necrosis occurred in one fascial flap+fascio subcutaneous flap post surgery. The survival rate of composite tissue flap post surgery was 96.9% (31/32). Twenty-nine wounds in the recipient sites were healed, and 2 wounds were torn at the flap pedicle due to improper postural changes, and healed one week after bedside debridement. One wound was partially necrotic due to the flap bruising, and healed 10 days after re-debridement. Thirty-one wounds in the donor sites (including 4 skin graft areas) were healed, and one wound in the donor site was torn due to improper handling at discharge, and healed 15 days after re-debridement and suture. The complication rate was 12.5% (4/32), mainly the incision dehiscence of the flap pedicle and the donor sites (3 wounds), followed by venous congestion at the distal end of flap (one wound). During the follow-up of 3 to 24 months, the pressure ulcers did not recur and the flaps had good appearance and soft texture. Conclusions: The island posterior femoral composite tissue flaps has good blood circulation, large rotation radius, and sufficient tissue volume. It has a high survival rate, good wound healing, low skin grafting rate in the donor site, few postoperative complications, and good long-term effect in the repair of sinus cavity pressure ulcers in the areas of ischial tuberosity and greater trochanter.
Male ; Female ; Humans ; Plastic Surgery Procedures ; Pressure Ulcer/etiology* ; Soft Tissue Injuries/surgery* ; Treatment Outcome ; Skin Transplantation ; Femur/surgery* ; Necrosis/surgery* ; Perforator Flap

Humans ; China/epidemiology* ; SARS-CoV-2 ; COVID-19

Bone defects caused by different causes such as trauma, severe bone infection and other factors are common in clinic and difficult to treat. Usually, bone substitutes are required for repair. Current bone grafting materials used clinically include autologous bones, allogeneic bones, xenografts, and synthetic materials, etc. Other than autologous bones, the major hurdles of rest bone grafts have various degrees of poor biological activity and lack of active ingredients to provide osteogenic impetus. Bone marrow contains various components such as stem cells and bioactive factors, which are contributive to osteogenesis. In response, the technique of bone marrow enrichment, based on the efficient utilization of components within bone marrow, has been risen, aiming to extract osteogenic cells and factors from bone marrow of patients and incorporate them into 3D scaffolds for fabricating bone grafts with high osteoinductivity. However, the scientific guidance and application specification are lacked with regard to the clinical scope, approach, safety and effectiveness. In this context, under the organization of Chinese Orthopedic Association, the Expert consensus for the clinical application of autologous bone marrow enrichment technique for bone repair ( version 2023) is formulated based on the evidence-based medicine. The consensus covers the topics of the characteristics, range of application, safety and application notes of the technique of autologous bone marrow enrichment and proposes corresponding recommendations, hoping to provide better guidance for clinical practice of the technique.

At present, effective reconstruction of the integrity and functionality of damaged skin tissue remains an important medical problem in the field of wound repair. In recent years, the rapid development of nanozymes and tissue engineering scaffolds in the field of regenerative medicine has made it possible to develop new skin wound repair materials. Based on the process of skin wound repair and regeneration, this review briefly describes the nanozymes and its catalytic mechanism. At the same time, the common tissue engineering scaffolds loaded with nanozymes and their manufacturing strategies are introduced, the application of tissue engineering scaffolds loaded with nanozymes during the stages of anti-bacteria and anti-inflammation in the process of wound repair is summarized, and their future development direction is discussed.

COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.

Humans ; Consensus ; Hypersensitivity ; Desensitization, Immunologic/adverse effects* ; Immunotherapy/adverse effects* ; Injections, Subcutaneous ; Allergens

OBJECTIVE: To develop and validate a user-friendly risk score for older mitral regurgitation (MR) patients, referred to as the Elder-MR score. METHODS: The China Senile Valvular Heart Disease (China-DVD) Cohort Study functioned as the development cohort, while the China Valvular Heart Disease (China-VHD) Study was employed for external validation. We included patients aged 60 years and above receiving medical treatment for moderate or severe MR (2274 patients in the development cohort and 1929 patients in the validation cohort). Candidate predictors were chosen using Cox's proportional hazards model and stepwise selection with Akaike's information criterion. RESULTS: Eight predictors were identified: age ≥ 75 years, body mass index < 20 kg/m², NYHA class III/IV, secondary MR, anemia, estimated glomerular filtration rate < 60 mL/min per 1.73 m², albumin < 35 g/L, and left ventricular ejection fraction < 60%. The model displayed satisfactory performance in predicting one-year mortality in both the development cohort (C-statistic = 0.73, 95% CI: 0.69-0.77, Brier score = 0.06) and the validation cohort (C-statistic = 0.73, 95% CI: 0.68-0.78, Brier score = 0.06). The Elder-MR score ranges from 0 to 15 points. At a one-year follow-up, each point increase in the Elder-MR score represents a 1.27-fold risk of death (HR = 1.27, 95% CI: 1.21-1.34, P < 0.001) in the development cohort and a 1.24-fold risk of death (HR = 1.24, 95% CI: 1.17-1.30, P < 0.001) in the validation cohort. Compared to EuroSCORE II, the Elder-MR score demonstrated superior predictive accuracy for one-year mortality in the validation cohort (C-statistic = 0.71 vs. 0.70, net reclassification improvement = 0.320, P < 0.01; integrated discrimination improvement = 0.029, P < 0.01). CONCLUSIONS The Elder-MR score may serve as an effective risk stratification tool to assist clinical decision-making in older MR patients.