Osteoarthritis (OA), a highly prevalent degenerative joint disease worldwide, is defined by articular cartilage degradation, abnormal bone remodeling, and persistent chronic inflammation. It severely compromises patients’ quality of life, and currently, there is no radical cure. Abnormal mechanical stress is widely regarded as a core driver of OA pathogenesis, and the exploration of mechanical signal perception and transduction mechanisms has become crucial for deciphering OA’s pathophysiological processes. Piezo1, a key mechanosensitive cation channel belonging to the Piezo protein family, has recently gained significant attention due to its pivotal role in mediating cellular responses to mechanical stimuli in joint tissues. This review systematically examines Piezo1’s expression patterns, regulatory mechanisms, and pathological functions in OA, with a particular focus on its dual roles in modulating chondrocyte homeostasis and bone metabolism disorders, while also delving into the underlying molecular signaling pathways and potential therapeutic implications. Piezo1, consisting of approximately 2 500 amino acids and forming a unique trimeric propeller-like structure, is widely expressed in chondrocytes, osteocytes, mesenchymal stem cells, and synovial cells. It exhibits permeability to cations such as Ca²⁺, K⁺, and Na⁺, and directly responds to membrane tension changes induced by mechanical stimuli like fluid shear stress and mechanical overload. In OA patients and animal models, Piezo1 expression is significantly upregulated, especially in cartilage regions subjected to abnormal mechanical stress (e.g., human temporomandibular joint cartilage). This overexpression is closely associated with aggravated cartilage degeneration, increased chondrocyte apoptosis, accelerated cellular senescence, and intensified inflammatory responses. Mechanical overload and pro-inflammatory cytokines (e.g., IL-1β) are key inducers of Piezo1 upregulation: IL-1β activates the PI3K/AKT/mTOR signaling pathway to enhance Piezo1 expression, forming a pathogenic positive feedback loop that inhibits chondrocyte autophagy, promotes apoptosis, and further accelerates joint degeneration. Mechanistically, Piezo1 mediates OA progression through multiple interconnected pathways. When activated by mechanical stress, Piezo1 triggers excessive Ca²⁺ influx, leading to endoplasmic reticulum stress (ERS) and mitochondrial dysfunction, which directly induce chondrocyte apoptosis. This process involves the activation of downstream signaling cascades such as cGAS-STING and YAP-MMP13/ADAMTS5. YAP, a transcriptional regulator, upregulates the expression of matrix metalloproteinase 13 (MMP13) and aggrecanase (ADAMTS5), thereby accelerating cartilage matrix degradation. Additionally, Piezo1-driven Ca²⁺ overload promotes the accumulation of reactive oxygen species (ROS) and upregulates senescence markers (p16 and p21), accelerating chondrocyte senescence via the p38MAPK and NF-κB pathways. Senescent chondrocytes secrete senescence-associated secretory phenotype (SASP) factors (e.g., IL-6, IL-1β), further amplifying joint inflammation. In terms of bone metabolism, Piezo1 maintains joint homeostasis by promoting the differentiation of fibrocartilage stem cells into chondrocytes and balancing bone formation and resorption through regulating the FoxC1/YAP axis and RANKL/OPG ratio. Therapeutically, targeting Piezo1 shows promising potential. Preclinical studies have demonstrated that Piezo1 inhibitors (e.g., GsMTx4) can reduce joint damage and alleviate pain in OA mice. Simultaneously, siRNA-mediated co-silencing of Piezo1 and TRPV4 (another mechanosensitive channel) decreases intracellular Ca²⁺ concentration, inhibits chondrocyte apoptosis, and promotes cartilage repair. Conditional knockout of Piezo1 using Gdf5-Cre transgenic mice alleviates cartilage degeneration in post-traumatic OA models by downregulating MMP13 and ADAMTS5 expression. Despite existing challenges, such as off-target effects of inhibitors, inefficient local drug delivery, and interindividual genetic variability, strategies like developing selective Piezo1 antagonists, optimizing targeted nanocarriers, and combining Piezo1-targeted therapy with physical therapy provide viable avenues for clinical translation. The authors propose that Piezo1 serves as a critical therapeutic target for OA, and future research should focus on deciphering its context-dependent regulatory networks, developing tissue-specific intervention strategies, and validating their efficacy and safety in clinical trials to address the unmet medical needs of OA patients.

AIM:To investigate the effects of high-dose methotrexate(MTX)on alkaline phosphatase(ALP)and the effects of ALP changes on bone me-tabolism,bone marrow granulogram function,liver function and excretion.METHODS:Aspartate ami-notransferase(AST),alanine aminotransferase(ALT)and albumin(ALB)were used as liver function indi-cators,serum calcium(Ca)and phosphorus(P)were used as bone metabolism indicators,neutro-phil(ANC)and white blood cell count(WBC)were used as bone marrow granuloline function indica-tors,and methotrexate C48h concentration ≥1 μmol/L was used as the excretion delay.One-way ANOVA analysis was performed on the ALP levels before and after the first chemotherapy and the second chemotherapy,and the children were divided into normal group and low group according to the ALP level,and the seven indexes before and after che-motherapy were quantitatively and qualitatively an-alyzed,and univariate and multivariate Logistic re-gression analysis was performed on the concentra-tion of methotrexate C48h and the above indexes in the children treated with the second chemothera-py.RESULTS:After the first chemotherapy and the second chemotherapy,ALP was significantly de-creased[(204.0±83.6)U/L vs.(172.8±67.3)U/L,(179.4±59.3)U/L vs.(169.6±57.1)U/L,all P＜0.05],and the serum Ca,P,ANC,WBC,and ALB were sig-nificantly decreased(P＜0.05),and AST and ALT were increased(P＜0.05),and ALT was an indepen-dent risk factor for delayed excretion(OR=1.049,95％CI 1.023-1.077,P＜0.001),ALB was an indepen-dent protective factor for delayed excretion(OR=0.551,95％CI 0.460-0.660,P＜0.001),and ALP was not a significant contributor to MTX excretion de-lay.CONCLUSION:ALP is not a good predictor of liv-er function and bone marrow granulopathy func-tion due to a significant decrease in ALP caused by high-dose MTX,and ALP together with serum calci-um and phosphorus levels can constitute an early warning indicator of bone metabolism disorders.

Objective:To evaluate the association between heatwaves and fall-related mortality.Methods:A total of 61 421 fall-related mortality from 2013 to 2022 in 7 provinces of China were included in a time-stratified case-crossover design, with daily meteorological data derived from the fifth generation European Reanalysis dataset produced by the European Centre for Medium-Range Weather Forecasts. Conditional logistic regression chimeric distributed lag nonlinear model was used to analyze the association between heatwaves and fall-related mortality and stratified analysis was conducted according to gender and age.Results:Heatwaves were associated with an increased risk of fall-related morality. The risk of fall-related mortality during heatwaves was higher than during non-heatwave periods ( OR=1.11, 95% CI: 1.05-1.18). The attributable fraction of fall-related motality due to heatwaves was 10.25% (95% CI: 4.49%-15.36%). For each 1 ℃ increase above the heatwave threshold, the risk of fall-related mortality increased by 34% ( OR=1.34, 95% CI: 1.02-1.76). The effect of heatwave duration on fall-related mortality was not statistically significant. Stratified analyses indicated that women experienced a higher risk of fall-related mortality during heatwaves ( OR=1.13, 95% CI: 1.04-1.22) compared to man ( OR=1.10, 95% CI: 1.04-1.17). Conclusions:Heatwave increases the risk of fall-related mortality, and the intensity of heatwaves modify this risk. Women are vulnerable populations.

ObjectiveTo investigate the effect of Danggui Shaoyaosan on ferroptosis in the rat model of non-alcoholic fatty liver disease （NAFLD） and explore the underlying mechanism based on the nuclear factor E₂-related factor 2 （Nrf2）/solute carrier family 7 member 11 （SLC7A11）/glutathione peroxidase 4 （GPX4） signaling pathway. MethodsThe sixty SD rats were randomly grouped as follows： control， model， Yishanfu （0.144 g·kg^-1）， and low-， medium-， and high-dose （2.44， 4.88， and 9.76 g·kg^-1， respectively） Danggui Shaoyaosan. A high-fat diet was used to establish the rat model of NAFLD. After 12 weeks of modeling， rats were treated with corresponding agents for 4 weeks. Then， the body weight and liver weight were measured， and the liver index was calculated. At the same time， serum and liver samples were collected. The levels or activities of total cholesterol （TC）， triglycerides （TG）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， and Fe²⁺ in the serum and TC， TG， free fatty acids （FFA）， malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione peroxidase （GPX）， and Fe²⁺ in the liver were measured. Hematoxylin-eosin staining and oil red O staining were employed to observe the pathological changes in the liver. Immunofluorescence was used to assess the reactive oxygen species （ROS） content in the liver. Mitochondrial morphology was observed by transmission electron microscopy. The protein levels of Nrf2， SLC7A11， GPX4， transferrin receptor 1 （TFR1）， and divalent metal transporter 1 （DMT1） in the liver were determined by Western blot. ResultsCompared with the control group， the model group showed increases in the body weight， liver weight， liver index， levels or activities of TC， TG， ALT， AST， and Fe²⁺ in the serum， levels of TC， TG， FFA， MDA， Fe²⁺， and ROS in the liver， and protein levels of TFR1 and DMT1 in the liver （P<0.01）， and decreases in the activities of SOD， GPX and the protein levels of Nrf2， SLC7A11， and GPX4 in the liver （P<0.05， P<0.01）. Meanwhile， the liver tissue in the model group presented steatosis， iron deposition， mitochondrial shrinkage， and blurred or swollen mitochondrial cristae. Compared with the model group， all doses of Danggui Shaoyaosan reduced the body weight， liver weight， liver index， levels or activities of TC， TG， ALT， AST， and Fe²⁺ in the serum， levels of TC， TG， FFA， MDA， Fe²⁺， and ROS in the liver， and protein levels of TFR1 and DMT1 in the liver （P<0.01）， while increasing the activities of SOD and GPX and the protein levels of Nrf2， SLC7A11， and GPX4 in the liver （P<0.01）. Furthermore， Danggui Shaoyaosan alleviated steatosis， iron deposition， and mitochondrial damage in the liver. ConclusionDanggui Shaoyaosan may inhibit lipid peroxidation and ferroptosis by activating the Nrf2/SLC7A11/GPX4 signaling pathway to treat NAFLD.

Objective To investigate the dosimetric effect of a biological optimization approach combining physical optimization with generalized equivalent uniform dose(gEUD)on hippocampus avoidance whole-brain radiotherapy(HA-WBRT).Methods A retrospective review was conducted of 20 patients with multiple brain metastases who underwent whole-brain radiotherapy at a certain hospital between May 2021 and December 2022.Two radiotherapy plans including plan_DV and plan_gEUD were designed for each patient by using Eclipse V15.6 planning system.Plan_DB used conven-tional dose-volume(DV)physical optimization,and plan_gEUD went through re-optimization with an Upper gEUD function applied to hippocampal region and hippocampal protection zone.Evaluation was carried out in accordance with RTOG 0933 guidance for the absolute values D2%,D98%and D50%received by 2%,98%,and 50%of the target volume in the planning target volume,conformity index(CI),homogeneity index(HI),gradient index(GI)and the dosimetric indexes of hippocampal region,hippocampal protection zone and other organs at risk(OARs).SPSS 26.0 software was used for statistical analysis.Results The two kinds of plans both had the target volume coverage meet the requirements of RTOG 0933 guidance.Plan_gEUD had the D98%,D2%and V105 of the planning target volume lower than those of plan_DV,with the differences being statistically significant(all P<0.05).The two kinds of plans had no significant differences in monitor unit,D50%and Dmax of PTV,HI,CI and GI(all P>0.05).Plan_gEUD had the Dmax and Dmean of hippocampal region and them of hippocampal pro-tection zone lower than those of plan_DV,and the optic nerve Dmax of plan_gEUD was higher than that of plan_DV,with the differences being statistically significant(all P<0.05).There were no statistically significant differences between the two kinds of plans in the Dmax of inner ear,optic chiasm,lens,and eyeball(all P>0.05).Conclusion Physical optimization in the HA-WBRT plan combined with gEUD optimization results in a greater dose reduction to the hippocampus while maintaining target coverage.

Objective:To evaluate the association between heatwaves and fall-related mortality.Methods:A total of 61 421 fall-related mortality from 2013 to 2022 in 7 provinces of China were included in a time-stratified case-crossover design, with daily meteorological data derived from the fifth generation European Reanalysis dataset produced by the European Centre for Medium-Range Weather Forecasts. Conditional logistic regression chimeric distributed lag nonlinear model was used to analyze the association between heatwaves and fall-related mortality and stratified analysis was conducted according to gender and age.Results:Heatwaves were associated with an increased risk of fall-related morality. The risk of fall-related mortality during heatwaves was higher than during non-heatwave periods ( OR=1.11, 95% CI: 1.05-1.18). The attributable fraction of fall-related motality due to heatwaves was 10.25% (95% CI: 4.49%-15.36%). For each 1 ℃ increase above the heatwave threshold, the risk of fall-related mortality increased by 34% ( OR=1.34, 95% CI: 1.02-1.76). The effect of heatwave duration on fall-related mortality was not statistically significant. Stratified analyses indicated that women experienced a higher risk of fall-related mortality during heatwaves ( OR=1.13, 95% CI: 1.04-1.22) compared to man ( OR=1.10, 95% CI: 1.04-1.17). Conclusions:Heatwave increases the risk of fall-related mortality, and the intensity of heatwaves modify this risk. Women are vulnerable populations.

Objective To investigate the dosimetric effect of a biological optimization approach combining physical optimization with generalized equivalent uniform dose(gEUD)on hippocampus avoidance whole-brain radiotherapy(HA-WBRT).Methods A retrospective review was conducted of 20 patients with multiple brain metastases who underwent whole-brain radiotherapy at a certain hospital between May 2021 and December 2022.Two radiotherapy plans including plan_DV and plan_gEUD were designed for each patient by using Eclipse V15.6 planning system.Plan_DB used conven-tional dose-volume(DV)physical optimization,and plan_gEUD went through re-optimization with an Upper gEUD function applied to hippocampal region and hippocampal protection zone.Evaluation was carried out in accordance with RTOG 0933 guidance for the absolute values D2%,D98%and D50%received by 2%,98%,and 50%of the target volume in the planning target volume,conformity index(CI),homogeneity index(HI),gradient index(GI)and the dosimetric indexes of hippocampal region,hippocampal protection zone and other organs at risk(OARs).SPSS 26.0 software was used for statistical analysis.Results The two kinds of plans both had the target volume coverage meet the requirements of RTOG 0933 guidance.Plan_gEUD had the D98%,D2%and V105 of the planning target volume lower than those of plan_DV,with the differences being statistically significant(all P<0.05).The two kinds of plans had no significant differences in monitor unit,D50%and Dmax of PTV,HI,CI and GI(all P>0.05).Plan_gEUD had the Dmax and Dmean of hippocampal region and them of hippocampal pro-tection zone lower than those of plan_DV,and the optic nerve Dmax of plan_gEUD was higher than that of plan_DV,with the differences being statistically significant(all P<0.05).There were no statistically significant differences between the two kinds of plans in the Dmax of inner ear,optic chiasm,lens,and eyeball(all P>0.05).Conclusion Physical optimization in the HA-WBRT plan combined with gEUD optimization results in a greater dose reduction to the hippocampus while maintaining target coverage.

AIM:To investigate the effects of high-dose methotrexate(MTX)on alkaline phosphatase(ALP)and the effects of ALP changes on bone me-tabolism,bone marrow granulogram function,liver function and excretion.METHODS:Aspartate ami-notransferase(AST),alanine aminotransferase(ALT)and albumin(ALB)were used as liver function indi-cators,serum calcium(Ca)and phosphorus(P)were used as bone metabolism indicators,neutro-phil(ANC)and white blood cell count(WBC)were used as bone marrow granuloline function indica-tors,and methotrexate C48h concentration ≥1 μmol/L was used as the excretion delay.One-way ANOVA analysis was performed on the ALP levels before and after the first chemotherapy and the second chemotherapy,and the children were divided into normal group and low group according to the ALP level,and the seven indexes before and after che-motherapy were quantitatively and qualitatively an-alyzed,and univariate and multivariate Logistic re-gression analysis was performed on the concentra-tion of methotrexate C48h and the above indexes in the children treated with the second chemothera-py.RESULTS:After the first chemotherapy and the second chemotherapy,ALP was significantly de-creased[(204.0±83.6)U/L vs.(172.8±67.3)U/L,(179.4±59.3)U/L vs.(169.6±57.1)U/L,all P＜0.05],and the serum Ca,P,ANC,WBC,and ALB were sig-nificantly decreased(P＜0.05),and AST and ALT were increased(P＜0.05),and ALT was an indepen-dent risk factor for delayed excretion(OR=1.049,95％CI 1.023-1.077,P＜0.001),ALB was an indepen-dent protective factor for delayed excretion(OR=0.551,95％CI 0.460-0.660,P＜0.001),and ALP was not a significant contributor to MTX excretion de-lay.CONCLUSION:ALP is not a good predictor of liv-er function and bone marrow granulopathy func-tion due to a significant decrease in ALP caused by high-dose MTX,and ALP together with serum calci-um and phosphorus levels can constitute an early warning indicator of bone metabolism disorders.

177Lu-prostate specific membrane antigen(PSMA)radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China.Based on domestic clinical practice and experimental data and referred to international experience and viewpoints,the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Hereditary hemochromatosis is a rare autosomal genetic disorder that can cause multi-organ dysfunction in the liver,pancreas,spleen,heart and pituitary gland,with diverse clinical manifestations,make the diagnosis difficult.In recent years,with the deepening of clinical understanding and the development of genetic diagnosis tools,the diagnostic rate of this disease has increased significantly.In this paper,we report a case of hereditary hemochromatosis type 3 involving multiple organs and complicated by severe heart failure,aiming to improve the clinicians'understanding of this disease and reduce the leakage and misdiagnosis.