Background Prolonged vibration exposure can lead to vascular endothelial cell dysfunction and cellular injury. However, research on the association between vibration and ferroptosis in vascular endothelial cells remains insufficient. Objective To explore whether occupational vibration exposure is associated with alterations in serum markers related to ferroptosis in patients with hand-arm vibration disease (HAVD), and to further investigate, through in vitro cell experiments, whether vibration exposure may induce ferroptosis in vascular endothelial cells. Methods ①A judgmental sampling method was employed to select 50 workers with HAVD (the HAVD group), 50 vibration-exposed workers without HAVD (the vibration exposure group), and 50 non–hand-transmitted vibration-exposed workers (the control group). Serum iron levels, malondialdehyde (MDA) content, and superoxide dismutase (SOD) levels were measured using serum iron assay kits, MDA detection kits, and SOD detection kits, respectively. One-way analysis of variance and binary logistic regression analysis were performed to examine the relationships between these indicators and HAVD. ②Human umbilical vein endothelial cells (HUVEC) were divided into a vibration group and a control group. The vibration group was subjected to vibration at 120 Hz with an acceleration of 6.5 m·s⁻² and further subdivided into four subgroups: 1 d 2 h, 1 d 4 h, 2 d 2 h, and 2 d 4 h. The control group was treated identically except for vibration exposure. Cellular iron (Fe²⁺) content and reduced glutathione (GSH) levels in HUVEC were measured using ferrous iron colorimetric assay kits and GSH colorimetric assay kits, respectively, to assess the effects of different vibration exposure schedules. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to detect the mRNA expression levels of ferroptosis-related genes, including acyl-CoA synthetase long-chain family member 4 (ACSL4), tumor suppressor protein P53 (P53), ferritin heavy chain 1 (FTH1), and glutathione peroxidase 4 (GPX4). Western blot analysis was conducted to determine the protein expression levels of ferroptosis-related markers in HUVEC. Results ①Compared with the control group, the patients in the HAVD group showed increased serum iron and MDA levels, along with decreased SOD levels (P<0.05). The logistic regression analysis indicated that elevated serum iron levels were significantly associated with an increased risk of HAVD (OR=4.034; 95%CI: 2.063, 7.887), and elevated MDA levels were also associated with an increased risk of HAVD (OR=1.523; 95%CI: 1.026, 1.936). ②Compared with the control group, increased intracellular Fe²⁺ content and decreased GSH content were observed in HUVECs in the 1 d 4 h and 2 d 4 h vibration subgroups (P<0.05). The RT-qPCR results showed that, compared with the control group, vibration exposures of 1 d 4 h and 2 d 4 h significantly upregulated the expression of ACSL4 and P53 (P<0.05), whereas the mRNA expression levels of GPX4 and FTH1 were downregulated in all vibration-exposed endothelial cells (P<0.05). The Western blot results revealed that, compared with the control group, the vibration exposure schedules of 1 d 2 h and 1 d 4 h significantly upregulated the protein expression levels of ACSL4 and P53 (P<0.05), while the vibration exposure schedules of 1 d 4 h, 2 d 2 h, and 2 d 4 h significantly downregulated the protein expression levels of FTH1 and GPX4 (P<0.05). Conclusion Occupational vibration exposure is associated with alterations in iron metabolism and oxidative stress status in workers with HAVD. The in vitro experiments further demonstrates that vibration stimulation induces intracellular iron accumulation and reduces antioxidant capacity in vascular endothelial cells, accompanied by dysregulated expression of ferroptosis-related molecules. These findings suggest that ferroptosis may play a role in vibration-induced vascular injury and the pathogenesis of HAVD.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired motility of cilia and flagella. Mutations in cilia- and flagella-associated protein 300 ( CFAP300 ) are associated with human PCD and male infertility; however, the underlying pathogenic mechanisms remain poorly understood. In a consanguineous Chinese family, we identified a homozygous CFAP300 loss-of-function variant (c.304delC) in a proband presenting with classical PCD symptoms and severe sperm abnormalities, including dynein arm deficiency and acrosomal malformation, as confirmed by transmission electron microscopy (TEM). Histological analysis revealed multiple morphological abnormalities of the sperm flagella in CFAP300 -mutant individual, whereas immunofluorescence demonstrated markedly reduced CFAP300 expression in the spermatozoa of the proband. Furthermore, tandem mass tag (TMT)-based quantitative proteomics showed that the CFAP300 mutation reduced key spermatogenesis proteins (e.g., sperm flagellar 2 [SPEF2], solute carrier family 25 member 31 [SLC25A31], and A-kinase anchoring protein 3 [AKAP3]) and mitochondrial ATP synthesis factors (e.g., SLC25A31, cation channel sperm-associated 3 [CATSPER3]). It also triggered abnormal increases in autophagy-related proteins and signaling mediator phosphorylation. These molecular alterations are likely to contribute to progressive deterioration of sperm ultrastructure and function. Notably, successful pregnancy was achieved via intracytoplasmic sperm injection (ICSI) using the proband's sperm. Overall, this study expands the known CFAP300 mutational spectrum and offers novel mechanistic insights into its role in spermatogenesis.
Humans ; Male ; Infertility, Male/pathology* ; Acrosome/pathology* ; Sperm Tail/pathology* ; Pedigree ; Spermatozoa ; Adult ; Loss of Function Mutation ; Ciliary Motility Disorders/genetics* ; Spermatogenesis/genetics* ; Female

OBJECTIVE: To explore the effect and mechanism of DNA methyltransferase 1 (DNMT1) knockout on the inhibition of acute myeloid leukemia (AML) by natural killer (NK) cells. METHODS: The peripheral blood NK cells of AML patients and controls were collected, and the mRNA and protein level of DNMT1 were measured by PCR and Western blot, respectively. The DNMT1 knockout mice were constructed to obtain NK^DNMT1-/- cells. The NK cells were stimulated with interleukin (IL)-12, IL-15, and IL-18 to construct memory NK cells, and then the interferon-γ (IFN-γ) levels were measured by ELISA. After co-culturing with memory NK cells and HL60 cells, the killing effect of NK^DNMT1-/- cells on HL60 cells was detected by LDH assay. Then, the HL60 cell apoptosis and NK cell NKG2D level were measured by flow cytometry. The perforin and granzyme B protein levels of NK cells were measured by Western blot. The AML model mice were constructed by injecting HL60 cells into the tail vein, meanwhile, memory NK cells were also injected, and then the mouse weights, CD33 positive rates, and survival time were detected. RESULTS: The mRNA and protein levels of DNMT1 in NK cells of AML patients were significantly higher than those in the control group (both P < 0.01), while the IFN-γ level induced by interleukin was significantly lower than that in the control group (P < 0.05). Compared with NK^DNMT1+/+ cells, the ability of NK^DNMT1-/- cells to secrete IFN-γ after interleukin stimulation was significantly increased (P < 0.05). The killing and apoptosis-inducing effects of NK^DNMT1-/- cells on HL60 cells were significantly stronger than those of NK^DNMT1+/+ cells (both P < 0.05). The NKG2D level and expression of perforin and granzyme B of NK^DNMT1-/- cells were significantly increased compared with NK^DNMT1+/+ cells (all P < 0.05). Compared with AML mice injected with NK^DNMT1+/+ cells, AML mice injected with NK^DNMT1-/- cells showed significantly increased body weight, decreased CD33 positive rate, and prolonged survival time (all P < 0.05). CONCLUSION Knocking out DNMT1 can enhance the inhibitory effect of NK cells on AML, which may be related to enhancing NK cell memory function.
Killer Cells, Natural/metabolism* ; Animals ; Leukemia, Myeloid, Acute ; Humans ; DNA (Cytosine-5-)-Methyltransferase 1 ; Mice ; Mice, Knockout ; HL-60 Cells ; Apoptosis ; Interferon-gamma/metabolism* ; Granzymes/metabolism* ; Perforin/metabolism* ; NK Cell Lectin-Like Receptor Subfamily K/metabolism*

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Objective To retrospectively analyze the association between metabolic factors and high-risk colorectal adenoma(CRA).Methods The medical records of patients aged 18-75 years who underwent their initial colonoscopy at Karamay Central Hospital of Xinjiang Uygur Autonomous Region from Jul 2000 to Mar 2017 were collected.The comparison between normal colonoscopy(NC)and high-risk CRA patients was conducted using an unpaired t-test,while chi-square test was used for categorical variables.Least absolute shrinkage and selection operator(LASSO)regression and Logistic regression were utilized to analyze the association between metabolic factors and high-risk CRA.Results A total of 1 798 patients meeting the inclusion and exclusion criteria were enrolled and divided into normal colonoscopy(NC)findings group(n=972)and high-risk CRA group(n=826).The high-risk CRA group exhibited significantly lower levels of high-density lipoprotein cholesterol(HDL-C)in comparison to the NC group,while uric acid and fibrosis 4(FIB-4)index levels were significantly higher than those observed in the NC group(all P<0.05).Based on LASSO regression analysis,we identified 12 variables that potentially influence the occurrence of high-risk CRA,including age,gender,smoking history,alcohol consumption history,non-alcoholic fatty liver disease(NAFLD),hypertension,coronary artery disease,hyperglycemia,hypercholesterolemia,low levels of HDL-C,elevated alanine aminotransferase,and elevated gamma-glutamyl transferase.Multivariate analysis revealed that individuals aged over 50 years,male gender,cigarette and alcohol consumption,low HDL-C levels,history of NAFLD and hypertension were identified as independent risk factors associated with high-risk CRA(P<0.05).In addition,without or with adjusting for age,sex,smoking,and drinking history,patients with a high TG/HDL-C ratio(the ratio≥2.68)had a significantly higher risk of high-risk CRA than those with a low TG/HDL-C ratio(the ratio<2.68)[odds ratios(ORs)were1.430 and 1.235 respectively,all P<0.05)].Without or with adjusting variables,the ORs for NAFLD patients with FIB-4 index>2.67 were 1.849(P=0.466)and 1.435(P=0.707),respectively.Conclusion A significant association exists between metabolic factors and high-risk CRA.Independent risk factors for high-risk CRA include older age(≥50 years),male,smoking history,alcohol consumption history,low levels of HDL-C,and a history of NAFLD and hypertension.Individuals exhibiting a TG/HDL-C ratio exceeding 2.68 manifest a significantly heightened susceptibility to the development of high-risk CRA.Therefore,elderly males with one or more aforementioned metabolic abnormalities should be considered a priority population for colorectal screening.

Objective:To investigate the correlation between interleukin-10, albumin levels and short-term prognosis in patients with acute lung injury.Methods:A retrospective study was conducted to collect data on 150 patients with acute lung injury admitted to the Fourth People′s Hospital of Longgang District, Shenzhen from January 2021 to December 2023. The short-term prognosis was evaluated based on the mortality rate within 28 d of admission, and the patients were divided into a mortality group 53 cases and a survival group 97 cases. General information, levels of interleukin-10 and albumin within 24 h of admission, and other laboratory indicators were compared between the two groups, with a focus on analyzing the correlation between interleukin-10, albumin levels and the short-term prognosis of patients.Results:Murray lung injury score, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score and levels of C-reactive protein, interleukin-10 in the mortality group were higher than those in the survival group: (2.27 ± 0.36) scores vs. (1.98 ± 0.28) scores, (22.72 ± 3.27) scores vs. (19.85 ± 3.12) scores, (106.27 ± 14.22) mg/L vs. (93.22 ± 15.27) mg/L, (51.75 ± 8.12) ng/L vs. (46.27 ± 9.47) ng/L, the levels of platelet and albumin were lower than those in the survival group: (186.67 ± 23.11) ×10 9/L vs. (203.25 ± 25.36) ×10 9/L, (27.86 ± 4.75) g/L vs. (32.21 ± 5.61) g/L, with statistical significant differences ( P<0.05). Cox regression analysis showed that the mortality risk of patients with acute lung injury was related to Murray lung injury score, APACHEⅡ score, platelet, C-reactive protein, interleukin-10 and albumin levels at admission ( P<0.05). Restricted cubic spline (RCS) analysis and interaction testing found that the mortality risk of patients with acute lung injury showed a non-linear dose-response relationship with serum interleukin-10 and albumin levels ( P<0.05), and the two had a negative interaction with the mortality risk of patients. The interleukin-10, albumin-assisted Murray lung injury score, APACHE Ⅱ score, platelet and C-reactive protein were used to construct a nomogram prediction model, and the decision curve and nomogram measurement model were drawn. The model has certain predictive value for the short-term risk of death in patients with acute lung injury. Conclusions:The short-term mortality risk in patients with acute lung injury may be related to abnormal levels of interleukin-10 and albumin, which can assist in the early screening of high-risk mortality patients and serve as clinical intervention targets.

Objective:To explore the factors influencing ethical sensitivity of oncology nurses.Methods:Using purposive sampling, 15 oncology nurses from 13 tertiary general hospitals in Foshan, Guangdong Province were selected as research participants from July to September 2023. In-depth semi-structured interviews were conducted, and Colaizzi's seven-step content analysis method was applied to organize and analyze the collected data.Results:A total of 4 themes were summarized: insufficient clinical experience and knowledge reserve; lack of ethical education and management system processes; high-pressure working environment and communication barriers; and the constraints of the cultural concept of "valuing life over death".Conclusions:Oncology nurses have insufficient ethical sensitivity. Nursing managers should establish a systematic ethical education system, improve ethical management systems, optimize the clinical working environment, and integrate cultural sensitivity education to jointly enhance nurses' communication skills. Attention should also be paid to the inheritance of clinical experience from senior nurses, so as to improve the ethical sensitivity of oncology nurses in a multidimensional way.

Postoperative infection of internal fixation of closed fractures the lower limbs in adults represents a devastating complication, characterized by diagnostic challenges, prolonged treatment duration and high disability rates. Current management of these infections faces multiple challenges, such as difficulties in early accurate diagnosis, and various controversies about the treatment plan, leading to poor overall diagnosis and treatment results. To address these issues, based on evidence-based medicine and principles with emphasis on scientific rigor, clinical applicability and innovation, the Trauma Branch of the Chinese Medical Association, Orthopedic Branch of the Chinese Medical Doctor Association, Orthopedics Branch of the Chinese Medical Association, and Trauma Orthopedics and Polytrauma Group of the Resuscitation and Emergency Committee of the Chinese Medical Doctor Association have collaboratively organized a panel of relevant experts to develop the Guideline for diagnosis and treatment of infection after internal fixation of closed lower limb fractures in adults ( version 2025). The guideline proposed 10 recommendations, aiming to provide a foundation for standardized diagnosis and treatment of postoperative infection in adults with closed lower limb fractures.

Objective:To explore the impact of age on the genetic variant spectrum and prognosis of patients with previously untreated Diffuse large B-cell lymphoma (DLBCL).Methods:A retrospective analysis was conducted on the clinical data and follow-up information of 254 previously untreated DLBCL patients from 14 hospitals in the Jiangsu Cooperative Lymphoma Group (JCLG) enrolled from July 2018 and July 2023. Following extraction of DNA from tumor tissue samples, next-generation sequencing (NGS) technique was employed to analyze the genetic variant spectrum of the DLBCL patients, with an evaluation of the relationship between age and genetic variants as well as prognosis. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Nantong University (Ethics No.: 2023-K048-01).Results:The median age of the 254 DLBCL patients was 62 years old, with 55% of patients aged 60 years or above. Clinical evaluation showed that younger (< 60 years) patients had higher complete response (CR) (70% vs. 59%), and objective response rate (ORR) (88% vs. 79%) than older patients, though the difference between the two groups was not statistically. Survival analysis indicated that both the five-year overall survival (OS) (82.7% vs. 71.7%, P=0.006) and progression-free survival (PFS) (70.6% vs. 50.2%, P<0.05) rates were significantly higher in younger patients. NGS showed that 99.6% of the patients harbored genetic variants, with PIM1, KMT2D, TP53, MYD88, and CD79B being the most common genes. Age significantly affected the variant frequency of certain genes, with MYC variants serving an adverse prognostic factor for OS in younger patients ( P=0.001), while TP53 ( P=0.024) and BCL2 ( P=0.002) variants significantly impacted OS in older patients. Prognostic analysis identified age ≥ 60 years ( HR=3.439, 95% CI=1.318~9.874), presence of B symptoms ( HR = 2.871, 95% CI=1.133~7.307), and elevated lactate dehydrogenase ( HR=3.528, 95% CI=1.231~10.66) as independent adverse prognostic factors. Conclusion:Age, genetic variants, and clinical factors may significantly affect the prognosis of the DLBCL patients. Younger patients have better survival compared to older patients. Variants of the MYC, BCL2, and TP53 genes are closely associated with poor prognosis.