Objective:To study the role of cadherin 1 (CDH1) gene DNA methylation in autoimmune thyroiditis (AIT) in population from different water-iodine regions.Methods:From May to June 2019, the information of AIT cases and healthy individuals in Shandong Province were collected in three types of water-iodine regions: iodine-fortification (IF) region, iodine-adequate (IA) region and iodine-excess (IE) region. A case-control study design was applied to match 176 AIT cases (case group) with age, gender, body mass index, and place of residence in a 1 ∶ 1 ratio to 176 healthy individuals (control group). Fasting urine and whole blood samples were collected to test the contents of urinary iodine, thyroid function indicators [serum free triiodothyronine (FT 3), free thyroxine (FT 4), thyroid stimulating hormone (TSH)], and serum iodine. The DNA methylation levels of the target region of the CDH1 gene and its four CpG sites in whole blood were determined using methylation sequencing technology for target regions (MethylTarget TM). Results:The DNA methylation level of the target region of CDH1 gene in the case group was 0.832 ± 0.044, and that in the control group was 0.828 ± 0.049, there was no statistically significant difference between the two groups ( t = 0.76, P = 0.448). There was no statistically significant difference in DNA methylation levels of the four CpG sites in the target region of CDH1 gene between the case group and the control group ( P > 0.05). There was no statistically significant difference in the DNA methylation level of the CDH1 gene target region between the case group and the control group in IF, IA and IE regions ( P > 0.05). The detection results of DNA methylation levels at CpG sites in the target region of CDH1 gene in different water iodine regions showed that the DNA methylation level at site 83 in case group in IF region was higher than that in the control group ( t = 2.30, P = 0.023). However, there was no statistically significant difference in the DNA methylation levels of the four CpG sites between the case group and the control group in IA and IE regions ( P > 0.05). The DNA methylation level of CDH1 gene target region in AIT patients was not significantly correlated with urinary iodine, serum iodine, and serum FT 3, FT 4, and TSH contents ( P > 0.05), but was significantly negatively correlated with age ( r =-0.19, P = 0.014). Conclusions:The DNA methylation level at CpG site 83 of CDH1 gene in AIT patients in IF region is significantly higher than that in control population, indicating that DNA methylation at this locus may be involved in the occurrence and development of AIT after iodine fortification. The DNA methylation level of CDH1 gene is negatively correlated with age.

Objective To investigate the current situation of off-label use of immune checkpoint inhibitors(ICIs)in China and the cognition of medical staff.Methods From August 31 to September 9,2022,a nationwide survey questionnaire was sent to medical staff in the form of electronic questionnaire.The questionnaire included 13 questions,covering four dimensions:Drug allocation,current situation of medication beyond the instructions,cognition of medication beyond the instructions and current situation of medication beyond the instructions.Results A total of 745 questionnaires were collected.75.70％of respondents reported off-label use of ICIs in their hospitals,with the most common type being off-label indications.The primary reasons for such practices included support from authoritative domestic and international guidelines,clinical research data validation,and approved indications in foreign regulatory documents.85.37％of respondents believed off-label use could offer new hope for patients,while 68.86％considered it unlikely to increase adverse reactions.44.97％of respondents' hospitals had not established off-label use registration systems for ICIs.88.86％of respondents emphasized the need for stricter regulations governing off-label use of immunotherapeutic agents.Conclusion Off-label use of ICIs is common,and there is a lack of unified guidance in clinical practice.It is urgent to form norms and consensus on the management of off-label use of ICIs.

BACKGROUND:Neuroinflammation is a major cause of exacerbation after spinal cord injury.In recent years,pyroptosis has received much attention due to its remarkable pro-inflammatory features.Some of these natural products can significantly inhibit the inflammatory response and improve the damaged nerve function by regulating the level of pyroptosis after spinal cord injury,which provides a new therapeutic idea for spinal cord injury.OBJECTIVE:To summarize the mechanism of action of natural products in regulating pyroptosis for the treatment of spinal cord injury,with a view to providing lessons and references for future research on the treatment of spinal cord injury.METHODS:The search terms"spinal cord injury,pyroptosis,inflammasome,natural products,natural compounds,traditional Chinese medicine"in Chinese and English were used to search for relevant literature since the establishment of the database up to September 2024 in the databases of PubMed,Web of Science,WanFang,and CNKI.According to the inclusion and exclusion criteria,75 relevant articles were finally obtained.RESULTS AND CONCLUSION:(1)Pyroptosis is an important pro-inflammatory pathway in spinal cord injury,and controlling pyroptosis is an effective way to improve damaged nerve function.(2)Some natural products can regulate pyroptosis via the NLRP3/Caspase-1 classical pyroptosis pathway,the NF-κB-related pathway,other upstream pathways such as Nrf2/HO-1,and autophagy,thereby affecting the level of tissue inflammation and accelerating neurological recovery after spinal cord injury.(3)The anti-pyroptosis effects of these natural products are mostly dependent on the NLRP3 classical pyroptosis pathway,and there is a lack of studies on other pyroptosis pathways.(4)There are still many problems in this field,such as the fact that these natural products are not currently supported by evidence from appropriate clinical studies.(5)The natural product has great potential in regulating pyroptosis and is expected to be a powerful weapon in the treatment of spinal cord injury.

Uncontrolled hemorrhage is the leading cause of potentially survivable combat casualty death,dominated by non-compressible hemorrhage in the torso and junctional areas.Rapid hemostasis using war trauma dressings is the mainstay of treatment for such casualties.The article reviews the research progress of novel hemostatic dressings for war trauma,including novel improved dressings,multifunctional dressings,electrospinning wound dressings,and smart dressings in order to provide references for the research on war trauma dressings.

Objective:To investigate the impact of circumferential tumor location (anterior wall, nonanterior wall, or circumferential) on circumferential resection margin (CRM) status, local recurrence, and survival in patients with mid-low rectal cancer.Methods:A retrospective cohort study was conducted using data from 696 patients with mid-low rectal adenocarcinoma who underwent surgery in the Department of Colorectal Surgery at the First Affiliated Hospital of Naval Medical University between December, 2018 and December, 2019. Based on MRI or contrast-enhanced CT findings, the rectal wall was divided into four quadrants: anterior, posterior, left, and right. Tumors were classified into three groups: anterior wall group ( n = 245), nonanterior wall group ( n = 286, tumors predominantly located on the posterior or lateral walls), and circumferential group ( n = 165, tumors involving ≥ 3/4 of the circumference). Propensity score matching (PSM) was used to balance baseline characteristics. Outcomes included pathological CRM positivity, local recurrence rate (LRR), overall survival (OS), and disease-free survival (DFS). Cox regression analysis was performed to identify risk factors for recurrence, and subgroup analysis was conducted in patients who did not receive neoadjuvant therapy. Results:After PSM, both the anterior and circumferential groups had significantly higher pathological CRM positivity rates compared to the nonanterior wall group ( P=0.040 and P=0.039, respectively). The median follow-up time was 64 months (range: 1-71 months). Compared to the nonanterior wall group, the anterior wall group also had a significantly higher 5-year LRR (8.8% vs. 2.3%, P=0.003), and significantly lower 5-year OS (80.7% vs. 91.6%, P=0.001) and DFS (76.6% vs. 84.6%, P=0.029). The circumferential group had a significantly higher 5-year LRR than the nonanterior wall group (11.4% vs. 3.8%, P=0.020), but no significant differences were observed in 5-year OS (81.8% vs. 89.5%, P=0.100) or DFS (70.7% vs. 78.3%, P=0.101). No significant differences were found between the anterior and circumferential groups in 5-year LRR (11.1% vs. 9.7%), OS (76.3% vs. 83.7%), or DFS (69.8% vs. 74.1%) either (all P>0.05). Cox univariate analysis and multivariate analysis identified anterior wall tumors (HR=3.751, 95%CI: 1.373-10.215, P=0.010), circumferential tumors (HR=3.240, 95%CI: 1.109-9.466, P=0.032), pathological CRM positivity (HR=3.071, 95%CI: 1.144-8.245, P=0.026), and lymph node metastasis (HR=2.584, 95%CI: 1.192-5.601, P=0.016) as independent risk factors for LRR. Conversely, a greater distance from tumor to the anal verge (per 1 cm increase, HR=0.831, 95%CI: 0.712-0.970, P=0.019), and neoadjuvant therapy (HR=0.442, 95%CI: 0.204-0.957, P=0.038) were identified as independent protective factors against LRR. In patients who did not receive neoadjuvant therapy, locally advanced nonanterior wall tumors exhibited markedly low LRR (1.3% for pathological stage II-III, 1.6% for pT3-4 stage). Conclusion:Rectal tumors located in the anterior wall or involving the circumference are associated with higher CRM positivity rates, increased local recurrence, and poorer survival. These patients should be prioritized for neoadjuvant therapy. In contrast, nonanterior wall tumors have a low recurrence rate, and selective omission of neoadjuvant therapy may be considered for these cases.

Background and Aims:Intrahepatic cholangiocarcinoma(ICC)is a highly malignant liver tumor,with an increasing incidence worldwide,particularly in Asia.Although radical surgical resection is currently the only potentially curative treatment,the high recurrence rate and low postoperative overall survival(OS)rate of ICC remain major clinical challenges.Adjuvant therapy(AT)and neoadjuvant therapy(NAT)are important strategies to reduce postoperative recurrence and prolong OS.Several studies have shown certain efficacy of these treatments.However,the specific efficacy and safety of combined NAT and AT in ICC treatment require further validation.This study was conducted to evaluate the value of combining NAT and AT in improving the therapeutic outcomes of ICC patients through a multicenter retrospective analysis,so as to provide scientific evidence for optimizing treatment strategies.Methods:The clinicopathologic data of 576 patients with ICC who underwent radical resection and were pathologically confirmed from 13 hospitals in China between December 2011 and December 2017 were retrospectively collected.Patients were grouped based on their treatment modality:NAT+AT group,AT group,and non-NAT/AT group.The three patient groups were matched pairwise in a 1∶1 ratio using propensity score matching(PSM)to balance baseline data.The Kaplan-Meier method was used to analyze OS and disease-free survival(DFS),and subgroup analyses were conducted according to the 8th edition of the AJCC TNM staging system.Results:A total of 395 ICC patients were included in the final analysis,with 42 patients(10.6%)in the NAT+AT group,62 patients(15.7%)in the AT group,and 291 patients(73.7%)in the non-NAT/AT group.Before PSM,significant differences were observed between groups in terms of CA19-9,liver function Child-Pugh classification,intraoperative blood loss,surgical margin,differentiation grade,vascular invasion,ECOG score,and lymph node dissection ratio(all P<0.05).After PSM,there were no significant differences in baseline characteristics between the groups(all P>0.05).After matching,the median OS and DFS in the NAT+AT group were significantly better than in the AT and non-NAT/AT groups(both P<0.05),while there were no significant differences in OS and DFS between the AT and non-NAT/AT groups(both P>0.05).Subgroup analysis showed that in TNM stage I patients,DFS in the NAT+AT group was significantly better than in the non-NAT/AT group(P<0.05),but OS was not significantly different(P>0.05).In TNM stage Ⅱ and Ⅲ patients,both OS and DFS in the NAT+AT and AT groups were significantly better than in the non-NAT/AT group(both P<0.05),and DFS in the NAT+AT group was significantly better than in the AT group in TNM stage Ⅲ patients(P<0.05).Conclusion:NAT combined with AT provides better survival benefits for patients with locally advanced ICC,but its benefit for early-stage ICC patients is limited.However,the retrospective design and sample size limitations of this study may affect the stability of the results,and future large-sample,multicenter,prospective studies are needed for further validation.

Objective:A model for predicting sentinel lymph node metastasis was established based on positron emission tomography(PET)-related metabolic parameters and clinicopathological characteristics.Methods:A retro-spective analysis was conducted on 211 patients diagnosed with breast cancer through surgical pathology from January 2016 to March 2023 in Meizhou People's Hospital,who underwent whole-body PET/CT examinations prior to surgery.Clinical,pathological,and PET-related metabolic parameters were collected.The study analyzed the association be-tween clinicopathological characteristics of the primary breast cancer lesion,PET metabolic parameters,and sentinel lymph node metastasis.A logistic regression predictive model was constructed using Broussonetia papyrifera.Results:Breast cancer primary lesion PET-suspicious axillary lymph nodes,vascular tumor thrombus,estrogen receptor(ER),and progesterone receptor(PR)showed statistically significant differences between the two groups(all P<0.05),while maxi-mum tumor diameter,SUVmax tumor location,maximum standardized uptake value(SUVmax),metabolic tumor volume(MTV),total lesion glycolysis(TLG),tumor location,number of lesions,pathological type,histological grade,neural inva-sion,Homo sapiens epidermal growth factor receptor 2(HER-2),and nuclear-associated antigen Ki-67(Ki-67)showed no statistically significant differences between the two groups(all P>0.05).Parameters with P<0.05 in the univariate analysis were subjected to multivariate logistic regression analysis,and the logistic regression model was established as Logit(P)=-0.437×vascular tumor thrombus+4.685×suspicious axillary lymph node metastasis.The predictive model AUC was 0.738(P<0.001,95%CI:0.664～0.812),with sensitivity and specificity of 63.4%and 74.4%,respectively.Con-clusion:PET findings of the primary breast cancer lesion regarding suspicious axillary lymph node metastasis,vascular tumor thrombus,ER and PR are associated with sentinel lymph node metastasis.The predictive model established based on PET-detected suspicious axillary lymph node metastasis and vascular tumor thrombus in primary breast cancer lesions has certain value in predicting sentinel lymph node metastasis,potentially providing a non-invasive examination modality for clinical practice.

This paper reports a 45-year-old female patient with lung squamous cell carcinoma who received chemotherapy for multiple systemic metastases,and then 171 mg of the immune checkpoint inhibitor serplulimab was added,ivd,d1(21 d as a cycle).After 2 cycles of treatment,the patient developed dizziness and nausea,and tumor brain metastasis was considered.The lung CT showed that the irregular mass shadow in the anterior segment of the upper lobe of the right lung was enlarged compared with the previous one,and MRI of the liver showed patchy abnormal signal in the liver segment Ⅳ.PET-CT showed that the lung,liver,adrenal gland,left groin and multiple bones were all progressed compared with the previous progress.It was considered to be tumor hyperprogression caused by serplulimab.Serplulimab was immediately discontinued and methylprednisolone was given for symptomatic treatment,but the patient still died due to overprogression.The Naranjo's Assessment Scale was used to evaluate the correlation between the tumor progression and serplulimab in this case,and the result was' likely to be related'.This case suggested that,the prognosis of tumor hyperprogression caused by immune checkpoint inhibitors has a poor prognosis,the clinical use of immune checkpoint inhibitors should be alert to this situation,and pay attention to early differential diagnosis and timely treatment to avoid serious consequences.

Objective:To study the role of cadherin 1 (CDH1) gene DNA methylation in autoimmune thyroiditis (AIT) in population from different water-iodine regions.Methods:From May to June 2019, the information of AIT cases and healthy individuals in Shandong Province were collected in three types of water-iodine regions: iodine-fortification (IF) region, iodine-adequate (IA) region and iodine-excess (IE) region. A case-control study design was applied to match 176 AIT cases (case group) with age, gender, body mass index, and place of residence in a 1 ∶ 1 ratio to 176 healthy individuals (control group). Fasting urine and whole blood samples were collected to test the contents of urinary iodine, thyroid function indicators [serum free triiodothyronine (FT 3), free thyroxine (FT 4), thyroid stimulating hormone (TSH)], and serum iodine. The DNA methylation levels of the target region of the CDH1 gene and its four CpG sites in whole blood were determined using methylation sequencing technology for target regions (MethylTarget TM). Results:The DNA methylation level of the target region of CDH1 gene in the case group was 0.832 ± 0.044, and that in the control group was 0.828 ± 0.049, there was no statistically significant difference between the two groups ( t = 0.76, P = 0.448). There was no statistically significant difference in DNA methylation levels of the four CpG sites in the target region of CDH1 gene between the case group and the control group ( P > 0.05). There was no statistically significant difference in the DNA methylation level of the CDH1 gene target region between the case group and the control group in IF, IA and IE regions ( P > 0.05). The detection results of DNA methylation levels at CpG sites in the target region of CDH1 gene in different water iodine regions showed that the DNA methylation level at site 83 in case group in IF region was higher than that in the control group ( t = 2.30, P = 0.023). However, there was no statistically significant difference in the DNA methylation levels of the four CpG sites between the case group and the control group in IA and IE regions ( P > 0.05). The DNA methylation level of CDH1 gene target region in AIT patients was not significantly correlated with urinary iodine, serum iodine, and serum FT 3, FT 4, and TSH contents ( P > 0.05), but was significantly negatively correlated with age ( r =-0.19, P = 0.014). Conclusions:The DNA methylation level at CpG site 83 of CDH1 gene in AIT patients in IF region is significantly higher than that in control population, indicating that DNA methylation at this locus may be involved in the occurrence and development of AIT after iodine fortification. The DNA methylation level of CDH1 gene is negatively correlated with age.

Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.
Female ; Mice ; Demethylation/drug effects* ; Embryonic Stem Cells ; Estrogens/administration & dosage* ; Gene Expression/drug effects* ; Histones/metabolism* ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Mice, Inbred C57BL ; Oocytes ; Ovary/drug effects* ; Reproductive Techniques, Assisted ; Animals