Definitive treatment of lung cancer with radiotherapy is challenging, as respiratory motion and anatomical changes can increase the risk of severe off-target effects during radiotherapy. Online adaptive radiotherapy (ART) is an evolving approach that enables timely modification of a treatment plan during the interfraction of radiotherapy, in response to physiologic or anatomic variations, aiming to improve the dose distribution for precise targeting and delivery in lung cancer patients. The effectiveness of online ART depends on the seamless integration of multiple components: sufficient quality of linear accelerator-integrated imaging guidance, deformable image registration, automatic recontouring, and efficient quality assurance and workflow. This review summarizes the present status of online ART for lung cancer, including key technologies, as well as the challenges and areas of active research in this field.
Humans ; Lung Neoplasms/radiotherapy* ; Radiotherapy Planning, Computer-Assisted/methods*

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Acute lung injury (ALI) is a severe disease caused by viral infection that triggers an uncontrolled inflammatory response. This study investigated the capacity of jasurolignoside (JO), a natural compound, to bind to Toll-like receptor 4 (TLR4) and treat ALI. The anti-inflammatory properties of JO were evaluated in vitro through Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and co-immunoprecipitation. The investigation utilized a lipopolysaccharide (LPS)-induced ALI animal model to examine the therapeutic efficacy and mechanism of JO in vivo. JO attenuated inflammatory symptoms in infected cells and tissues by modulating the NOD-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome and the nuclear factor κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathway. Molecular docking simulations revealed JO binding to TLR4 active sites, confirmed by cellular thermal shift assay. Surface plasmon resonance (SPR) demonstrated direct interaction between JO and TLR4 with a Kd value of 35.1 μmol·L^-1. Moreover, JO inhibited tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 secretion and reduced leukocyte, neutrophil, lymphocyte, and macrophage infiltration in ALI-affected mice. JO also enhanced lung function and reduced ALI-related mortality. Immunohistochemical staining demonstrated JO's ability to suppress TLR4 expression in ALI-affected mouse lung tissue. This study establishes that JO can bind to TLR4 and effectively treat ALI, indicating its potential as a therapeutic agent for clinical applications.
Toll-Like Receptor 4/chemistry* ; Animals ; Acute Lung Injury/chemically induced* ; Mice ; Humans ; Ilex/chemistry* ; Molecular Docking Simulation ; Male ; NF-kappa B/immunology* ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology* ; Tumor Necrosis Factor-alpha/genetics* ; Interleukin-1beta/genetics* ; RAW 264.7 Cells ; Disease Models, Animal

Objective To develop and evaluate a diagnostic model for autoimmune liver disease(AILD)using clinical indicators.Methods A total of 181 AILD patients(AILD group)diagnosed in the Department of Gastroenterology or Rheumatology and Immunology,the First Medical Center of Chinese PLA General Hospital,from June 2019 to February 2024,133 patients with hepatitis B virus cirrhosis(HBVC)(HBVC group),and 100 healthy individuals(HC group)were included in the study cohort for retrospective analysis.Clinical data,blood routine tests,and biochemical indicators were compared among the groups.Propensity score matching was used to balance the effects of factors such as gender and age.Multivariate logistic regression analysis was applied to identify characteristic indicators for AILD.Receiver operating characteristic(ROC)curves were used to evaluate the diagnostic efficacy of single and combined indicators,and the optimal diagnostic model for AILD was constructed.The Hosmer-Lemeshow test was performed to assess the model's goodness-of-fit,while ROC analysis was employed to evaluate the predictive validity.Additionally,an independent validation cohort,including 91 AILD patients(AILD validation group),82 HBVC patients(HBVC validation group),and 40 healthy individuals(HC validation group)who visited during the same period,was used to validate the diagnostic model.False-positive and false-negative rates were calculated to assess the diagnostic efficacy and clinical utility of the model.Results The age and the proportion of male patients in AILD and HBVC groups were higher than those in HC group,and the proportion of male patients in AILD group was higher than in HBVC group,the differences were statistically significant(P＜0.05).Prior to matching,compared with HC group,HBVC group and AILD group had significantly lower levels of hemoglobin(HB),red blood cell count(RBC),white blood cell count(WBC),platelet count(PLT),and albumin(ALB)(P＜0.05),but significantly higher levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),gamma-glutamyl transferase(GGT),total bilirubin(TBIL),and direct bilirubin(DBIL)(P＜0.05).Compared with HBVC group,AILD group had significantly higher levels of WBC,PLT,ALB,ALP,and GGT(P＜0.05 or P＜0.001)but significantly lower levels of TBIL and DBIL(P＜0.001).After maching,compared with HC group,AILD group still had significantly lower levels of HB,RBC,WBC,PLT,and ALB,but significantly higher levels of ALT,AST,ALP,GGT,TBIL,and DBIL(P＜0.05).Compared with HBVC group,AILD group had significantly higher levels of HB,RBC,WBC,PLT,ALB,ALT,ALP,and GGT,but significantly lower levels of DBIL(P＜0.05).ROC analysis results showed that AST,GGT,ALP,and DBIL had high predictive values for differentiating AILD from HC(AUC=0.843,0.804,0.802,0.773),while PLT,WBC,GGT,and ALP had high predictive values for differentiating AILD from HBVC(AUC=0.780,0.739,0.729,0.702).For distinguishing AILD from HC,the combined model of AST,ALP,and DBIL(Model e)had an AUC of 0.887,with a sensitivity of 82.2％,and a specificity of 94.7％.For distinguishing AILD from HBVC,the combined model of ALP,GGT,and PLT(Model D)had an AUC of 0.829,with a sensitivity of 78.5％and a specificity of 80.6％.Conclusions The combined diagnostic model based on AST,ALP,and DBIL can effectively differentiate healthy individuals without liver diseases from AILD patients,while the combined diagnostic model based on PLT,ALP,and GGT can effectively distinguish HBVC from AILD patients.

Objective:To investigate the role of the angiopoietin (Ang)/tyrosine kinase receptor 2 (Tie2) pathway in mediating histone-induced coagulation activation in mice with acute lung injury, and the protective mechanism of unfractionated heparin (UFH).Methods:Twenty-four mice were randomly divided into three groups ( n=8 per group): Control group, Histone group, and Histone + UFH group using the random number table method. The Histone group and Histone + UFH group were administered 50 mg/kg histone via the tail vein. One hour later, UFH was given at a dosage of 400 U/kg by the same way. The Control group was administered an equivalent volume of sterile saline solution. Four hours after modeling, tissue samples were collected. HE staining was performed to observe the pathology of lung tissue. Lung lobe wet and dry weights were measured to assess the degree of pulmonary edema. Immunohistochemistry was used to observe the expression of fibrinogen (FIB) in lung tissue. ELISA was used to detect the levels of thrombin-antithrombin complex (TAT), plasminogen activator inhibitor type-1 (PAI-1), and D-dimer (D-D) in plasma. The qRT-PCR was used to measure the mRNA expression levels of tissue factor (TF), FIB, PAI-1, angiopoietin (Ang)-1, Ang-2, and Tie2 in lung tissue. Western blot was used to measure the protein expression levels of TF, FIB, Ang-1, Ang-2, and pTie2 in lung tissue. Results:The HE staining results revealed that, compared to the Control group, the Histone group exhibited thickened alveolar walls, significant neutrophil infiltration, and alveolar congestion with edema, indicating histone-induced ALI ( P<0.001). In contrast, the Histone + UFH group exhibited milder lung injury ( P<0.001), suggesting that UFH mitigated the lung damage induced by histones. The lung wet/dry weight ratio and lung water content percentage were significantly higher in the Histone group than in the Control group ( P<0.001), while UFH reduced the severity of pulmonary edema ( P<0.01). Immunohistochemistry revealed intravascular thrombus formation and fibrin deposition in the Histone group, which were reduced by UFH. ELISA results showed significantly elevated levels of TAT, PAI-1, and D-D in the Histone group ( P<0.001), and UFH decreased the levels of these parameters stimulated by histone ( P<0.05). The qRT-PCR showed increased mRNA expression of TF, FIB, PAI-1, and Ang-2, and decreased expression of Ang-1 and Tie2 in lung tissues in the Histone group, while UFH mitigated the effects of histones on mRNA expression of these parameters. Western blot analysis indicated increased protein expression of TF, FIB, and Ang-2 ( P<0.01), and decreased expression of Ang-1 and Tie2 in lung tissues in the Histone group ( P<0.01), and UFH reduced the impact of histones on the protein expression of these parameters ( P<0.05). Conclusions:Histones can cause lung injury, pulmonary edema, and coagulation activation in mice lung tissue. UFH can effectively alleviate histone induced lung injury, and coagulation activation in by histones via the Ang/Tie2 signaling pathway.

Refractory prolactinoma is the most common pituitary neuroendocrine tumor.Dopamine receptor agonists(DA)are the primary choice for drug treatment.Most patients with prolactinomas respond well to DA.However,a minority of prolactinomas patients still show resistance to DA.Although drug-resistant and refractory prolactinomas are rare in clinical practice,their treatment is extremely challenging.Even a combination of drug therapy,multiple surgeries,and radiotherapy may not yield satisfactory outcomes.Therefore,standardizing the diagnosis and treatment process and pathway for refractory prolactionmas and exploring more effective multidisciplinary collaborative treatment strategies are urgent problems to be solved.In the clinical management of refractory prolactinomas,it is often necessary to consider the patient's condition comprehensively,replace other types of DA,or consider surgery,radiotherapy,and immunotherapy,which requires multidisciplinary diagnosis and treatment.This review synthesizes the latest literature at home and abroad to systematically discuss the latest advances in drug therapy,surgery,and radiotherapy treatments for refractory prolactionmas,aiming to provide new ideas for basic research,clinical diagnosis and treatment.

Objective:We aimed to develop a novel visualized model based on nomogram to predict postoperative overall survival.Methods:This was a multicenter, retrospective, observational cohort study, including participants with histologically confirmed gastric and colorectal cancer who underwent radical surgery from 11 medical centers in China from August 1, 2015 to June 30, 2018. Baseline characteristics, histopathological data and nutritional status, as assessed using Nutrition Risk Screening 2002 (NRS 2002) score and the scored Patient-Generated Subjective Global Assessment, were collected. The least absolute shrinkage and selection operator regression and Cox regression were used to identify variables to be included in the predictive model. Internal and external validations were performed.Results:There were 681 and 127 patients in the training and validation cohorts, respectively. A total of 188 deaths were observed over a median follow-up period of 59 (range: 58 to 60) months. Two independent predictors of NRS 2002 and Tumor-Node-Metastasis (TNM) stage were identified and incorporated into the prediction nomogram model together with the factor of age. The model's concordance index for 1-, 3- and 5-year overall survival was 0.696, 0.724, and 0.738 in the training cohort and 0.801, 0.812, and 0.793 in the validation cohort, respectively.Conclusions:In this study, a new nomogram prediction model based on NRS 2002 score was developed and validated for predicting the overall postoperative survival of patients with gastric colorectal cancer. This model has good differentiation, calibration and clinical practicability in predicting the long-term survival rate of patients with gastrointestinal cancer after radical surgery.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.

This study aimed to investigate the underlying mechanism of Zhenwu Decoction in the treatment of heart failure by regulating electrical remodeling through the transient outward potassium current(I_(to))/voltage-gated potassium(Kv) channels. Five normal SD rats were intragastrically administered with Zhenwu Decoction granules to prepare drug-containing serum, and another seven normal SD rats received an equal amount of distilled water to prepare blank serum. H9c2 cardiomyocytes underwent conventional passage and were treated with angiotensin Ⅱ(AngⅡ) for 24 h. Subsequently, 2%, 4%, and 8% drug-containing serum, simvastatin(SIM), and BaCl_2 were used to interfere in H9c2 cardiomyocytes for 24 h. The cells were divided into a control group [N, 10% blank serum + 90% high-glucose DMEM(DMEM-H)], a model group(M, AngⅡ + 10% blank serum + 90% DMEM-H), a low-dose Zhenwu Decoction-containing serum group(Z1, AngⅡ + 2% drug-containing serum of Zhenwu Decoction + 8% blank serum + 90% DMEM-H), a medium-dose Zhenwu Decoction-containing serum group(Z2, AngⅡ + 4% drug-containing serum of Zhenwu Decoc-tion + 6% blank serum + 90% DMEM-H), a high-dose Zhenwu Decoction-containing serum group(Z3, AngⅡ + 8% drug-containing serum of Zhenwu Decoction + 2% blank serum + 90% DMEM-H), an inducer group(YD, AngⅡ + SIM + 10% blank serum + 90% DMEM-H), and an inhibitor group(YZ, AngⅡ + BaCl_2 + 10% blank serum + 90% DMEM-H). The content of ANP in cell extracts of each group was detected by ELISA. The relative mRNA expression levels of ANP, Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 were detected by real-time quantitative PCR. The protein expression of Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 was detected by Western blot. I_(to) was detected by the whole cell patch-clamp technique. The results showed that Zhenwu Decoction at low, medium, and high doses could effectively reduce the surface area of cardiomyocytes. Compared with the M group, the Z1, Z2, Z3, and YD groups showed decreased ANP content and mRNA level, increased protein and mRNA expression of Kv4.2, Kv4.3, DPP6, and KChIP2, and decreased protein and mRNA expression of Kv1.4, and the aforementioned changes were the most notable in the Z3 group. Compared with the N group, the Z1, Z2, and Z3 groups showed significantly increased peak current and current density of I_(to). The results indicate that Zhenwu Decoction can regulate myocardial remodeling and electrical remodeling by improving the expression trend of Kv1.4, Kv4.2, Kv4.3, KChIP2, and DPP6 proteins and inducing I_(to) to regulate Kv channels, which may be one of the mechanisms of Zhenwu Decoction in treating heart failure and related arrhythmias.
Rats ; Animals ; Myocytes, Cardiac ; Atrial Remodeling ; Rats, Sprague-Dawley ; Heart Failure/metabolism* ; RNA, Messenger/metabolism* ; Potassium