The v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene is one of the most critical proto-oncogenes and functions as a key regulator in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. The incidence of BRAF mutations in non-small cell lung cancer (NSCLC) patients ranges from 1.5% to 5.5%, with BRAF V600 mutations accounting for approximately 30%-50% of all BRAF mutations, among which BRAF V600E represents the most prevalent mutation type. Currently, the combination of Dabrafenib and Trametinib has been recommended as first-line therapy for BRAF V600-mutant NSCLC by multiple domestic and international guidelines including National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and Chinese Society of Clinical Oncology (CSCO). However, there are no clear targeted treatment recommendations for BRAF non-V600 mutations. Although case reports suggest that Dabrafenib combined with Trametinib may be effective for patients with BRAF non-V600 mutations, the efficacy and safety require further validation due to limited sample size and lack of large-scale clinical trial data. This article reports a case of NSCLC with a rare BRAF insertion and deletion mutation that responded well to the treatment of Dabrafenib in combination with Trametinib, aiming to enhance clinicians' understanding of such NSCLC cases with extremely rare mutation and provide a reference for future treatment strategies.
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Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Imidazoles/administration & dosage* ; Lung Neoplasms/pathology* ; Mutation ; Neoplasm Metastasis ; Oximes/administration & dosage* ; Proto-Oncogene Mas ; Proto-Oncogene Proteins B-raf/genetics* ; Pyridones/administration & dosage* ; Pyrimidinones/administration & dosage*

Objective To investigate the prognostic value of triglyceride-glucose index(TyG index)in non-diabetic patients with acute coronary syndrome(ACS)who underwent percutaneous coronary intervention(PCI).Methods A total of 529 non-diabetic ACS patients who had successfully underwent PCI in our hospital from January 2019 to December 2020 were selected.According to the median TyG index(8.98),the patients were divided into low TyG index group(TyG＜8.98)and high TyG index group(TyG≥8.98).All the patients were followed up for major adverse cardiovascular events(MACE).Results Overall,55(10.4％)endpoint events were documented during a 24-month follow-up.Kaplan-Meier survival curves showed that the cumulative incidence of MACE was significantly higher in patients in the high TyG group than in the low TyG group(Log Rank P=0.001).Multivariate Cox analysis showed that after adjusting other confounding factors,TyG index was an independent predictor of MACE(HR=3.50,95％CI:1.44-8.53,P＜0.01).The risk of MACE in the high TyG group was 1.12-fold increased compared with the low TyG group(95％CI:1.19-3.79,P=0.011).The subgroup analysis results were generally consistent.Conclusion TyG index is an independent predictor of MACE in non-diabetic ACS patients who underwent PCI.

Compared with conventional transdermal drug delivery systems, dissolving microneedles significantly enhance drug bioavailability by penetrating the stratum corneum barrier and achieving intradermal drug delivery. In order to improve the transdermal bioavailability of dexmedetomidine hydrochloride, in this study, a novel microneedle delivery system was developed for dexmedetomidine hydrochloride based on 3D printing combined with micro-molding. By systematically optimizing the microneedle geometrical parameters, array arrangement, and preparation process parameters, we determined the optimal ratio of drug-carrying matrix as 15% PVP (polyvinyl pyrrolidone) K90. The microneedles exhibited significant drug loading gradients, with mean content of (209.99±27.56) μg/patch, (405.31±30.31) μg/patch, and (621.61±34.43) μg/patch. They showed a regular pyramidal structure under SEM and handheld electron microscopy, and their mechanical strength allowed effective penetration into the stratum corneum. The surface contact angles were all < 90°, indicating excellent hydrophilicity. The microneedles dissolved completely within 10 min after skin insertion, achieving a cumulative release rate of 90% (Higuchi model, r=0.996) during 2 hours of in vitro transdermal permeation. The cytotoxicity test and hemolysis test verified good biocompatibility. Pharmacodynamic evaluation showed that the microneedle group demonstrated pain-relieving effect within 15 min, with the pain threshold at the time point of 60 min being 3 times that in the transdermal cream group. The microneedle system developed in this study not only offers an efficient drug delivery option for patients but also establishes an innovative platform for rapid percutaneous delivery of hydrophilic drugs, demonstrating significant potential in perioperative pain management.
Dexmedetomidine/pharmacokinetics* ; Printing, Three-Dimensional ; Needles ; Drug Delivery Systems/methods* ; Administration, Cutaneous ; Animals ; Microinjections/instrumentation* ; Skin Absorption ; Skin/metabolism*

Objective To evaluate the clinical efficacy and application value of digital subtraction angiography (DSA) in the management of delayed pancreaticoduodenectomy(PD) hemorrhage(PPH).Methods A retrospective analysis was conducted on the clinical data of 38 patients who underwent DSA for delayed PPH at Zhongshan Hospital, Fudan University, between January 2019 and December 2024. The technical success rate and clinical outcomes of interventional treatment were the primary focus of the evaluation.Results Among 726 patients who underwent PD, 38 (5.2%) experienced delayed bleeding. Of these, 30 (78.9%) showed positive findings on DSA. The distribution of bleeding sites was as follows: gastroduodenal artery (18 cases), common hepatic artery (1 case), the first branch of the jejunal artery (2 cases), proper hepatic artery (2 cases), right hepatic artery (1 case), middle hepatic artery (1 case), left hepatic artery (3 cases), origin of the splenic artery (1 case), and right gastroepiploic artery (1 case). Interventional treatments included microcoil embolization (17 cases), microcoil combined with gelatin sponge embolization (4 cases), covered stent implantation (7 cases), and gelatin sponge embolization alone and microspheres embolization (1 case each). Successful hemostasis was achieved in 28 (93.3%) patients through DSA-guided interventional treatment, while 2 patients required surgical hemostasis due to recurrent bleeding.Conclusions DSA-guided interventional embolization offers advantages such as minimal invasiveness, precise localization, and effective hemostasis, making it the preferred treatment strategy for delayed PPH.

Objective:To investigate the relationship between lean lipid accumulation product (LAP) and metabolic associated fatty liver disease (MAFLD).Methods:This cross-sectional study consecutively enrolled 1 990 adult subjects who underwent health examinations at the Second Affiliated Hospital of Xi′an Jiaotong University between June 2021 and May 2023. All recruited participants had a body mass index (BMI)<23 kg/m2. Data collection included general information, physical examination, serum biochemical parameter measurements, and liver ultrasonography. Participants were divided into four groups (Q1-Q4) according to quartiles value of LAP from low to high. The differences of biochemical parameters and the prevalence of lean MAFLD were compared among the groups. Logistic regression, restricted cubic spline (RCS) and receiver operating characteristic (ROC) curve analysis were used to explore the relationship between LAP and lean MAFLD and assess the diagnostic predictive value of LAP for lean MAFLD.Results:A total of 1990 participants were selected, and the detection rate of lean MAFLD was 4.97% (99 cases). The detection rate of lean MAFLD showed a significant increasing trend from Q1 to Q4 groups ( P<0.001) and respectively was 0.40%, 0.81%, 4.01% and 14.70%. The average age, male proportion, BMI and waist circumference significantly increased in a dose-response manner from Q1 to Q4 (all P<0.001). Indirect bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltranspeptidase, alkaline phosphatase, total cholesterol, triglycerides, low-density lipoprotein, serum uric acid, fasting blood glucose, fatty liver index, fibrosis-4 index and every metabolic syndrome component in groups Q2 to Q4 were significantly higher than in the Q1 group, while high-density lipoprotein levels gradually decreased (all P<0.05). RCS showed that the risk of lean MAFLD rose significantly with the increase of LAP ( P<0.005), presenting a nonlinear relationship between them ( P for nonlinear<0.001). Logistic regression analysis revealed that after adjusting other confounding factors, the risk of lean MAFLD in the Q4 group remained 4.75 times higher than that in the Q1 group (95% CI: 11.22-31.69, P<0.05). ROC curve demonstrated that LAP had a better predictive value for lean MAFLD than BMI and waist circumference, with area under the curve of 0.839, critical value of 19.59, diagnostic sensitivity of 82.8% and specificity of 75.1%. Conclusions:Elevated LAP is independently and positively correlated with the risk of lean MAFLD, and its predictive efficacy is significant superior to traditional obesity indicators.

Objective To investigate the association between plasma atherogenic index of plasma(AIP)and metabolism-associated steatotic liver disease(MASLD),and to evaluate the potential value of AIP as a predictive marker for MASLD risk.Methods We enrolled a total of 4 850 health check-up participants from The Second Affiliated Hospital of Xi'an Jiaotong University between June 2021 and May 2023.The participants were divided into quartiles(Q1-Q4)according to their AIP level.Biochemical indicators and MASLD prevalence were compared across groups.Logistic regression,subgroup analysis,and restricted cubic splines(RCS)were used to explore the relationship between AIP and MASLD.Results Among the 4 850 participants,the prevalence of MASLD was 26.08％(1 265/4 850).MASLD prevalence increased across AIP quartiles:4.0％,13.8％,30.8％,and 55.6％in Q1-Q4,respectively(P＜0.001).Compared with Q1,Q2-Q4 groups showed higher proportions of males,BMI,smokers,overweight/obesity,central obesity,prediabetes,hypertension,serum uric acid,and fatty liver index(FLI)(all P＜0.001).Lipid profiles worsened with increased AIP:total cholesterol,triglycerides,and LDL-C increased,while HDL-C decreased(P＜0.001).RCS analysis demonstrated a significant linear relationship between AIP and MASLD risk.After adjusting for confounders,the participants in Q4 had an 8.71-fold higher risk of MASLD than those in Q1(OR:8.71,95％CI:6.20-12.23,P＜0.001).A composite model incorporating AIP,BMI,and FLI showed superior discriminative performance(AUC:0.883,95％CI:0.873-0.892).Interaction analysis suggested that AIP had significant interactions with BMI,hypertension,and prediabetes(P＜0.05).In individuals without these metabolic abnormalities,the association between AIP and MASLD was more pronounced.Conclusion Elevated AIP was significantly associated with an increased risk of MASLD,with a stronger association observed in individuals with normal BMI,blood pressure,and blood glucose levels,suggesting that AIP may serve as a potential indicator for early screening of MASLD.

Objective:To investigate the drug resistance of newly diagnosed HIV-1 infected patients in Shanghai and to provide reference value for clinical antiretroviral therapy (ART).Methods:The peripheral venous blood plasma of 196 newly diagnosed HIV-1 infected patients screened according to the inclusion and exclusion criteria at the Shanghai Public Health Clinical Center from April to June 2023 was collected, HIV-1 RNA was extracted, the pol region was amplified by reverse transcription-polymerase chain reaction (RT-PCR) for sequencing, the mutation sites and ART drug resistance were analyzed.Results:The plasma of 196 newly diagnosed HIV-1 infected patients was amplified successfully in 162 cases (amplification success rate was 82.65%). The subtypes consisted of CRF07_BC(51.23%), CRF01_AE (27.78%), and others (6.79%), CRF55_01B (5.56%), B (3.70%), CRF01_AE/B (3.70%) and CRF08_BC (1.23%). The overall transmitted drug resistance rate was 7.41%, the protease inhibitors (PIs), non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), integrase inhibitors (INSTIs) resistance rates were 3.09%, 3.70%, 0.00% and 0.62%, respectively. The proportion of NNRTIs-related mutation sites in B (66.67%) and CRF55_01B (88.89%) was higher than that in CRF07_BC (13.25%); the proportion of NNRTIs-related mutation sites in CRF55_01B (88.89%) was higher than that in CRF01_AE (22.22%) and other subtypes (18.18%), the difference was statistically significant (all P<0.05). Multivariate logistic regression analysis showed that the probability of PIs-related mutation sites in CRF01_AE/B was 21.71 times that of CRF07_BC[odds ratio ( OR)=21.71, 95% confidence interval ( CI): 3.36-140.27, P=0.001]. Conclusions:The transmitted drug resistance among newly diagnosed HIV-1 infected patients in Shanghai is at the moderate epidemic level, mainly NNRTIs and PIs-related drug resistance, and the INSTIs resistance rate is low, the use of INSTIs in ART regimens should be considered.

Objective:To investigate the short-term efficacy and safety of rituximab (RTX) in children with calcineurin inhibitor (CNI) resistant steroid resistant nephrotic syndrome (SRNS).Methods:A retrospective case analysis was conducted. Thirteen children with CNI resistant SRNS who were regularly treated with RTX (375 mg/m 2 per dose (maximum dose 500 mg), 1 dose per week, a total of 4 doses) in Department of Nephrology, Children′s Hospital of Fudan University from January 2016 to December 2023 were enrolled. The general data, disease related information, urinary protein/creatinine, serum albumin, blood creatinine before RTX treatment, immunosuppressants, adverse events, and monthly urinary protein/creatinine, serum albumin, and blood creatinine indexes within 6 months after RTX treatment were collected. The changes of urinary protein/creatinine, serum albumin and estimated glomerular filtration rate (eGFR) before and after RTX at 3 and 6 months were analyzed by using paired sample t test and Wilcoxon signed-rank test. Results:Among the 13 patients, 8 were male and 5 were female. The age of disease onset was 4.0 (2.9, 6.8) years and the age of RTX treatment was 9.8 (5.9, 13.6) years. There were 8 cases of focal segmental glomerulosclerosis, 3 cases of minimal change disease and 2 cases of mesangial proliferative glomerulonephritis. No clinically significant gene variation was detected in 12 cases and the other one did not receive gene test. Before RTX treatment, 11 cases were in chronic kidney disease stage G1, and 1 case each was in stage G2 and stage G3. Ten children completed 4 doses of RTX treatment, 1 patient completed 3 doses, and 2 patients completed 2 doses. Urinary protein/creatinine in 13 children at 3 and 6 months after RTX treatment was significantly lower than baseline (0.60 (0.13, 2.04), 0.49 (0.28, 1.10) vs. 1.44 (0.76, 4.11) mg/mg, Z=-2.34, -2.34, both P<0.05), and serum albumin was significantly higher than baseline ((35±8), (34±7) vs. (30±6) g/L, t=2.30, 2.60, both P<0.05). The eGFR at 6 months after RTX treatment was not significantly different from the baseline ((110±32) vs. (113±35) ml/(min·1.73 m 2), t=-0.76, P>0.05)). No serious adverse reactions occurred in this study. Conclusion:RTX could reduce urinary protein and increase serum albumin in short-term treatment in children with CNI resistant SRNS without significant side effects.

Objective To investigate the effect of irisin regulating early B cytokine 3(EBF3)/arachidonic acid-15-lipoxygenase(ALOX15)pathway on the proliferation and migration of lung adenocarcinoma cells.Methods A549 cells were assigned into the irisin solvent group,the irisin group,the sh-NC group,the EBF3 inhibitor(sh-EBF3)group,the irisin+sh-NC group and the irisin+sh-EBF3 group randomly.5-bromo-2-deoxyuracil(EdU)staining and CCK-8 method were applied to detect cell proliferation.5-Scratch experiment was applied to detect the scratch healing rate.2',7'-dichlorofluorescein diacetate(DCFH-DA)staining was applied to detect the level of reactive oxygen species(ROS)in cells.The reagent kit was used to detect glutathione(GSH),malondialdehyde(MDA)and ferrous ion(Fe2+)in cells.Transmission electron microscopy was applied to observe mitochondrial morphology in A549 cells.QRT-PCR was applied to detect mRNA levels of proliferating cell nuclear antigen(PCNA),matrix metalloproteinase 2(MMP-2)and glutathione peroxidase 4(GPX4)in A549 cells.Western blot assay was applied to detect EBF3 and ALOX15 proteins in cells.Results Compared with the irisin solvent group,the mitochondria of A549 cells in the irisin group showed ferroptosis characteristics,the positive rate of EdU,OD450 value,scratch healing rate,GSH level,PCNA,MMP-2 and GPX4 mRNA levels decreased,and the ROS relative fluorescence intensity,MDA,Fe2+level,and EBF3 and ALOX15 protein levels increased(P＜0.05).Compared with the sh-NC group,the mitochondrial ferroptosis phenomenon of A549 cells was reduced in the sh-EBF3 group,the positive rate of EdU,OD450 value,scratch healing rate,GSH level,PCNA,MMP-2 and GPX4 mRNA levels increased,and the ROS relative fluorescence intensity,MDA,Fe2+levels and EBF3 and ALOX15 protein levels reduced(P＜0.05).Sh-EBF3 reversed the effect of irisin on ferroptosis,proliferation and migration of A549 cells.Conclusion Irisin may induce ferroptosis in A549 cells and inhibit cell proliferation and migration by activating the EBF3/ALOX15 pathway.

Objective To investigate the association between plasma atherogenic index of plasma(AIP)and metabolism-associated steatotic liver disease(MASLD),and to evaluate the potential value of AIP as a predictive marker for MASLD risk.Methods We enrolled a total of 4 850 health check-up participants from The Second Affiliated Hospital of Xi'an Jiaotong University between June 2021 and May 2023.The participants were divided into quartiles(Q1-Q4)according to their AIP level.Biochemical indicators and MASLD prevalence were compared across groups.Logistic regression,subgroup analysis,and restricted cubic splines(RCS)were used to explore the relationship between AIP and MASLD.Results Among the 4 850 participants,the prevalence of MASLD was 26.08％(1 265/4 850).MASLD prevalence increased across AIP quartiles:4.0％,13.8％,30.8％,and 55.6％in Q1-Q4,respectively(P＜0.001).Compared with Q1,Q2-Q4 groups showed higher proportions of males,BMI,smokers,overweight/obesity,central obesity,prediabetes,hypertension,serum uric acid,and fatty liver index(FLI)(all P＜0.001).Lipid profiles worsened with increased AIP:total cholesterol,triglycerides,and LDL-C increased,while HDL-C decreased(P＜0.001).RCS analysis demonstrated a significant linear relationship between AIP and MASLD risk.After adjusting for confounders,the participants in Q4 had an 8.71-fold higher risk of MASLD than those in Q1(OR:8.71,95％CI:6.20-12.23,P＜0.001).A composite model incorporating AIP,BMI,and FLI showed superior discriminative performance(AUC:0.883,95％CI:0.873-0.892).Interaction analysis suggested that AIP had significant interactions with BMI,hypertension,and prediabetes(P＜0.05).In individuals without these metabolic abnormalities,the association between AIP and MASLD was more pronounced.Conclusion Elevated AIP was significantly associated with an increased risk of MASLD,with a stronger association observed in individuals with normal BMI,blood pressure,and blood glucose levels,suggesting that AIP may serve as a potential indicator for early screening of MASLD.