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*

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 palatability and chewability of chewable tablets， and provide reference for the quality evaluation of various types of chewable tablets. METHODS Using self-made Glucosamine hydrochloride chewable tablets as the model drug， the quality test was conducted. The in vitro simulation system for chewable tablets was established by using a texture analyzer and rheometer， and an oral simulation experiment was conducted on chewable tablets. The texture analyzer was used to measure the force required for chewing and simulate the static disintegration process of chewable tablets； the rheometer was adopted to measure the viscoelasticity， thixotropy， and deformability of chewable tablets during the chewing process. RESULTS The disintegration time limit， principal component content， and dissolution of self-made Glucosamine hydrochloride chewable tablets all met the limit requirements. The in vitro simulation results of the texture analyzer showed that self-made chewable tablets were easy to chew in both axial and radial directions， and the force required for chewing was within the range of the chewing force of the teeth； chewable tablets could disintegrate at an appropriate time without being chewed and only taken in the oral cavity. The in vitro simulation results of the rheometer showed that the chewable tablets in the oral cavity exhibited a behavior of elasticity as the main factor and viscosity as the secondary factor through the continuous stirring of the tongue， and the viscosity of the chewable tablets gradually decreased with tongue stirring or tooth chewing； when chewing with teeth， the internal force of the chewing tablets decreased， causing plastic deformation and crushing. After being crushed， the shape couldn’t be restored， making it easy to chew and swallow. CONCLUSIONS The combination of texture analyzer and rheometer can be used to simulate the oral chewing process and evaluate the palatability and chewability of self-made Glucosamine hydrochloride chewable tablets. This model can provide reference for the evaluation of various chewable tablets.

Objective To investigate the inhibitory effects of magnesium citrate(MgCit)on oxidative stress in chronic renal failure(CRF).Methods SD rats were divided into CRF model group,MgCit groups(375 and 750 mg/kg),normal control group,and MgCit control group(750 mg/kg).The morphology of mitochondria in thoracic artery vascular smooth muscle cells(VSMCs)was observed by transmission electron microscopy.The content of superoxide dismutase(SOD)and malonaldehyde(MDA)in rat aorta and plasma was detected by the kit.The VSMCs were divided into normal control group,CRF model group,and MgCit groups(1.5 and 3 mmol/L).The levels of superoxide anion(DHE)and apoptosis were quantitatively detected by flow cytometry.Results Compared with the control groups,the mitochondria were swollen and the cristae fractured or disappeared in the model group;MgCit intervention could reduce mitochondrial swelling,but not cristae fracture.In the model group,SOD level in aorta and plasma decreased(P＜0.05)while MDA level increased(P＜0.05).MgCit intervention could increase SOD in aorta and plasma,but decrease MDA level(P＜0.05).In the CRF environment,the DHE content of VSMCs and apoptosis in CRF model group increased(P＜0.05).MgCit intervention could decrease DHE content and inhibit apoptosis(P＜0.05).Conclusion MgCit inhibits oxidative stress levels in vivo and in vitro in CRF.

Objective To explore the association between visceral adiposity index(VAI)and nonalcoholic fatty liver disease(NAFLD)in lean population and the predictive value of VAI.Methods A total of 2 576 healthy subjects,body mass index(BMI)＜24 kg/m2,from The Second Affiliated Hospital of Xi'an Jiaotong University from June 2020 to May 2021 were randomly included and divided into lean NAFLD(n=213)and healthy control group(n=2 363).According to the VAI quartiles,they were divided into Q1-Q4 groups from low to high.The differences in biochemical parameters and the prevalence of NAFLD were compared among groups.The correlation between VAI and lean NAFLD was analyzed with restricted cubic spline(RCS),and the predictive value of VAI was explored by Logistic regression and receiver operating characteristic(ROC)curve.Results A total of 2 576 participants were included,and the prevalence of lean NAFLD was 8.3％(213 cases).The mean age,male ratio,BMI and waist circumference(WC)from group Q1 to group Q4 were significantly increased in a dose-response relationship(all P＜0.001).Compared with those in group Q1,systolic blood pressure,diastolic blood pressure,white blood cell count,hemoglobin concentration,alanine aminotransferase,aspartate aminotransferase,γ-glutamyl transpeptidase,alkaline phosphatase,total cholesterol,triglyceride,low-density lipoprotein cholesterol,blood uric acid,and fasting blood glucose levels in groups Q2 to Q4 were significantly increased,while direct bilirubin and high-density lipoprotein cholesterol levels were gradually decreased(both P＜0.001).The prevalence rate of NAFLD in groups Q1-Q4 was 0.6％,3.3％,7.0％and 22.2％,respectively(P＜0.001).RCS showed that the risk of NAFLD in lean population rose significantly with the increase of VAI(P＜0.001),and there was a nonlinear relationship between them(P for nonlinear＜0.001).Logistic regression showed that after adjusting other confounding factors,the risk of lean NAFLD in groups Q2,Q3 and Q4 was still 2.926 times(95％CI:0.971-8.811),3.435 times(95％CI:1.154-10.230),and 5.920 times(95％CI:1.873-18.719)that Q1 group.ROC curve showed that VAI had a good predictive value for lean NAFLD,with area under the curve of 0.815,critical value of 1.532,diagnostic sensitivity of 77.9％and specificity of 72.8％,which were better than BMI and WC.Conclusion VAI is significantly associated with the risk of NAFLD in lean population,and thus has a good predictive value.It can be used for early screening and diagnosis of lean NAFLD.

[Purpose]To analyze the incidence and mortality trends,and survival of gallbladder cancer in Nantong City of Jiangsu Province from 2013 to 2017.[Methods]The gallbladder cancer incidence and mortality data from 2013 to 2017 were collected from Nantong cancer registries.The crude incidence/mortality rates,age-standardized incidence/mortality rates by Chinese and world standard population(ASIRC/ASMRC,ASIRW/ASMRW)were calculated by sex,age and regions(urban and rural).Joinpoint software was used to analyze the incidence and mortality trends of gallbladder cancer.The observed survival rate and relative survival rate were calculated by using life table method and Ederer Ⅱ method.[Results]From 2013 to 2017,the gallbladder cancer crude incidence and mortality rates were 6.36/105 and 4.91/105,ASIRC and ASMRC were 2.62/105 and 1.94/105,respectively.The crude incidence and mortality,and ASMRC showed an upwards trend(all P＜0.05).The ASIRC for men and women was 2.43/105 and 2.83/105,the ASMRC for men and women was 1.74/105 and 2.16/105,respectively.ASIRC and ASMRC in women were higher than those in men.The ASIRC in urban and rural areas was 2.40/105 and 2.69/105,and the ASMRC was 1.61/105 and 2.05/105,respectively.ASIRC and ASMRC in rural areas were higher than those in urban areas.The average age of onset was 70.33 years old and the average age of death was 71.86 years old.The 5-year observed survival rate was 12.90％,and the 5-year relative survival rate was 14.47％.Both the 5-year observed survival rate and relative survival rate showed an upwards trend(both P＜0.05).[Conclusion]The incidence and mortality rates of gall-bladder cancer in Nantong City are relatively high and the survival rate is generally low.It is sug-gested that targeted prevention and control measures of gallbladder cancer in Nantong City should be strengthened,particularly in rural areas and for middle-aged and elderly women.

Objective To observe the difference and clinical significance of expression levels of microRNA-155(miR-155)mRNA and interleukin-6(IL-6)in very preterm neonates with preeclampsia.Methods Twenty-eight cases of very preterm newborns(gestational age<32 weeks and/or body weight<1500 g)from preeclampsia pregnant women admitted to the department of obstetrics of Liaocheng People's Hospital from January to December 2021 were selected as the observation group,and 26 cases of very preterm neonates hospitalized for other reasons during the same period were selected as the control group.Electronic medical record clinical data related to children were collected,and the differences between the two groups were compared,including general conditions of preterm infants and pregnant mothers(gender,gestational age,birth weight,preeclampsia or not),proportion of invasive ventilation,proportion of bronchopulmonary dysplasia(BPD),incidence of acute respiratory distress syndrome(ARDS)and early-onset sepsis,white blood cell count(WBC),neutrophil count(NEUT),and expression of miR-155 mRNA and IL-6 levels in the serum of umbilical arterial blood after birth.Pearson correlation analysis was used to analyze the correlation between miR-155 and IL-6 levels Results The birth body weight of the observation group was significantly lower than that of the control group(kg:1.21±0.22 vs.1.32±0.33,P<0.05),the proportion of invasive ventilation,the proportion of BPD,the incidence of ARDS and sepsis were significantly higher than those in the control group[the proportion of invasive ventilation:75.0%(21/28)vs.57.7%(15/26),the proportion of BPD:35.7%(10/28)vs.11.5%(3/26),incidence of ARDS:100.0%(28/28)vs.84.6%(22/26),incidence of sepsis:71.4%(20/28)vs.53.8%(14/26),all P<0.05],the level of miR-155 mRNA expression and IL-6 were significantly higher than those in the control group[miR-155 mRNA(2-ΔΔCt):0.93±0.18 vs.0.17±0.03,IL-6(ng/L):73.84(33.44,429.00)vs.19.05(9.30,47.20),both P<0.05].Pearson correlation analysis showed that miR-155 and IL-6 levels were significantly positively correlated(r=0.782,P<0.01).With the extension of birth time,both WBC and NEUT gradually decreased in the two groups,and there were statistically significant differences in WBC and NEUT at each time point after birth,with counts significantly lower at 48 hours and 72 hours compared to 24 hours after birth(both P<0.05).The WBC of the observation group at 24,48 and 72 hours after birth was significantly lower than that of the control group(×109/L:7.85±2.44 vs.12.28±6.81 at 24 hours after birth,7.31±3.53 vs.10.98±7.91 at 48 hours after birth,4.97±2.05 vs.7.82±4.65 at 72 hours after birth,all P<0.05),NEUT in observation group was significantly lower than of control group at 24 hours and 48 hours after birth(×109/L:24 hours after birth was 4.13±1.93 vs.7.45±5.67,48 hours after birth was 3.96±2.64 vs.6.89±6.24,both P<0.05).Conclusion The expression level of miR-155 mRNA and IL-6 in very preterm neonates with preeclampsia is significantly up-regulated at the time of birth,and the inflammatory response of the body is disturbed,which has certain value for early assessment of the disease.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To investigate the association of triglyceride-glucose index(TyG)with non-alcoholic fatty liver disease(NAFLD)and its diagnostic value for NAFLD in non-obese individuals.Methods We retrospectively collected the data of non-obese individuals(BMI<25 kg/m2)undergoing routine health examination at Second Affiliated Hospital of Xi'an Jiaotong University between May,2020 and December,2023,who all received abdominal ultrasound examination for NAFLD screening.The nonlinear relationship between TyG and non-obese NAFLD was explored using restricted cubic splines(RCS),and LASSO regression was used for variable screening;the correlation between TyG and NAFLD risk was analyzed using multivariate logistic regression.The diagnostic value of TyG for non-obese NAFLD was assessed using receiver-operating characteristic(ROC)curves and sensitivity analysis.Results A total of 3723 non-obese subjects were enrolled in this study,including 432(11.6%)patients with NAFLD.Compared with the healthy individuals,the patients with NAFLD had significant elevations of systolic and diastolic blood pressures,total cholesterol,triglycerides,LDL-C,blood uric acid,fasting blood glucose,and TyG index and a decreased HDL-C level(P<0.05).Multivariate logistic regression revealed that for each one-unit increase of TyG,the risk of non-obese NAFLD increased by 2.2 folds(OR=3.22,95%CI:2.53-4.12,P<0.001).Compared with a TyG index in the lowest quartile Q1,a TyG index in the Q2,Q3 and Q4 quartiles was associated with an increased risk of NAFLD by 1.52 folds(OR=2.52,95%CI:1.20-5.95),3.56 folds(OR=4.56,95%CI:2.28-10.46),and 8.66-folds(OR=9.66,95%CI:4.83-22.18),respectively.The RCS curve demonstrated a significant linear correlation between TyG index and non-obese NALFD risk(P for nonlinear=0.019).For diagnosing non-obese NALFD,TyG index had an area under ROC curve of 0.819 with a sensitivity of 78.0%and a specificity of 71.2%.Conclusion An increase of TyG index is correlated with increased risks of NAFLD in non-obese individuals and can serve as an indicator for screening early NAFLD in healthy individuals.

From October 2021 to February 2023, we retrospectively analyzed the clinical and laboratory data of six patients (three male and three female, median age: 54 years, age range: 29-73 years) with mast cell leukemia (MCL) diagnosed in the First Affiliated Hospital of Soochow University (The Mastocytosis Collaborative Network of China). All patients had acute MCL, with at least one C-finding present. The main clinical presentations were hypoalbuminemia ( n=4), fatigue ( n=3), fever ( n=2), abdominal discomfort ( n=2), osteolytic lesions ( n=2), dizziness ( n=1), skin flushing ( n=1), and weight loss ( n=1). Splenomegaly and lymphadenopathy were noted in six and three patients, respectively. Six patients were strongly positive for CD117, five were positive for CD30 and CD25, and four were positive for CD2. Four patients had a normal karyotype and two patients had an abnormal karyotype. Gene mutations were detected in 4/6 cases. The median serum tryptase level was 24.9 (range: 20.1-171.9) μg/L. Two patients were treated with venetoclax and azacitidine for induction (one patient achieved partial remission by combination with afatinib, while there was no remission after combination with dasatinib in the other patient). Two patients did not achieve complete remission despite treatment with cladribine and imatinib, respectively. One patient treated with interferon combined with glucocorticoids was lost to follow-up, and one patient abandoned treatment. The follow-up time ranged from 1.1 to 21.7 months. Three patients died and two survived. Overall, MCL is a rare subtype of systemic mastocytosis with heterogeneous clinical course, and these patients have poor outcome. A better understanding of the clinical characteristics, treatment, and prognosis of MCL is urgently needed.