This article elucidates therapeutic approaches for KRAS G12C-mutant advanced non-small cell lung cancer, with focus on global advancements in inhibitor research. It also summarizes clinical evidence on the efficacy of targeted agents in monotherapy and combination therapies, analyzes their clinical advantages and challenges, and explores future directions for novel treatment modalities.

As a new generation of time-of-flight mass spectrometry,multiple-reflection time-of-flight mass spectrometry(MR-TOF-MS)has been increasingly applied in the fields such as nuclear physics,chemistry,and biology due to its ultra-high resolution and rapid analysis capabilities.However,the analytical performance of MR-TOF-MS largely depends on the ion bunch state entering the mass analyzer.In this study,a rectangular ion trap(RIT)was developed,designed and processed using printed circuit board technology,as an ion accumulating and focusing device for MR-TOF mass analyzer.Compared to traditional ion traps composed of two sets of planar electrodes,this RIT had higher voltage utilization efficiency,resulting in more efficient ion collection and focusing.The ions were cooled to a sufficiently small bunch for precise mass measurement with MR-TOF-MS mass spectrometry in only 1 ms of cooling time in the RIT,then orthogonally ejected to the MR-TOF mass spectrometer for mass analysis.Experimental results indicated that the working cycle,ion flux,and ion focusing state of the RIT fully met the requirements of the MR-TOF mass analyzer.When coupled with the MR-TOF mass analyzer,the RIT enabled MR-TOF-MS to achieve a mass resolution of 1.5×105.

Objective To evaluate the application of problem-based learning(PBL)and case-based learning(CBL)combined with ideological-political elements in surgical clinical ethics.Methods Eighty graduate students of grade 2022 majoring in surgery from Peking Union Medical College were selected as the subjects for the clinical ethics course offered in the first semester of the 2022-2023 academic year.They underwent the innovative pedago-gies of PBL and CBL combined with ideological-political elements.The satisfaction investigation and questionnaire surveys were performed to evaluate the effects.Results A total of 78 valid questionnaires were received.The results showed that 96.2%of students believed that this course supported them to understand the fundamental prin-ciples and knowledge of surgical clinical ethics and 94.9%of students expressed their willingness to expand their knowledge,indicating high satisfaction with the course.There were 91%of students acknowledged this model in terms of improving active learning and 93.6%stated that the course helped in developing good professional ethics.Most students responded positively to this model because of its contribution to enhance core clinical competencies.Conclusions The PBL and CBL combined with ideological-political elements have a better effect on surgical clini-cal ethics with high satisfaction of the students.

Objective To investigate the predictive value of temperature gradients on the mortality of sepsis patients and their correlation with fluid input.Methods By means of a prospective observational method,154 patients with sepsis or septic shock admitted to the Department of Critical Care Medicine at Nanfang Hospital,Southern Medical University from November 2019 to November 2021 were included as research subjects.They were divided into a survivor group(n=118)and a non-survivor group(n=36)according to whether they survived within 28 days.The core-to-toe temperature gradient(CTTG)and toe-to-room temperature gradient(TRTG)were monitored and calculated immediately upon admission to the intensive care unit(ICU)and 6 hours after admission.Receiver operating characteristic(ROC)curve was used to explore the predictive value of temperature gradients on mortality,and multivariate Cox regression analysis was performed to explore the risk factors of 28-day mortality in sepsis patients.The results were verified through survival analysis.Correlation analysis and multivariate analysis of variance were used to explore the correlation between temperature gradients and fluid input,as well as noradrenaline doses.Results Among the 154 patients,118 survived within 28 days(survivor group),and 36 died(non-survivor group).ROC curve and multivariate Cox regression analysis showed that a toe-to-room temperature gradient of≤5.35℃within 6 hours after admission was a risk factor for 28-day mortality.Compared with patients with a high toe-to-room temperature gradient(>5.35℃),patients with a low toe-to-room temperature gradient(≤5.35℃)had a 2.74-fold increase in the risk of 28-day mortality(P=0.004,95%CI 1.54,9.12).The CTTG and TRTG upon admission to the ICU and 6 hours after admission were not significantly associated with fluid input or noradrenaline doses(P>0.05).Conclusions A toe-to-room temperature gradient of less than or equal to 5.35℃within 6 hours after ICU admission is a risk factor for 28-day mortality in sepsis patients.The improvement of temperature gradients at different time points is not associated with fluid input.

Objective To investigate the anatomical and microscopic structures of interstitial fluid flow channels in the skin tissue of hand dorsum in human cadavers.Methods Totally 7 fresh cadavers within 12 hours post-mortem were included.MRI was used to observe the distribution of interstitial fluid flow from the first phalanx of the fingers to the wrist,precisely locating the flow channels.Based on imaging results,histological analyses were conducted to determine the histological characteristics of the flow channels.Furthermore,multi-immunofluorescence and microcomputed tomography(Micro-CT)techniques were employed to analyze the channels,and image post-processing was used to elucidate their anatomical structures at the microscopic level.Results After injecting a contrast agent into the first phalanx of ten finger specimens and applying repeated pressure,MRI image revealed centripetal long-range interstitial fluid flow along channels distinct from blood vessels and lymphatic vessels.Histological analysis and Micro-CT further confirmed that the flow primarily occurred within the fibrous connective tissue and adventitia of the skin.Conclusion The orderly fibrous connective tissue and adventitia in the skin form the interstitial fluid flow channels in the human hand dorsum skin,named as"stromal membrane channels"in the skin.

Jiuwei Xifeng Granules have become a Chinese patent medicine in the market. Because the formula contains Os Draconis, a top-level protected fossil of ancient organisms, the formula was to be improved by replacing Os Draconis with Ostreae Concha. To evaluate whether the improved formula has the same effectiveness and safety as the original formula, a randomized, double-blind, parallel-controlled, equivalence clinical trial was conducted. This study enrolled 288 tic disorder(TD) of children and assigned them into two groups in 1∶1. The treatment group and control group took the modified formula and original formula, respectively. The treatment lasted for 6 weeks, and follow-up visits were conducted at weeks 2, 4, and 6. The primary efficacy endpoint was the difference in Yale global tic severity scale(YGTSS)-total tic severity(TTS) score from baseline after 6 weeks of treatment. The results showed that after 6 weeks of treatment, the declines in YGTSS-TSS score showed no statistically significant difference between the two groups. The difference in YGTSS-TSS score(treatment group-control group) and the 95%CI of the full analysis set(FAS) were-0.17[-1.42, 1.08] and those of per-protocol set(PPS) were 0.29[-0.97, 1.56], which were within the equivalence boundary [-3, 3]. The equivalence test was therefore concluded. The two groups showed no significant differences in the secondary efficacy endpoints of effective rate for TD, total score and factor scores of YGTSS, clinical global impressions-severity(CGI-S) score, traditional Chinese medicine(TCM) response rate, or symptom disappearance rate, and thus a complete evidence chain with the primary outcome was formed. A total of 6 adverse reactions were reported, including 4(2.82%) cases in the treatment group and 2(1.41%) cases in the control group, which showed no statistically significant difference between the two groups. No serious suspected unexpected adverse reactions were reported, and no laboratory test results indicated serious clinically significant abnormalities. The results support the replacement of Os Draconis by Ostreae Concha in the original formula, and the efficacy and safety of the modified formula are consistent with those of the original formula.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Double-Blind Method ; Drugs, Chinese Herbal/therapeutic use* ; Tic Disorders/drug therapy* ; Treatment Outcome

This study aimed to explore the effects and mechanisms of total extracts from Anthriscus sylvestris on pulmonary hypertension in rats. Sixty male SD rats were divided into normal(NC) group, model(M) group, positive drug sildenafil(Y) group, low-dose A. sylvestris(ES-L) group, medium-dose A. sylvestris(ES-M) group, and high-dose A. sylvestris(ES-H) group. On day 1, rats were intraperitoneally injected with monocrotaline(60 mg·kg~(-1)) to induce pulmonary hypertension, and the rat model was established on day 28. From days 15 to 28, intragastric administration of the respective treatments was performed. After modeling and treatment, small animal echocardiography was used to detect the right heart function of the rats. Arterial blood gas was measured using a blood gas analyzer. Hematoxylin and eosin(HE) staining and Masson staining were performed to observe cardiopulmonary pathological damage. Flow cytometry was used to detect apoptosis in the lung and myocardial tissues and reactive oxygen species(ROS) levels. Western blot was applied to detect the expression levels of transforming growth factor-β1(TGF-β1), phosphorylated mothers against decapentaplegic homolog 3(p-Smad3), Smad3, tissue plasminogen activator(t-PA), and plasminogen activator inhibitor-1(PAI-1) in lung tissue. A blood routine analyzer was used to measure inflammatory immune cell levels in the blood. Enzyme-linked immunosorbent assay(ELISA) was used to detect the expression levels of P-selectin and thromboxane A2(TXA2) in plasma. The results showed that, compared with the NC group, right heart hypertrophy index, right ventricular free wall thickness, right heart internal diameter, partial carbon dioxide pressure(PaCO_2), apoptosis in cardiopulmonary tissue, and ROS levels were significantly increased in the M group. In contrast, the ratio of pulmonary blood flow acceleration time(PAT)/ejection time(PET), right cardiac output, change rate of right ventricular systolic area, systolic displacement of the tricuspid ring, oxygen partial pressure(PaO_2), and blood oxygen saturation(SaO_2) were significantly decreased in the M group. After administration of the total extract of A. sylvestris, right heart function and blood gas levels were significantly improved, while apoptosis in cardiopulmonary tissue and ROS levels significantly decreased. Further testing revealed that the total extract of A. sylvestris significantly decreased the levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and PAI-1 proteins in lung tissue, while increasing the expression of t-PA. Additionally, the extract reduced the levels of inflammatory cells such as leukocytes, lymphocytes, granulocytes, and monocytes in the blood, as well as the levels of P-selectin and TXA2 in plasma. Metabolomics results showed that the total extract of A. sylvestris significantly affected metabolic pathways, including arginine biosynthesis, tyrosine metabolism, and taurine and hypotaurine metabolism. In conclusion, the total extract of A. sylvestris may exert an anti-pulmonary hypertension effect by inhibiting the TGF-β1/Smad3 signaling pathway, thereby alleviating immune-inflammatory responses and thrombosis.
Animals ; Male ; Smad3 Protein/metabolism* ; Transforming Growth Factor beta1/metabolism* ; Rats, Sprague-Dawley ; Rats ; Signal Transduction/drug effects* ; Hypertension, Pulmonary/genetics* ; Thrombosis/immunology* ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Apoptosis/drug effects*

This paper aimed to explore the effects of Duzhong Decoction(DZD)-containing serum on the proliferation and osteoblast differentiation of MC3T3-E1 cells through L-type voltage-gated calcium channels(L-VGCCs). L-VGCCs inhibitors, nifedipine and verapamil, were used to block L-VGCCs in osteoblasts. MC3T3-E1 cells were divided into a control group, a low-dose DZD-containing serum(L-DZD) group, a medium-dose DZD-containing serum(M-DZD) group, a high-dose DZD-containing serum(H-DZD) group, a nifedipine group, a H-DZD + nifedipine group, verapamil group, and a H-DZD + verapamil group. The CCK-8 method was used for cell proliferation analysis, alkaline phosphatase(ALP) assay kits for intracellular ALP activity measurement, Western blot for protein expression level in cells, real-time fluorescence quantitative PCR technology for intracellular mRNA expression level determination, fluorescence spectrophotometer for free Ca~(2+) concentration determination in osteoblasts, and alizarin red staining(ARS) for mineralized nodule formation in osteoblasts. The experimental results show that compared to the control group, DZD groups can promote MC3T3-E1 cell proliferation, ALP activity, and mineralized nodule formation, increase intracellular Ca~(2+) concentrations, and upregulate the protein expression of bone morphogenetic protein 2(BMP2), collagen Ⅰ(COL1), α2 subunit protein of L-VGCCs(L-VGCCα2), and the mRNA expression of Runt-related transcription factor 2(RUNX2), and BMP2. After blocking L-VGCCs with nifedipine and verapamil, the intervention effects of DZD-containing serum were inhibited to varying degrees. Both nifedipine and verapamil could inhibit ALP activity, reduce mineralized nodule areas, and downregulate the expression of bone formation-related proteins. Moreover, the effects of DZD-containing serum on increasing MC3T3-E1 cell proliferation, osteoblast differentiation, and Ca~(2+) concentrations, upregulating the mRNA expression of osteoprotegerin(OPG) and protein expression of phosphorylated protein kinase B(p-Akt) and phosphorylated forkhead box protein O1(p-FOXO1), and upregulating phosphatase and tensin homolog(PTEN) expression were reversed by nifedipine. The results indicate that DZD-containing serum can increase the Ca~(2+) concentration in MC3T3-E1 cells to promote bone formation, which may be mediated by L-VGCCs and the PTEN/Akt/FoxO1 signaling pathway, providing a new perspective on the mechanism of DZD in treating osteoporosis.
Animals ; Osteoblasts/metabolism* ; Cell Proliferation/drug effects* ; Cell Differentiation/drug effects* ; Mice ; Drugs, Chinese Herbal/pharmacology* ; Calcium Channels, L-Type/genetics* ; Alkaline Phosphatase/genetics* ; Serum/chemistry* ; Cell Line ; Osteogenesis/drug effects* ; Bone Morphogenetic Protein 2/genetics*

OBJECTIVE: To screen out the key metabolites related to diabetic foot (DF) by integrating genome-wide association studies (GWAS) and metabolome genome-wide association studies (mGWAS). METHODS: The literature databases such as PubMed and China national knowledge infrastructure(CNKI), as well as genomics databases such as PAN UKBB, FinnGen, and IEU Open GWAS were systematically retrieved from database estobilishment to November 2024 on DF-related single nucleotide polymorphisms and genome-wide association studies. DF-single nucleotide polymorphism-metabolite network was constructed by mGWAS package and mGWAS-Explorer platform. The causal relationship between key factors was evaluated by two-sample Mendelian randomization. The genetic correlation between DF and 575 metabolites (source:IEU Open GWAS) was evaluated by linkage disequilibrium score regression. In vitro experiments were conducted to induce injury of human umbilical vein endothelial cells with 30 mM glucose and intervene with 20 μM γ-tocopherol. Changes in cell migration, scratch healing and tube formation function were detected. RESULTS: Twenty-senen literatures on single nucleotide polymorphism literatures and 3 studies on GWAS were included. Genetic analysis results showed DF-related single nucleotide polymorphisms were enriched in vascular endothelial dysfunction-related pathways (such as fluid shear stress and atherosclerosis). The results of metabolic network analysis screened out 19 associated metabolites, among which 12 such as γ -tocopherol and pyruvate had significant genetic correlations with DF. Mendelian randomization suggested matrix metalloproteinase-9(MMP-9) might be a potential driver of DF (β=0.658, P=0.063 8), and the occurrence of DF could reduce the level of high-density lipoprotein (β=-0.002, P=0.015 2). The results of in vitro experiments confirmed that γ -tocopherol could improve endothelial dysfunction induced by high glucose, specifically manifested as an increase in the number of cell migrations, improvement in the scratch healing rate, and recovery of tubule formation ability (P<0.05). CONCLUSION DF has a genetic basis centered on vascular endothelial dysfunction, and its occurrence can lead to further metabolic disorders. The key single nucleotide polymorphism loci integrated provided molecular markers for the risk stratification of foot ulcers in diabetic patients. In addition, γ -tocopherol has demonstrated clinical application potential as a therapeutic drug for DF by significantly improving the function of vascular endothelial cells in a high-glucose environment.
Humans ; Diabetic Foot/drug therapy* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Genomics ; Metabolomics ; Metabolome

OBJECTIVE: To observe the clinical efficacy and safety of automatic pressure-controlled pressure cupping in patients with lumbar disc herniation, and compare it with traditional cupping. METHODS: A total of 100 patients diagnosed with lumbar disc herniation from January 2022 to August 2024 were selected and divided into two groups:the automatic pressure-controlled pressure cupping group (controlled pressure cupping group) and the traditional cupping group (control group), 50 cases in each group. In the controlled pressure cupping group, there were 18 males and 32 females, with an age of (51.98±12.69) years;in the control group, there were 16 males and 34 females, with an age of (51.32±12.05) years. The visual analogue scale(VAS), comfort score, and lumbar range of motion were observed before treatment and after the 1st, 3rd, and 7th treatments to evaluate the efficacy and safety. RESULTS: All patients completed the treatment intervention, with complete follow-up data collected. No adverse reactions or complications occurred during treatment and follow-up. After the 3rd treatment, the VAS score of the controlled pressure cupping group was (2.38±0.49), which was lower than that of the control group (2.94±0.68), with a statistically significant difference (P<0.001). In the controlled pressure cupping group, the VAS scores after the 1st, 3rd, and 7th treatments were significantly better than those before treatment (P=0.026);in the control group, the VAS scores after the 3rd and 7th treatments were better than those before treatment, but the difference was not statistically significant(P=0.182). Repeated-measures analysis of variance (ANOVA) on VAS scores at different time points in both groups showed that there were statistically significant differences in inter-group, time, and interaction effects (P<0.05). After the 1st treatment, in the controlled pressure cupping group, 0 patients felt comfortable, 42 patients (84%) felt mild discomfort, and 8 patients (16%) felt moderate discomfort;in the control group, 0 patients felt comfortable, 28 patients (56%) felt mild discomfort, and 22 patients(44%) felt moderate discomfort;the difference between the two groups was statistically significant(P=0.005). After the 3rd treatment, in the controlled pressure cupping group, 30 patients(60%) felt comfortable, 20 patients (40%) felt mild discomfort, and 0 patients felt moderate discomfort; in the control group, 9 patients (18%) felt comfortable, 41 patients (82%) felt mild discomfort, and 0 patients felt moderate discomfort;the difference between the two groups was statistically significant(P<0.001). There was no statistically significant difference in comfort between the two groups after the 7th treatment(P>0.001). There was no statistically significant difference in lumbar range of motion between the two groups before and after treatment(P>0.05);compared with before treatment, the lumbar range of motion of both groups after treatment was significantly improved, with statistically significant differences (P<0.001). CONCLUSION Automatic pressure-controlled pressure cupping can effectively relieve symptoms in patients with lumbar disc herniation, with excellent safety.
Humans ; Female ; Male ; Intervertebral Disc Displacement/physiopathology* ; Middle Aged ; Adult ; Lumbar Vertebrae/physiopathology* ; Cupping Therapy/methods* ; Pressure ; Aged ; Treatment Outcome