Dynamical encircling of multiple exceptional points in anti-PT symmetry system.

Exceptional points (EPs) in non-Hermitian systems have turned out to be at the origin of many intriguing effects with no counterparts in Hermitian cases. A typically interesting behavior is the chiral mode switching by dynamically winding the EP. Most encircling protocols focus on the two-state or parity-time (PT) symmetry systems. Here, we propose and investigate the dynamical encircling of multiple EPs in an anti-PT-symmetric system, which is constructed based on a one-dimensional lattice with staggered lossy modulation. We reveal that dynamically encircling the multiple EPs results in the chiral dynamics via multiple non-Hermiticity-induced nonadiabatic transitions, where the output state is always on the lowest-loss energy sheet. Compared with the PT-symmetric systems that require complicated variation of the gain/loss rate or on-site potentials, our system only requires modulations of the couplings which can be readily realized in various experimental platforms. Our scheme provides a route to study non-Hermitian physics by engineering the EPs and implement novel photonic devices with unconventional functions.

The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma.

Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptome, proteome and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with NL tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics through interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo.

Hypoxia differently regulates the proportion of ALDHhi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/ß-catenin pathway.

BACKGROUND: Cancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self-renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non-small cell lung cancer (NSCLC) remains unclear. METHODS: The proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit ß-catenin while pcDNA3-ß-catenin (S33Y) plasmid enhanced the expression of ß-catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real-time PCR. RESULTS: We found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, ß-catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by ß-catenin inhibitor or siRNA knockdown, whereas increased after ß-catenin overexpression. Furthermore, hypoxia treatment suppressed E-cadherin expression in H520 cells and enhanced N-cadherin and ß-catenin expression, while this effect was completely opposite in A549 cells. CONCLUSION: The hypoxia-EMT-ß-catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.

Observation of continuum Landau modes in non-Hermitian electric circuits.

Continuum Landau modes - predicted recently in a non-Hermitian Dirac Hamiltonian under a uniform magnetic field - are continuous bound states with no counterparts in Hermitian systems. However, they have still not been confirmed in experiments. Here, we report an experimental observation of continuum Landau modes in non-Hermitian electric circuits, in which the non-Hermitian Dirac Hamiltonian is simulated by non-reciprocal hoppings and the pseudomagnetic field is introduced by inhomogeneous complex on-site potentials. Through measuring the admittance spectrum and the eigenstates, we successfully verify key features of continuum Landau modes. Particularly, we observe the exotic voltage response acting as a rainbow trap or wave funnel through full-field excitation. This response originates from the linear relationship between the modes' center position and complex eigenvalues. Our work builds a bridge between non-Hermiticity and magnetic fields, and thus opens an avenue to explore exotic non-Hermitian physics.

Recent trends in treatment strategies for Alzheimer's disease and the challenges: A topical advancement.

Alzheimer's Disease (AD) is an irreversible and progressive neurological disease that has affected at least 50 million people around the globe. Considering the severity of the disease and the continuous increase in the number of patients, the development of new effective drugs or intervention strategies for AD has become urgent. AD is caused by a combination of genetic, environmental, and lifestyle factors, but its exact cause has not yet been clarified. Given the current challenges being faced in the clinical treatment of AD, such as complex AD pathological network and insufficient early diagnosis, herein, we have focused on the three core pathological features of AD, including amyloid-ß (Aß) aggregation, tau phosphorylation and tangles, and activation of inflammatory factors. In this review, we have briefly underscored the primary evidence supporting each pathology and discuss AD pathological network among Aß, tau, and inflammation. We have also comprehensively summarized the most instructive drugs and their treatment strategies against Aß, tau, or neuroinflammation used in basic research and clinical trials. Finally, we have discussed and outlined the pros and cons of each pathological approach and looked forward to potential personalized diagnosis and treatment strategies that are beneficial to AD patients.

Schaumann bodies deposited along myenteric plexus of the muscularis propria is a unique histopathological feature of Crohn's disease.

AIMS: Schaumann bodies were first identified in sarcoidosis by Dr Schaumann in 1941. They were also detected in 10% of Crohn's disease (CD) cases in a study involving patients with surgically resected CD. However, the characteristics and significance of Schaumann bodies in CD have yet to be fully elucidated. This study aimed to determine the pathological features and diagnostic significance of Schaumann bodies in various bowel diseases. METHODS: Overall, 278 bowel specimens were collected from patients with CD, intestinal tuberculosis, ulcerative colitis, intestinal schistosomiasis, diverticulosis and idiopathic mesenteric vasculopathy. The frequency, pathology and clinical features of patients with Schaumann bodies were studied. RESULTS: Schaumann bodies were present exclusively in CD (27.0%, 38 of 141) and were not detected in other intestinal diseases within the series. In CD, Schaumann bodies were deposited along the myenteric plexus of the muscularis propria (84.2%, 32 of 38). These bodies were small (diameter: 60.3±32.7 µm) and exhibited a low density in the intestinal wall (1.1±0.4 per low-power field). The majority were located within the cytoplasm of multinucleated giant cells (84.2%, 32 of 38) and were not found within or adjacent to granulomas. Notably, the number of female patients with CD and Schaumann bodies was higher than that of males. CONCLUSION: Schaumann bodies are common in resected CD specimens, and their characteristic deposition pattern may serve as a diagnostic indication for CD.

Efficacy of immune checkpoint inhibitors in non-small cell lung cancer with NTRK family mutations.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients harboring neurotrophin receptor kinase (NTRK) family mutations remains obscure. METHODS: The Zehir cohort from cBioPortal was used to analyze the mutations (MT) frequency of NTRK family in patients with NSCLC, and their correlation with clinical characteristics and patient survival. The influence of NTRK MT on ICIs efficacy was evaluated in ICIs-treated patients from Samstein cohort and further validated by use of data from OAK/POPLAR cohort. RESULTS: In the Zehir cohort, a significant difference was observed in median overall survival (mOS) between patients with NTRK MT and wild-type (WT) (mOS: 18.97 vs. 21.27 months, HR = 1.34, 95%CI 1.00-1.78; log-rank P = 0.047). In Samstein cohort, the mOS of NTRK mutant patients receiving ICIs has improved compared to WT patients (mOS: 21.00 vs. 11.00 months, log-rank P = 0.103). Notably, in subgroup analysis, ICIs significantly prolonged mOS in patients with NTRK3 MT than in WT patients (mOS: not available vs. 11.00 months, HR = 0.36, 95%CI 0.16-0.81; log-rank P = 0.009). Identical mOS between NTRK MT and WT patients receiving ICIs treatment (mOS: 13.24 vs. 13.50 months, log-rank P = 0.775) was observed in OAK/POPLAR cohort. Moreover, a similar programmed death ligand 1 (PD-L1) expression, but higher tumor mutational burden (TMB), blood TMB (bTMB) and enriched anti-tumor immunity were observed in NTRK MT compared to WT (P < 0.05). CONCLUSION: Taking high TMB or bTMB into consideration, patients with NTRK mutant NSCLC could benefit from ICIs treatment.

Exploration of the minimal clinically important difference value of the 3-min simulated pedal motion in patients with chronic obstructive pulmonary disease: A self-controlled prospective clinical trial.

BACKGROUND: To help elderly patients with severe or very severe chronic obstructive pulmonary disease (COPD) with pulmonary rehabilitation, we have developed Zheng's supine rehabilitation exercise (ZSRE). Currently, none of the terminal or critically ill patients with severe exercise limitation can complete the 6-min walking distance (6MWD) and cardiopulmonary exercise testing (CPET). METHODS: In this study, we discuss the definition of the standardized 3-min simulated pedal motion (3MSPM) test and its operational specifications. Also, we evaluate the minimal clinically important difference (MCID) value of the 3MSPM. RESULTS: The results showed that the mMRC score of COPD patients with acute exacerbation of dyspnea was progressively reduced from the second day of respiratory rehabilitation, and the difference between the first and seventh days was statistically significant (p < 0.000, χ2 = 176.664). 6MWD increased progressively, and the difference between 6MWD on day 1-7 was statistically significant (p = 0.024, F = 2.443). The difference between 3MSPM on day 1-7 was also statistically significant (p < 0.000, F = 4.481). Further analysis showed that 6MWD was negatively correlated with mMRC (p < 0.000, OR = -0.524). 3MSPM was positively correlated with 6MWD (p < 0.000, OR = 0.640) but negatively correlated with mMRC (p < 0.000, OR = -0.413). There is a linear regression relationship between 6MWD and 3MSPM, that is, 6MWD = 14.151 + 0.301 * 3MSPM, adjusted R2 = 0.401. CONCLUSION: Based on the regression equation, 3MSPM can predict 6MWD, and it can be used as a simple exercise endurance method to evaluate patients with safety hazards in underground activities or who cannot complete the 6MWD test. The minimum clinically important difference value is increased by 23.

Zeolitic imidazolate framework/aptamer-based fluorescence assay for the facile and high-sensitivity detection of acetamiprid.

Accurate monitoring of trace pesticides in complex matrix remains a challenge in food safety supervision. Herein, we designed a facile zeolitic imidazolate framework (ZIF)-8/aptamer-based assay for the sensitive detection of acetamiprid. ZIF-8 efficiently adsorbs 6-carboxyfluorescein-labeled complementary DNA (cDNA-FAM) via electrostatic interaction, hydrogen bonding and Zn2+ coordination, which contributed to resistance to cDNA-FAM displacement by biological ligands. ZIF-8 serves as an "ion pump" that contains lots of Zn2+ who boosts cDNA-FAM adsorption and triggers the photoinduced electron transfer (PET) effect from FAM to ZIF-8, improving the sensing sensitivity. Acetamiprid could trigger the change in the adsorption state of cDNA-FAM, further tuning the PET effect and causing fluorescence conversion. The fluorescence assay showed a high sensitivity for monitoring acetamiprid with a detection limit of 0.05 ng mL-1 in the apple sample. This ZIF/DNA-based analytical platform provides a powerful tool for facile and low-cost screening of pesticide residues, with promising applications in food safety monitoring.

Relationship between Macrophages and Tissue Microenvironments in Diabetic Kidneys.

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Increasing evidence has suggested that inflammation is a key microenvironment involved in the development and progression of DN. Studies have confirmed that macrophage accumulation is closely related to the progression to human DN. Macrophage phenotype is highly regulated by the surrounding microenvironment in the diabetic kidneys. M1 and M2 macrophages represent distinct and sometimes coexisting functional phenotypes of the same population, with their roles implicated in pathological changes, such as in inflammation and fibrosis associated with the stage of DN. Recent findings from single-cell RNA sequencing of macrophages in DN further confirmed the heterogeneity and plasticity of the macrophages. In addition, intrinsic renal cells interact with macrophages directly or through changes in the tissue microenvironment. Macrophage depletion, modification of its polarization, and autophagy could be potential new therapies for DN.

Evaluation of safety and efficacy of inhaled ambroxol in hospitalized adult patients with mucopurulent sputum and expectoration difficulty.

Background: Ambroxol is a widely used mucoactive drug in sputum clearance of respiratory diseases taken orally and by injection. However, there is a paucity of evidence for inhaled ambroxol in sputum clearance. Methods: This study performed a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial at 19 centers in China. Hospitalized adult patients with mucopurulent sputum and expectoration difficulty were recruited. Patients were randomized by 1:1 to receive inhalation of either ambroxol hydrochloride solution 3 mL (22.5 mg) + 0.9% sodium chloride 3 mL or 0.9% sodium chloride 6 mL twice daily for 5 days, with an interval of more than 6 h. The primary efficacy endpoint was the absolute change in the sputum property score after treatment compared to the baseline in the intention-to-treat population. Results: Between 10 April 2018 and 23 November 2020, 316 patients were recruited and assessed for eligibility, of whom 138 who received inhaled ambroxol and 134 who received a placebo were included. Patients who received inhaled ambroxol had a significantly greater decrease in the sputum property score compared with patients who received inhalation of placebo (difference: -0.29; 95% CI: -0.53 to -0.05; p = 0.0215). Compared with the placebo, inhaled ambroxol also significantly reduced more expectoration volume in 24 h (difference: -0.18; 95% CI: -0.34 to -0.03; p = 0.0166). There was no significant difference in the proportion of adverse events between the two groups, and no deaths were reported. Discussion: In hospitalized adult patients with mucopurulent sputum and expectoration difficulty, inhaled ambroxol was safe and effective for sputum clearance compared with a placebo. Clinical trial registration: [https://www.chictr.org.cn/showproj.html?proj=184677], Chinese Clinical Trial Registry [ChiCTR2200066348].

Association of genetic polymorphisms in the C19orf66 gene and biochemical indices of HBV infected individuals in Yunnan.

Introduction: Hepatitis B virus (HBV) infection causes serious liver diseases and is a healthy problem worldwide. Although vaccines are administered to infants after birth, there is no effective medicine for HBV infection. The interferon-stimulated genes (ISGs) are important factors in the host that can aid in restraining the virus, and the C19orf66 gene has a wide-antiviral spectrum. Methods: In this study, three SNPs in the C19orf66 gene were sequenced and genotyped, and their potential function were predicted and further verified by dual-luciferase reporter assay. Results: Although no significant difference of genotype and allele frequency was observed between HBV patients and the controls, the genotype and allele frequency showed significant difference between HBV patients with HBsAg-positive and HBV patients with HBsAg-negative or controls. Genotype AA (P= 0.009) and AT (P= 0.019) of rs77076061 showed higher and lower frequency in HBV patients with HBsAg-positive than in patients with HBsAg-negative, respectively. Genotype AG of rs1979262 played a risk role in HBV patients with HBsAg-positive (13.22%) than in patients with HBsAg-negative (7.53%, P= 0.036) or controls (8.48%, P= 0.033). The frequency of allele A of rs1979262 was higher in patients with HBsAg-positive (6.61%) than in patients with HBsAg-negative (3.77%, P= 0.042), while it was the opposite for the allele G. Moreover, the associations between genotypes of SNPs in the C19orf66 gene and the ALT, AST, and DBIL level were also identified. The functional assay suggested that the SNPs might influence the C19orf66 expression by changing the connection of transcriptional factors. Conclusion: In summary, the association between genetic polymorphisms in the C19orf66 gene and HBV infection/biochemical indices of patients was firstly identified in Yunnan Province.

Curcumin protects against doxorubicin induced oxidative stress by regulating the Keap1-Nrf2-ARE and autophagy signaling pathways.

BACKGROUND: Doxorubicin (DOX)-induced neurotoxicity is widely reported in previous studies. Oxidative stress has been validated as a critical event involved in DOX-induced neurotoxicity. As a selective autophagy adaptor protein, p62 is reported to regulate Keap1-Nrf2-ARE antioxidant pathway in response to oxidative stress. Curcumin (CUR) relieves depressive-like state through the mitigation of oxidative stress and the activation of Nrf2-ARE signaling pathway. However, the exact mechanism of CUR in alleviating DOX-induced neurotoxicity is still unknown. MATERIALS AND METHODS: The rats were randomly divided into three groups: control group, DOX group, and DOX + CUR group. At the end of 3 weeks, the behavior tests as sucrose preference test (SPT), forced swimming test (FST), and novelty-suppressed feeding test (NSFT) were performed to assess anxiety- and depression-like behaviors. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis. RESULTS: It was observed that the administration of CUR could effectively reverse DOX-induced depressive-like behaviors. The exposure of DOX activated autophagy and increased oxidative stress levels, and the administration of CUR could significantly inhibit DOX-induced autophagy and suppress oxidative stress. More importantly, we also found that Keap1-Nrf2-ARE signaling pathway was involved in DOX-induced neurotoxicity and oxidative stress regulated by autophagy. CONCLUSION: Our study demonstrated that CUR could effectively reverse DOX-induced neurotoxicity through suppressing autophagy and mitigating oxidative stress and endoplasmic reticulum (ER) stress.

Application of EEG in migraine.

Migraine is a common disease of the nervous system that seriously affects the quality of life of patients and constitutes a growing global health crisis. However, many limitations and challenges exist in migraine research, including the unclear etiology and the lack of specific biomarkers for diagnosis and treatment. Electroencephalography (EEG) is a neurophysiological technique for measuring brain activity. With the updating of data processing and analysis methods in recent years, EEG offers the possibility to explore altered brain functional patterns and brain network characteristics of migraines in depth. In this paper, we provide an overview of the methodology that can be applied to EEG data processing and analysis and a narrative review of EEG-based migraine-related research. To better understand the neural changes of migraine or to provide a new idea for the clinical diagnosis and treatment of migraine in the future, we discussed the study of EEG and evoked potential in migraine, compared the relevant research methods, and put forwards suggestions for future migraine EEG studies.

Gold nanoclusters-manganese dioxide composite-based fluorescence immunoassay for sensitive monitoring of fenitrothion degradation in Chinese cabbage.

Understanding the residues and degradation of organophosphorus pesticides (OPs) in crops has attracted increasing attention. Herein, we designed a sensitive fluorescence immunoassay (FIA) by employing nanobody-linked alkaline phosphatase (Nb-ALP) and gold nanoclusters anchored manganese dioxide (AuNCs-MnO2) composite. In immunoassay protocol, Nb-ALP is used to competitively recognize the coating antigen and pesticide. After competitive immunoreaction, alkaline phosphatase catalyzes l-ascorbic acid-2-phosphate to produce ascorbic acid that can trigger the decomposition of the AuNCs-MnO2 composite, regulating the fluorescence response. As a proof-of-concept, fenitrothion (FNT) is chosen as the target analyte. As a result, the developed FIA exhibits high detection sensitivity (IC10 = 5.78 pg/mL), which is about 56-times higher than that of the conventional enzyme-linked immunosorbent assay. The developed FIA has been successfully applied for precisely monitoring the degradation of FNT in Chinese cabbage with excellent anti-interference ability and reproducibility, paving the way for the determination of pesticide residues in real food samples.

Molecular mechanism of naringenin regulation on flavonoid biosynthesis to improve the salt tolerance in pigeon pea (Cajanus cajan (Linn.) Millsp.).

Flavonoids are important secondary metabolites in the plant growth and development process. As a medicinal plant, pigeon pea is rich in secondary metabolites. As a flavonoid, there are few studies on the regulation mechanism of naringenin in plant stress resistance. In our study, we found that naringenin can increase the pigeon pea's ability to tolerate salt and influence the changes that occur in flavonoids including naringenin, genistein and biochanin A. We analyzed the transcriptome data after 1 mM naringenin treatment, and identified a total of 13083 differentially expressed genes. By analyzing the metabolic pathways of these differentially expressed genes, we found that these differentially expressed genes were enriched in the metabolic pathways of phenylpropanoid biosynthesis, starch and sucrose metabolism and so on. We focused on the analysis of flavonoid biosynthesis related pathways. Among them, the expression levels of enzyme genes CcIFS, CcCHI and CcCHS in the flavonoid biosynthesis pathway had considerably higher expression levels. By counting the number of transcription factors and the binding sites on the promoter of the enzyme gene, we screened the transcription factors CcMYB62 and CcbHLH35 related to flavonoid metabolism. Among them, CcMYB62 has a higher expression level than the others. The hairy root transgene showed that CcMYB62 could induce the upregulation of CcCHI, and promote the accumulation of naringenin, genistein and biochanin A. Our study revealed the molecular mechanism of naringenin regulating flavonoid biosynthesis under salt stress in pigeon pea, and provided an idea for the role of flavonoids in plant resistance to abiotic stresses.

Altered brain activities in mesocorticolimbic pathway in primary dysmenorrhea patients of long-term menstrual pain.

Background: Patients with primary dysmenorrhea (PDM) often present with abnormalities other than dysmenorrhea including co-occurrence with other chronic pain conditions and central sensitization. Changes in brain activity in PDM have been demonstrated; however, the results are not consistent. Herein, this study probed into altered intraregional and interregional brain activity in patients with PDM and expounded more findings. Methods: A total of 33 patients with PDM and 36 healthy controls (HCs) were recruited and underwent a resting-state functional magnetic resonance imaging scan. Regional homogeneity (ReHo) and mean amplitude of low-frequency fluctuation (mALFF) analysis were applied to compare the difference in intraregional brain activity between the two groups, and the regions with ReHo and mALFF group differences were used as seeds for functional connectivity (FC) analysis to explore the difference of interregional activity. Pearson's correlation analysis was conducted between rs-fMRI data and clinical symptoms in patients with PDM. Results: Compared with HCs, patients with PDM showed altered intraregional activity in a series of brain regions, including the hippocampus, the temporal pole superior temporal gyrus, the nucleus accumbens, the pregenual anterior cingulate cortex, the cerebellum_8, the middle temporal gyrus, the inferior temporal gyrus, the rolandic operculum, the postcentral gyrus and the middle frontal gyrus (MFG), and altered interregional FC mainly between regions of the mesocorticolimbic pathway and regions associated with sensation and movement. The anxiety symptoms are correlated with the intraregional activity of the right temporal pole superior temporal gyrus and FC between MFG and superior frontal gyrus. Conclusion: Our study showed a more comprehensive method to explore changes in brain activity in PDM. We found that the mesocorticolimbic pathway might play a key role in the chronic transformation of pain in PDM. We, therefore, speculate that the modulation of the mesocorticolimbic pathway may be a potential novel therapeutic mechanism for PDM.

The safety profile of EGFR/ALK-TKIs administered immediately before or after ICIs in advanced NSCLC.

BACKGROUND: As more therapeutic targets are being discovered in advanced non-small cell lung cancer (NSCLC), it is pivotal for clinicians to correctly sequence immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for delivery of safe and effective treatment. Our present study aimed to assess the safety profile of sequential treatment of TKIs and ICIs in advanced NSCLC. METHODS: We retrospectively analyzed the data of 64 patients who underwent sequential treatment of EGFR/ALK-TKIs and ICIs, including all the EGFR/ALK-TKIs and ICIs approved by National Medical Products Administration (NMPA) in China. RESULTS: The decrease in hemoglobin was the most common adverse event (54.5 % and 44.4 %) for all patients. For TKIs post-treatment with ICIs group, the incidence rate of decrease in white blood cells was 32.7 %. Liver toxicity was also common for this sequential therapy: treatment-related elevation in ALT (30.9 %) and AST (25.5 %). In addition, grade 3 or higher skin toxicity occurred in 2 patients, and grade 3 or higher neuritis was observed in 1 patient. Interstitial pneumonia was also observed in 1 patient. For patients within the group of TKIs pre-treatment with ICIs, the most common adverse event was hepatic toxicity, the elevation in ALT and AST was 33.3 % and 22.2 % respectively. It was worth noting that the incidence rate of grade 3 or higher elevation in ALT and AST was 22.2 %. Other adverse events such as blood toxicity, skin rash, and diarrhea were also observed in this sequential treatment, but most of which was slight. CONCLUSION: Although the adverse event did not significantly increase in the sequential treatment pattern of our study, careful consideration should be given to the possibility of an increased risk of some adverse event when TKIs were pre/post-treated with ICIs.