Effects of electroacupuncture on mitophagy mediated by SIRT3/PINK1/Parkin pathway in Parkinson's disease mice. / ç”µé’ˆå¯¹å¸•é‡‘æ£®ç— å°é¼ SIRT3/PINK1/Parkin通路介导的线粒体自噬的影响.

OBJECTIVES: To observe the effects of electroacupuncture (EA) at "Fengfu"(GV16), "Taichong"(LR3), and "Zusanli"(ST36) on mitophagy mediated by silencing regulatory protein 3 (SIRT3)/ PTEN induced putative kinase 1 (PINK1)/PARK2 gene coding protein (Parkin) in the midbrain substantia nigra of Parkinson's disease (PD) mice, and to explore the potential mechanisms of EA in treating PD. METHODS: C57BL/6 mice were randomly divided into the control, model, EA, and sham EA groups, with 12 mice in each group. The PD mouse model was established by intraperitoneal injection of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). The EA group received EA stimulation at GV16, LR3 and ST36, while the sham EA group received shallow needling 1 mm away from the above acupoints without electrical stimulation. The motor ability of mice in each group was evaluated using an open field experiment. Immunohistochemistry was used to detect the expression of tyrosine hydroxylase (TH) and α-synuclein (α-syn) in the substantia nigra of mice. The ultrastructure of neurons in substantia nigra was observed by transmission electron microscope (TEM). Immunofluorescence was used to detect the expression of the autophagy marker autophagy-associated protein light chain 3 (LC3). The expression levels of TH, α-syn, SIRT3, PINK1, Parkin, P62, Beclin-1, LC3Ⅱ mRNA and protein were detected by PCR and Western blot. RESULTS: Compared with the control group, mice in the model group showed a decrease in the total exercise distance, time, movement speed and times of crossing central region (P<0.01)；the positive expressions of TH and LC3 were decreased (P<0.01), while the positive expression of α-syn increased (P<0.01), accompanied by mitochondrial swelling, mitochondrial cristae fragmentation and decrease, and decreased lysosome count；the expression levels of TH, SIRT3, PINK1, Parkin, Beclin-1, and LC3Ⅱ mRNA and protein in the midbrain substantia nigra were decreased (P<0.01), while the expression levels of α-syn and P62 mRNA and protein were increased (P<0.01, P<0.05). Compared with the model group, the mice in EA group showed a significant increase in the total exercise distance, time, movement speed and times of crossing central region (P<0.01, P<0.05)；the positive expressions of TH and LC3 were increased (P<0.01, P<0.05), while the positive expression of α-syn was decreased (P<0.01), accompanied by an increase in mitochondrial count, appearance of autophagic va-cuoles, and a decrease in swelling, the expression levels of TH, SIRT3, PINK1, Parkin, Beclin-1 and LC3Ⅱ mRNA and protein in the midbrain substantia nigra were increased (P<0.01, P<0.05), while the mRNA and protein expression levels of α-syn and P62 were decreased (P<0.01)；the sham EA group showed an increase in the total exercise distance and time(P<0.05), with an increase in the positive expression of TH (P<0.05) and a decrease in the positive expression of α-syn (P<0.05)；some mitochondria exhibited swelling, and no autophagic vacuoles were observed；the protein expression levels of TH, SIRT3, Parkin and LC3Ⅱ were increased (P<0.01, P<0.05), and the expression levels of P62 mRNA, α-syn mRNA and protein were decreased (P<0.01, P<0.05), and LC3Ⅱ mRNA expression was increased (P<0.05). In comparison to the sham EA group, the EA group showed an extension in the total exercise time (P<0.01), the positive expression and mRNA expression levels of α-syn were decreased (P<0.01, P<0.05), while the expression levels of TH, SIRT3, PINK1, Parkin mRNA and SIRT3 protein were increased (P<0.05). CONCLUSIONS: EA at GV16, LR3, and ST36 can exert neuroprotective function and improve the motor ability of PD mice by activating the SIRT3/PINK1/Parkin pathway to enhance the expression of TH and reduce α-syn aggregation in the substantia nigra of PD mice.

Influence of PD-L1 expression on the efficacy of EGFR-TKIs in EGFR-mutant non-small cell lung cancer.

BACKGROUND: Evidence on the influence of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients is at variance. METHODS: A single-center retrospective study was conducted to evaluate the influence of PD-L1 expression on the efficacy of EGFR-TKIs for NSCLC patients with EGFR mutation. Clinical information was retrieved from electronic medical records. The patients were divided into three subgroups according to PD-L1 expression level: PD-L1 < 1% (negative), PD-L1 1%-49% and PD-L1 ≥ 50%. The clinicopathological features, overall response rate (ORR), progression-free survival (PFS) and comutation information were collected and compared between the three subgroups. RESULTS: A total of 117 patients were included. For PD-L1 < 1%, PD-L1 1%-49% and PD-L1 ≥ 50% group, there were 39 (33.3%), 51 (43.5%) and 27 (23.0%) patients respectively, and the ORR was 43.2%, 64.0%, and 51.9%, respectively (p = 0.162), and the median progression-free survival (mPFS) was 22.0 months (95% CI: 14.0-29.9 months), 15.4 months (95% CI: 8.9-21.8 months) and 13.0 months (95% CI: 10.6-15.3 months), respectively (log-rank, p = 0.01). The mPFS was negatively correlated with PD-L1 expression level (r = -0.264, p = 0.041) and PD-L1 expression was an independent risk factor for worse PFS of EGFR-TKIs in multivariate Cox regression. Patients with concurrent TP53 mutation had shorter PFS (p = 0.039) and the patients harboring both mutant TP53 and positive PD-L1 had the shortest PFS (p = 0.006). CONCLUSIONS: The efficacy of EGFR-TKIs was influenced by the baseline PD-L1 expression. Higher PD-L1 expression was associated with shorter PFS. The combined indicators of TP53 and PD-L1 identified subgroups showing divergent benefits from EGFR-TKIs.

SmDXS5, acting as a molecular valve, plays a key regulatory role in the primary and secondary metabolism of tanshinones in Salvia miltiorrhiza.

Red sage, the dry root and rhizome of the herbaceous plant Salvia miltiorrhiza Bunge, is widely used for treating various diseases. The low content of tanshinones (terpenoids) has always restricted development of the S. miltiorrhiza industry. Here, we found that SmDXS5, a rate-limiting enzyme-coding gene located at the intersection of primary and secondary metabolism, can effectively change the transcription level and secondary metabolome profile of hairy roots of S. miltiorrhiza, and significantly increase the content of tanshinones. Agrobacterium rhizogenes was used to infuse S. miltiorrhiza explants, and hairy roots of S. miltiorrhiza expressing the SmDXS5 gene were obtained successfully. We identified 39 differentially accumulated metabolites (DAMs) by metabolomics based on ultra-high performance liquid chromatography quadrupole exactive mass spectrometry and multivariate statistics. These DAMs might be key metabolites of SmDXS5 gene regulation. RNA sequencing was used to compare gene expression between the hairy roots of the SmDXS5 overexpressing group and the blank control (BC) group. Compared with the BC group, 18,646 differentially expressed genes were obtained: 8994 were upregulated and 9,652 downregulated. The combined transcriptome and metabolome analyses revealed that the mevalonate and methylerythritol phosphate pathways and synthase gene expression levels in the SmDXS5 overexpressing group were upregulated significantly, and the accumulation of tanshinone components was increased significantly, which promoted the process of glycolysis and promoted the transformation of carbohydrates to secondary metabolism. Moreover, the expression of SmPAL, the first rate-limiting enzyme gene of the phenylpropane pathway, decreased, reducing the accumulation of phenolic acid, another secondary metabolite. Therefore, SmDXS5 can be defined as a 'valve' gene, mainly responsible for regulating the distribution of primary and secondary metabolic flow of tanshinones in S. miltiorrhiza, and for other secondary metabolic pathways. The discovery of SmDXS5 and its molecular valve function in regulating primary and secondary metabolism will provide a basis for the industrial production of tanshinone components, and cultivation of high quality S. miltiorrhiza.

Efficacy and safety of concomitant immunotherapy and denosumab in patients with advanced non-small cell lung cancer carrying bone metastases: A retrospective chart review.

Background: Synergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC). Methods: Consecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups. Results: A total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group (p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups (p = 0.814), but patients with single-site bone metastasis (p = 0.319) and high PD-L1 expression (p = 0.100) appeared to benefit more, though no significant differences were observed. Conclusions: Denosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases.

Bu Shen Yi Sui Capsule Promotes Myelin Repair by Modulating the Transformation of A1/A2 Reactive Astrocytes In Vivo and In Vitro.

Background/Aims. Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS) primarily hallmarked by neuroinflammation and demyelination. The activation of astrocytes exerts double-edged sword effects, which perform an integral function in demyelination and remyelination. In this research, we examined the therapeutic effects of the Bu Shen Yi Sui capsule (BSYS), a traditional Chinese medicine prescription, in a cuprizone- (CPZ-) triggered demyelination model of MS (CPZ mice). This research intended to evaluate if BSYS might promote remyelination by shifting A1 astrocytes to A2 astrocytes. Methods. The effects of BSYS on astrocyte polarization and the potential mechanisms were explored in vitro and in vivo utilizing real-time quantitative reverse transcription PCR, immunofluorescence, and Western blotting. Histopathology, expression of inflammatory cytokines (IL-10, IL-1ß, and IL-6), growth factors (TGF-ß, BDNF), and motor coordination were assessed to verify the effects of BSYS (3.02 g/kg/d) on CPZ mice. In vitro, A1 astrocytes were induced by TNF-α (30 ng/mL), IL-1α (3 ng/mL), and C1q (400 ng/mL), following which the effect of BSYS-containing serum (concentration of 15%) on the transformation of A1/A2 reactive astrocytes was also evaluated. Results and Conclusions. BSYS treatment improved motor function in CPZ mice as assessed by rotarod tests. Intragastric administration of BSYS considerably lowered the proportion of A1 astrocytes, but the number of A2 astrocytes, MOG+, PLP+, CNPase+, and MBP+ cells was upregulated. Meanwhile, dysregulation of glutathione peroxidase, malondialdehyde, and superoxide dismutase was reversed in CPZ mice after treatment with BSYS. In addition, the lesion area and expression of proinflammatory cytokines were decreased and neuronal protection factors and anti-inflammatory cytokines were increased. In vitro, BSYS-containing serum suppressed the A1 astrocytic markers' expression and elevated the expression levels of A2 markers in primary astrocytes triggered by C1q, TNF-α, and IL-1α. Importantly, the miR-155/SOCS1 signaling pathway was involved in the modulation of the A1/A2 phenotype shift. Overall, this study demonstrated that BSYS has neuroprotective effects in myelin repair by modulating astrocyte polarization via the miR-155/SOCS1 pathway.

Study on the Anti-demyelination Mechanism of Bu-Shen-Yi-Sui Capsule in the Central Nervous System Based on Network Pharmacology and Experimental Verification.

Methods: The potential active ingredients and corresponding potential targets of BSYS Capsule were obtained from the TCMSP, BATMAN-TCM, Swiss Target Prediction platform, and literature research. Disease targets of CNSD were explored through the GeneCards and the DisGeNET databases. The matching targets of BSYS in CNSD were identified from a Venn diagram. The protein-protein interaction (PPI) network was constructed using bioinformatics methods. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the mechanisms of BSYS. Furthermore, the neuroprotective effects of BSYS were evaluated using a cell model of hydrogen peroxide- (H2O2-) induced cell death in OLN-93 cells. Results: A total of 59 potential bioactive components of BSYS Capsule and 227 intersection targets were obtained. Topological analysis showed that AKT had the highest connectivity degrees in the PPI network. Enrichment analysis revealed that the targets of BSYS in the treatment of CNSD were the PI3K-Akt and MAPK signaling pathway, among other pathways. GO analysis results showed that the targets were associated with various biological processes, including apoptosis, reactive oxygen species metabolic process, and response to oxidative stress, among others. The experimental results demonstrated that BSYS drug-containing serum alleviated the H2O2-induced increase in LDH, MDA, and ROS levels and reversed the decrease in SOD and mitochondrial membrane potential induced by H2O2. BSYS treatment also decreased the number of TUNEL (+) cells, downregulated Bcl-2 expression, and upregulated Bax and c-caspase-3 expression by promoting Akt phosphorylation. Conclusion: BSYS Capsule alleviated H2O2-induced OLN-93 cell injury by increasing Akt phosphorylation to suppress oxidative stress and cell apoptosis. Therefore, BSYS can be potentially used for CNSD treatment. However, the results of this study are only derived from in vitro experiments, lacking the validation of in vivo animal models, which is a limitation of our study. We will further verify the underlying mechanisms of BSYS in animal experiments in the future.

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China.

Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited. Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1-2 months. Adverse events were assessed by CTCAE 5.0. Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1-14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4-5 adverse events (AEs) occurred, but all patients had grade 1-2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs. Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a real-world study.

Background: Dacomitinib is a first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on NSCLC with complex EGFR mutations is limited. Methods: Patients harboring complex (common mutations co-existing with uncommon mutations), or common (comparison cohort) EGFR mutations, who were treated with dacomitinib, were retrospectively evaluated in the Chinese National Cancer Center and the China PLA hospital between August 2019 and August 2021. Results: In total, 72 patients with NSCLC harboring complex (C+U group, n=18) or common (C group, n=54) EGFR mutations and being treated with dacomitinib were enrolled. In the C+U group, 16 cases (88.9%) harbored L858R mutations co-existing with uncommon mutations located from exon 18 to exon 25 of EGFR (mostly E709X), and two cases harbored exon 19 deletion co-existing with G724S or K754E. Among the 15 evaluable patients, the objective response rate (ORR) was 40% (6/15), and the disease control rate (DCR) was 73.3% (11/15). The median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI), 4.4-10.6 months]. Except for the application line of dacomitinib (P=0.039), no significant statistical differences were found in other characteristics and adverse events between the two groups. The Kaplan-Meier method revealed no significant differences in PFS (P=0.889) and overall survival (OS) (P=0.703). However, the stratified analysis found worse PFS in the C+U group than that observed in the C group when receiving 1st and ≥3rd line dacomitinib treatment, while its OS was worse than that of group C when receiving ≥3rd line treatment. Furthermore, in a multivariate analysis, complex mutation status was an independent prognostic factor for OS (P=0.038) in the entire cohort. Conclusions: This study indicated a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Further studies and data are needed to confirm this conclusion.

Bu Shen Yi Sui Capsules Promote Remyelination by Regulating MicroRNA-219 and MicroRNA-338 in Exosomes to Promote Oligodendrocyte Precursor Cell Differentiation.

Remyelination is a refractory feature of demyelinating diseases such as multiple sclerosis (MS). Studies have shown that promoting oligodendrocyte precursor cell (OPC) differentiation, which cannot be achieved by currently available therapeutic agents, is the key to enhancing remyelination. Bu Shen Yi Sui capsule (BSYSC) is a traditional Chinese herbal medicine over many years of clinical practice. We have found that BSYSC can effectively treat MS. In this study, the effects of BSYSC in promoting OPCs differentiation and remyelination were assessed using an experimental autoimmune encephalomyelitis (EAE) model in vivo and cultured OPCs in vitro. The results showed that BSYSC reduced clinical function scores and increased neuroprotection. The expression of platelet-derived growth factor receptor α (PDGFR-α) was decreased and the level of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) was increased in the brains and spinal cords of mice as well as in OPCs after treatment with BSYSC. We further found that BSYSC elevated the expression of miR-219 or miR-338 in the serum exosomes of mice with EAE, thereby suppressing the expression of Sox6, Lingo1, and Hes5, which negatively regulate OPCs differentiation. Therefore, serum exosomes of BSYSC-treated mice (exos-BSYSC) were extracted and administered to OPCs in which miR-219 or miR-338 expression was knocked down by adenovirus, and the results showed that Sox6, Lingo1, and Hes5 expression was downregulated, MBP expression was upregulated, OPCs differentiation was increased, and the ability of OPCs to wrap around neuronal axons was improved. In conclusion, BSYSC may exert clinically relevant effects by regulating microRNA (miR) levels in exosomes and thus promoting the differentiation and maturation of OPCs.

Survival and pretreatment prognostic factors for extensive-stage small cell lung cancer: A comprehensive analysis of 358 patients.

BACKGROUND: Extensive-stage small cell lung cancer (ES-SCLC) is deemed as a fatal malignancy with a poor prognosis. Although immunotherapy has gradually played an important role in the treatment of ES-SCLC since 2018, ES-SCLC treatment data and patient outcome before 2018, when chemotherapy served as a fundamental therapeutic strategy, is still meaningful as a summary of the situation regarding previous medical treatment and is a baseline for comparative data. In addition, the prognostic factors of ES-SCLC have failed to reach a consensus until now. Therefore, this study aimed to evaluate survival and identify the prognostic factors in an ES-SCLC population. METHODS: We retrospectively collected the detailed medical records of 358 patients with ES-SCLC from January 1, 2011 to December 31, 2018 in a Chinese top-level cancer hospital. The prognostic factors were evaluated by Cox univariate and multivariate analysis. RESULTS: The median overall survival (OS) of ES-SCLC patients (N = 358) was 14.0 months, the one- and two-year OS rates were 56.2% and 21.7%, respectively. Moreover, we identified two demographic characters (age ≥ 70, smoking index ≥ 400), one tumor burden factor (bone multimetastasis), two tumor biomarkers (cyfra211, CA125) and two laboratory indexes (decreased Na, PLR < 76) as independent prognostic factors for OS in this patient population. Progression-free survival (PFS) data of 238 patients was obtained for further analysis, and the median PFS was 6.2 months, and six-month and one-year PFS rates were 51.7% and 14.3%, respectively. Elevated cyfra211, decreased Hb and Na were identified as independent prognostic factors for PFS. CONCLUSIONS: This study provides real-world evidence of the survival and prognosis of ES-SCLC patients which will enable better evaluation and clinical decision-making in the future.

Bu Shen Yi Sui Capsule Alleviates Neuroinflammation and Demyelination by Promoting Microglia toward M2 Polarization, Which Correlates with Changes in miR-124 and miR-155 in Experimental Autoimmune Encephalomyelitis.

BACKGROUND: Bu Shen Yi Sui capsule (BSYS) is a traditional Chinese medicine prescription that has shown antineuroinflammatory and neuroprotective effects in treating multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE). Microglia play an important role in neuroinflammation. The M1 phenotype of microglia is involved in the proinflammatory process of the disease, while the M2 phenotype plays an anti-inflammatory role. Promoting the polarization of microglia to M2 in MS/EAE is a promising therapeutic strategy. This study is aimed at exploring the effects of BSYS on microglial polarization in mice with EAE. METHODS: The EAE model was established by the intraperitoneal injection of pertussis toxin and subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG)35-55 in C57BL/6J mice. The mice were treated with BSYS (3.02 g/kg), FTY720 (0.3 mg/kg), or distilled water by intragastric administration. H&E and LFB staining, transmission electron microscopy, qRT-PCR, immunofluorescence, ELISA, fluorescence in situ hybridization, and western blotting were used to detect the histological changes in myelin, microglial M1/M2 polarization markers, and the expression of key genes involved in EAE. Results and Conclusions. BSYS treatment of EAE mice increased the body weight, decreased the clinical score, and reduced demyelination induced by inflammatory infiltration. BSYS also inhibited the mRNA expression of M1 microglial markers while increasing the mRNA level of M2 markers. Additionally, BSYS led to a marked decrease in the ratio of M1 microglia (iNOS+/Iba1+) and an obvious increase in the number of M2 microglia (Arg1+/Iba1+). In the EAE mouse model, miR-124 expression was decreased, and miR-155 expression was increased, while BSYS treatment significantly reversed this effect and modulated the levels of C/EBP α, PU.1, and SOCS1 (target genes of miR-124 and miR-155). Therefore, the neuroprotective effect of BSYS against MS/EAE was related to promoting microglia toward M2 polarization, which may be correlated with changes in miR-124 and miR-155 in vivo.

Changes and Influential Factors of Chemotherapy Usage for Non-Small Cell Lung Cancer Patients in China: A Multicenter 10-Year (2005-2014) Retrospective Study.

BACKGROUND: Chemotherapy has improved the survival of non-small cell lung cancer (NSCLC) patients over the past few decades. However, there have not been any epidemiological studies on chemotherapy for Chinese NSCLC patients. PATIENTS AND METHODS: The patients diagnosed as primary lung cancer between January 1, 2005, and December 31, 2014, in eight hospitals from eight provinces in China were retrospectively reviewed. Demographic and clinical data were extracted from medical history systems. Chi-square test and logistic regression were used to analyze the changes of chemotherapy usage and influential factors. RESULTS: A total of 7184 lung cancer cases were eligible, among which 6481 NSCLC cases were included in this analysis. Among stage I/II patients, the percentages of receiving adjuvant chemotherapy did not change significantly between the earlier (28.5%) and the latter five years (25.7%) (p = 0.1288). Among stage IIIA patients, the percentages of chemotherapy usage did not change significantly between the earlier and the latter five years in neo-adjuvant (7.5% vs 5.6%, p = 0.1478) and adjuvant (23.1% vs 26.8%, p = 0.1129) treatment. The proportions of first-line platinum-based doublets for stage IIIB/IV patients changed significantly over the 10 years (p < 0.0001). Patients from provinces with inferior gross domestic product, with lower medical reimbursement rates and without smoking history were more likely to use the docetaxel/paclitaxel doublets, comparing with the gemcitabine doublets. CONCLUSION: From 2005 to 2014, there was no significant change in the chemotherapy pattern of early NSCLC. Economic factors mainly contributed to the significant changes in the first-line chemotherapy regimen selection for advanced patients.

Depth of Response was Associated with Progression-Free Survival in Patients with Advanced Non-small Cell Lung Cancer treated with EGFR-TKI.

Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate new therapeutic strategies in cancer. However, RECIST fails to assess the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as the maximum percentage change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or exon 19 deletion) treated with EGFR-TKI from August 2014 to July 2017 from two sites were retrospetively collected for analysis. Patients were divided into four groups by DepOR (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS against DepOR and the hazard ratio (HR) was determined through univariable and multivariable cox regression models. Results: In total, 265 patients were included for analysis. The number of patients in Group Q1-Q4 were 91 (34.3%), 73 (27.5%), 65 (24.5%) and 36 (13.6%), respectively. A greater DepOR was significantly associated with a longer PFS (Log-rank P<0.0001). The HRs (95% CI) for PFS comparing patients with different DepOR status were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3, and 0.33 (0.22-0.50) for Q4, all compared with patients in Q1. DepOR as a continuous variable was also associated with prolonged PFS (HR, 0.20; 95% CI, 0.13-0.33; P<0.001). Additionally, in the multivariable cox regression model, abnormal LDH, brain metastasis and male were found to be associated with worse PFS outcomes (P<0.05). Conclusion: A greater DepOR is significantly associated with PFS benefit in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to evaluate the response of targeted therapy.

Comparative review of drug-drug interactions with epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

The development of small-molecule tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) has revolutionized the management of non-small-cell lung cancer (NSCLC). Because these drugs are commonly used in combination with other types of medication, the risk of clinically significant drug-drug interactions (DDIs) is an important consideration, especially for patients using multiple drugs for coexisting medical conditions. Clinicians need to be aware of the potential for clinically important DDIs when considering therapeutic options for individual patients. In this article, we describe the main mechanisms underlying DDIs with the EGFR-TKIs that are currently approved for the treatment of NSCLC, and, specifically, the potential for interactions mediated via effects on gastrointestinal pH, cytochrome P450-dependent metabolism, uridine diphosphate-glucuronosyltransferase, and transporter proteins. We review evidence of such DDIs with the currently approved EGFR-TKIs (gefitinib, erlotinib, afatinib, osimertinib, and icotinib) and discuss several information sources that are available online to aid clinical decision-making. We conclude by summarizing the most clinically relevant DDIs with these EFGR-TKIs and provide recommendations for managing, minimizing, or avoiding DDIs with the different agents.

Performance of common imaging techniques vs serum biomarkers in assessing fibrosis in patients with chronic hepatitis B: A systematic review and meta-analysis.

BACKGROUND: Noninvasive biomarkers have been developed to predict hepatitis B virus (HBV) related fibrosis owing to the significant limitations of liver biopsy. Both serum biomarkers and imaging techniques have shown promising results and may improve the evaluation of liver fibrosis. However, most of the previous studies focused on the diagnostic effects of various imaging techniques on fibrosis in all chronic liver diseases. AIM: To compare the performance of common imaging methods and serum biomarkers for prediction of significant fibrosis caused only by HBV infection. METHODS: A systematic review was conducted on the records available in PubMed, EMBASE, and the Cochrane Library electronic databases until December 2018. We systematically assessed the effectiveness of two serum biomarkers and three imagine techniques in predicting significant fibrosis solely caused by HBV infection. The serum biomarkers included aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on the 4 factors (FIB-4). The three imaging techniques included acoustic radiation force impulse (ARFI), FibroScan, and magnetic resonance elastography (MRE). Three parameters, the area under the summary receiver operating characteristic curve (AUSROC), the summary diagnostic odds ratio, and the summary sensitivity and specificity, were used to examine the accuracy of all tests for liver fibrosis. RESULTS: Out of 2831 articles evaluated for eligibility, 204 satisfied the predetermined inclusion criteria for this current meta-analysis. Eventually, our final data contained 81 studies. The AUSROCs of serum biomarkers of APRI and FIB-4 were both 0.75. For imaging techniques (ARFI, FibroScan, and MRE), the areas were 0.89, 0.83, and 0.97, respectively. The heterogeneities of ARFI and FibroScan were statistically significant (I 2 > 50%). The publication bias was not observed in any of the serum biomarkers or imaging methods. CONCLUSION: These five methods have attained an acceptable level of diagnostic accuracy. Imaging techniques, MRE in particular, demonstrate significant advantages in accurately predicting HBV-related significant fibrosis, while serum biomarkers are admissible methods.

Circular RNA profiling identified as a biomarker for predicting the efficacy of Gefitinib therapy for non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become important treatment options for non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. However, the detection of EGFR driver mutation is impeded by the lack of adequate tumor tissues, histopathological type, long detection period, and the heterogeneity of a tumor. Therefore, it is necessary to develop a more convenient method to guide the clinical use of EGFR-TKI. Circular RNAs (circRNAs) are characterized as a closed structure with covalently joined ends resistant to exonucleases may be a potential biomarker. In the present study, we aimed to screen circRNAs that may be associated with the efficacy of EGFR-TKI. METHODS: The expression of circRNAs sequenced by circular microarray in plasma samples between gefitinib effective and ineffective groups were compared. RT-qPCR further validated the results in an independent cohort. Kaplan-Meier curves were used to analyze the association between circRNA and progression-free survival (PFS) of NSCLC patients treated with gefitinib. RESULTS: In total, 52 NSCLC patients treated with gefitinib were included for analysis. 1,377 circRNAs were differentially expressed in gefitinib effective and ineffective groups, among which 989 circRNAs were up-regulated, and 388 circRNAs were down-regulated in the effective group. Furthermore, two differentially expressed circRNAs, hsa_circ_0109320 and hsa_circ_0134501, were validated by RT-qPCR in an independent cohort of 38 gefitinib-treated NSCLC patients. Elevated hsa_circ_0109320 was associated with longer PFS in gefitinib-treated NSCLC patients. CONCLUSIONS: Taken together, hsa_circ_0109320 may be a potential biomarker for the efficacy of EGFR-TKI in NSCLC patients. This provides a new molecular typing method for individualized precision treatment.

What are the clinical symptoms and physical signs for non-small cell lung cancer before diagnosis is made? A nation-wide multicenter 10-year retrospective study in China.

BACKGROUND: Most lung cancer patients are diagnosed after the onset of symptoms. However, whether the symptoms of lung cancer were independently associated with the diagnosis of lung cancer is unknown, especially in the Chinese population. METHODS: We conducted a 10 years (2005-2014) nationwide multicenter retrospective clinical epidemiology study of lung cancer patients diagnosed in China. As such, this study focused on nonsmall cell lung cancer (NSCLC). We calculated the odds ratios (ORs) for variables associated with the symptoms and physical signs using multivariate unconditional logistic regressions. RESULTS: A total of 7184 lung cancer patients were surveyed; finally, 6398 NSCLC patients with available information about their symptoms and physical signs were included in this analysis. The most common initial symptom and physical sign was chronic cough (4156, 65.0%), followed by sputum with blood (2110, 33.0%), chest pain (1146, 17.9%), shortness of breath (1090, 17.0%), neck and supraclavicular lymphadenectasis (629, 9.8%), weight loss (529, 8.3%), metastases pain (378, 5.9%), fatigue (307, 4.8%), fever (272, 4.3%), and dyspnea (270, 4.2%). Patients with squamous carcinoma and stage III disease were more likely to present with chronic cough (P < 0.0001) and sputum with blood (P < 0.0001) than patients with other pathological types and clinical stages, respectively. Metastases pain (P < 0.0001) and neck and supraclavicular lymphadenectasis (P = 0.0006) were more likely to occur in patients with nonsquamous carcinoma than in patients with other carcinomas. Additionally, patients with stage IV disease had a higher percentage of chest pain, shortness of breath, dyspnea, weight loss, and fatigue than patients with other stages of disease. In multivariable logistic analyses, compared with patients with adenocarcinoma, patients with squamous carcinoma were more likely to experience symptoms (OR = 2.885, 95% confidence interval [CI] 2.477-3.359) but were less likely to present physical signs (OR = 0.844, 95% CI 0.721-0.989). The odds of having both symptoms and physical signs were higher in patients with late-stage disease than in those with early-stage disease (P < 0.0001). CONCLUSIONS: The symptoms and physical signs of lung cancer were associated with the stage and pathological diagnosis of NSCLC. Patients with squamous carcinoma were more likely to develop symptoms, but not signs, than patients with adenocarcinoma. The more advanced the stage at diagnosis, the more likely that symptoms or physical signs are to develop. Further prospective cohort studies are needed to explore these results.

Apatinib, a novel VEGFR inhibitor plus docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR: a phase I trial.

Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m2 doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.

Clinical characteristics and medical service utilization of lung cancer in China, 2005-2014: Overall design and results from a multicenter retrospective epidemiologic survey.

OBJECTIVES: This study aimed to explore the clinical profile and its trajectory of lung cancer on clinicopathological characteristics and medical service utilization in China. METHODS: Patients diagnosed with primary lung cancer in tertiary hospitals during 2005-14 were selected from seven geographic regions of China. Data on clinical characteristics and medical service utilization was extracted from medical record, and the ten-year trends were explored. RESULTS: A total of 7184 patients were included, the mean age was 58.3 years and the male-to-female-ratio was 2.7. From 2005 to 2014, the proportion of ≥60 year-old patients increased from 41.2% to 56.2% (p < 0.001). The smoking rate decreased from 62.9% to 51.1% (p < 0.001) and the proportion of females increased from 23.5% to 31.9% (p < 0.001). The proportion of advanced stage increased from 41.9% to 47.4% (p < 0.001). Adenocarcinoma's proportion increased from 36.4% to 53.5% (p < 0.001) while that of squamous carcinoma decreased from 45.4% to 34.4% (p < 0.001). The application of chest X-ray dropped from 50.2% to 31.0% (p < 0.001) but that of chest CT increased from 65.8% to 81.4% (p < 0.001). As two main treatment options, chemotherapy (p = 0.290) and surgery (p = 0.497) remained stable. The medical expenditure per patient increased from 40,508 to 66,020 Chinese Yuan (p < 0.001). CONCLUSIONS: The sustaining high smoking exposure, increasing proportion of female patients, advancing clinical stage, shifting of predominant pathology and increasing medical expenditure demonstrate potential challenges and directions on lung cancer prevention and control in China. Despite substantial changes of clinical characteristics, main treatment options remained unchanged, which needs further investigation.

Houttuynia cordata polysaccharide alleviated intestinal injury and modulated intestinal microbiota in H1N1 virus infected mice / 中国天然药物

Houttuynia cordata polysaccharide (HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg(kg(d. H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus, the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1β in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP.