Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and its rearrangements occur in non-small cell lung cancer (NSCLC), resulting in signal dysregulation in kinase domain. As a new generation of potent ALK tyrosine kinase inhibitors (TKIs), Brigatinib was approved in China in March 2022 as a treatment for locally advanced or metastatic NSCLC patients with ALK rearrangement positive. Brigatinib significantly improved the survival, cranial efficacy and quality of life compared to Crizotinib in clinical trials. Brigatinib is generally well tolerated. Brigatinib has been one of the preferred treatments and an addition of options in ALK-rearranged NSCLC. Pulmonary toxicity is one of the adverse effects observed during the treatment of TKIs and deserves the intense attention of clinicians, despite of its low incidence rate. Pulmonary toxicity reported during the treatment of Brigatinib has shown distinct clinical presentations, such as early-onset (median time to onset, 2 days) and rapid tolerance and reversibility of symptoms. In view of this, the concept of early-onset pulmonary events (EOPEs) was proposed and established during the submission for regulatory review and approval. We focused on clinical characteristics, potential mechanism of etiology, and management strategies of EOPEs to provide clinicians evidence for better clinical decision support.
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Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/genetics* ; Quality of Life ; Receptor Protein-Tyrosine Kinases ; Protein Kinase Inhibitors/adverse effects*

Nonalcoholic fatty liver disease (NAFLD) includes a series of diseases affected by various complex factors. Mitochondrial dysfunction often occurs in NAFLD and may lead to the progression of hepatitis and liver fibrosis. This article reviews the important role of mitochondrial oxidative stress, respiration, energy metabolism, quality control, and mitochondrial DNA in NAFLD and summarizes the current status of mitochondria-targeted therapy for NAFLD, hoping to provide a new direction for the research and clinical treatment of NAFLD.

microRNAs (miRNAs) are low-molecular-weight non-coding RNAs that regulate various physiological and pathological functions through the regulation of gene expression at the post-transcriptional level. More and more evidence has shown that microRNA-27a (miRNA-27a) plays a role in the development and pathogenesis of liver diseases. By reviewing and updating related studies, this article introduces the research advances in the role of miRNA-27a in various liver diseases including fatty liver disease, hepatitis, hepatic fibrosis, and liver cancer and analyzes the role of miRNA-27a in liver regeneration and its potential as a biomarker, so as to provide a reference for future studies and more possibilities for new treatment ideas for chronic hepatic diseases.

Objective To investigate the mechanism of occurrence and development of zinc-alpha-2-glycoprotein (AZGP1) in the activated hepatic stellate cells (HSCs) and liver fibrosis.Methods The activated human hepatic stellate cell line LX2 was induced by the stimulation of transforming growth factor-β1 to construct carbon tetrachloride liver fibrosis mice model.The situation expression of AZGP1 in liver cells and tissues were observed.Plasmid transfection method was used to detect the activation,proliferation,apoptotic functions and changes in related factors of LX2 cells,respectively,after the overexpression and inhibition of AZGP1expression.Univariate analysis of variance was used for multiple group comparison.Results The results of immunofluorescence staining showed that AZGP1 protein was decreased and α-smooth muscle actin was increased in the activated LX2 cells,and the two were negatively correlated.AZGP1 gene and protein were significantly under-expressed in activated LX2 cells and liver tissues of mice with carbon tetrachloride liver fibrosis.Collagen I,matrix metalloproteinase-2,and α-smooth muscle actin genes and proteins were significantly down-regulated in LX2 cells after over-expression of AZGP 1.Cell fluorescence showed that AZGP 1-overexpressing cells were activated and α-smooth muscle actin protein was reduced.In addition,the proliferative activity and G1/S-specific cyclin D1 protein of LX2 cells were significantly reduced after overexpression of AZGP1,while cell cycle experiments showed that the proportion of cells overexpressing AZGP1 was significantly increased in the G0/G1 phase,and the proportion of S phase was significantly reduced.AZGP1 had no significant effect on the apoptosis of LX2 cells.Conclusion AZGP1 can reverse liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells,and thereby overexpression of AZGP1 is expected to become a new target for liver fibrosis treatment.

Objective To evaluate the therapeutic effect of endovenous laser ablation (ELA) combined with foam sclerotherapy (FS) and mucopolysaccharide polysulfate (MP)cream on stasis dermatitis.Methods From December 2015 to May 2017,52 patients with 60 lesional limbs were enrolled from Department of Dermatology of Sichuan Provincial People's Hospital.The 60 lesional limbs were randomly and equally divided into 3 groups by a random number table and remainder grouping:combination group,MP group and control group.All the 3 groups were firstly treated with ELA in the main great saphenous vein.Then,the combination group was treated with FS followed by topical MP cream for 4 weeks.After the laser therapy,the MP group was treated with topical MP cream for 4 weeks,and the control group was treated with topical mometasone furoate cream alone for 4 weeks.The eczema area and severity index (EASI) and visual analogue scale (VAS) for itching scores in the above 3 group were recorded before treatment and 4 weeks after treatment.Statistical analysis was done by paired t-test for comparisons before and after treatment,one-way analysis of variance (ANOVA) for intergroup comparison,and least significant difference (LSD)-t test for multiple comparisons.Results No significant difference was observed before treatment among the combination group,MP group and control group in the EASI (9.64 ± 4.58,9.94 ± 4.18,9.50 ± 4.41 respectively,F =0.052,P ＞ 0.05) or VAS scores (7.25 ± 1.29,7.50 ± 1.19,7.45 ± 1.32 respectively,F =0.218,P ＞ 0.05).After 4-week treatment,the combination group,MP group and control group all showed significantly decreased EASI (3.54 ± 1.57,5.86 ± 2.39,7.04 ± 2.75 respectively) and VAS scores (2.35 ± 0.67,3.85 ± 0.67,4.65 ± 1.23 respectively) compared with those before treatment (t =4.30-18.80,all P ＜ 0.05).After 4-week treatment,the EASI score was significantly lower in the combination group than in the MP group and control group (both P ＜ 0.05),while there was no significant difference between the MP group and control group (P ＞ 0.05).Additionally,the VAS score was significantly lower in the combination group than in the MP group and control group (both P ＜ 0.05),as well as in the MP group than in the control group (P ＜ 0.05).Conclusions ELA combined with FS and topical MP cream shows better short-term efficacy for the treatment of stasis dermatitis compared with ELA combined with topical MP cream or mometasone furoate cream.The combination with topical MP cream is superior to that with topical mometasone furoate cream in improving itching.The long-term efficacy needs to be observed further.

Objective To investigate therapeutic effects and complications of three kinds of minimally invasive therapies for varicosis of the lower extremities.Methods Totally,79 patients with 94 affected limbs were enrolled into this study.According to their clinical manifestations,3 kinds of minimally invasive therapies alone or in combination were selected,including endovenous laser treatment (EVLT) with saphenofemoral ligation and stripping of the great saphenous vein,microphlebectomy,foam sclerotherapy,EVLT with saphenofemoral ligation and stripping of the great saphenous vein + microphle-bectomy,and EVLT with saphenofemoral ligation and stripping of the great saphenous vein + foam sclerotherapy.Physical examination and color Doppler ultrasonography were performed to evaluate the regression and recurrence of varicosis,as well as complications.Meanwhile,dermatology life quality index (DLQI) was used to evaluate the improvement of life quality of the patients after the treatment.Results All the patients were followed up for 1-6 months (average,4.2 months),and no recurrence was observed.One month after the treatment,all the patients were re-evaluated.Of the 94 affected limbs,46 (48.9％) were cured,43 (45.7％) were improved,and 5 (5.3％) were unimproved.Three months after the treatment,69 patients with 82 limbs completed the re-examination.Of the 82 limbs,71 (86.6％)were cured,9 (11.0％) were improved,and 2 (2.4％) were unimproved.Six months after the treatment,61 patients with 70 limbs completed the follow-up.Of the 70 limbs,62 (88.6％) were cured,7 (10.0％) were improved,1 (1.4％) was unimproved.Repeated-measures analysis of variance revealed that the total DLQI scores before the treatment (9.12 ± 2.87),one month after the treatment (6.97 ± 2.39),3 months after the treatment (5.12 ± 1.96) and 6 months after the treatment (3.69 ± 1.45) significantly differed (F =328.84,P ＜ 0.01),and there were significantly differences between any two time points of re-evaluations (all P ＜ 0.01).In the 79 patients,postoperative complications included subcutaneous ecchymosis (7 patients,8.9％),numb sensation in the foot and boot area of the legs (6 patients,7.6％),and cord-like subcutaneous induration =(3 patients,3.8％).Conclusions The three kinds of minimally invasive therapies alone or in combination are all effective for the treatment of varicosis of the lower extremities with rapid recovery.The life quality of patients was obviously improved after the treatment,and the complications were acceptable.

Objective To study the surgical treatment of hepatic hemangiomas and the timing of surgery.Methods A retrospective study was conducted on 908 patients with giant hemangiomas who underwent surgery between December 1997 and December 2017.The clinical data,surgical indications,surgical outcomes,lesion size,and the effect of TAE were compared.Results The diameter (mean + /-S.D.)of the resected hepatic cavernous hemangiomas was (11.1 ± 6.2) cm (the longest diameter was 60 cm).585 patients (64.4％) underwent enucleation of hepatic hemangiomas and 323 patients (35.6％) underwent anatomical hepatectomy.Six patients died perioperatively (mortality rate 0.7％).The incidence of severe complication (Clavien-Dindo grade 3 ～ 5) was 3.8％.The incidence of severe postoperative complication for enucleation (2.7％) was significantly less than anatomic liver resection (5.6％,P ＜0.05).When the lesion was more than 20 cm,the complication and mortality rates were significantly higher than those less than 20 cm (P ＜ 0.05).The complication and mortality rates in patients who underwent TAE before surgery were significantly higher than those without TAE (P ＜ 0.05).Conclusions Surgical enucleation of hemangiomas was superior to anatomical hepatectomy.With increase in tumor size,the risk of surgery increased.Surgical treatment was safe and effective for giant hepatic hemangiomas.For giant hepatic hemangiomas with significant increase in size,prompt surgical treatment is recommended.

OBJECTIVETo investigate the role of TGF-beta1 and STAT3 signaling in liver fibrosis using a rat model system and to determine the therapeutic mechanism of AG490 in relation to this signaling pathway.

METHODSRats were randomly divided into a control group and DENA-induced liver fibrosis model group, and then subdivided into AG490 treatment groups. During fibrosis development, liver tissue samples were collected at different time points (0, 4 and 8 weeks) and evaluated according to the Scheuer scoring system. Expression of STAT3, TGFbeta1, alpha-SMA, E-cadherin, MMP2 and TIMP1 was measured by PCR (mRNA) and immunohistochemistry and western blotting (protein).

RESULTSIncreasing degrees of inflammation and fibrosis were observed in liver tissues of DENA-treated rats throughout model establishment. The mRNA expression of TGFbeta1 and STAT3 was significantly increased in DENA-induced rats with advanced fibrosis (AF) compared to those with early fibrosis (EF) (P = 0.034 and P = 0.012 respectively). The protein expression of TGF-beta1, phospho-Smad2, alpha-SMA, E-cadherin, STAT3 and phospho-STAT3 was significantly increased in DENA-induced rats with AF compared to the unmodeled control group (P = 0.048, P = 0.003, P = 0.002, P = 0.028, P = 0.009 and P = 0.039). The protein expression of E-cadherin was lower in the DENA-induced rats with AF than in those with EF (P = 0.026). STAT3 and TGF-beta1 co-expression was detected in AF tissues. DENA-induced AG490-treated rats with AF showed substantially lower protein expression of STAT3, TGF-beta1, MMP2 and TIMP1 compared to DENA-induced untreated rats with AF (P = 0.006, P = 0.018, P = 0.010 and P = 0.005); in addition, the degrees of fibrosis and inflammation were also greatly reduced in the DENA-induced AG490-treated rats with AF compared to DENA-induced untreated rats with AF (P = 0.042 and P = 0.021). Conclusions STAT3 signal transduction may regulate the TGF-beta1 pathway and affect liver fibrosis, especially in the advanced phase. AG490 can inhibit TGFbeta1-STAT3 signaling, resulting in reversal of liver fibrosis.

Animals ; Disease Models, Animal ; Liver Cirrhosis ; chemically induced ; metabolism ; Rats ; Rats, Sprague-Dawley ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; Transforming Growth Factor beta1 ; metabolism ; Tyrphostins ; pharmacology

Objective To analyze the learning curve of microendoscopic lumbar discectomy (MED) and summarize the operative experience. Methods From July 2010 to March 2012, the first 100 patients with single level lumbar disc herniation managed with MED were divided into chronological groups (A, B, C and D), 30 patients in group A, B, C and 10 patients in group D. The comparsons were conducted in terms of operative time , estimated blood loss , number of cases with transition from MED to open surgey or for reoperation , rate of complications and postoperative efficacy. Results The mean operative time and the mean estimated blood loss in each group was valuated respectively. In group A , the operative time and estimated blood loss were significantly decreased as compared with those in group B, C and D respectively (P < 0.05), but those in group B were not significantly different from those in group C and D (P > 0.05). There were 6 complications in group A, 1 complication in group B and C respectively and no complication in group D. The leg pain visual analogue scale and Oswestry disability index at the first month and the twelfth month postoperatively were all improved respectively as compared with those preoperatively (P < 0.01). Conclusion The learning curve of microendoscopic lumbar discectomy generally may reach the plateau when about 30 cases are operated on. The key procedure to pass over the learning curve includes puncture and location , flavectomy , anatomy mark identification, and precaution of damage in dural sac.

This study was aimed to optimize the extraction process of resveratrol by central composite design (CCD) and response surface method (RSM), based on the result of single factor experiment. Resveratrol was extracted from Polygonum cuspidatum by water bath extraction of organic solvent. And content of resveratrol was taken as index in the investigation of solvent concentration effect, extraction time and solvent content on extraction process. The results showed that the optimum condition was 12.7 times amount of 72.0% ethanol and extract for 2 times under the temperature of 50℃, 1.1 h for each time; the average deviation between the maximum theoretical value and measured value was 0.83%. It was concluded that this extraction process was highly predictive, which provided experimental evidence for the industrial production of P. cuspidatum extraction.