Lung adenocarcinoma with brain metastasis detected dual fusion of LOC399815-ALK and ALK-EML4 in combined treatment of Alectinib and CyberKnife: A case report.

INTRODUCTION: The anaplastic lymphoma kinase (ALK) gene fusion occurs in approximately 3% to 7% of nonsmall cell lung cancer (NSCLC), in which occurs approximately 23% to 31% of brain metastasis patients in poor prognosis. ALK tyrosine kinase inhibitors have shown efficacy in treating ALK-positive (ALK+) NSCLC. More than 90 distinct subtypes of ALK fusions have been identified through sequencing technique and would lead to significant differences in clinical efficacy, it is necessary to guide clinical treatment effectively by gene detection. PATIENT CONCERNS: A 56-year-old nonsmoking female admitted to hospital due to cough, expectoration, and chest pain. Chest computed tomography revealed a space-occupying lesion in the upper left lobe (5.0 cm × 2.4 cm × 2.9 cm), multiple enlarged lymph nodes in mediastinum 3A and 5 (largest size 1.5 cm × 1.4 cm), and evidence of thoracic vertebral metastasis, brain magnetic resonance imaging also showed brain metastasis. DIAGNOSES: Lung adenocarcinoma with brain metastasis. INTERVENTIONS: The patient initially received conventional first-line chemotherapy, which led to a deteriorated condition. Blood-base liquid biopsy by next-generation sequencing resulted in double ALK fusions, in which with a neo-partner of lncRNA (LOC399815-ALK). Following subsequent treatment with Alectinib and stereotactic radiotherapy (CyberKnife) was subsequently employed to manage the brain metastatic lesions, resulting in a substantial decreased in both the number and size of tumor lesions. OUTCOMES: The patient's response to therapy efficacy resulted in a substantial decreased in both the number and size of tumor lesions that assessed comprehensively evaluated through computed tomography imaging and ctDNA sequencing. Patient's condition has been under control for over 29 months. CONCLUSION: Liquid biopsy may reveal the rare fusion forms of ALK, precisely guiding personalized treatment, and providing a reference method for longitudinal monitoring and efficacy evaluation of ALK-tyrosine kinase inhibitors in NSCLC patients.

Exosomal microRNA Therapy for Non-Small-Cell Lung Cancer.

With the progress of molecular diagnosis research on non-small cell lung cancer (NSCLC) cells, four identified categories of microRNAs have been found to be related to disease diagnosis, diagnosis of treatment resistance, prediction of prognosis, and drugs for treatment. To date, nine target mRNA/signal pathways have been confirmed for microRNA drug therapy both in vitro and in vivo. When microRNA drugs enter blood vessels, they target the tumor site and play a similar role to that of targeted drugs. However, whether they will produce serious off-target effects remains unknown, and further clinical research is needed. This review provides the first summary of microRNA therapy for NSCLC.

Impact of Herbal Preparations on Outcomes of Highly Active Antiretroviral Therapy: A One-Year Prospective Cohort Study.

OBJECTIVE: To investigate the impacts of two herbal preparations for human immunodeficiency virus/aquired immune deficiency syndrome (HIV/AIDS) patients, Shenling Fuzheng Capsule (, SLFZC) and Qingdu Capsule (, QDC), on the efficacy of highly active antiretroviral therapy (HAART). METHODS: HIV/AIDS patients met the criteria were all enrolled in a 1-year cohort study, in which patients receiving HAART alone were designated as Group A, those receiving HAART in combination with SLFZC were designated as Group B, and those receiving HAART in combination with QDC were designated as Group C, 100 cases in each group. The dose of SLFZC was 1.48 g (4 capsules), 3 times daily, and QDC 1.56 g (4 capsules), 3 times daily. T cell subsets, HIV RNA and HIV-1 drug resistance were detected at enrollment and 1 year after treatment. Patients were followed up every 3 months, during which side-effects and other clinical data were recorded. RESULTS: After 1-year treatment, the median increment in CD4 counts was 165.0, 178.0 and 145.0 cells/µL for Group A, B and C, respectively. HIV RNA was undetectable in 94% of patients in Group A, 96% in Group B and 92% in Group C. There were no differences regarding the increment in CD4 counts, HIV RNA and frequency of HIV-1 drug resistance mutations. Two of the 14 suspected side-effect symptoms, i.e. fatigue and dizziness, were lower in Groups B and C than in Group A (P<0.05, respectively) CONCLUSIONS: SLFZC and QDC do not have a negative impact on immunological and virological response to HAART; however, these preparations are not as potent in reducing HAART-associated side-effects as anticipated.

Efficacy of Stereotactic Body Radiotherapy for Recurrent or Residual Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization.

AIM: To evaluate the efficacy and toxicity of hypofractionated stereotactic body radiotherapy (SBRT) for patients with recurrent or residual hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). METHODS: Between June 2008 and July 2015, thirty-three patients with HCC were treated by SBRT. There were 63 lesions in 33 patients. A total dose of 39-45 Gy/3-5 fractions was delivered to the 70-80% isodose line. RESULTS: Objective response rate (CR + PR) was 84.8% at 6 months. The overall survival rate was 87.9%, 75.8%, 57.6%, and 45.5% at 6, 12, 18, and 24 months, respectively. Median overall survival was 19 months. At 3 months, AFP decreased by more than 75% in 51.5% of patients (17/33). Overall survival was significantly different (P < 0.001) between the group of patients for whom AFP decreased more than 75% and the group for whom AFP decreased by less than 75%. The AFP-negative rate was 48.5% (16/33) after 6 months. Eight patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. CONCLUSION: SBRT is a promising noninvasive and palliative treatment with acceptable toxicity for recurrent or residual HCC after TACE.

Clinical application of fast-track surgery with Chinese medicine treatment in the devascularization operation for cirrhotic portal hypertension.

OBJECTIVE: To investigate the clinical effect of fast-track surgery combined with Chinese medicine treatment in devascularization operation for cirrhotic esophageal varices. METHODS: Seventy-two patients with cirrhotic esophageal varices were selected from January 2009 to June 2013, and randomly assigned to a conventional group and a fast-track group (fast-track surgery combined with Chinese medicine treatment) using a randomized digital table, 36 cases in each group. Operation and anesthesia recovery time, postoperative hospitalization and quality of life were recorded and compared between groups during the perioperative period. RESULTS: Compared with the conventional group, the fast-track group had longer operation time (253.6±46.4 min vs. 220.6±51.0 min) and anesthesia recovery time (50.5±15.9 min vs. 23.5±9.6 min; P<0.01); less bleeding (311.3±46.8 mL vs. 356.2±57.5 mL; P<0.01) and less transfusion (1932.3±106.9 mL vs. 2045.6±115.4 mL; P<0.01); as well as faster recovery of gastrointestinal function, shorter postoperative hospitalization and higher quality of life. There were no serious postoperative complications and no further bleeding occurred. CONCLUSION: Fast-track surgery combined with Chinese medicine treatment is a safe and feasible approach to accelerate the recovery of patients with cirrhotic portal hypertension in perioperative period of devascularization operation.

Ultrasmall [(64)Cu]Cu nanoclusters for targeting orthotopic lung tumors using accurate positron emission tomography imaging.

Positron emission tomography (PET) imaging has received special attention owing to its higher sensitivity, temporal resolution, and unlimited tissue penetration. The development of tracers that target specific molecules is therefore essential for the development and utility of clinically relevant PET procedures. However, (64)Cu as a PET imaging agent generally has been introduced into biomaterials through macrocyclic chelators, which may lead to the misinterpretation of PET imaging results due to the detachment and transchelation of (64)Cu. In this study, we have developed ultrasmall chelator-free radioactive [(64)Cu]Cu nanoclusters using bovine serum albumin (BSA) as a scaffold for PET imaging in an orthotopic lung cancer model. We preconjugated the tumor target peptide luteinizing hormone releasing hormone (LHRH) to BSA molecules to prepare [(64)Cu]CuNC@BSA-LHRH. The prepared [(64)Cu]Cu nanoclusters showed high radiolabeling stability, ultrasmall size, and rapid deposition and diffusion into tumor, as well as predominantly renal clearance. [(64)Cu]CuNC@BSA-LHRH showed 4 times higher tumor uptake compared with that of [(64)Cu]CuNC@BSA by analyzing the (64)Cu radioactivity of tissues via gamma counting. The PET imaging using [(64)Cu]Cu nanoclusters as tracers showed more sensitive, accurate, and deep penetration imaging of orthotopic lung cancer in vivo compared with near-infrared fluorescence imaging. The nanoclusters provide biomedical research tools for PET molecular imaging.

Treatment of posthepatitic cirrhosis by Fuzheng Huayu Tablet for reinforcing qi and resolving stasis.

OBJECTIVE: To investigate the efficacy and safety of the Fuzheng Huayu Tablet FZHYT), which is used to reinforce qi and resolve stasis in patients with posthepatitic cirrhosis (PHC). METHODS: A multicenter, randomized, controlled clinical trial was conducted in 180 patients with PHC. The patients were randomly assigned using random numbers to a treatment group treated with FZHYT and a placebo group; the treatment course was 6 months for both groups. Overall response, adverse events (AEs), and the 2-year survival rate were assessed after treatment. Evaluations were made on changes in liver function, liver fibrosis, coagulation, hemodynamics, degrees of esophagogastric varices, ascites, quality of life (QOL), and scores of main symptoms. RESULTS: The overall response was significantly higher in the treatment group than the placebo group (86.7% vs. 62.2%, P<0.01). Patients in both groups had significant improvements in liver function [total bilirubin (TBIL), albumin (ALB)], liver fibrosis [hyaluronic acid (HA), type IV collagen (CIV)], coagulation [prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and thrombin time (TT)], hemodynamics portal venous flow (PVF), and splenic vein flow (SVF) after treatment. Between-group comparisons showed that compared with the placebo group patients in the treatment group achieved significantly greater improvements in TBIL, ALB, HA, C IV, PT, APTT, PVF, SVF, time to ascites resolution, 2-year survival, QOL, and symptom scores (P<0.05 or P<0.01). There were no significant AEs during the treatment. CONCLUSION: FZHYT is effective and safe for the treatment of hepatic cirrhosis as it is associated with improved liver function, liver fibrosis, coagulation, portal hypertension state, QOL, 2-year survival rate, and fewer AEs.

Transcriptomic and proteomic analysis of human hepatic stellate cells treated with natural taurine.

The aim of this study was to investigate the differential expression of genes and proteins between natural taurine (NTau)­treated hepatic stellate cells (HSCs) and control cells as well as the underlying mechanism of NTau in inhibiting hepatic fibrosis. A microculture tetrazolium (MTT) assay was used to analyze the proliferation of NTau­treated HSCs. Flow cytometry was performed to compare the apoptosis rate between NTau-treated and non­treated HSCs. Proteomic analysis using a combination of 2-dimensional gel electrophoresis (2DE) and mass spectrometry (MS) was conducted to identify the differentially expressed proteins. Microarray analysis was performed to investigate the differential expression of genes and real-time polymerase chain reaction (PCR) was used to validate the results. The experimental findings obtained demonstrated that NTau decreased HSC proliferation, resulting in an increased number of cells in the G0/G1 phase and a reduced number of cells in the S phase. Flow cytometric analysis showed that NTau-treated HSCs had a significantly increased rate of apoptosis when compared with the non­treated control group. A total of 15 differentially expressed proteins and 658 differentially expressed genes were identified by 2DE and MS, and microarray analysis, respectively. Gene ontology (GO) functional analysis indicated that these genes and proteins were enriched in the function clusters and pathways related to cell proliferation, cellular apoptosis and oxidation. The transcriptome and proteome analyses of NTau-treated HSCs demonstrated that NTau is able to significantly inhibit cell proliferation and promote cell apoptosis, highlighting its potential therapeutic benefits in the treatment of hepatic fibrosis.

Entecavir versus lamivudine for the treatment of chronic hepatitis B: a systematic review.

The aim of this study was to systematically review the efficacy and safety of entecavir versus lamivudine for the treatment of chronic hepatitis B (CHB). A computerized search of The Cochrane Library (CENTRAL, Issue 5, 2011), MEDLINE (PubMed, 1978-June 2011), EMbase (1974-June 2011) and CNKI (1978-June 2011) databases was conducted. In addition, a manual search was made of the references of the included studies and relevant articles. The searches were restricted to studies published in Chinese or English from the time the database was created to June 2011. Studies were selected according to prespecified inclusion and exclusion criteria and then subjected for quality assessment and data extraction. Meta-analysis was performed using the statistical software (RevMan 5.1.1) provided by the Cochrane Collaboration. A total of 8 studies, all of which were randomized clinical trials (RCTs), involving 2178 patients with CHB were included. Subgroup analyses by treatment duration were conducted. The quality of the evidence was classified as moderate by the GRADED approach for all the included RCTs. Meta-analysis showed the following. Entecavir was associated with significantly improved liver histology, compared with lamivudine (RR 1.16, 95, CI [1.07, 1.26], P=0.0004). Patients were significantly more likely to experience HBV-DNA loss and have normalized ALT levels when treated with entecavir versus lamivudine for either 48 or 96 weeks (RR 1.65, 95, CI [1.37, 1.98], P<0.00001; RR 1.15, 95, CI [1.11, 1.20], P<0.00001, respectively). There were no statistically significant differences in the proportion of patients who achieved HBeAg loss or HBeAg seroconversion, or who developed adverse events between entecavir and lamivudine treatments (RR 1.03, 95, CI [0.83, 1.26], P=0.81; RR 0.92, 95, CI [0.75, 1.12], P=0.39; RR 1.09, 95, CI [0.92, 1.30], P=0.31, respectively). Current clinical evidence suggests that despite of short- or long-term use, entecavir appears to be more effective than lamivudine in reducing serum HBV-DNA load, improving liver histology, and normalizing ALT in patients with CHB. However, the probability for patients to experience HBeAg loss or HBeAg seroconversion, or the risk for adverse events seems to be similar between entecavir and lamivudine regimens.

A clinical study of weining granules in the treatment of gastric precancerous lesions.

OBJECTIVE: To investigate the clinical effects of Weining granules on gastric precancerous lesions (GPLs). METHODS: 120 patients with GPLs were randomly assigned in a 1:1 ratio to receive Weining granules (trial group) or the comparator Weifuchun tablets (control group) for 6 months. Outcomes were compared between the two groups including: overall response; gastroscopically-determined response; pathologically-confirmed response; eradication of Helicobacter pylori (HP); microvessel density (MVD) in the gastric mucosa; expression of vascular endothelial growth factor (VEGF); interleukin 2 (IL-2); interleukin 6 (IL-6); T lymphocyte subsets; immunoglobulins; symptom scores; quality of life (QOL); and adverse reactions. RESULTS: Patients in the trial group had a significantly higher (P < 0.05) overall response rate (81.7%) as compared with those in the control group (63.3%). Relative to treatment with Weifuchun tablets treatment with Weining granules resulted in a significant improvement (P < 0.05) in the scores for gastric pain, distension and stuffiness in the hypochondrium, and anorexia. As compared with the tablets the granules were associated with a significantly higher overall gastroscopically-determined response rate (78.3%; P < 0.05). Pathological examination of tissue samples indicated that 61.7% of patients receiving the granules were cured with an overall response rate of 75.5%; these rates were significantly higher than in the control group (P < 0.05). In comparison with patients receiving the tablets, those given the granules were significantly more likely to have their HP eradicated (75.0% vs. 51.4%; P < 0.05). Improvements in MVD, VEGF, CD4+, CD4+/ CD8+, IL-2, IL-6 and IgG were significantly greater with the Weining Granules than with the Weifuchun tablets (P < 0.05 or P < 0.01). After follow-up of 1 year, 17.5% of patients in the trial group relapsed as compared with 39.5% in the control group (P < 0.05). Relative to the control group, the trial group showed significantly greater improvements in physical, psychological and social relationships, and in environmental domains (P < 0.05 or P < 0.01). No significant adverse reactions were observed during treatment. CONCLUSION: The Weining granules appear to be effective in improving the gastric precancerous state and the main symptoms, in inhibiting angiogenesis, enhancing immune function and QOL, and in reducing 1-year relapses. In addition, this preparation seems to be associated with a low risk of adverse events, making it a safe and efficacious option for the treatment of GPLs.

Influence of Fuzheng Huayu Tablet on mental state and social function of patients with post-hepatitis B liver cirrhosis.

OBJECTIVE: To observe the influence of Fuzheng Huayu Tablet on mental state and social activity of patients with post-hepatitis B liver cirrhosis (LC-HB). METHODS: Adopting grouped randomized double-blinded control method, 180 LC-HB patients in 3 research centers were distributed to 2 groups, the treated group and the control group, 90 in each group. Patients in the treated group were administered with FZHYT; while those in the control group treated with conventional therapy combined with placebo, the course for all patients were 6 months. Their mental state and social activity were evaluated before treatment, after 3 months' treatment and at terminal of the 6-month therapeutic course by estimating with Zung self-rating anxiety scale (SAS), self-rating depression scale (SDS) and social deficit screening scale (SDSS). Additionally, the basic demographic materials, liver function, cirrhosis index, hepatic and splenic images, blood coagulation function, etc. in the patients were tested and compared as well. RESULTS: As compared with before treatment, the normal rate of SAS and SDS scores increased and the social deficit rate decreased in the treated group significantly after treatment, showing statistical significance (P<0.05 or P<0.01); while in the control group, change was only shown in the social deficit (P<0.01), inter-group comparisons after treatment showed significant differences in all the three indexes (P<0.05 or P<0.01). Additionally, after treatment, levels of liver function, cirrhosis, blood coagulation function and splenomegaly in the treated group were all improved significantly P<0.05 or P<0.01), and the improvements were better than those in the control group (P<0.01) in levels of total bilirubin (TBIL), albumin (ALB), type IV collagen (IV-C), prothrombin time (PT), prothrombin activity (PTA). CONCLUSION: Most patients of LC-HB have mental disturbance and social activity deficit, which could definitely be improved by intervention with Chinese FZHYT.

Mitogen activated protein kinase signaling pathways participate in the active principle region of Buyang Huanwu decoction-induced differentiation of bone marrow mesenchymal stem cells.

Our preliminary studies confirmed that an active principle region of Buyang Huanwu decoction, comprising alkaloid, polysaccharide, aglycon, glucoside and volatile oil, can induce bone marrow mesenchymal stem cell differentiation into neurons. Mitogen-activated protein kinase signaling was identified as one of the key pathways underlying this differentiation process. The present study shows phosphorylated extracellular signal-regulated protein kinase and phosphorylated p38 protein expression was increased after differentiation. Cellular signaling pathway blocking agents, PD98059 and SB203580, inhibited extracellular signal-regulated protein kinase and p38 in mitogen-activated protein kinase signaling pathways respectively. mRNA and protein expression of the neuronal marker, neuron specific enolase, and neural stem cell marker, nestin, were decreased in bone marrow mesenchymal stem cells after treatment with the active principle region of Buyang Huanwu decoction. Experimental findings indicate that, extracellular signal-regulated protein kinase and p38 in mitogen-activated protein kinase signaling pathways participate in bone marrow mesenchymal stem cell differentiation into neuron-like cells, induced by the active principle region of Buyang Huanwu decoction.

Effects of the Ganning formula on liver fibrosis in patients with chronic hepatitis B.

OBJECTIVE: To investigate the clinical efficacy and safety of the Ganning formula for the treatment of liver fibrosis in patients with chronic hepatitis B. METHODS: In a multicenter, randomized, controlled clinical trial, 150 patients with liver fibrosis secondary to hepatitis B virus (HBV) infection were randomly assigned in equal numbers to receive either the Ganning formula (a Chinese herbal decoction; active treatment group) or oral entecavir (control group) for two 3-month courses. Patients were monitored for any treatment-induced changes in liver function test parameters (ALT, AST, and GGT), liver fibrosis markers (LN, HA, IV-C, and PCIII), HBV DNA level, hepatosplenic imaging, quality of life scores, or psychological and social functioning scores. Patients were also observed for any adverse effects. RESULTS: After treatment, patients in both groups experienced significant improvements in liver function, HBV DNA load, hepatosplenic B-mode ultrasonography, quality of life, and psychological and social functioning (P < 0.05 or P < 0.01). Patients receiving the Ganning formula achieved greater improvements in HA, IV-C, quality of life, and psychological and social functioning compared with those on entecavir (P < 0.05 or P < 0.01). There were no abnormal changes in blood tests, urine, feces, renal function, or electrocardiogram. Additionally, no adverse effects were observed in any patients in either group. CONCLUSIONS: The Ganning formula appears to have the potential to inhibit liver fibrosis and therefore improve liver function by inhibiting HBV replication in patients with chronic hepatitis B. Additionally, this formula is helpful in improving quality of life and psychological and social functioning.

Natural taurine promotes apoptosis of human hepatic stellate cells in proteomics analysis.

AIM: To study the differential expression of proteins between natural taurine treated hepatic stellate cells and controls, and investigate the underlying regulatory mechanism of natural taurine in inhibiting hepatic fibrosis. METHODS: A proteomic strategy combining two-dimensional gel electrophoresis and ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) was used to study the differential expression of proteins and Western blotting was used to validate the results. Gene ontology (GO) method was utilized to analyze the functional enrichment of differentially expressed proteins. Flow cytometry was performed to compare the apoptosis rate between taurine-treated and untreated hepatic stellate cells (HSCs). RESULTS: Nineteen differentially expressed proteins (11 up-regulated and 8 down-regulated) were identified by 2D/MS, and the expression profiles of GLO1 and ANXA1 were validated by Western blotting. GO analysis found that these differentially expressed proteins were enriched within biological processes such as "cellular apoptosis", "oxidation reaction" and "metabolic process" in clusters. Flow cytometric analysis showed that taurine-treated HSCs had a significantly increased apoptosis rate when compared with the control group. CONCLUSION: Natural taurine can promote HSC apoptosis so as to inhibit hepatic fibrosis.