Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.

BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Molecular signalling involved in upper airway remodelling is enhanced in patients with obstructive sleep apnoea.

OBJECTIVE: This study aimed to elucidate whether molecular signalling involved in upper airway remodelling is enhanced in patients with obstructive sleep apnoea. METHOD: Twenty patients with mild obstructive sleep apnoea (control group) and 40 patients with moderate to severe obstructive sleep apnoea (obstructive sleep apnoea group) who desired uvulopalatopharyngoplasty were recruited for the study. After uvulopalatopharyngoplasty, surgical specimens of the uvula were subjected to haematoxylin and eosin, Masson's trichrome and immunohistochemical staining. Western blot and reverse transcriptase-polymerase chain reaction were used to evaluate the protein and messenger RNA expressions. RESULTS: The obstructive sleep apnoea group showed more severe inflammation, increased collagen deposition and higher immunohistochemical staining intensity for TGF-ß and MMP-9 as well as higher protein and messenger RNA expression of MMP-9, VEGF, TGF-ß, p38 MAPK, SMAD 2/3, AKT and JNK in the uvula than control group. CONCLUSION: Patients with obstructive sleep apnoea demonstrated more severe inflammation, increased airway remodelling, and increased protein and messenger RNA expression of pro-inflammatory and pro-fibrotic cytokines in the uvula than control participants.

Lifetime risks of hip fracture in patients with type 2 diabetic: Taiwan Diabetes Study.

This study is to estimate the lifetime risks of hip fracture in Chinese patients with type 2 diabetes. INTRODUCTION: The lifetime risks of hip fracture have not been reported across the age spectrum in male adults and female adults with type 2 diabetes. METHODS: A retrospective cohort study was conducted on 25275 men and 27953 women with type 2 diabetes aged 30-100 years old and participated in the National Diabetes Case Management Program in 2002-2004 in Taiwan. Sociodemographic factors, biomarkers, and comorbidity at the baseline and hip fracture events were analyzed with Cox proportional hazards regression models with age as the time scale. RESULTS: Significant differences in the lifetime risks of hip fracture were observed between men and women with type 2 diabetes. The cumulative lifetime incidences (%) of hip fracture at 50, 60, 65, 70, 75, 80, and 85 years old for men were 0.11, 0.40, 0.84, 1.84, 3.82, 8.53, and 16.72, respectively. The corresponding lifetime incidences (%) for women at 50, 60, 65, 70, 75, 80, and 85 years old were 0.05, 0.50, 1.36, 3.89, 9.56, 21.19, and 35.45, respectively. With competing risks, the significant multivariate-adjusted hazard ratio of developing hip fracture included smoking, alcohol drinking, duration of diabetes, type of oral hypoglycemic drugs use (no medication, sulfonylurea only, thiazolidinediones (TZD) only or TZD plus others, other single or multiple oral agents, insulin use, insulin plus oral hypoglycemic drug use), loop diuretics use, use of corticosteroids, normal weight or underweight, hyperlipidemia, and chronic obstructive pulmonary disease. CONCLUSIONS: The gender differences in lifetime hip fracture risk were significant. Thiazolidinediones and insulin use are factors with the greater magnitude of strength of association among those significantly associated with hip fracture.

Severe myocardial bridge presenting as paroxysmal atrioventricular block.

Chest pain complicated with electrocardiographic changes is not an uncommon scenario in emergency departments, which should be examined cautiously. We describe a 51-years-old man with a myocardial bridge of coronary artery presenting with simultaneous Mobitz type I atrioventricular block on electrocardiography. Echocardiography excluded valvular abnormality and systolic/diastolic dysfunction. Coronary angiography confirmed the diagnosis of a myocardial bridge at the middle segment of the left anterior descending artery, involving the most dominant septal perforator branch with marked systolic compression. The patient underwent coronary artery bypass grafting surgery and was followed up uneventfully at the outpatient department with medical treatment of diltiazem and clopidogrel. The present case is being reported to highlight that clinicians should be alert to such a congenital abnormality as a potential cause of repeated myocardial infarction and conduction abnormality.

Association of fine-particulate and acidic-gas air pollution with premenstrual syndrome risk.

OBJECTIVE: Air pollution had been reported to be associated with the reproductive health of women. However, the association of particulate matter (PM) and acid gases air pollution with premenstrual syndrome (PMS) warrants investigation. This study investigated the effects of air pollution on PMS risk. POPULATION: We combined data from the Taiwan Air Quality-Monitoring Database and the Longitudinal Health Insurance Database. In total, an observational cohort of 85 078 Taiwanese women not diagnosed as having PMS. METHODS: Air pollutant concentrations were grouped into four levels based on the concentration quartiles of several types of air pollutants. MAIN OUTCOME MEASURES: We then applied univariable and multivariable Cox proportional hazard regression models to assess PMS risk in association with each pollutant type. RESULTS: Women exposed to Q4-level SO2 exhibited a 7.77 times higher PMS risk compared with those to Q1-level SO2 (95% confidence interval [CI] = 6.22-9.71). Women exposed to Q4-level NOx exhibited a 2.86 times higher PMS risk compared with those exposed to Q1-level NOx (95% CI = 2.39-3.43). Women exposed to Q4-level NO exhibited a 3.17 times higher PMS risk compared with women exposed to Q1-level NO (95% CI = 2.68-3.75). Finally, women exposed to Q4-level PM with a ≤2.5-µm diameter (PM2.5) exhibited a 3.41 times higher PMS risk compared with those exposed to Q1-level PM2.5 (95% CI = 2.88-4.04). CONCLUSIONS: High incidences of PMS were noted in women who lived in areas with higher concentrations of SO2, NOx, NO, NO2 and PM2.5.

Photoinduced antibacterial activity of NRC03 peptide-conjugated dopamine/nano-reduced graphene oxide against Staphylococcus aureus.

In recent years, several drugs have become relatively easy to obtain with the rapid development of the economy and improvement in people's living standards. However, pathogenic bacteria have evolved strains that are resistant to certain drugs, such as antibiotics. Peptides are generally considered to be safe, have high tolerance to drugs, and are easy to manufacture. However, peptides are easily decomposed in complex biological environments. To solve this problem, many studies have modified peptides on the surface of nanomaterials to increase their functionality, biocompatibility, and stability. Meanwhile, nanomaterials have exhibited good absorption of near-infrared (NIR) light. When the NIR laser is focused on nanomaterials, photons are absorbed and the energy of the photons is converted into heat. Low-toxicity NRC03 peptide-conjugated dopamine/nano-reduced-graphene oxide (NRC03-DA/nRGO) nanomaterials are synthesized in this study for antibacterial testing using photothermal technology. The strains used in this study were Gram-positive Staphylococcus aureus (S. aureus). Our results indicated that the synthesized NRC03-DA/nRGO exhibits good absorption of NIR light and high photothermal conversion efficiency. Moreover, the synthesized NRC03-DA/nRGO inhibits the growth and survival of S. aureus. When the NRC03 peptide is modified on the surface of DA/nRGO, its biological stability is improved and the photothermal effect generated by NIR light produces additive effects, thereby indicating potential antibacterial applications.

Pre-treatment quality of life as a predictor of distant metastasis-free survival and overall survival in patients with head and neck cancer who underwent free flap reconstruction.

PURPOSE: This study examined the prognostic associations of pre-treatment quality of life (QoL) with overall survival (OS) and distant metastasis-free survival (DFMS) among patients with head and neck cancer (HNC) who underwent free flap reconstruction. METHODS: A cohort of 127 HNC patients who received free flap reconstruction between November 2010 and June 2014 at a hospital were recruited. Pre-treatment QoL was measured by the University of Washington Quality of Life Questionnaire, which contains six physical domains, including speech, swallowing, appearance, saliva, taste and chewing, as well as the six social-emotional domains of pain, activity, recreation, shoulder, mood, and anxiety. Cox regression analyses were performed. RESULTS: Results showed that pre-treatment QoL was predictive of OS and DMFS. Of the domains, swallowing, chewing, speech, taste, saliva, pain and shoulder were demonstrated to be significant predictors of OS. Additionally, swallowing, chewing, speech, pain and activity were demonstrated making significant contributions to DMFS. CONCLUSION: Our data supported that physical domains of pre-treatment QoL were predictors for OS and DFMS in HNC patients with free-flap reconstruction. Longitudinal studies are warranted to clarify the prognostic abilities of social-emotional domains. Information on pre-treatment QoL should be taken into account to individualize care plan for these patients, and hence prolong their survival.

[The role and mechanism of 2-deoxyglucose in reversing osimertinib-acquired resistance of non-small cell lung cancer cell line].

Objective: To explore the role and mechanism of 2-deoxyglucose (2-dg) in reversing osimertinib- acquired resistance of non-small cell lung cancer(NSCLC)cell line. Methods: The NSCLC line H1975 (purchased from the American Type Culture Collection) was conducted by induction method in vitro to construct the osimertinib-resistance NSCLC cell line H1975-OR. The osimertinib-resistance of H1975-OR cell line was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony-formation assay, Ki67 incorporation assay and the expression of apoptosis-related protein. The glycolysis level was assayed by the lactic acid production measured in the culture medium supernatant of H1975 and H1975-OR. The expression of glycolysis key enzymes (HK2, GLUT1, P-PKM2) and apoptosis-related protein (BIM, Bcl-2) were detected by Western blot. The cells were divided into control group, 2-deoxyglucose (4 mmol/L) monotherapy group, osimertinib (3 µmol/L) monotherapy group and 2-deoxyglucose (4 mmol/L)+ osimertinib (3 µmol/L) combination therapy group, then the apoptosis rate of cells was measured by flow cytometry to evaluate the pro-apoptotic ability of drugs. Date were analyzed by Independent-Samples t-test using SPSS 16.0 statistical software. Results: The glycolysis level of osimertinib-sensitive cell line H1975 was lower than that of osimertinib-resistance cell line H1975-OR [the yield of lactic acid, respectively, was (21.0±0.9) and (26.5±2.8) mmol·L(-1)·10(4)cells(-1), P<0.05]. The osimertinib- acquired resistance of H1975-OR could be reversed by 4 mmol/L 2-deoxyglucose(the IC(50) value of osimertinib in H1975-OR cell line decreased from (7.0±1.9) µmol/L to (1.4±0.1) µmol/L, which was close to the IC(50) value of osimertinib in H1975 cell line (1.0±0.2) µmol/L. The apoptosis rate of H1975-OR was significantly higher in 2-deoxyglucose + osimertinib combination therapy group (26.7±2.4)%, compared to control group (5.1±0.7)%, 2-deoxyglucose monotherapy group (6.1±2.5)% and osimertinib monotherapy group (11.4±2.7)%(all P<0.05). The expression of pro-apoptotic protein BIM in H1975-OR was significantly higher in 2-deoxyglucose+ osimertinib combination therapy group (177.8±28.1)% and the expression of anti-apoptotic protein Bcl-2 in H1975-OR was significantly lower in 2-deoxyglucose+ osimertinib combination therapy group (24.6±5.2)%, compared to control group (100±0)%, all P<0.05. Conclusion: 2-deoxyglucose can reverse the acquired resistance of NSCLC cell line to osimertinib, which may be related to the inhibition of cell glycolysis and the induction of apoptosis.

Predicting Hepatic Steatosis in Living Liver Donors Via Controlled Attenuation Parameter.

BACKGROUND: Hepatic steatosis (HS) can cause substantial problems for both donors and recipients in living donor liver transplantation. The controlled attenuation parameter (CAP) is a noninvasive method of measuring HS using a process based on transient elastography. AIM: To evaluate the accuracy of CAP in quantifying HS during living donor liver transplantation. METHODS: A total of 54 liver donors who received CAP and intraoperative liver biopsy (LB) were enrolled in this study. The performance of CAP compared with LB for diagnosing HS was assessed using areas under receiver operating characteristic curves. HS was defined by the presence of steatosis in >5% of hepatocytes. RESULTS: No HS was found in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Using CAP, the area under receiver operating characteristic curve was 0.96 (95% CI, 0.91-1; P < .001) for HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%). Among the 42 candidates with CAP <257 dB/m, none had HS, while of the 12 candidates with CAP ≥257 dB/m, 7 had HS. In a multivariate linear regression analyses, body mass index (ß = 0.71, P < .001) was found to be independently associated with CAP in those without HS. CONCLUSIONS: CAP might be a promising tool to exclude HS in East Asian living liver donors. Body mass index was found to be independently associated with CAP values in those without HS.

Cost Analysis and Determinants of Living Donor Liver Transplantation in Taiwan.

BACKGROUND: Liver transplantation (LT) has become established therapy for end-stage liver disease and small-cell hepatocellular carcinoma (HCC), relying mainly on living donor LT (LDLT) in Taiwan. The cost of LDLT varies in different countries depending on the insurance system, the costs of the facility, and staff. In this study we aimed to investigate cost outcomes and determinants of LDLT in Taiwan. METHODS: From January 2014 to December 2015, 184 LDLT patients were enrolled in a study performed at the Kaohsiung Chang Gung Memorial Hospital. Patients' transplantation costs were defined as expense from immediately after surgery to discharge during hospitalization for LDLT. Antiviral therapy and hepatitis B immunoglobulin (HBIG) for prevention of hepatitis B virus (HBV) were included, but direct-acting antiviral (DAA) therapy for hepatitis C (HCV) was excluded. RESULTS: The median total, intensive care unit (ICU), and ward costs of LT were US$64,250, $43,357, and $16,138 (currency ratio 1:30), respectively. HBV significantly increased the total cost of LT, followed by postoperative reintubation and bile duct complications. CONCLUSION: The charges associated with anti-HBV viral therapy and HBIG increase the cost of LDLT. Disease severity of liver cirrhosis showed less importance in predicting cost. Postoperative complications such as reintubation or bile duct complications should be avoided to reduce the cost of LT.

Change in symptom clusters in head and neck cancer patients undergoing postoperative radiotherapy: A longitudinal study.

PURPOSE: Research on symptom clusters is a newly emerging field in oncology; however, little evidence regarding symptom clusters in head and neck cancer (HNC) is currently available. To clarify this under-researched area, we investigated symptom clusters among patients with HNC treated with surgery and postoperative radiotherapy. We also examined the pattern of symptom clusters throughout the treatment course. METHOD: A convenience sample of 100 patients with HNC was recruited in the Ear, Nose, and Throat unit of a medical center in Taiwan. Before undergoing postoperative radiotherapy, patients were asked to complete the MD Anderson Symptom Inventory and a demographic sheet. Patients completed the same inventory questionnaire at week 1, 2, 3, 4, 5, and 6 of radiotherapy. RESULT: Two symptom clusters were observed, and they were stable throughout the course of radiotherapy. Cluster 1, the HNC-specific cluster, comprised the symptoms of pain, dry mouth, lack of appetite, sleep disturbance, fatigue, drowsiness, distress, and sadness. Cluster 2, the gastrointestinal cluster, included nausea, vomiting, numbness, shortness of breath, and difficulty remembering. CONCLUSION: This study advanced our knowledge of symptom clusters in patients with HNC. The results are expected to contribute to the development of appropriate assessment and nursing interventions targeting multiple symptoms that may coexist in postoperative radiotherapy.

AFP role in predicting recurrence of hepatocellular carcinoma after living donor liver transplantation in HCV patients.

HCC is one of the leading causes of death worldwide. Liver transplantation including living donor transplantation is the best available treatment. We have analyzed our experience with LDLT in patients with HCC and HCV in order to determine if alpha feto-protein (AFP) is a better predictor of recurrence than the tumor burden. We have identified all patients with HCV related liver disease and HCC who have undergone LDLT in one center during the period from December 2000 to December 2014. Outcomes from the prospective database were compared for patients who met Milan criteria (single tumor ≤5 cm, maximum of 3 total tumors with none >3 cm) or not. Uni- and multi-variable analyses of factors influencing recurrence free survival (RFS) were performed. A total of 142 patients with HCC and HCV associated liver disease underwent LDTL during the study period. RFS was 96.4% at 1 years, 91.8% at 3 years and 91.8% at 5 years. Gender, model for End-Stage Liver disease (MELD), pre-transplant therapy, AFP level, tumor number, total tumor size were predictors of recurrence on univariable analysis. On multivariable analysis MELD score (Hazard ratio (HR) 1.16) and Log10 AFP (HR 3.14) were predictors of RFS. In the ROC curve analysis with an AUC of 0.76 the optimal cut-off value of AFP was 26ng/mL. In conclusion MELD score and pre-transplant AFP predict recurrence after LDLT for HCC with HCV infection.

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Phosphorylation of threonine residues on Shc promotes ligand binding and mediates crosstalk between MAPK and Akt pathways in breast cancer cells.

Scaffold proteins play important roles in regulating signalling network fidelity, the absence of which is often the basis for diseases such as cancer. In the present work, we show that the prototypical scaffold protein Shc is phosphorylated by the extracellular signal-regulated kinase, Erk. In addition, Shc threonine phosphorylation is specifically up-regulated in two selected triple-negative breast cancer (TNBC) cell lines. To explore how Erk-mediated threonine phosphorylation on Shc might play a role in the dysregulation of signalling events, we investigated how Shc affects pathways downstream of EGF receptor. Using an in vitro model and biophysical analysis, we show that Shc threonine phosphorylation is responsible for elevated Akt and Erk signalling, potentially through the recruitment of the 14-3-3 ζ and Pin-1 proteins.

Laparoscopic Repair of Incisional Hernia Following Liver Transplantation-Early Experience of a Single Institution in Taiwan.

BACKGROUND: Ventral incisional hernia (VIH) is not uncommon following liver transplantation. Open repair was traditionally adopted for its management. Laparoscopic repair of VIH has been performed successfully in nontransplant patients with evidence of reduced recurrence rates and hospital stay. However, the application of VIH in post-transplantation patients has not been well established. Herein, we provide our initial experience with laparoscopic repair of post-transplantation VIH. METHODS: From March 2015 to March 2016, 18 cases of post-transplantation VIH were subjected to laparoscopic repair (laparoscopy group). A historical control group of 17 patients who underwent conventional open repair (open group) from January 2013 to January 2015 were identified for comparison. The demographics and clinical outcomes were retrospectively compared. RESULTS: There were no significant differences among basic demographics between the 2 groups. No conversion was recorded in the laparoscopy group. Recurrence of VIH up to the end of the study period was not noted. In the laparoscopy group, the minor complications were lower (16.7% vs 52.9%; P = .035), the length of hospital stay was shorter (3 d vs 7 d, P = .007), but the median operative time was longer (137.5 min vs 106 min; P = .003). CONCLUSIONS: Laparoscopic repair of post-transplantation VIH is a safe and feasible procedure with shorter length of hospital stay.

[Effect and mechanism of silibinin on the inhibition of ALK positive NSCLC cells by sensitizing crizotinib].

Objective: To explore the synergistic effect of silibinin combined with crizotinib on anaplastic lymphoma kinase positive (ALK+ ) non-small cell lung cancer (NSCLC) cells and its mechanism. Methods: H2228 and H3122 cells were treated with silibinin, crizotinib alone or in combination. Cell proliferation was measured by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and colony formation assay. Migration or invasion ability was tested by wound healing assay or transwell assay, respectively. Expressions of E-Cadherin and vimentin protein were examined by immunofluorescence staining. The protein expressions of ALK, p-ALK, E-Cadherin and Vimentin were detected by western blotting.The anti-cancer effect of silibinin combined with crizotinib in vivo was determined by subcutaneously injecting 2×10(6) H2228 cells into immunodeficient nude mice. Results: The result of MTT assay showed that the cell viability of H2228 or H3122 treated with 100 µmol/L silibinin was (88.38±4.10)% or (72.27±3.62)%, respectively, marginally decreased compared with that of the control. The 50% inhibitory concentration (IC(50)) of H2228 cells treated with crizotinib alone or combined with 100 µmol/L silibinin was (917.10±7.75) nmol/L or (238.73±7.67) nmol/L, respectively. The IC(50) of H3122 cells treated with crizotinib alone or combined with 100 µmol/L silibinin was (472.50±15.70) nmol/L or (206.10±12.01) nmol/L, respectively. The IC(50s) of H2228 and H3122 cells were significantly decreased by combined treatment of crizotinib and silibinin compared to crizotinib treatment alone (P<0.01). When compared with the control group, colony forming ratios of H2228 cells were (83.34±2.72)% in 100 µmol/L silibinin treatment group, (69.42±3.06)% in 400 nmol/L crizotinib treatment group and (27.32±1.42)% in combined treatment group. When compared with the control group, colony forming ratios of H3122 cells were (84.45±5.67)% in 100 µmol/L silibinin treatment group, (45.02±5.83)% in 400 nmol/L crizotinib treatment group and (17.43±3.83)% in combined treatment group. Silibinin combined with crizotinib treatment significantly inhibited the colony formation ability of H2228 and H3122 cells (P<0.01). Migration and invasion results showed that combined treatment of crizotinib and silibinin markedly inhibited the migration and invasion ability of H2228 cells (P<0.01). Western blot results indicated that treated with silibinin alone or in combination of crozitinib for 48 hours, the protein level of E-cadherin in H2228 cells was upregulated, while the expressions of p-ALK and vimentin were downregulated, without obvious alteration of ALK protein expression. In the xenograft model, the mean tumor weight was (9.40±2.58)g in crizotinib treatment group and (4.58±1.07)g in the combined treatment group. The inhibitory effect of tumor growth in vivo of combined treatment was significantly superior to that of crizotinib treatment alone (P<0.05). Conclusion: Silibinin enhances the inhibitory effect of crizotinib on ALK positive NSCLC cells, which may be associated with suppression of ALK activity and mesenchymal-epithelial transition.

Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia.

Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.

Eradication of hepatitis C virus profoundly prolongs survival in hepatocellular carcinoma patients receiving transarterial chemoembolization.

Adjuvant pegylated interferon plus ribavirin treatment (PegIFN/RBV) reduces recurrence and prolongs survival in early stage hepatocellular carcinoma (HCC) patients with chronic hepatitis C (CHC) infection receiving resection or ablation. However, the impact of antiviral therapy in intermediate and advanced stage of CHC-HCC patients is uncertain. This study aimed to investigate the impact PegIFN/RBV treatment on recurrence-free interval and survival in patients with HCC receiving transarterial chemoembolization (TACE). From 2010 to 2013, 274 CHC patients from a 1073 patient-based cohort composed of freshly diagnosed HCC and receiving TACE treatment the Chang Gung Memorial Hospital, Linkou Medical Center were recruited. Propensity score matching (PSM) (age, gender, AST to Platelet Ratio Index (APRI), tumour size, tumour number and Child-Turcotte-Pugh score) with the ratio 1:2 for patients with and without PegIFN/RBV treatment was performed. Statistics were performed with SPSS V.20 (IBM, USA). After matching, 153 patients were analysed and 27 patients (17.6%) achieved sustained virologic response (SVR). The 2-year cumulative overall survival rate and recurrence-free survival rate among patients with SVR, non-SVR, and untreated were 85.2% vs 58.3% vs 69.6% (P=.001) and 73.3% vs 53.8% vs 58.5% (P=.013). By Cox regression analysis, non-SVR, untreated, increase CTP score and nonresponder to TACE were independent factors related to mortality. The SVR achieved by PegIFN/RBV treatment markedly improves survival and reduces tumour recurrence in CHC-HCC patients receiving TACE treatment after complete response.

The potential impact of sleep-related movement disorders on stroke risk: a population-based longitudinal study.

BACKGROUND: Sleep-related movement disorders (SRMD) have been shown to increase the risk of cardiovascular diseases. However, the relationship between SRMD and stroke remains unclear. AIM: To explore the relationship between SRMD and stroke in the general population. DESIGN: Two cohorts of patients with SRMD and without SRMD were followed up for the occurrence of hemorrhagic and ischemic stroke. METHODS: The study cohort enrolled 604 patients who were initially diagnosed as SRMD between 2000 and 2005. 2,416 age- and sex-matched patients without prior stroke were selected as the comparison cohort. A Cox-proportional hazard regression analysis was performed for multivariate adjustment. RESULTS: Patients with SRMD had a higher risk for developing all-cause stroke [adjusted hazard ratio (HR) = 2.29, 95% confidence interval (CI) = 1.42-3.80]. Patients of below 45 years old had the greatest stroke risk (HR = 4.03, 95% CI = 3.11-5.62), followed by patients aged ≥65 years (HR = 2.64, 95% CI = 1.12-3.44) and 45-64 years (HR = 1.07, 95% CI = 1.02-1.71). The age-stratified analysis suggested that the increased risk of hemorrhagic stroke was more significant than ischemic stroke among all age groups. Furthermore, males with SRMD were at greater risk to develop all-cause stroke (HR = 2.98, 95% CI = 1.74-4.50) than that of females (HR = 1.94, 95% CI = 1.01-3.77). CONCLUSIONS: Patients with SRMD were found to have an increased risk of all-cause stroke along with a higher possibility of hemorrhagic stroke over ischemic stroke.