Closed-loop process for selective leaching and recovery of palladium from spent auto-exhaust catalysts using iodotrihalide ionic liquids.

The recovery of palladium from spent auto-exhaust catalysts (SAE-catalysts) is of great significance for resource sustainability. Herein, we proposed an efficient closed-loop leaching and recovery method for palladium from SAE-catalysts using iodotrihalide ionic liquids (ILs). Recovery design was explored aimed at green leaching and process simplification. Iodotrihalide ILs exhibited exceptional performance in terms of leaching efficiency (99.1%), selectivity (selectivity > 6.8 ×103) and reusability (over 6 cycles). The mechanism study revealed that excellent leaching performance was attributed to the redox and complexation. Additionally, the chemical reaction-controlled model was best suited to describe the leaching process. Notably, under the optimal conditions determined by the response surface methodology, a high-purity Pd(II) solution (purity > 99.8%) was obtained. More significantly, it was ideal for practical applications due to the low-viscosity (36.0 cP), mild (55 °C) and one-step leaching and recovery. In conclusion, this work provides an eco-friendly method for recovering palladium from SAE-catalysts with its non-high corrosiveness and low environmental impact.

Association of leisure sedentary time with common chronic disease risk factors: A longitudinal study of China Health and Nutrition Surveys.

BACKGROUND: Although the common risk factors were identified and controlled for many years, the overall prevalence of chronic diseases continued to increase in China. OBJECTIVE: We presumed the leisure sedentariness as a latent but pivotal factor of chronic diseases, and examined its distribution and changing trend, analysed its interaction effects on common risk factors, which could provide a new perspective for the prevention and management. METHODS: A total of 5013 participants were screened out from China Health and Nutrition Survey. Random-effects ordered logistic models were used for ordinal dependent variables, and fixed-effects or random-effects logit models were used for binary dependent variables. RESULTS: From 2004 to 2011, the prevalence of high leisure sedentary time (LSED) increased by 58.58%. Members of the high LSED group were likely to choose fast food, salty snacks, soft drinks and more likely to smoke or drink alcohol compared with those of the low LSED group. However, they preferred walking, sports and body building more than those of the low LSED group. CONCLUSIONS: For the unhealthy dietary, tobacco and alcohol consumption, more targeted introduction and guidance related to sedentary time should be promoted. Meanwhile, the appeal for physical exercise as well as adequate facilities should be initiated.

Silk sericin has significantly hypoglycaemic effect in type 2 diabetic mice via anti-oxidation and anti-inflammation.

The sericin protein from silk-processing waste added to the normal diet at 0.8% (g%) level was administered orally to type 2 diabetic (T2D) mice to investigate its hypoglycaemic effects and mechanism. The oral protein is in the form of silk sericin hydrolysate, obtained from a boiling treatment of 0.025% calcium hydroxide solution. The protein significantly decreased fasting blood glucose, fasting plasma insulin, and glycosylated serum protein levels; improved oral glucose tolerance and insulin tolerance, and enhanced antioxidative activities. The protein could ameliorate the pathological damage in pancreatic ß-cells and the liver tissue. It enhanced the expression of key proteins and enzymes, including insulin receptor, insulin receptor substrate, PI3K, phosphorylated-AKT, hepatic kinase, GLUT4, glycogen synthase, GSK3ß, GLK, PFK1, PKM2, and AMPKα, which are related to insulin metabolism and glycolysis. The protein also reduced the expression of G6Pase, PCK, and ACC, which are related to gluconeogenesis and lipid metabolism in the liver, and decreased the expression of TNF-α, IL-6, P65, and IKKß related to inflammation. In general, sericin could maintain normal glucose levels and regulate insulin secretion, insulin and lipid metabolism, and inhibition of inflammation. Therefore, sericin protein could be developed into a novel functional health food with significantly hypoglycaemic effect.

Prospective study revealed prognostic significance of responses in leptomeningeal metastasis and clinical value of cerebrospinal fluid-based liquid biopsy.

OBJECTIVE: Leptomeningeal metastasis (LM) secondary to non-small cell lung cancer (NSCLC) is a devastating complication associated with poor prognosis. Diagnosis and assessment of responses in LM have been challenging due to limitation of traditional imaging tools and lack of standard evaluation criteria until very recently. To bridge this gap, we conducted the first prospective, observational study in cytologically diagnosed NSCLC-LM patients (NCT02803619). PATIENTS AND METHODS: A total of 49 NSCLC-LM patients were enrolled. LM responses were evaluated with a composite endpoint integrating neurological symptoms, cerebrospinal fluid (CSF) parameters and central nervous system (CNS) imaging. Primary outcome was overall survival (OS) after diagnosis of LM. Exploratory endpoint was the association between OS and prognostic factors. Primary tumor and CSF samples were collected for biomarker analysis. RESULTS: 93.9% of the cohort carried oncogenic drivers, and 85.7% harbored EGFR activating mutations. Median OS since LM diagnosis of the overall population was 9.7 months. EGFR mutant LM patients had a longer survival compared with wildtype ones. LM clinical responses assessed by the composite endpoint showed significant correlation with OS. Status of EGFR activating mutations was highly concordant between primary tumor and CSF. T790 M occurrence in CNS lesions was relatively rare and associated with intracranial exposure level of EGFR-TKIs. CONCLUSION: Our results supported the composite endpoint for objective response evaluation of LM was valid, suggested LM outweighed peripheral lesions on the impact to patient survival, and emphasized the urge and promise of development of CNS-penetrant targeted therapies to improve clinical outcome of NSCLC-LM patients.

Gynura divaricata rich in 3, 5-/4, 5-dicaffeoylquinic acid and chlorogenic acid reduces islet cell apoptosis and improves pancreatic function in type 2 diabetic mice.

BACKGROUND: Diabetes mellitus is one of the most common chronic diseases that accompanied by severe complications. Gynura divaricata (GD), a medicinal and edible plant that is usually used for the treatment of diabetes. Therefore, this study investigates the chemical components of GD with hypoglycemic effect and the possible mechanism lowering blood sugar in T2D diabetic mice. METHODS: The methanol extract of GD was analysed by HPLC-DAD. And then mice with type 2 diabetes induced by a high-fat diet in combination with streptozotocin feed the diet containing lyophilized GD powder for 4 weeks. During this period, fasting blood glucose (FBG) levels and body weight were measured. RESULTS: GD was rich in four bioactive components of dicaffeoylquinic acid and chlorogenic acid. These components occupied about 2.37% in the GD powder in which the highest level was 3, 5-dicaffeoylquinic acid. Oral GD significantly reduced FBG, fasting serum insulin, and glycosylated serum protein levels, and enhanced antioxidative activities. HE-staining showed that the pathological damage in pancreatic ß-cells was ameliorated. An immunohistochemical assay also showed that GD promoted marked pancreatic ß-cell regeneration. GD also caused notable increase in GLUT2, GK, MafA, PDX-1, and Bcl-2 as well as reduction in Bax and caspase-3 expression as shown by western blot analysis. CONCLUSIONS: GD exerts the pronounced hypoglycaemic effect by inhibiting islet cell apoptosis and improving pancreatic function. Therefore, GD might have a potential to improve diabetes.

Author Correction: Large T1 contrast enhancement using superparamagnetic nanoparticles in ultra-low field MRI.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Large T1 contrast enhancement using superparamagnetic nanoparticles in ultra-low field MRI.

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely investigated and utilized as magnetic resonance imaging (MRI) contrast and therapy agents due to their large magnetic moments. Local field inhomogeneities caused by these high magnetic moments are used to generate T2 contrast in clinical high-field MRI, resulting in signal loss (darker contrast). Here we present strong T1 contrast enhancement (brighter contrast) from SPIONs (diameters from 11 nm to 22 nm) as observed in the ultra-low field (ULF) MRI at 0.13 mT. We have achieved a high longitudinal relaxivity for 18 nm SPION solutions, r1 = 615 s-1 mM-1, which is two orders of magnitude larger than typical commercial Gd-based T1 contrast agents operating at high fields (1.5 T and 3 T). The significantly enhanced r1 value at ultra-low fields is attributed to the coupling of proton spins with SPION magnetic fluctuations (Brownian and Néel) associated with a low frequency peak in the imaginary part of AC susceptibility (χ"). SPION-based T1-weighted ULF MRI has the advantages of enhanced signal, shorter imaging times, and iron-oxide-based nontoxic biocompatible agents. This approach shows promise to become a functional imaging technique, similar to PET, where low spatial resolution is compensated for by important functional information.

Morusin suppresses A549 cell migration and induces cell apoptosis by downregulating the expression of COX­2 and VEGF genes.

The present study aimed to examine the inhibitory effects of morusin on the human lung cancer cell line A549. Various doses of morusin were applied to A549 cells and the effects were assessed by wound­healing and MTT assays, flow cytometry analysis of apoptosis, a mitochondrial membrane potential assay and RT­PCR. The results indicated that the concentrations of 10 and 30 µg/ml morusin significantly inhibited A549 cells and signs of apoptosis were observed. In addition, the wound­healing assay results revealed that morusin inhibited cell migration. Flow cytometry analysis demonstrated that the rates of apoptosis were 16.46, 55.80 and 70.80% following treatment with 1, 10 and 30 µg/ml of morusin, respectively, and that the mitochondrial membrane potentials also decreased with the increase of morusin. Furthermore, morusin increased the antioxidant activities of the A549 cells. RT­PCR analysis revealed that the expression levels of COX­2 and VEGF were downregulated following morusin treatment. In conclusion, morusin significantly inhibited the proliferation of the lung cancer cell line A549, and may have affected the invasion and migration of the cells by downregulating the expression of tumor angiogenesis­related genes.

Mulberry branch bark powder significantly improves hyperglycemia and regulates insulin secretion in type II diabetic mice.

This experiment, based on the previous study on R. mori, introduces whole mulberry branch powder into the diet to treat diabetic mice. Mulberry branch bark powder (MBBP) was administered orally to streptozotocin (STZ)-induced type II diabetic (T2D) mice to investigate hypoglycemic effects. After a 4-week period of diet consumption containing 5%, 10% and 20% MBBP, the fasting blood glucose, body weight and the related western blotting were measured, pathologic and immunohistochemical were observed. The 20% MBBP group showed a significant reduction in hyperglycemia and hyperinsulinemia; fasting blood glucose and insulin decreased from 25.0 to 14.8 mmol/L and 26.5 to 16.0 mU/L, respectively. Pathologic and immunohistochemical observation showed that MBBP administration lead to the repair of pancreas cells and restoration of insulin secretion. Dietary MBBP was associated with the decrease in the contents of 3, 4-methylenedioxeamphetamine, 8-OHdG, aspartate aminotransferase, and alanine aminotransferase, and the increase in antioxidative ability and glucose tolerance. Western blotting (WB) analysis suggested that MBBP decreased the TNF-α levels, thus relieving inflammation and improving liver function. It also led to the downregulation of apoptosis factor expression. WB also confirmed that MBBP enhanced the gene expression of the key enzymes: insulin receptor, insulin receptor substrate, p-AKT, GSK3ß, glycogen synthase, G6Pase and phosphoenolpyruvate carboxykinase, which are related to glucose metabolism in the liver, and increase the expression of the genes PDX-1, GLUT2, MafA, and glucokinase, related to insulin secretion. Thus, oral administration of MBBP regulated insulin secretion and effectively maintained normal levels of glucose metabolism in mice, which may be done by improving the antioxidant capacity and activating insulin signaling with T2D..

PD-L1 expression and its relationship with oncogenic drivers in non-small cell lung cancer (NSCLC).

In order to explore the potential patient population who could benefit from anti PD-1/PD-L1 mono or combination therapies, this study aimed to profile a panel of immunotherapy related biomarkers (PD-1, PD-L1, CTLA-4 and CD8) and targeted therapy biomarkers (EGFR, KRAS, ALK, ROS1 and MET) in NSCLC.Tumor samples from 297 NSCLC patients, including 156 adenocarcinomas (AD) and 129 squamous cell carcinomas (SCC), were analyzed using immunohistochemistry, immunofluorescence, sequencing and fluorescence in situ hybridization.43.1% of NSCLC patients had PD-L1 positive staining on ≥ 5% tumor cells (TC). Furthermore, dual color immunofluorescence revealed that the majority of PD-L1/CD8 dual positive tumor infiltrating lymphocytes (TIL) had infiltrated into the tumor core. Finally, combined analysis of all eight biomarkers showed that tumor PD-L1 positivity overlapped with known alterations in NSCLC oncogenic tumor drivers in 26% of SCC and 76% of AD samples.Our illustration of the eight biomarkers' overlap provides an intuitive overview of NSCLC for personalized therapeutic strategies using anti-PD-1/PD-L1 immune therapies, either as single agents, or in combination with targeted therapies. For the first time, we also report that PD-L1 and CD8 dual positive TILs are predominantly located within the tumor core.

AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases.

Non-small-cell lung cancer patients with activating mutations in epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) treatment. Nevertheless, patients often develop central nervous system (CNS) metastases during treatment, even when their extracranial tumors are still under control. In the absence of effective options, much higher doses of EGFR TKIs have been attempted clinically, with the goal of achieving high enough drug concentrations within the CNS. Although limited tumor responses have been observed with this approach, the toxicities outside the CNS have been too high to tolerate. We report the discovery and early clinical development of AZD3759, a selective EGFR inhibitor that can fully penetrate the blood-brain barrier (BBB), with equal free concentrations in the blood, cerebrospinal fluid, and brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer models and prevents the development of BM in nude mice. An early clinical study in patients with BM and LM treated with AZD3759 confirms its BBB-penetrant properties and antitumor activities. Our data demonstrate the potential of AZD3759 for the treatment of BM and LM and support its further clinical evaluation in larger trials.

Expression of potential biomarkers associated with homologous recombination repair in patients with ovarian or triple-negative breast cancer.

BACKGROUND: Poly(ADP)-ribose polymerase (PARP) inhibitors such as olaparib can induce cell death in cancer cells with homologous recombination (HR) DNA repair deficiencies, such as BRCA1/2 mutations. AIM: To identify prognostic biomarkers of long-term outcomes in cancer patients. METHODS: Immunohistochemistry was used to analyse expression of key HR pathway proteins (ATM, ATR, BRCA1, MDC1, MRE11) and PARP-1 in 100 serous ovarian cancer (SOC) and 100 triple-negative breast cancer (TNBC) tumour samples from Japanese patients. RECIST assessment was used. RESULTS: Patient demographic data and BRCA1/2 mutation status were unavailable. Most proteins listed previously were detected in > 80% of tissue samples, with BRCA1 expression detected in 60-65%. A potential link between BRCA1 expression and overall survival (M stage adjusted) in SOC patients was observed, but was not statistically significant after multiple testing adjustment. Correlations between other biomarker expression and survival were not observed. In TNBC patients, MDC1 staining was associated with progressive disease, but this was not statistically significant; the analysis did not identify significant correlations between biomarker expression and disease control. Limited event numbers prevented assessment of the prognostic value of BRCA1 in TNBC. CONCLUSION: BRCA1 expression may be a candidate for a prognostic biomarker in SOC. Further studies are warranted.

Relationships between Chromosome 7 Gain, MET Gene Copy Number Increase and MET Protein Overexpression in Chinese Papillary Renal Cell Carcinoma Patients.

To investigate the relationships between Chromosome 7 gain, mesenchymal-epithelial transition factor (MET) gene copy number increase and MET protein overexpression in Chinese patients with papillary renal cell carcinoma (PRCC), immunohistochemistry (IHC), immunofluorescence (IF) and fluorescence in situ hybridization (FISH) were performed on 98 formalin-fixed, paraffin-embedded (FFPE) PRCC samples. Correlations between MET gene copy number increase, Chromosome 7 gain and MET protein overexpression were analyzed statistically. A highly significant correlation was observed between the percentage of tumor cells with MET gene copy number ≥3 and CEP7 copy number ≥3 (R2 = 0.90, p<0.001) across two subtypes of PRCC. In addition, the percentage of tumor cells with MET gene copy number ≥3 was found to increase along with increases in MET IHC score. This correlation was further confirmed in those PRCC tumor cells with average MET gene copy number >5 using combined IF and FISH methodology. Overall, this study provides evidence that Chromosome 7 gain drives MET gene copy number increase in PRCC tumors, and appears to subsequently lead to an increase in MET protein overexpression in these tumor cells. This supports MET activation as a potential therapeutic target in sporadic PRCC.

Intra-Tumoral Heterogeneity of HER2, FGFR2, cMET and ATM in Gastric Cancer: Optimizing Personalized Healthcare through Innovative Pathological and Statistical Analysis.

Current drug development efforts on gastric cancer are directed against several molecular targets driving the growth of this neoplasm. Intra-tumoral biomarker heterogeneity however, commonly observed in gastric cancer, could lead to biased selection of patients. MET, ATM, FGFR2, and HER2 were profiled on gastric cancer biopsy samples. An innovative pathological assessment was performed through scoring of individual biopsies against whole biopsies from a single patient to enable heterogeneity evaluation. Following this, false negative risks for each biomarker were estimated in silico. 166 gastric cancer cases with multiple biopsies from single patients were collected from Shanghai Renji Hospital. Following pre-set criteria, 56 ~ 78% cases showed low, 15 ~ 35% showed medium and 0 ~ 11% showed high heterogeneity within the biomarkers profiled. If 3 biopsies were collected from a single patient, the false negative risk for detection of the biomarkers was close to 5% (exception for FGFR2: 12.2%). When 6 biopsies were collected, the false negative risk approached 0%. Our study demonstrates the benefit of multiple biopsy sampling when considering personalized healthcare biomarker strategy, and provides an example to address the challenge of intra-tumoral biomarker heterogeneity using alternative pathological assessment and statistical methods.

Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.

PURPOSE: Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. PATIENTS AND METHODS: In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). RESULTS: One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. CONCLUSION: Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

Patient-Derived Gastric Carcinoma Xenograft Mouse Models Faithfully Represent Human Tumor Molecular Diversity.

Patient-derived cancer xenografts (PDCX) generally represent more reliable models of human disease in which to evaluate a potential drugs preclinical efficacy. However to date, only a few patient-derived gastric cancer xenograft (PDGCX) models have been reported. In this study, we aimed to establish additional PDGCX models and to evaluate whether these models accurately reflected the histological and genetic diversities of the corresponding patient tumors. By engrafting fresh patient gastric cancer (GC) tissues into immune-compromised mice (SCID and/or nude mice), thirty two PDGCX models were established. Histological features were assessed by a qualified pathologist based on H&E staining. Genomic comparison was performed for several biomarkers including ERBB1, ERBB2, ERBB3, FGFR2, MET and PTEN. These biomarkers were profiled to assess gene copy number by fluorescent in situ hybridization (FISH) and/or protein expression by immunohistochemistry (IHC). All 32 PDGCX models retained the histological features of the corresponding human tumors. Furthermore, among the 32 models, 78% (25/32) highly expressed ERBB1 (EGFR), 22% (7/32) were ERBB2 (HER2) positive, 78% (25/32) showed ERBB3 (HER3) high expression, 66% (21/32) lost PTEN expression, 3% (1/32) harbored FGFR2 amplification, 41% (13/32) were positive for MET expression and 16% (5/32) were MET gene amplified. Between the PDGCX models and their parental tumors, a high degree of similarity was observed for FGFR2 and MET gene amplification, and also for ERBB2 status (agreement rate = 94~100%; kappa value = 0.81~1). Protein expression of PTEN and MET also showed moderate agreement (agreement rate = 78%; kappa value = 0.46~0.56), while ERBB1 and ERBB3 expression showed slight agreement (agreement rate = 59~75%; kappa value = 0.18~0.19). ERBB2 positivity, FGFR2 or MET gene amplification was all maintained until passage 12 in mice. The stability of the molecular profiles observed across subsequent passages within the individual models provides confidence in the utility and translational significance of these models for in vivo testing of personalized therapies.

Oncogenic HER2 fusions in gastric cancer.

BACKGROUND: Genetic amplification of HER2 drives tumorigenesis and cancer progression in a subset of patients with gastric cancer (GC), and treatment with trastuzumab, a humanized HER2-neutralizing antibody, improves the overall survival rate of HER2-positive patients. However, a considerable portion of the patients does not respond to trastuzumab and the molecular mechanisms underlying the intrinsic resistance to anti-HER2 therapy in GC is not fully understood. METHODS: We performed whole-transcriptome sequencing on 21 HER2-positive tumor specimens from Chinese GC patients. Whole genome sequencing was performed on the three samples with HER2 fusion to discover the DNA integration structure. A multicolor FISH assay for HER2 split screening was conducted to confirm HER2 fusion and IHC (HercepTest™) was used to detect the membranous expression of HER2. Fusion cDNA were transfected into NIH/3T3 cells and generate stable cell line by lentivirus. The expression of exogenous HER2 fusion proteins and pHER2 were examined by western blot analysis. In vitro efficacy studies were also conducted by PD assay and softagar assay in cell line expression wild type and fusion HER2. T-DM1 was used to assess its binding to NIH/3T3 cells ectopically expressing wild-type and fusion HER2. Finally, the anti-tumor efficacy of trastuzumab was tested in NIH/3 T3 xenografts expressing the HER2 fusion variants. RESULTS: We identified three new HER2 fusions with ZNF207, MDK, or NOS2 in 21 HER2-amplified GC samples (14%; 3/21). Two of the fusions, ZNF207-HER2, and MDK-HER2, which are oncogenic, lead to aberrant activation of HER2 kinase. Treatment with trastuzumab inhibited tumor growth significantly in xenografts expressing MDK-HER2 fusion. In contrast, trastuzumab had no effect on the growth of xenografts expressing ZNF207-HER2 fusion, due to its inability to bind to trastuzumab. CONCLUSIONS: Our results provide the molecular basis of a novel resistance mechanism to trastuzumab-based anti-HER2 therapy, supporting additional molecule stratification within HER2-positive GC patients for more effective therapy options.

Evaluation of Trastuzumab Anti-Tumor Efficacy and its Correlation with HER-2 Status in Patient-Derived Gastric Adenocarcinoma Xenograft Models.

The aim of the study was to investigate trastuzumab anti-tumor efficacy and its correlation with HER-2 status in primary xenograft models derived from Chinese patients with gastric adenocarcinoma. Patient-derived gastric adenocarcinoma xenograft (PDGAX) mouse models were firstly generated by implanting gastric adenocarcinoma tissues from patients into immune deficient mice. A high degree of histological and molecular similarity between the PDGAX mouse models and their corresponding patients' gastric adenocarcinoma tissues was shown by pathological observation, HER-2 expression, HER-2 gene copy number, and mutation detection. Based on Hoffmann's criteria in gastric cancer, three models (PDGAX001, PDGAX003 and PDGAX005) were defined as HER-2 positive with fluorescence in situ hybridization (FISH) amplification or immunohistochemistry (IHC) 2+/ 3+, while two models (PDGAX002, PDGAX004) were defined as HER-2 negative. Upon trastuzumab treatment, significant tumor regression (105 % TGI) was observed in model PDGAX005 (TP53 wt), while moderate sensitivity (26 % TGI) was observed in PDGAX003, and resistance was observed in PDGAX001, 002 and 004. A significant increase in HER-2 gene copy number was only observed in PDGAX005 (TP53 wt). Interestingly, trastuzumab showed no efficacy in PDGAX001 (HER2 IHC 3+ and FISH amplification, but with mutant TP53). Consistent with this finding, phosphor-HER2 modulation by trastuzumab was observed in model PDGAX005, but not in PDGAX001.

Visualization of a ferromagnetic metallic edge state in manganite strips.

Recently, broken symmetry effect induced edge states in two-dimensional electronic systems have attracted great attention. However, whether edge states may exist in strongly correlated oxides is not yet known. In this work, using perovskite manganites as prototype systems, we demonstrate that edge states do exist in strongly correlated oxides. Distinct appearance of ferromagnetic metallic phase is observed along the edge of manganite strips by magnetic force microscopy. The edge states have strong influence on the transport properties of the strips, leading to higher metal-insulator transition temperatures and lower resistivity in narrower strips. Model calculations show that the edge states are associated with the broken symmetry effect of the antiferromagnetic charge-ordered states in manganites. Besides providing a new understanding of the broken symmetry effect in complex oxides, our discoveries indicate that novel edge state physics may exist in strongly correlated oxides beyond the current two-dimensional electronic systems.

Assessment and prognostic analysis of EGFR, HER2, and HER3 protein expression in surgically resected gastric adenocarcinomas.

AIM: To investigate the significance of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, and HER3 expression on survival outcomes in Chinese gastric cancer patients. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded specimens from 121 patients who underwent gastrectomy at Shanghai Renji Hospital from 2007-2010 were retrospectively examined. Fluorescence in situ hybridization and immunohistochemistry techniques were used to identify gene amplification and protein overexpression. Correlations between the expression or amplification of HER family genes and clinicopathological parameters were then determined using statistical analysis. RESULTS: EGFR protein overexpression, an increase in HER2 copy number and gene amplification, and HER3 protein overexpression were identified in 33.1%, 17.4%, and 62.0% of samples, respectively. Statistical analysis showed a significant association between EGFR expression and tumor invasion depth or tumor stage. HER2 was also shown to be significantly associated with the tumor grade. In addition, EGFR protein overexpression was found to be significantly associated with worse overall survival (P=0.03). CONCLUSION: The HER family members showed a high expression in gastric cancer. EGFR protein expression was associated with overall survival.