Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Precision Control of the Electron Longitudinal Bunch Shape Using an Emittance-Exchange Beam Line.

We report on the experimental generation of relativistic electron bunches with a tunable longitudinal bunch shape. A longitudinal bunch-shaping (LBS) beam line, consisting of a transverse mask followed by a transverse-to-longitudinal emittance exchange (EEX) beam line, is used to tailor the longitudinal bunch shape (or current profile) of the electron bunch. The mask shapes the bunch's horizontal profile, and the EEX beam line converts it to a corresponding longitudinal profile. The Argonne wakefield accelerator rf photoinjector delivers electron bunches into a LBS beam line to generate a variety of longitudinal bunch shapes. The quality of the longitudinal bunch shape is limited by various perturbations in the exchange process. We develop a simple method, based on the incident slope of the bunch, to significantly suppress the perturbations.

Fabrication of biodegradable Zn-Al-Mg alloy: Mechanical properties, corrosion behavior, cytotoxicity and antibacterial activities.

In this work, binary Zn-0.5Al and ternary Zn-0.5Al-xMg alloys with various Mg contents were investigated as biodegradable materials for implant applications. Compared with Zn-0.5Al (single phase), Zn-0.5Al-xMg alloys consisted of the α-Zn and Mg2(Zn, Al)11 with a fine lamellar structure. The results also revealed that ternary Zn-Al-Mg alloys presented higher micro-hardness value, tensile strength and corrosion resistance compared to the binary Zn-Al alloy. In addition, the tensile strength and corrosion resistance increased with increasing the Mg content in ternary alloys. The immersion tests also indicated that the corrosion rates in the following order Zn-0.5Al-0.5Mg

Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders caused by various genetic and environmental factors that result in synaptic abnormalities. ASD development is suggested to involve microglia, which have a role in synaptic refinement during development. Autophagy and related pathways are also suggested to be involved in ASDs. However, the precise roles of microglial autophagy in synapses and ASDs are unknown. Here, we show that microglial autophagy is involved in synaptic refinement and neurobehavior regulation. We found that deletion of atg7, which is vital for autophagy, from myeloid cell-specific lysozyme M-Cre mice resulted in social behavioral defects and repetitive behaviors, characteristic features of ASDs. These mice also had increases in dendritic spines and synaptic markers and altered connectivity between brain regions, indicating defects in synaptic refinement. Synaptosome degradation was impaired in atg7-deficient microglia and immature dendritic filopodia were increased in neurons co-cultured with atg7-deficient microglia. To our knowledge, our results are the first to show the role of microglial autophagy in the regulation of the synapse and neurobehaviors. We anticipate our results to be a starting point for more comprehensive studies of microglial autophagy in ASDs and the development of putative therapeutics.

Navigation programs, are they helpful for perioperative care with thyroid cancer patients?

The purpose of this study was to develop and evaluate a navigation program for patients with thyroid cancer. The navigation program was developed following an analysis of the unmet needs of patients who underwent surgery for thyroid cancer. Ninety-nine patients in the control group received usual care, and 95 in the navigation group were managed with a navigation program during the perioperative period. The effectiveness of the navigation program was assessed by administering a questionnaire to both groups. Overall satisfaction scores were significantly higher in the navigation than in the control group (p = .025), as were satisfaction scores on the continuity of information (p < .001), the continuity of management (p = .002), the continuity of relationships with healthcare providers (p<.001), and patient empowerment (p < .001). The newly developed navigation program for patients with thyroid cancer was effective in raising satisfaction levels and in actively managing the disease during the perioperative period.

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Coincidence of late-onset cytomegalovirus-induced myositis and gastritis in a pediatric renal transplant recipient.

An 8-year-old girl with a renal transplant was admitted for myalgia and muscle weakness in both legs over the previous 2 weeks. She also had fever and intermittent epigastric pain. Based on these clinical manifestations, and laboratory and histopathological findings, the diagnosis was coincidence of late-onset cytomegalovirus (CMV)-induced myositis and gastritis in an immunocompromised child with a renal transplant. After administration of intravenous ganciclovir for 3 weeks, her symptoms resolved, with normalization of abnormal muscle enzymes, including lactate dehydrogenase, creatine kinase, aspartate aminotransferase, and the disappearance of CMV viremia.

Carrier Mobility Enhancement of Tensile Strained Si and SiGe Nanowires via Surface Defect Engineering.

Changes in the carrier mobility of tensile strained Si and SiGe nanowires (NWs) were examined using an electrical push-to-pull device (E-PTP, Hysitron). The changes were found to be closely related to the chemical structure at the surface, likely defect states. As tensile strain is increased, the resistivity of SiGe NWs deceases in a linear manner. However, the corresponding values for Si NWs increased with increasing tensile strain, which is closely related to broken bonds induced by defects at the NW surface. Broken bonds at the surface, which communicate with the defect state of Si are critically altered when Ge is incorporated in Si NW. In addition, the number of defects could be significantly decreased in Si NWs by incorporating a surface passivated Al2O3 layer, which removes broken bonds, resulting in a proportional decrease in the resistivity of Si NWs with increasing strain. Moreover, the presence of a passivation layer dramatically increases the extent of fracture strain in NWs, and a significant enhancement in mobility of about 2.6 times was observed for a tensile strain of 5.7%.

Only the chemical state of Indium changes in Mn-doped In3Sb1Te2 (Mn: 10 at.%) during multi-level resistance changes.

We fabricated and characterized the material with Mn (10 at.%: atomic percent) doped In3Sb1Te2 (MIST) using co-sputtering and synchrotron radiation, respectively. The MIST thin film showed phase-changes at 97 and 320 °C, with sheet resistances of ~10 kΩ(sq) (amorphous), ~0.2 kΩ(sq) (first phase-change), and ~10 Ω(sq) (second phase-change). MIST did not exhibit any chemical separation or increased structural instability during either phase-change, as determined with high-resolution x-ray photoelectron spectroscopy. Chemical state changes were only depended for In without concomitant changes of Sb and Te. Apparently, doped Mn atoms can be induced with movement of only In atoms.

2-amino-N-(2,6-dichloropyridin-3-yl)acetamide derivatives as a novel class of HBV capsid assembly inhibitor.

Capsid structure is crucial for the maturation and maintenance of the stable hepatitis B virion. Therefore, chemicals that inhibit capsid assembly might potentially act as potent antiviral compounds. However, only a few chemicals are known to block the capsid assembly process and further viral proliferation. In this study, we present a novel family of capsid assembly inhibitors that act against hepatitis B virus (HBV). Based on X-ray crystallographic data of the HBV core protein (Cp), we built dimer and hexamer structural models to be used in library searches. Several chemicals in the 2-amino-N-(2,6-dichloropyridin-3-yl)acetamide family were predicted to have high affinity for the groove structure in Cp. Using in vitro assembly and the HepG2.2.15 cell culture test, we verified that these chemicals demonstrated inhibitory effects on capsid assembly. Furthermore, we investigated the combinatorial effects of these assembly inhibitor chemicals with lamivudine and revealed that, in combination, they have synergistic inhibitory effects on decreasing viral concentration. We propose that these inhibitors could be utilized as an effective combination treatment against HBV infection.

Aerosol delivery of eukaryotic translation initiation factor 4E-binding protein 1 effectively suppresses lung tumorigenesis in K-rasLA1 mice.

Conventional radiotherapy or chemotherapy for the long-term survival of patients with lung cancer is still difficult for treatment in metastatic and advanced tumors. Therefore, the safe and effective approaches to the treatment of lung cancer are needed. In this study, the effect of delivered eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) on lung cancer progression was evaluated. Recombinant adeno-associated virus (rAAV)-M3/4E-BP1 was delivered into 6-week-old K-rasLA1 lung cancer model mice through a nose-only inhalation system twice a week for 4 weeks. Long-term repeated delivery of 4E-BP1 effectively reduced tumor progression in the lungs of K-rasLA1 mice. Reduction of eIF4E by overexpression of 4E-BP1 resulted in suppression of cap-dependent protein expression of basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF). In addition, delivered 4E-BP1 inhibited the proliferation of lung cancer cells in K-rasLA1 mice model. Our results suggest that long-term repeated viral delivery of 4E-BP1 may provide a useful tool for designing lung cancer treatment.

Co-delivery of LETM1 and CTMP synergistically inhibits tumor growth in H-ras12V liver cancer model mice.

As hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, development of novel therapeutic approaches for HCC is urgently needed. Two different genes, LETM1 and CTMP, which target mitochondrial functions, were chosen and linked using 2A-peptide sequence. Successful self-cleavage of 2A-peptide induced synergistic antitumor effect in the liver of H-ras12V, the HCC model mice, by simultaneous activation of LETM1 (Leucine zipper/EF hand-containing transmembrane-1) and CTMP (carboxyl-terminal modulator protein). Overexpression of LETM1 and CTMP significantly reduced the incidence of tumorigenesis, which were confirmed by gross and microscopic observations. Morphological changes in mitochondria, such as swelling and loss of cristae, were significant, and the prolonged activation of defects in mitochondrial function led to mitochondria-mediated apoptosis. Furthermore, with CTMP as a direct binding partner of Akt1, and LETM1 as a binding partner of CTMP, LETM1-2A-CTMP downregulated the Akt1 pathway at both Ser473 and Thr308 sites of phosphorylation. Proliferation and angiogenesis, which are important in cancer prognosis, were reduced in tumor sites after introduction of LETM1-2A-CTMP. Taken together, the results indicate that introduction of the mitochondria-targeting genes, LETM1 and CTMP, and self-processing capacity of 2A-peptide sequence exerts an antitumor effect in liver of H-ras12V mice, suggesting its potential as a tool for gene therapy.

Slewing Mirror Telescope optics for the early observation of UV/optical photons from Gamma-Ray Bursts.

We report on design, manufacture, and testing of a Slewing Mirror Telescope (SMT), the first of its kind and a part of Ultra-Fast Flash Observatory-pathfinder (UFFO-p) for space-based prompt measurement of early UV/optical light curves from Gamma-Ray Bursts (GRBs). Using a fast slewing mirror of 150 mm diameter mounted on a 2 axis gimbal stage, SMT can deliver the images of GRB optical counterparts to the intensified CCD detector within 1.5~1.8 s over ± 35 degrees in the slewing field of view. Its Ritchey-Chrétien telescope of 100 mm diameter provides a 17 × 17 arcmin² instantaneous field of view. Technical details of design, construction, the laboratory performance tests in space environments for this unique SMT are described in conjunction with the plan for in-orbit operation onboard the Lomonosov satellite in 2013.

α-secretase cleaved amyloid precursor protein (APP) accumulates in cholinergic dystrophic neurites in normal, aged hippocampus.

AIMS: Dystrophic neurites are associated with ß-amyloid (Aß) plaques in the brains of Alzheimer's disease (AD) patients and are also found in some specific areas of normal, aged brains. This study assessed the molecular characteristics of dystrophic neurites in normal ageing and its difference from AD. METHODS: We compared the dystrophic neurites in normal aged human brains (age 20-70 years) and AD brains (Braak stage 4-6) by immunostaining against ChAT, synaptophysin, γ-tubulin, cathepsin-D, Aß1-16, Aß17-24, amyloid precursor protein (APP)-CT695 and APP-NT. We then tested the reproducibility in C57BL/6 mice neurone cultures. RESULTS: In normal, aged mice and humans, we found an increase in clustered dystrophic neurites of cholinergic neurones in CA1 regions of the hippocampus and layer II and III regions of the entorhinal cortex, which are the major and earliest affected areas in AD. These dystrophic neurites showed accumulation of sAPPα peptides cleaved from the amyloid precursor protein by α-secretase rather than Aß or C-terminal fragments. In contrast, Aß and APP-CTFs accumulated in the dystrophic neurites in and around Aß plaques of AD patients. Several experiments suggested that the accumulation of sAPPα resulted from ageing-related proteasomal dysfunction. CONCLUSIONS: Ageing-associated impairment of the proteasomal system and accumulation of sAPPα at cholinergic neurites in specific areas of brain regions associated with memory could be associated with the normal decline of memory in aged individuals. In addition, these age-related changes might be the most vulnerable targets of pathological insults that result in pathological accumulation of Aß and/or APP-CTFs and lead to neurodegenerative conditions such as AD.

Effects of surface chemical structure on the mechanical properties of Si(1-x)Ge(x) nanowires.

The Young's modulus and fracture strength of Si(1-x)Ge(x) nanowires (NWs) as a function of Ge concentration were measured from tensile stress measurements. The Young's modulus of the NWs decreased linearly with increasing Ge content. No evidence was found for a linear relationship between the fracture strength of the NWs and Ge content, which is closely related to the quantity of interstitial Ge atoms contained in the wire. However, by removing some of the interstitial Ge atoms through rapid thermal annealing, a linear relationship could be produced. The discrepancy in the reported strength of Si and Ge NWs between calculated and experimented results could be related to SiO(2-x)/Si interfacial defects that are found in Si(1-x)Ge(x) NWs. It was also possible to significantly decrease the number of interfacial defects in the NWs by incorporating a surface passivated Al2O3 layer, which resulted in a substantial increase in fracture strength.

Genetic association between human chitinases and lung function in COPD.

Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

The necessity of voiding cystourethrography in children with prenatally diagnosed hydronephrosis.

The postnatal persistence of fetal hydronephrosis requires further evaluation to establish whether pathological abnormalities are present. This study determined the necessity for voiding cystourethrography (VCUG) to identify vesicoureteral reflux (VUR) in children (n = 195) with prenatally diagnosed hydronephrosis. Among the study population, the prevalence of VUR was 17.4% (24 males, 10 females). There was a poor correlation between the severity of hydronephrosis, ureteral dilatation, presence of bilateral hydronephrosis and presence of VUR. Except for the frequency of urinary tract infections and the presence of renal damage on (99m)Tc-dimercaptosuccinic acid scans, VCUG was the only reliable method for confirming VUR in this study. The diagnosis of VUR is important for the early detection of renal damage. Further information is needed to develop the optimal approach to the evaluation of prenatal hydronephrosis, with reliable parameters that avoid invasive procedures such as VCUG.

Suppression of tumor growth in xenograft model mice by programmed cell death 4 gene delivery using folate-PEG-baculovirus.

Cancer gene therapy using tumor suppressor genes is considered to be an attractive approach for arresting cell growth and inducing apoptosis. Programmed cell death 4 (Pdcd4) is a tumor suppressor gene, which prevents tumorigenesis and tumor progression. To address the issue of whether expression of PDCD4 protein induces apoptosis in cancerous cells, the Pdcd4 gene was delivered using folate-PEG-baculovirus. Folate-PEG-baculovirus containing Pdcd4 gene (F-P-Bac-Pdcd4) was constructed by attachment of F-PEG to the baculovirus surface using chemical modification. The F-P-Bac-Pdcd4 showed enhanced transduction efficiency, efficiently expressed PDCD4 protein, and induced apoptosis in human epidermal carcinoma (KB) cells as compared with an unmodified baculovirus. In a tumor xenograft study, injection of F-P-Bac-Pdcd4 into tumors established from the KB cell line by subcutaneous implantation significantly suppressed tumor growth and induced apoptosis. Thus, this study shows a new baculovirus-mediated tumor suppressor gene delivery system for cancer therapy.

Exposure to volatile organic compounds and loss of pulmonary function in the elderly.

Volatile organic compounds (VOCs) are reported to cause adverse effects on pulmonary function in occupationally exposed workers. However, evidence is lacking on the effect in the general population. We hypothesised that VOCs impair pulmonary function through enhancing oxidative stress, especially in the elderly population. A longitudinal panel study of 154 elderly people was performed in South Korea. Repeated spirometric tests were performed up to eight times on different days for each subject. We also measured urinary concentrations of metabolites of the VOC and markers of oxidative stress (malondialdehyde and 8-oxo-2'-deoxyguanosine) on the same day of spirometric tests. A mixed linear regression model was used to evaluate the association among the VOC metabolites, oxidative stress markers and spirometric tests. We found that the urinary levels of hippuric acid and methylhippuric acid, which are metabolites of toluene and xylene, respectively, were significantly associated with reduction of forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC. We also found significant associations between the metabolites of VOCs and the markers of oxidative stress. In addition, the oxidative stress markers were associated with pulmonary function parameters. This study suggests that exposure to toluene and xylene exert a harmful effect on pulmonary function by exacerbating oxidative stress in elderly people.