8-oxoguanine DNA glycosylase (Oggl) repairs 8-oxo-7,8-dihydroxyguanine (8-oxoG), one of the most abundant DNA adducts caused by oxidative stress. In the mitochondria, Oggl is thought to prevent activation of the intrinsic apoptotic pathway in response to oxidative stress by augmenting DNA repair. However, the predominance of the β-Oggl isoform, which lacks 8-oxoG DNA glycosylase activity, suggests that mitochondrial Oggl functions in a role independent of DNA repair. We report here that overexpression of mitochondria-targeted human α-hOggl (mt-hOggl) in human lung adenocarcinoma cells with some alveolar epithelial cell characteristics (A549 cells) prevents oxidant-induced mitochondrial dysfunction and apoptosis by preserving mitochondrial aconitase. Importantly, mitochondrial α-hOggl mutants lacking 8-oxoG DNA repair activity were as effective as wild-type mt-hOggl in preventing oxidant-induced caspase-9 activation, reductions in mitochondrial aconitase and apoptosis suggesting that the protective effects of mt-hOgg 1 occur independent of DNA repair. Notably, wild-type and mutant mt-hOggl co-precipitate with mitochondrial aconitase. Furthermore, overexpression of mitochondrial aconitase abolishes oxidant-induced apoptosis whereas hOggl silencing using shRNA reduces mitochondrial aconitase and augments apoptosis. These findings suggest a novel mechanism that mt-hOggl acts as a mitochondrial aconitase chaperone protein to prevent oxidant-mediated mitochondrial dysfunction and apoptosis that might be important in the molecular events underlying oxidant-induced toxicity.
DNA repair; aconitase; Oggl; free radicals; asbestos; mitochondria
Tubular atrophy and dysfunction is a critical process underlying diabetic nephropathy (DN). Understanding the mechanisms underlying renal tubular epithelial cell survival is important for the prevention of kidney failure associated with glucotoxicity. Autophagy is a cellular pathway involved in protein and organelle degradation. It is associated with many types of cellular homeostasis and human diseases. To date, little is known of the association between high concentrations of glucose and autophagy in renal tubular cells. In the present study, we investigated high glucose-induced toxicity in renal tubular epithelial cells by means of several complementary assays, including cell viability, cell death assays and changes in ultrastructure in an immortalized human kidney cell line, HK-2 cells. The extent of apoptosis was significantly increased in the HK-2 cells following treatment with high levels of glucose. In addition, in in vivo experiments using diabetic rats, high glucose exerted harmful effects on the tissue structure of the kidneys in the diabetic rats. Chronic exposure of the HK-2 cells and tubular epithelial cells of nephritic rats to high levels of glucose induced autophagy. Liraglutide inhibited these effects; however, treatment witht a glucagon-like peptide-1 receptor (GLP-1R) antagonist enhanced these effects. Our results also indicated that the exposure of the renal tubular epithelial cells to high glucose concentrations in vitro led to the downregulation of GLP-1R expression. Liraglutide reversed this effect, while the GLP-1R antagonist promoted it, promoting autophagy, suggesting that liraglutide exerts a renoprotective effect in the presence of high glucose, at least in part, by inhibiting autophagy and increasing GLP-1R expression in the HK-2 cells and kidneys of diabetic rats.
high glucose; autophagy; autophagy-related gene; glucagon-like peptide-1 receptor; liraglutide
Gelatin nanoparticles coated with Cathepsin D-specific peptides were developed as a vehicle for the targeted delivery of the cancer drug doxorubicin (DOX) to treat breast malignancy. Cathepsin D, a breast cancer cell secretion enzyme, triggered the release of DOX by digesting the protective peptide-coating layer of nanoparticles. Fabricated nanoparticles were successfully detected with ultrasound imaging in both in vitro conditions and in vivo mouse cancer models. Cell viability experiments were conducted to determine the efficacy of biomarker activation specific to breast cancer cell lines. These experimental results were compared with the outcome of a viability experiment conducted on noncancerous cells. Viability decreased in human MCF7 mammary adenocarcinoma and mouse 4T1 mammary carcinoma cells, while that of noncancerous 3T3 fibroblast cells remained unaffected. Next, a real-time video of nanoparticle flow in mouse models was obtained using in vivo ultrasound imaging. The fluorescent profile of DOX was used as a means to examine nanoparticle localization in vivo. Results show the distribution of nanoparticles concentrated primarily within bladder and tumor sites of subject mice bodies. These findings support the use of biomarker coated nanoparticles in target specific therapy for breast cancer treatment.
Chemotherapy; doxorubicin; gelatin nanoparticles; in vivo ultrasound imaging; targeted drug delivery
The aim of this study was to investigate the effect of propofol pretreatment on
lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of the
phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway in this procedure.
Survival was determined 48 h after LPS injection. At 1 h after LPS challenge, the
lung wet- to dry-weight ratio was examined, and concentrations of protein, tumor
necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid
(BALF) were determined using the bicinchoninic acid method or ELISA. Lung injury was
assayed via lung histological examination. PI3K and p-Akt expression levels in the
lung tissue were determined by Western blotting. Propofol pretreatment prolonged
survival, decreased the concentrations of protein, TNF-α, and IL-6 in BALF,
attenuated ALI, and increased PI3K and p-Akt expression in the lung tissue of
LPS-challenged rats, whereas treatment with wortmannin, a PI3K/Akt pathway specific
inhibitor, blunted this effect. Our study indicates that propofol pretreatment
attenuated LPS-induced ALI, partly by activation of the PI3K/Akt pathway.
Acute lung injury; Propofol; Lipopolysaccharide; PI3K/Akt pathway
Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment.
cancer; HDAC inhibitor; biology
Necrotising enterocolitis (NEC) is a major source of neonatal morbidity and mortality. The management of infants with NEC is currently complicated by our inability to accurately identify those at risk for progression of disease prior to the development of irreversible intestinal necrosis. We hypothesised that integrated analysis of clinical parameters in combination with urine peptide biomarkers would lead to improved prognostic accuracy in the NEC population.
Infants under suspicion of having NEC (n=550) were prospectively enrolled from a consortium consisting of eight university-based paediatric teaching hospitals. Twenty-seven clinical parameters were used to construct a multivariate predictor of NEC progression. Liquid chromatography/mass spectrometry was used to profile the urine peptidomes from a subset of this population (n=65) to discover novel biomarkers of NEC progression. An ensemble model for the prediction of disease progression was then created using clinical and biomarker data.
The use of clinical parameters alone resulted in a receiver-operator characteristic curve with an area under the curve of 0.817 and left 40.1% of all patients in an ‘indeterminate’ risk group. Three validated urine peptide biomarkers (fibrinogen peptides: FGA1826, FGA1883 and FGA2659) produced a receiver-operator characteristic area under the curve of 0.856. The integration of clinical parameters with urine biomarkers in an ensemble model resulted in the correct prediction of NEC outcomes in all cases tested.
Ensemble modelling combining clinical parameters with biomarker analysis dramatically improves our ability to identify the population at risk for developing progressive NEC.
We aimed to investigate miRNAs and related mRNAs through a network-based approach in
order to learn the crucial role that they play in the biological processes of
esophageal cancer. Esophageal squamous-cell carcinoma (ESCC) and adenocarcinoma
(EAC)-related miRNA and gene expression data were downloaded from the Gene Expression
Omnibus database, and differentially expressed miRNAs and genes were selected. Target
genes of differentially expressed miRNAs were predicted and their regulatory networks
were constructed. Differentially expressed miRNA analysis selected four miRNAs
associated with EAC and ESCC, among which hsa-miR-21 and
hsa-miR-202 were shared by both diseases.
hsa-miR-202 was reported for the first time to be associated with
esophageal cancer in the present study. Differentially expressed miRNA target genes
were mainly involved in cancer-related and signal-transduction pathways. Functional
categories of these target genes were related to transcriptional regulation. The
results may indicate potential target miRNAs and genes for future investigations of
Esophageal adenocarcinoma; Esophageal squamous-cell carcinoma; miRNA expression network; Pathway; Gene ontology
Pemetrexed, a folate antimetabolite, combined with cisplatin is used as a first-line therapy for malignant pleural mesothelioma (MPM) and locally advanced or metastatic non-small-cell lung cancer (NSCLC). Pemetrexed arrests cell cycle by inhibiting three enzymes in purine and pyrimidine synthesis that are necessary for DNA synthesis. Pemetrexed also promotes apoptosis in target cells, but little is known about its mechanism in cancer cells. We have previously shown that pemetrexed can result in endoplasmic reticulum (ER) stress, and it can lead to downstream apoptosis. In this study, we further elucidate this mechanism. Our data show that pemetrexed increases Noxa expression through activating transcription factor 4 (ATF4) and activating transcription factor 3 (ATF3) upregulation. Furthermore, pemetrexed induces apoptosis by activating the Noxa–Usp9x–Mcl-1 pathway. Inhibition of Noxa by small interfering RNA (siRNA) promotes Usp9x (ubiquitin-specific peptidase 9, X-linked) expression. Moreover, downregulation of the deubiquitinase Usp9x by pemetrexed results in downstream reduction of myeloid cell leukemia 1 (Mcl-1) expression. Mechanistically, Noxa upregulation likely reduces the availability of Usp9x to Mcl-1, thereby promoting its ubiquitination and degradation, leading to the apoptosis of neoplastic cells. Thus, our findings demonstrate that Noxa–Usp9x-Mcl–1 axis may contribute to pemetrexed-induced apoptosis in human lung cancer cells.
To investigate signal regulation models of gastric cancer, databases and literature
were used to construct the signaling network in humans. Topological characteristics
of the network were analyzed by CytoScape. After marking gastric cancer-related genes
extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software
was used for the mining of gastric cancer-related motifs in a network with three
vertices. The significant motif difference method was adopted to identify
significantly different motifs in the normal and cancer states. Finally, we conducted
a series of analyses of the significantly different motifs, including gene ontology,
function annotation of genes, and model classification. A human signaling network was
constructed, with 1643 nodes and 5089 regulating interactions. The network was
configured to have the characteristics of other biological networks. There were
57,942 motifs marked with gastric cancer-related genes out of a total of 69,492
motifs, and 264 motifs were selected as significantly different motifs by calculating
the significant motif difference (SMD) scores. Genes in significantly different
motifs were mainly enriched in functions associated with cancer genesis, such as
regulation of cell death, amino acid phosphorylation of proteins, and intracellular
signaling cascades. The top five significantly different motifs were mainly cascade
and positive feedback types. Almost all genes in the five motifs were cancer related,
including EPOR, MAPK14, BCL2L1,
KRT18, PTPN6, CASP3,
TGFBR2, AR, and CASP7. The
development of cancer might be curbed by inhibiting signal transductions upstream and
downstream of the selected motifs.
Significantly different motifs; Human signaling network; Gastric cancer
The selection and design of modern high-performance structural engineering materials such as nanostructured metallic multilayers (NMMs) is driven by optimizing combinations of mechanical properties and requirements for predictable and noncatastrophic failure in service. Here, the Cu/X (X = Zr, Cr) nanolayered micropillars with equal layer thickness (h) spanning from 5–125 nm are uniaxially compressed and it is found that these NMMs exhibit a maximum strain hardening capability and simultaneously display a transition from bulk-like to small-volume materials behavior associated with the strength at a critical intrinsic size h ~ 20 nm. We develop a deformation mode-map to bridge the gap between the interface characteristics of NMMs and their failure phenomena, which, as shrinking the intrinsic size, transit from localized interface debonding/extrusion to interface shearing. Our findings demonstrate that the optimum robust performance can be achieved in NMMs and provide guidance for their microstructure sensitive design for performance optimization.
As two important mechanical properties, strength and ductility generally tend to be muturally exclusive in conventional engineering materials. The breakthrough of such a trade-off has been potentiated by the recently developed CuZr-based bulk metallic glass (BMG) composites ductilized by a shape memory CuZr(B2) phase. Here the microstructural dependences of tensile properties for the CuZr-based BMG composites were elucidated qualitatively and modeled quantitatively, and the underlying mechanisms were unraveled. Through the microstructural percolation induced by matching the length scales of particle size and interparticle spacing, a notable breakthrough was achieved in the composites that the general conflicts between strength and ductility can be defeated. This study is expected to greatly aid in the microstructural design and tailoring for improved properties of BMG composites. It also has implications for the development of strong and ductile materials in the future.
Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16INK4a, p21Waf1/Cip1 and p27Kip1. Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.
chromosome 9p24; GASC1; UHRF2; gene amplification
Bulk ultrafine grained (UFG)/nanocrystal metals possess exceptional strength but normally poor ductility and thermal stability, which hinder their practical applications especially in high-temperature environments. Through microalloying strategy that enables the control of grains and precipitations in nanostructured regime, here we design and successfully produce a highly microstructure-stable UFG Al-Cu-Sc alloy with ~275% increment in ductility and simultaneously ~50% enhancement in yield strength compared with its Sc-free counterpart. Although the precipitations in UFG alloys are usually preferentially occurred at grain boundaries even at room temperature, minor Sc addition into the UFG Al-Cu alloys is found to effectively stabilize the as-processed microstructure, strongly suppress the θ-Al2Cu phase precipitation at grain boundary, and remarkably promote the θ′-Al2Cu nanoparticles dispersed in the grain interior in artificial aging. A similar microalloying strategy is expected to be equally effective for other UFG heat-treatable alloys.
This study evaluated racial differences in bone size and volumetric density at the spine and hip in pre-and postmenopausal Chinese American and White women. Compared with White women, Chinese American women have greater cortical volumetric bone density (vBMD) at the hip, congruent with the results at the peripheral skeleton.
Chinese American women have lower rates of fracture than White women despite lower areal bone density. At the forearm and tibia, however, Chinese American women have higher cortical vBMD as well as greater trabecular and cortical thickness, but smaller bone area as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) compared with White women. Since HR-pQCT data are obtained at peripheral sites, it is unclear whether these differences are relevant to the clinically important lumbar spine and hip. This study assesses racial differences in bone size and vBMD at the spine and hip in Chinese American and White women.
QCT of the spine and hip was measured to assess racial differences in bone size, structure, and vBMD in pre-(n=83) and postmenopausal (n=50) Chinese American and White women. Data were adjusted for weight, height, physical activity, total calcium intake, parathyroid hormone, and 25-hydroxyvitamin D levels.
Among premenopausal women, lumbar spine trabecular vBMD was 5.8% greater in Chinese American versus White women (p=0.01). At the hip, cortical vBMD was 3% greater at the femoral neck (p=0.05) and 3.6% greater at the total hip (p=0.01) in premenopausal Chinese American compared with White women. Among postmenopausal women, there was no difference in lumbar spine trabecular vBMD. Cortical vBMD was 4% greater at the total hip (p= 0.02) and tended to be greater at the femoral neck (p=0.058) in Chinese American versus White women.
Consistent with earlier findings in the peripheral skeleton, cortical vBMD is greater at the hip in Chinese American versus White women.
Central QCT; Chinese American; Race; Volumetric bone density; White
We report a clinical study that examines whether HIV infection affects Streptococcus mutans colonization in the oral cavity. Whole stimulated saliva samples were collected from 46 HIV-seropositive individuals and 69 HIV-seronegative control individuals. The level of S. mutans colonization was determined by conventional culture methods. The genotype of S. mutans was compared between 10 HIV-positive individuals before and after highly active antiretroviral therapy (HAART) and 10 non-HIV-infected control individuals. The results were analyzed against viral load, CD4+ and CD8+ T-cell counts, salivary flow rate, and caries status. We observed that S. mutans levels were higher in HIV-infected individuals than in the non-HIV-infected control individuals (p = 0.013). No significant differences in S. mutans genotypes were found between the two groups over the six-month study period, even after HAART. There was a bivariate linear relationship between S. mutans levels and CD8+ counts (r = 0.412; p = 0.007), but not between S. mutans levels and either CD4+ counts or viral load. Furthermore, compared with non-HIV-infected control individuals, HIV-infected individuals experienced lower salivary secretion (p = 0.009) and a positive trend toward more decayed tooth surfaces (p = 0.027). These findings suggest that HIV infection can have a significant effect on the level of S. mutans, but not genotypes.
HIV infections; Streptococcus mutans; genotype; saliva; CD8+ T-lymphocytes; HAART
The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor.
Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping.
In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure.
RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.
RO4929097; cediranib; phase I; combination study
In the early days of BOLD fMRI, the acquisition of T2* weighted data was greatly facilitated by rapid scan techniques such as EPI. The latter, however, was only available on a few MRI systems that were equipped with specialized hardware that allowed rapid switching of the imaging gradients. For this reason, soon after the invention of fMRI, the scan technique PRESTO was developed to make rapid T2* weighted scanning available on standard clinical scanning. This method combined echo shifting, which allows for echo times longer than the sequence repetition time, with acquisition of multiple k-space lines per excitation. These two concepts were combined in order to achieve a method fast enough for fMRI, while maintaining a sufficiently long echo time for optimal contrast. PRESTO has been primarily used for 3D scanning, which minimized the contribution of large vessels due to inflow effects. Although PRESTO is still being used today, its appeal has lessened somewhat due to increased gradient performance of modern MRI scanners. Compared to 2D EPI, PRESTO may have somewhat reduced temporal stability, which is a disadvantage for fMRI that may not outweigh the advantage of reduced inflow effects provided by 3D scanning. In this overview, the history of the development of the PRESTO is presented, followed by a qualitative comparison with EPI.
Functional magnetic resonance imaging (fMRI); Blood oxygenation level dependent (BOLD) contrast; PRESTO (Principles of Echo-Shifting with a Train of Observation); Echo shifting
Metallic glasses are lucrative engineering materials owing to their superior mechanical properties such as high strength and great elastic strain. However, the Achilles' heel of metallic amorphous materials — low plasticity caused by instantaneous catastrophic shear banding, significantly undercut their structural applications. Here, the nanolayered crystalline Cu/amorphous Cu-Zr micropillars with equal layer thickness spanning from 20–100 nm are uniaxially compressed and it is found that the Cu/Cu-Zr micropillars exhibit superhigh homogeneous deformation (≥ 30% strain) rather than localized shear banding at room temperature. This extraordinary plasticity is aided by the deformation-induced devitrification via absorption/annihilation of abundant dislocations, triggering the cooperative shearing of shear transformation zones in glassy layers, which simultaneously renders the work-softening. The synthesis of such heterogeneous nanolayered structure not only hampers shear band generation but also provides a viable route to enhance the controllability of plastic deformation in metallic glassy composites via deformation-induced devitrification mechanism.
Hepatic oval cells (HOCs) are recognized as facultative liver progenitor cells that
play a role in liver regeneration after acute liver injury. Here, we investigated the
in vitro proliferation and differentiation characteristics of
HOCs in order to explore their potential capacity for intrahepatic transplantation.
Clusters or scattered HOCs were detected in the portal area and interlobular bile
duct in the liver of rats subjected to the modified 2-acetylaminofluorene and partial
hepatectomy method. Isolated HOCs were positive for c-kit and CD90 staining (99.8%
and 88.8%, respectively), and negative for CD34 staining (3.6%) as shown by
immunostaining and flow cytometric analysis. In addition, HOCs could be
differentiated into hepatocytes and bile duct epithelial cells after leukemia
inhibitory factor deprivation. A two-cuff technique was used for orthotopic liver
transplantation, and HOCs were subsequently transplanted into recipients. Biochemical
indicators of liver function were assessed 4 weeks after transplantation. HOC
transplantation significantly prolonged the median survival time and improved the
liver function of rats receiving HOCs compared to controls (P=0.003, Student
t-test). Administration of HOCs to rats also receiving liver
transplantation significantly reduced acute allograft rejection compared to control
liver transplant rats 3 weeks following transplantation (rejection activity index
score: control=6.3±0.9; HOC=3.5±1.5; P=0.005). These results indicate that HOCs may
be useful in therapeutic liver regeneration after orthotopic liver
Hepatic oval cells; Proliferation; Differentiation; Liver transplantation
The objective of this study was to evaluate the application of flow cytometry total cell counts (TCCs) as a parameter to assess microbial growth in drinking water distribution systems and to determine the relationships between different parameters describing the biostability of treated water. A one-year sampling program was carried out in two distribution systems in The Netherlands. Results demonstrated that, in both systems, the biomass differences measured by ATP were not significant. TCC differences were also not significant in treatment plant 1, but decreased slightly in treatment plant 2. TCC values were found to be higher at temperatures above 15°C than at temperatures below 15°C. The correlation study of parameters describing biostability found no relationship among TCC, heterotrophic plate counts, and Aeromonas. Also no relationship was found between TCC and ATP. Some correlation was found between the subgroup of high nucleic acid content bacteria and ATP
(R2 = 0.63). Overall, the results demonstrated that TCC is a valuable parameter to assess the drinking water biological quality and regrowth; it can directly and sensitively quantify biomass, detect small changes, and can be used to determine the subgroup of active HNA bacteria that are related to ATP.
Heroin abuse and natural aging exert common influences on immunological cell functioning. This observation led to a recent and untested idea that aging may be accelerated in abusers of heroin. We examined this claim by testing whether heroin use is associated with premature aging at both cellular and brain system levels. A group of abstinent heroin users (n=33) and matched healthy controls (n=30) were recruited and measured on various biological indicators of aging. These measures included peripheral blood telomerase activity, which reflects cellular aging, and both structural and functional measures of brain magnetic resonance imaging. We found that heroin users were characterized by significantly low telomerase activity (0.21 vs 1.78; 88% reduction; t(61)=6.96, P<0.001; 95% confidence interval=1.12–2.02), which interacted with heroin use to affect the structural integrity of gray and white matter of the prefrontal cortex (PFC; AlphaSim corrected P<0.05), a key brain region implicated in aging. Using the PFC location identified from the structural analyses as a ‘seed' region, it was further revealed that telomerase activity interacted with heroin use to impact age-sensitive brain functional networks (AlphaSim corrected P<0.05), which correlated with behavioral performance on executive functioning, memory and attentional control (Pearson correlation, all P<0.05). To our knowledge, this study is the first to attempt a direct integration of peripheral molecular, brain system and behavioral measures in the context of substance abuse. The present finding that heroin abuse is associated with accelerated aging at both cellular and brain system levels is novel and forms a unique contribution to our knowledge in how the biological processes of drug abusers may be disrupted.
addiction; aging; heroin; MRI; prefrontal cortex; resting state; telomerase
The activation of NADPH oxidase has been implicated in NEFA-induced beta cell dysfunction. However, the causal role of this activation in vivo remains unclear. Here, using rodents, we investigated whether pharmacological or genetic inhibition of NADPH oxidase could prevent NEFA-induced beta cell dysfunction in vivo.
Normal rats were infused for 48 h with saline or oleate with or without the NADPH oxidase inhibitor apocynin. In addition, NADPH oxidase subunit p47phox-null mice and wild-type littermate controls were infused with saline or oleate for 48 h. This was followed by measurement of NADPH oxidase activity, reactive oxygen species (ROS) and superoxide imaging and assessment of beta cell function in isolated islets and hyperglycaemic clamps.
Oleate infusion in rats increased NADPH oxidase activity, consistent with increased total but not mitochondrial superoxide in islets and impaired beta cell function in isolated islets and during hyperglycaemic clamps. Co-infusion of apocynin with oleate normalised NADPH oxidase activity and total superoxide levels and prevented beta cell dysfunction. Similarly, 48 h NEFA elevation in wild-type mice increased total but not mitochondrial superoxide and impaired beta cell function in isolated islets. p47phox-null mice were protected against these effects when subjected to 48 h oleate infusion. Finally, oleate increased the levels of total ROS, in both models, whereas inhibition of NADPH oxidase prevented this increase, suggesting that NADPH oxidase is the main source of ROS in this model.
These data show that NADPH-oxidase-derived cytosolic superoxide is increased in islets upon oleate infusion in vivo; and whole-body NADPH-oxidase inhibition decreases superoxide in concert with restoration of islet function.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2858-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Beta cell dysfunction; In vivo; Lipotoxicity; NADPH oxidase; Oleate; Oxidative stress
Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy.
In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification.
Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5′ flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression.
This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.
Chemoradiation; Esophageal cancer; Radiation toxicity prediction; Single nucleotide polymorphism; Trimodality
This study aimed to investigate the value of ultrasound in the identification of benign and malignant parotid masses.
Data of 189 patients with parotid gland masses undergoing ultrasound-guided fine-needle aspiration (FNA), core biopsy or surgery were reviewed retrospectively and the presumed sonographic diagnoses were compared with the histopathology. The sensitivity, specificity and accuracy of sonographic diagnoses were assessed and the sonographic characteristics of those lesions, including shape, margin, echogenicity, echotexture and vascularization, were studied.
Of the 189 patients, the final pathological diagnosis included 18 malignant tumours and 171 benign masses; the presumed sonographic diagnoses showed 165 cases as benign and probably benign masses (11 cases were confirmed malignant, 154 cases benign) and 24 cases were diagnosed as probably malignant and malignant masses (7 cases were confirmed malignant, 17 cases benign). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of ultrasound for the diagnosis of parotid gland masses were 38.9%, 90.1%, 29.2%, 93.3% and 85.2%, respectively, and accuracy for malignant masses was 20%. The sonographic characteristics of parotid masses between benign and malignant lesions had no significant differences. The parotid gland masses in this study included pleomorphic adenoma, Warthin's tumour, retention cyst, haemangiomas, chronic granuloma, lymphoma, fibrolipoma, abscess, basal cell adenoma, oncocytoma, lymphatic tuberculosis, myoepithelioma, neurilemmoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, alveolar soft part sarcoma and retinal blastoma (metastasis).
It is challenging to use sonography for differentiating between benign and malignant parotid gland masses. To make a definite diagnosis, ultrasound-guided FNA or core biopsy is advocated.
parotid gland; mass; benign; malignant; ultrasound