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  • 1
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    Oncogenic driver mutations in patients with non-small-cell lung cancer at various clinical stages (2013)
    Oxford University Press
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    Publication Date: 2013-04-19
    Description: Background Oncogenic driver mutations are responsible for the initiation and maintenance of non-small-cell lung cancer (NSCLC). Elucidation of driver mutation occurrence in NSCLC has important clinical implications. Patients and methods NSCLC at various clinical stages were studied for their oncogenic mutations and their association with patients' disease-free survival (DFS). Results Of 488 patients with NSCLC, 28 had EML4-ALK fusions. Female, young age (〈60 years old), and nonsmoker patients had significant greater mutation frequencies than male, old age (≥60 years old), and smoker patients, respectively ( P 〈0.05). Of 392 patients with NSCLC, 13 had PIK3CA mutations and 3 had MEK1 mutations. EML4-ALK , PIK3CA , and MEK1 mutations were mutually exclusive. EML4-ALK fusion was found to be of coexistence with EGFR and KRAS mutations in two cases. In stage IA NSCLC, EML4-ALK -positive patients had longer DFS than EML4-ALK- negative patients ( P = 0.04). However, in stage IIIA NSCLC, EML4-ALK -positive patients had poorer DFS than EML4-ALK -negative patients ( P 〈 0.01). Moreover, multivariate analysis indicated that in stage IIIA NSCLC EML4-ALK fusion was the only significant indicator for poor DFS ( P 〈 0.001). Furthermore, tumors with EML4-ALK fusions had significantly higher levels of ERCC1, a molecule with a key role in platinum drug efficacy, than tumors without EML4-ALK fusions. Conclusion EML4-ALK , PIK3CA , and MEK1 mutations occurred in NSCLC with various distinct clinicopathological characteristics. EML4-ALK fusions could serve as a significant prognostic indicator for locally advanced NSCLC.
    Print ISSN: 0923-7534
    Electronic ISSN: 1569-8041
    Topics: Medicine
    Published by Oxford University Press
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  • 2
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    Renal function-adjusted safe contrast volume to prevent contrast-induced nephropathy and poor long-term outcomes in patients with chronic total occlusions undergoing cardiac catheterization (2015)
    Oxford University Press
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    Publication Date: 2015-06-26
    Description: We aimed to evaluate the value of the contrast volume to creatinine clearance (V/CrCl) ratio for predicting contrast-induced nephropathy (CIN) and to determine a safe V/CrCl cut-off value to avoid CIN in patients with chronic total occlusions (CTOs) undergoing cardiac catheterization. We prospectively enrolled 728 consecutive patients with CTOs undergoing cardiac catheterization. Receiver-operator characteristic (ROC) curves were used to identify the optimal sensitivity for the observed range of V/CrCl. The predictive value of V/CrCl for CIN was assessed using multivariate logistic regression. Twenty-one patients (2.88%) developed CIN. There was a significant association between a higher V/CrCl ratio and CIN risk ( P 〈 0.001). ROC curve analysis indicated that a V/CrCl ratio of 2.76 was a fair discriminator for CIN (C-statistic = 0.77). After adjusting for other known CIN predictors, V/CrCl ratio 〉2.76 remained significantly associated with CIN (OR = 5.22; 95% CI = 1.65–16.53, P = 0.005) or worse long-term outcomes [death: hazard ratio (HR) = 2.72, 95% CI = 1.32–5.60, P = 0.007; major adverse clinical events: HR = 1.46, 95% CI = 1.03–2.06, P = 0.034]. A V/CrCl ratio 〉2.76 was a predictor of CIN and was independently associated with poor long-term outcomes from our data.
    Print ISSN: 1520-765X
    Electronic ISSN: 1554-2815
    Topics: Medicine
    Published by Oxford University Press
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  • 3
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    N-glycosylation deficiency reduces ICAM-1 induction and impairs inflammatory response (2014)
    Oxford University Press
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    Publication Date: 2014-03-15
    Description: Congenital disorders of glycosylation (CDGs) result from mutations in various N-glycosylation genes. The most common type, phosphomannomutase-2 (PMM2)-CDG (CDG-Ia), is due to deficient PMM2 (Man-6-P -〉 Man-1-P). Many patients die from recurrent infections, but the mechanism is unknown. We found that glycosylation-deficient patient fibroblasts have less intercellular adhesion molecule-1 (ICAM-1), and because of its role in innate immune response, we hypothesized that its reduction might help explain recurrent infections in CDG patients. We, therefore, studied mice with mutations in Mpi encoding phosphomannose isomerase (Fru-6-P -〉 Man-6-P), the cause of human MPI-CDG. We challenged MPI-deficient mice with an intraperitoneal injection of zymosan to induce an inflammatory response and found decreased neutrophil extravasation compared with control mice. Immunohistochemistry of mesenteries showed attenuated neutrophil egress, presumably due to poor ICAM-1 response to acute peritonitis. Since phosphomannose isomerase (MPI)-CDG patients and their cells improve glycosylation when given mannose, we provided MPI-deficient mice with mannose-supplemented water for 7 days. This restored ICAM-1 expression on mesenteric endothelial cells and enhanced transendothelial migration of neutrophils during acute inflammation. Attenuated inflammatory response in glycosylation-deficient mice may result from a failure to increase ICAM-1 on the vascular endothelial surface and may help explain recurrent infections in patients.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Fish and squid behaviour at the mouth of a drop-chain trawl: factors contributing to capture or escape (2016)
    Oxford University Press
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    Publication Date: 2016-07-13
    Description: Underwater video recordings in the mouth of a squid trawl were used to evaluate the effectiveness of a trawl configured with drop-chain groundgear to catch longfin inshore squid ( Doryteuthis pealeii ) and reduce bycatch of finfish in the Nantucket Sound squid fishery off Cape Cod, Massachusetts, USA. Entrance through the trawl mouth or escape underneath the fishing line and between drop chains was quantified for targeted squid, and two major bycatch species, summer flounder ( Paralichthys dentatus ) and skates (family Rajidae). Additionally, contact and impingement between animals and groundgear were also quantified. Fish and squid swimming behaviours, positions, orientations, and time in the trawl mouth were quantified and related to capture or escape at the trawl mouth. Squid entered the trawl singly and in schools, and no squid were observed escaping under the fishing line. Most squid entered the trawl in the upper portion of the trawl mouth; mantle orientated away from the trawl and swimming in the same direction, and were gradually overtaken, not actively attempting to escape. Summer flounder and skates were observed to remain on or near the seabed, orientated, and swimming in the same direction as the approaching trawl. The majority (60.5%) of summer flounder entered the trawl above the fishing line. Summer flounder that changed their orientation and turned 180° were significantly more likely to enter the trawl ( p 〈 0.05). Most skates (89.7%) avoided trawl entrance and escaped under the fishing line. Neither squid nor summer flounder were observed to make contact or become impinged to the groundgear; however, 35.4% of skates had substantial contact with groundgear, with 12.3% becoming impinged. Video analysis results showed that the drop-chain trawl is effective at retaining targeted squid while allowing skates to escape. However, it is ineffective at avoiding the capture of summer flounder.
    Print ISSN: 1054-3139
    Electronic ISSN: 1095-9289
    Topics: Biology , Geosciences , Physics
    Published by Oxford University Press
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  • 5
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    Implementing balanced harvesting: practical challenges and other implications (2016)
    Oxford University Press
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    Publication Date: 2016-07-13
    Description: Balanced harvesting (BH) has been proposed as an alternative to the paradigm of more selective fishing as practiced in most European and North American fisheries management. We examine options for the implementation of BH and evaluate the issues raised in such an implementation. Implementation is considered at the whole ecosystem level, in terms of the patterns of removal for all species, both commercial and bycatch. We suggest that a "laissez-faire" approach analogous to the African lakes where BH was first observed is inappropriate in managed developed world fisheries. We consider two further approaches: focusing on either the species caught or on the sizes of animal alone. We find that aiming to harvest all species with an exploitation rate appropriate to their productivity would require a degree of micro-management that is probably unachievable, with all captured species "choking" the fishery in sequence. The size-based approach works with an exploitation rate appropriate to the productivity at size, with no consideration of the species involved. This might superficially be easier to implement, as management would involve a limited number of size classes only. However, problems may arise due to the likely faster capture of the more easily catchable fish, and also likely targeting of the more valuable species within a size class. We identify a possible third option of "broad brush" métier-based management that may resolve some of these problems. Other issues include the management of protected, endangered, and threatened species (including mammals, reptiles, and birds), the management of already severely depleted stocks, and the capture of benthic invertebrates.
    Print ISSN: 1054-3139
    Electronic ISSN: 1095-9289
    Topics: Biology , Geosciences , Physics
    Published by Oxford University Press
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  • 6
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    MicroRNA-205 regulates the expression of Parkinson's disease-related leucine-rich repeat kinase 2 protein (2013)
    Oxford University Press
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    Publication Date: 2013-01-12
    Description: Recent genome-wide association studies indicate that a simple alteration of Leucine-rich repeat kinase 2 ( LRRK2 ) gene expression may contribute to the etiology of sporadic Parkinson's disease (PD). However, the expression and regulation of LRRK2 protein in the sporadic PD brains remain to be determined. Here, we found that the expression of LRRK2 protein was enhanced in the sporadic PD patients using the frontal cortex tissue from a set of 16 PD patients and 7 control samples. In contrast, no significant difference was detected in the level of LRRK2 mRNA expression between the control and PD cases, suggesting a potential post-transcriptional modification of the LRRK2 protein expression in the sporadic PD brains. Indeed, it was identified that microRNA-205 (miR-205) suppressed the expression of LRRK2 protein through a conserved-binding site at the 3'-untranslated region (UTR) of LRRK2 gene. Interestingly, miR-205 expression was significantly downregulated in the brains of patients with sporadic PD, showing the enhanced LRRK2 protein levels. Also, in vitro studies in the cell lines and primary neuron cultures further established the role of miR-205 in modulating the expression of LRRK2 protein. In addition, introduction of miR-205 prevented the neurite outgrowth defects in the neurons expressing a PD-related LRRK2 R1441G mutant. Together, these findings suggest that downregulation of miR-205 may contribute to the potential pathogenic elevation of LRRK2 protein in the brains of patients with sporadic PD, while overexpression of miR-205 may provide an applicable therapeutic strategy to suppress the abnormal upregulation of LRRK2 protein in PD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    Deficiency of Patched 1-induced Gli1 signal transduction results in astrogenesis in Swedish mutated APP transgenic mice (2014)
    Oxford University Press
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    Publication Date: 2014-11-21
    Description: Normally, sonic hedgehog (Shh) signaling induces high levels of Patched 1 (Ptc1) and its associated transcription factor Gli1 with genesis of specific neuronal progeny. But their roles in the neural stem cells (NSCs), including glial precursor cells (GPCs), of Alzheimer's disease (AD) are unclear. Here, we show that Ptc1 and Gli1 are significantly deficits in the hippocampus of an aged AD transgenic mouse mode, whereas these two molecules are highly elevated at young ages. Our similar findings in autopsied AD brains validate the discovery in AD mouse models. To examine whether Aβ peptides, which are a main component of the amyloid plaques in AD brains, affected Ptc1-Gli1 signaling, we treated GPCs with Aβ peptides, we found that high dose of Aβ 1–42 but not Aβ 1–40 significantly decreased Ptc1-Gli1, while Shh itself was elevated in hippocampal NSCs/GPCs. Furthermore, we found that deficits of Ptc1-Gli1 signaling induced NSCs/GPCs into asymmetric division, which results in an increase in the number of dividing cells including transit-amplifying cells and neuroblasts. These precursor cells commit to apoptosis-like death under the toxic conditions. By this way, adult neural precursor cell pool is exhausted and defective neurogenesis happens in AD brains. Our findings suggest that Ptc1-Gli1 signaling deregulation resulting abnormal loss of GPCs may contribute to a cognition decline in AD brains. The novel findings elucidate a new molecular mechanism of adult NSCs/GPCs on neurogenesis and demonstrate a regulatory role for Ptc1-Gli1 in adult neural circuit integrity of the brain.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Statistical computation of Boltzmann entropy and estimation of the optimal probability density function from statistical sample (2014)
    Oxford University Press
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    Publication Date: 2014-11-06
    Description: In this work, we investigate the statistical computation of the Boltzmann entropy of statistical samples. For this purpose, we use both histogram and kernel function to estimate the probability density function of statistical samples. We find that, due to coarse-graining, the entropy is a monotonic increasing function of the bin width for histogram or bandwidth for kernel estimation, which seems to be difficult to select an optimal bin width/bandwidth for computing the entropy. Fortunately, we notice that there exists a minimum of the first derivative of entropy for both histogram and kernel estimation, and this minimum point of the first derivative asymptotically points to the optimal bin width or bandwidth. We have verified these findings by large amounts of numerical experiments. Hence, we suggest that the minimum of the first derivative of entropy be used as a selector for the optimal bin width or bandwidth of density estimation. Moreover, the optimal bandwidth selected by the minimum of the first derivative of entropy is purely data-based, independent of the unknown underlying probability density distribution, which is obviously superior to the existing estimators. Our results are not restricted to one-dimensional, but can also be extended to multivariate cases. It should be emphasized, however, that we do not provide a robust mathematical proof of these findings, and we leave these issues with those who are interested in them.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 9
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    Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated I{kappa}B{alpha} (2014)
    Oxford University Press
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    Publication Date: 2014-08-22
    Description: Tumor necrosis factor receptor II (TNFRII) is one of the TNF receptor superfamily members and our recent pathological studies show that TNFRII is deficient in the brains of Alzheimer's disease (AD). However, the mechanisms of TNFRII in AD pathogenesis remain unclear. In the present study, by using the gene-targeting approach to delete TNFRII in AD transgenic mouse model, we found that, in the brain of APP23 mice with TNFRII deletion (APP23/ TNFRII –/– ), AD-like pathology, i.e. plaque formation and microglial activation, occurs as early as 6 months of age. To test whether the increased levels of Aβ plaques was due to elevated Aβ, we measured Aβ and found that Aβ levels indeed were significantly increased at this age. Because β-secretase, BACE1, is critical enzyme for Aβ production, we have examined BACE1 and found that BACE1 is increased in both protein levels and enzymatic activity as early as 6 months of age; Having shown that BACE1 promoter region contains NF-B binding sites, we found that cytoplasmic NF-B was elevated and SUMO1 binding to IBα was decreased. To further verify these findings, we have overexpressed TNFRII and identified that overexpressing TNFRII can reverse the findings from APP23/TNFRII –/– mice. Altogether, our results demonstrate novel roles of TNFRII in the regulation of Aβ production, suggesting a potential therapeutic strategy for AD by up-regulating TNFRII levels and elevating phosphorylated IBα by SUMOylation.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 10
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    Diversity and distribution of catechol 2, 3-dioxygenase genes in surface sediments of the Bohai Sea (2016)
    Oxford University Press
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    Publication Date: 2016-05-05
    Description: Catechol 2, 3-dioxygenase (C23O) is the key enzyme for aerobic aromatic degradation. Based on clone libraries and quantitative real-time polymerase chain reaction, we characterized diversity and distribution patterns of C23O genes in surface sediments of the Bohai Sea. The results showed that sediments of the Bohai Sea were dominated by genes related to C23O subfamily I.2.A. The samples from wastewater discharge area (DG) and aquaculture farm (KL) showed distinct composition of C23O genes when compared to the samples from Bohai Bay (BH), and total organic carbon was a crucial determinant accounted for the composition variation. C6BH12-38 and C2BH2-35 displayed the highest gene copies and highest ratios to the 16S rRNA genes in KL, and they might prefer biologically labile aromatic hydrocarbons via aquaculture inputs. Meanwhile, C7BH3-48 showed the highest gene copies and highest ratios to the 16S rRNA genes in DG, and this could be selective effect of organic loadings from wastewater discharge. An evident increase in C6BH12-38 and C7BH3-48 gene copies and reduction in diversity of C23O genes in DG and KL indicated composition perturbations of C23O genes and potential loss in functional redundancy. We suggest that ecological habitat and trophic specificity could shape the distribution of C23O genes in the Bohai Sea sediments.
    Keywords: Environmental Microbiology
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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