bluuebunny/crossref_metadata_2025 huggingface dataset:
Inheritance of spiral grain in the juvenile core of Pinus radiata
Authors: Gapare Washington , Hathorn Adrian , Kain Dominic , Matheson Colin , Wu Harry
Published: May 2007

Spiral grain is the angular arrangement of fibres in a tangential plane with reference to the pith or vertical tree axis. Spiral grain angles exceeding 5° can cause wood to twist, which may result in a considerable amount of waste and degrade. We assessed spiral grain at breast height in two related progeny tests of radiata pine (Pinus radiata D. Don) aged 8 and 9 years established at two different sites in Australia. Radial trends for grain angle at the two sites were similar. Mean spiral grain (MSG) across the two trials was 4.3° with a standard deviation of 1.5° and a range of 0.8–10°. Estimates of individual tree heritabilities on a single-site basis for individual rings and MSG suggested that spiral grain is lowly to highly inherited (h2 = 0.11 ± 0.08 to 0.66 ± 0.21 for individual rings and 0.44 ± 0.12 for MSG). Additive genotypic correlations between individual rings grain angle and MSG were generally high, above 0.71, suggesting a favourable expected correlated response of mean grain angle in the juvenile wood to selection for grain angle of individual rings. Selection to reduce spiral grain on any of rings 2–4 (at a selection intensity of 1.755, i.e., selecting the best 10% of trees) would result in a predicted correlated genetic gain in MSG of 1.0°. Our results suggest that selection could be performed in any of the individual rings 2, 3, or 4 (equivalent to ages 4–6) and still achieve at least 75% of the genetic gain possible from selection on the mean of all rings 1–5 (MSG). This suggests that there is an optimum stage (rings 2–4) in which selection for this trait should take place. Our results suggest that a reduction in spiral grain angle in the juvenile core is one strategy to reduce the amount of lower grade timber owing to twist.
Stand mortality in buffer strips and the supply of woody debris to streams in Southeast Alaska
Authors: Martin Douglas J , Grotefendt Richard A
Published: May 2007

We compared the stand conditions in buffer strips with those in unlogged riparian stands with similar site characteristics using large-scale aerial photography to deduce differences in stand mortality and large woody debris (LWD) recruitment. We found the cumulative stand mortality (CSM) was significantly greater in buffer units compared with reference units and that mortality varied with distance from the stream. In the inner zone (0–10 m from stream), the mean difference in CSM between buffer and reference units was relatively small (22% of unlogged CSM), but the CSM in the buffer units of the outer zone (10–20 m from stream) was more than double (120%) the CSM in the reference units. The greater CSM in the buffer units is primarily the result of a significant increase in mortality by windthrow at a small proportion (11%) of the logged units. We found that logging caused an increase in the proportion of tree recruitment to the stream from the outer zone of buffers and changed the shape of the LWD source distance recruitment curve. Based on our findings, we estimate the future potential supply of LWD is diminished by 10% compared with an unlogged reference stand.
The introduced bark beetles Hylurgus ligniperda and Hylastes ater (Coleoptera: Scolytidae) in Chile: seasonal flight and effect of Pinus radiata log placement on colonization
Authors: Mausel David L , Gara Robert I , Lanfranco Dolly , Ruiz Cecilia , Ide Sandra , Azat Rodrigo
Published: May 2007

The seasonal flight of Hylurgus ligniperda (Fabr.) and Hylastes ater (Paykull) and the effect of log placement in Pinus radiata D. Don plantations on colonization by these species in Chile are described. Seasonal flight activity was monitored with α-pinene and ethanol-baited traps at three sites and colonization synchrony with trap logs. In two experiments with individual logs and log decks, data were recorded on adults found under the logs, attacks on the bark surface, and adults beneath the bark of logs in three storage treatments: individual logs and log decks (1) touching the soil; (2) elevated above the soil; and (3) touching other logs (individual logs) or logs separated with spacers (log decks). Each treatment was replicated in a plantation and a clearcut. At San José (region IX) and Peña Blanca (region VIII), H. ligniperda flew primarily in spring and H. ater flew in spring and fall. At Brasil (region VIII), H. ligniperda and H. ater flew primarily in summer through fall. The flight of H. ligniperda was more synchronized with colonization of logs than was that of H. ater. The mean number of attacks was significantly higher on individual logs and log decks stored on the soil than on those elevated above the soil, and significantly higher in the clearcut than in the plantation. Mean numbers of adults beneath the bark did not vary significantly among individual-log treatments, but were significantly lower in the log decks separated by spacers. Logging during nondispersal periods (June–August in regions VIII–X) and storing log decks above the soil could reduce beetle colonization of newly cut logs. With this information, management of recently cut logs (harvesting, transport, and storage operations) could be scheduled and executed so as to reduce the risk of these species being introduced into log-importing countries.
Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway
Authors: Villacorta Luis , Zhang Jifeng , Garcia-Barrio Minerva T. , Chen Xi-lin , Freeman Bruce A. , Chen Yuqing E. , Cui Taixing
Published: April 2007

Nitroalkenes, the nitration products of unsaturated fatty acids formed via NO-dependent oxidative reactions, have been demonstrated to exert strong biological actions in endothelial cells and monocytes/macrophages; however, little is known about their effects on vascular smooth muscle cells (VSMCs). The present study examined the role of nitro-linoleic acid (LNO2) in the regulation of VSMC proliferation. We observed that LNO2inhibited VSMC proliferation in a dose-dependent manner. In addition, LNO2induced growth arrest of VSMCs in the G1/S phase of the cell cycle with an upregulation of the cyclin-dependent kinase inhibitor p27kip1. Furthermore, LNO2triggered nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and activation of the antioxidant-responsive element-driven transcriptional activity via impairing Kelch-like ECH-associating protein 1 (Keap1)-mediated negative control of Nrf2 activity in VSMCs. LNO2upregulated the expression of Nrf2 protein levels, but not mRNA levels, in VSMCs. A forced activation of Nrf2 led to an upregulation of p27kip1and growth inhibition of VSMCs. In contrast, knock down of Nrf2 using an Nrf2 siRNA approach reversed the LNO2-induced upregulation of p27kip1and inhibition of cellular proliferation in VSMCs. These studies provide the first evidence that nitroalkene LNO2inhibits VSMC proliferation through activation of the Keap1/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology.
Transgenic mice expressing Na+-K+-ATPase in smooth muscle decreases blood pressure
Authors: Pritchard Tracy J. , Parvatiyar Michelle , Bullard Daniel P. , Lynch Ronald M. , Lorenz John N. , Paul Richard J.
Published: April 2007

The Na+-K+-ATPase (NKA) is a transmembrane protein that sets and maintains the electrochemical gradient by extruding three Na+in exchange for two K+. An important physiological role proposed for vascular smooth muscle NKA is the regulation of blood pressure via modulation of vascular smooth muscle contractility ( 5 ). To investigate the relations between the level of NKA in smooth muscle and blood pressure, we developed mice carrying a transgene for either the NKA α1- or α2-isoform (α1sm+or α2sm+mice) driven by the smooth muscle-specific α-actin promoter SMP8. Interestingly, both α-isoforms, the one contained in the transgene and the one not contained, were increased to a similar degree at both protein and mRNA levels. The total α-isoform protein was increased from 1.5-fold (α1sm+mice) to 7-fold (α2sm+mice). The increase in total NKA α-isoform protein was accompanied by a 2.5-fold increase in NKA activity in α2sm+gastric antrum. Immunocytochemistry of the α1- and α2-isoforms in α2sm+aortic smooth muscle cells indicated that α-isoform distributions were similar to those shown in wild-type cells. α2sm+Mice (high expression) were hypotensive (109.9 ± 1.6 vs. 121.3 ± 1.4 mmHg; n = 13 and 11, respectively), whereas α1sm+mice (low expression) were normotensive (122.7 ± 2.5 vs. 117.4 ± 2.3; n = 11 or 12). α2sm+Aorta, but not α1sm+aorta, relaxed faster from a KCl-induced contraction than wild-type aorta. Our results show that smooth muscle displays unique coordinate expression of the α-isoforms. Increasing smooth muscle NKA decreases blood pressure and is dependent on the degree of increased α-isoform expression.
Role of sensory nerves in the cutaneous vasoconstrictor response to local cooling in humans
Authors: Hodges Gary J. , Traeger J. Andrew , Tang Tri , Kosiba Wojciech A. , Zhao Kun , Johnson John M.
Published: April 2007

Local cooling (LC) causes a cutaneous vasoconstriction (VC). In this study, we tested whether there is a mechanism that links LC to VC nerve function via sensory nerves. Six subjects participated. Local skin and body temperatures were controlled with Peltier probe holders and water-perfused suits, respectively. Skin blood flow at four forearm sites was monitored by laser-Doppler flowmetry with the following treatments: untreated control, pretreatment with local anesthesia (LA) blocking sensory nerve function, pretreatment with bretylium tosylate (BT) blocking VC nerve function, and pretreatment with both LA and BT. Local skin temperature was slowly reduced from 34 to 29°C at all four sites. Both sites treated with LA produced an increase in cutaneous vascular conductance (CVC) early in the LC process (64 ± 55%, LA only; 42 ± 14% LA plus BT; P < 0.05), which was absent at the control and BT-only sites (5 ± 8 and 6 ± 8%, respectively; P > 0.05). As cooling continued, there were significant reductions in CVC at all sites ( P < 0.05). At control and LA-only sites, CVC decreased by 39 ± 4 and 46 ± 8% of the original baseline values, which were significantly ( P < 0.05) more than the reductions in CVC at the sites treated with BT and BT plus LA (−26 ± 8 and −22 ± 6%). Because LA affected only the short-term response to LC, either alone or in the presence of BT, we conclude that sensory nerves are involved early in the VC response to LC, but not for either adrenergic or nonadrenergic VC with longer term LC.
Lymphangion coordination minimally affects mean flow in lymphatic vessels
Authors: Venugopal Arun M. , Stewart Randolph H. , Laine Glen A. , Dongaonkar Ranjeet M. , Quick Christopher M.
Published: April 2007

The lymphatic system returns interstitial fluid to the central venous circulation, in part, by the cyclical contraction of a series of “lymphangion pumps” in a lymphatic vessel. The dynamics of individual lymphangions have been well characterized in vitro; their frequencies and strengths of contraction are sensitive to both preload and afterload. However, lymphangion interaction within a lymphatic vessel has been poorly characterized because it is difficult to experimentally alter properties of individual lymphangions and because the afterload of one lymphangion is coupled to the preload of another. To determine the effects of lymphangion interaction on lymph flow, we adapted an existing mathematical model of a lymphangion (characterizing lymphangion contractility, lymph viscosity, and inertia) to create a new lymphatic vessel model consisting of several lymphangions in series. The lymphatic vessel model was validated with focused experiments on bovine mesenteric lymphatic vessels in vitro. The model was then used to predict changes in lymph flow with different time delays between onset of contraction of adjacent lymphangions (coordinated case) and with different relative lymphangion contraction frequencies (noncoordinated case). Coordination of contraction had little impact on mean flow. Furthermore, orthograde and retrograde propagations of contractile waves had similar effects on flow. Model results explain why neither retrograde propagation of contractile waves nor the lack of electrical continuity between lymphangions adversely impacts flow. Because lymphangion coordination minimally affects mean flow in lymphatic vessels, lymphangions have flexibility to independently adapt to local conditions.
Uncoupling protein 2 modulates cell viability in adult rat cardiomyocytes
Authors: Bodyak Natalya , Rigor Debra L. , Chen Yee-Shiuan , Han Yuchi , Bisping Egbert , Pu William T. , Kang Peter M.
Published: April 2007

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane proton carrier that uncouples ATP synthesis. The aim of this study was to determine whether UCP2 plays a role in survival of adult rat cardiac myocytes. We first studied the effects of UCP2 overexpression in vitro. Overexpression of UCP2 in primary cardiomyocytes led to a significant decline in ATP level and the development of acidosis but had no observable effect on cell survival. When cardiomyocytes were challenged with hypoxia-reoxygenation, cells overexpressing UCP2 survived significantly less compared with control. This finding was associated with upregulation of proapoptotic protein Bcl-2 and 19-kDa interacting protein 3 (BNIP3). Furthermore, UCP2 short interfering RNA prevented both the increase in cell death and BNIP3 expression. To examine the in vivo role of UCP2 in the heart, we used the Dahl salt-sensitive rat heart-failure model. Northern blot analysis revealed that UCP2 mRNA level was significantly upregulated in rat heart failure along with BNIP3 protein level. In conclusion, UCP2 increases sensitivity of adult rat cardiac myocytes to hypoxia-reoxygenation by way of ATP depletion and acidosis, which in turn causes accumulation of prodeath protein BNIP3.
Involvement of A1adenosine receptors and neural pathways in adenosine-induced bronchoconstriction in mice
Authors: Hua Xiaoyang , Erikson Christopher J. , Chason Kelly D. , Rosebrock Craig N. , Deshpande Deepak A. , Penn Raymond B. , Tilley Stephen L.
Published: April 2007

High levels of adenosine can be measured from the lungs of asthmatics, and it is well recognized that aerosolized 5′AMP, the precursor of adenosine, elicits robust bronchoconstriction in patients with this disease. Characterization of mice with elevated adenosine levels secondary to the loss of adenosine deaminase (ADA) expression, the primary metabolic enzyme for adenosine, further support a role for this ubiquitous mediator in the pathogenesis of asthma. To begin to identify pathways by which adenosine can alter airway tone, we examined adenosine-induced bronchoconstriction in four mouse lines, each lacking one of the receptors for this nucleoside. We show, using direct measures of airway mechanics, that adenosine can increase airway resistance and that this increase in resistance is mediated by binding the A1receptor. Further examination of this response using pharmacologically, surgically, and genetically manipulated mice supports a model in which adenosine-induced bronchoconstriction occurs indirectly through the activation of sensory neurons.
Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-β
Authors: Xie Shaoping , Sukkar Maria B. , Issa Razao , Khorasani Nadia M. , Chung Kian Fan
Published: April 2007

Airway smooth muscle (ASM) hyperplasia is a characteristic feature of the asthmatic airway, but the underlying mechanisms that induce ASM hyperplasia remain unknown. Because transforming growth factor (TGF)-β is a potent regulator of ASM cell proliferation, we determined its expression and mitogenic signaling pathways in ASM cells. We obtained ASM cells by laser capture microdissection of bronchial biopsies and found that ASM cells from asthmatic patients expressed TGF-β1 mRNA and protein to a greater extent than nonasthmatic individuals using real-time RT-PCR and immunohistochemistry, respectively. TGF-β1 stimulated the growth of nonconfluent and confluent ASM cells either in the presence or absence of serum in a time- and concentration-dependent manner. The mitogenic activity of TGF-β1 on ASM cells was inhibited by selective inhibitors of TGF-β receptor I kinase (SD-208), phosphatidylinositol 3-kinase (PI3K, LY-294002), ERK (PD-98059), JNK (SP-600125), and NF-κB (AS-602868). On the other hand, p38 MAPK inhibitor (SB-203580) augmented TGF-β1-induced proliferation. To study role of the Smads, we transduced ASM cells with an adenovirus vector-expressing Smad4, Smad7, or dominant-negative Smad3 and found no involvement of these Smads in TGF-β1-induced proliferation. Dexamethasone caused a dose-dependent inhibition in TGF-β1-induced proliferation. Our findings suggest that TGF-β1 may act in an autocrine fashion to induce ASM hyperplasia, mediated by its receptor and several kinases including PI3K, ERK, and JNK, whereas p38 MAPK is a negative regulator. NF-κB is also involved in the TGF-β1 mitogenic signaling, but Smad pathway does not appear important.
Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C
Authors: Barman Scott A.
Published: April 2007

Although one of the common characteristics of pulmonary hypertension is abnormal sustained vasoconstriction, the signaling pathways that mediate this heightened pulmonary vascular response are still not well defined. Protein kinase C (PKC) and Rho-kinase are regulators of smooth muscle contraction induced by G protein-coupled receptor agonists including endothelin-1 (ET-1), which has been implicated as a signaling pathway in pulmonary hypertension. Toward this end, it was hypothesized that both Rho-kinase and PKC mediate the pulmonary vascular response to ET-1 in hypertensive pulmonary arterial smooth muscle, and therefore, the purpose of this study was to determine the role of PKC and Rho-kinase signaling in ET-1-induced vasoconstriction in both normotensive (Sprague-Dawley) and hypertensive (Fawn-Hooded) rat pulmonary arterial smooth muscle. Results indicate that ET-1 caused greater vasoconstriction in hypertensive pulmonary arteries compared with the normal vessels, and treatment with the PKC antagonists chelerythrine, rottlerin, and Gö 6983 inhibited the vasoconstrictor response to ET-1 in the hypertensive vessels. In addition, the specific Rho-kinase inhibitor Y-27632 significantly attenuated the effect of ET-1 in both normotensive and hypertensive phenotypes, with greater inhibition occurring in the hypertensive arteries. Furthermore, Western blot analysis revealed that ET-1 increased RhoA expression in both normotensive and hypertensive pulmonary arteries, with expression being greater in the hypertensive state. These results suggest that both PKC and Rho/Rho-kinase mediate the heightened pulmonary vascular response to ET-1 in hypertensive pulmonary arterial smooth muscle.
Perinatal increases in TGF-α disrupt the saccular phase of lung morphogenesis and cause remodeling: microarray analysis
Authors: Kramer Elizabeth L. , Deutsch Gail H. , Sartor Maureen A. , Hardie William D. , Ikegami Machiko , Korfhagen Thomas R. , Le Cras Timothy D.
Published: April 2007

Transforming growth factor-α (TGF-α) and its receptor, the epithelial growth factor receptor (EGFR), have been associated with lung remodeling in premature infants with bronchopulmonary dysplasia (BPD). The goal of this study was to target TGF-α overexpression to the saccular phase of lung morphogenesis and determine early alterations in gene expression. Conditional lung-specific TGF-α bitransgenic mice and single-transgene control mice were generated. TGF-α overexpression was induced by doxycycline (Dox) treatment from embryonic day 16.5 (E16.5) to E18.5. After birth, all bitransgenic pups died by postnatal day 7 (P7). Lung histology at E18.5 and P1 showed abnormal lung morphogenesis in bitransgenic mice, characterized by mesenchymal thickening, vascular remodeling, and poor apposition of capillaries to distal air spaces. Surfactant levels (saturated phosphatidylcholine) were not reduced in bitransgenic mice. Microarray analysis was performed after 1 or 2 days of Dox treatment during the saccular (E17.5, E18.5) and alveolar phases (P4, P5) to identify genes induced by EGFR signaling that were shared or unique to each phase. We found 196 genes to be altered (>1.5-fold change; P < 0.01 for at least 2 time points), with only 32% similarly altered in both saccular and alveolar phases. Western blot analysis and immunostaining showed that five genes selected from the microarrays (egr-1, SP-B, SP-D, S100A4, and pleiotrophin) were also increased at the protein level. Pathological changes in TGF-α-overexpressing mice bore similarities to premature infants born in the saccular phase who develop BPD, including remodeling of the distal lung septae and arteries.
Matrix Metalloproteinase Polymorphisms Are Associated with Bladder Cancer Invasiveness
Authors: Kader A. Karim , Liu Jun , Shao Lina , Dinney Colin P. , Lin Jie , Wang Yunfei , Gu Jian , Grossman H. Barton , Wu Xifeng
Published: May 2007

Purpose: Matrix metalloproteinases (MMP) promote tumor invasion and alter microenvironment. MMP levels are elevated in bladder cancer patients correlating with more advanced stage. We tested whether polymorphisms in MMP genes modify the risk of bladder cancer invasiveness and whether smoke exposure modifies this risk.

Experimental Design: Using a case-only study, we examined the association of 11 single-nucleotide polymorphisms and one microsatellite polymorphism in MMP genes MMP1, MMP2, MMP3, MMP8, MMP9, and MMP12 with the risk of invasive bladder cancer in 243 Caucasian patients with muscle invasive compared with 315 Caucasian patients with superficial disease.

Results: The MMP9 microsatellite ≥24 CA repeat and MMP12 −82 G alleles were associated with a higher risk of bladder cancer invasiveness [odds ratio (OR), 3.10; 95% confidence interval (95% CI) 1.17-8.23 and OR, 1.50; 95% CI, 1.00-2.28, respectively]. Ever smokers with the MMP9 ≥24 CA repeat allele had a 5.16-fold (95% CI, 1.56-17.1) increased risk of invasiveness compared with wild-type never smokers. Ever smokers with the MMP12 G allele also had an increased risk of bladder cancer invasiveness (OR, 2.32; 95% CI, 1.30-4.12).

Conclusions: Our results suggest that genetic changes in MMPs are associated with the development of invasive bladder cancer.
Limited Tissue Penetration of Taxanes: A Mechanism for Resistance in Solid Tumors
Authors: Kyle Alastair H. , Huxham Lynsey A. , Yeoman Devon M. , Minchinton Andrew I.
Published: May 2007

Purpose: Limited drug penetration in solid tumors is a potential mechanism of resistance for many anticancer drugs. Taxanes represent a class of drugs that are currently undergoing a new round of development, but with little known of their ability to penetrate and distribute relative to blood vessels within solid tumors.

Experimental Design: We assessed the tissue penetration of paclitaxel and docetaxel in HCT-116 tumor xenografts and in multilayered cell culture (MCC), a three-dimensional cell culture model of the tumor extravascular compartment. In xenografts, taxanes were mapped relative to blood vessels to obtain drug profiles as a function of distance from vasculature. For MCC, cultures were exposed to stirred drug reservoirs and taxanes measured as a function of depth into tissue.

Results: Both taxanes exhibited limited penetration, with little drug reaching further than 100 μm into the tissue. Of the two, paclitaxel exhibited up to 2-fold greater penetration than docetaxel. Mapping tumor cell proliferation following treatment allowed the consequences of limited drug penetration to be assessed. In tumor xenografts where reduced drug exposure to cells far from vasculature is one of several factors influencing response to treatment, up to a 75% reduction in S-phase cells was achieved in cells nearest the vessels, but only 50% reduction was observed in the tissue 150 μm away. In MCC-based data, where the influence of reduced cell proliferation with depth into tissue was circumvented, a 5-fold (paclitaxel) and 10-fold (docetaxel) increase in reservoir drug concentration was required to produce a response in cells 150 μm into the tissue equivalent to that seen in cells directly exposed to the drug.

Conclusion: These results indicate that limited distribution is an important mechanism of tumor resistance to taxanes.
MDM2 Promoter SNP309 Is Associated with Risk of Occurrence and Advanced Lymph Node Metastasis of Nasopharyngeal Carcinoma in Chinese Population
Authors: Zhou Gangqiao , Zhai Yun , Cui Ying , Zhang Xiumei , Dong Xiaojia , Yang Hao , He Ying , Yao Kaitai , Zhang Hongxing , Zhi Lianteng , Yuan Xiaoyan , Qiu Wei , Zhang Xiaoai , Shen Yan , Qiang Boqing , He Fuchu
Published: May 2007

Purpose: Mouse double minute 2 (MDM2) is a key negative regulator of the p53 activity. Recently, a polymorphism in the MDM2 intronic promoter, SNP309, was shown to influence MDM2 expression and p53 activity. We examined whether the SNP309 was related to the risk of developing nasopharyngeal carcinoma (NPC) among Chinese populations.

Experimental Design: We genotyped the SNP309 in two independent case-control populations in southern China, one is from Guangxi province (including 593 NPC patients and 480 controls) and the other is from Guangdong province (including 239 patients and 286 controls), by PCR direct sequencing. Multivariate logistic regression analysis was used to calculate adjusted odds ratio (OR) and 95% confidence interval (95% CI).

Results: We observed that compared with the TT genotype, the genotypes containing G allele (GT + GG genotype) were associated with significant increased susceptibility to NPC in both Guangxi (OR, 1.43; 95% CI, 1.04-1.91) and Guangdong population (OR, 1.53; 95% CI, 1.00-2.36). When these two sample sets were combined, the OR of the GT + GG genotype developing NPC was 1.45 (95% CI, 1.12-1.85) compared with the TT genotype. Furthermore, compared with the TT genotype, the GT + GG genotype was also significantly associated with the advanced lymph node metastasis (OR, 1.84; 95% CI, 1.09-3.05).

Conclusions: Our findings suggest that the MDM2 SNP309 may be a risk factor for the occurrence and advanced neck lymph node metastasis of NPC in Chinese population.
Association between Functional EGF+61 Polymorphism and Glioma Risk
Authors: Costa Bruno Marques , Ferreira Paulo , Costa Sandra , Canedo Paulo , Oliveira Pedro , Silva Ana , Pardal Fernando , Suriano Gianpaolo , Machado José Carlos , Lopes José Manuel , Reis Rui Manuel
Published: May 2007

Purpose: Epidermal growth factor (EGF) plays a critical role in cancer. A polymorphism in the EGF gene (EGF+61) may influence its expression and contribute to cancer predisposition and aggressiveness. In the present study, we aimed to elucidate the role of EGF+61 in glioma susceptibility and prognosis.

Experimental Design: A case-control study involving 197 glioma patients and 570 controls was done. Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). False-positive report probability was also assessed. The luciferase reporter gene assay was used to ascertain the functional consequences of this polymorphism.

Results: Corroborating the univariate analysis, the multivariate model showed that the G allele conferred higher risks for gliomas (OR, 1.32; 95% CI, 1.04-1.67), glioblastomas (OR, 1.47; 95% CI, 1.02-2.10), and oligodendrogliomas (OR, 1.55; 95% CI, 1.07-2.23). The GG genotypes were associated with increased risk for gliomas (OR, 1.71; 95% CI, 1.07-2.73), glioblastomas (OR, 2.03; 95% CI, 1.02-4.05), and oligodendrogliomas (OR, 2.72; 95% CI, 1.18-6.28). In addition, the AG+GG genotypes were associated with higher risk for gliomas (OR, 1.52; 95% CI, 1.03-2.23) and oligodendrogliomas (OR, 2.80; 95% CI, 1.35-5.79). No significant association was observed between the EGF+61 polymorphism and glioblastoma or oligodendroglioma patients' overall survival. The luciferase reporter gene assay exhibited a significant increased promoter activity for the G variant compared with the reference A allele.

Conclusions: These findings support the role of the EGF+61 polymorphism as a susceptibility factor for development of gliomas and show its implication on EGF promoter activity.
A Mosaic Fiber Adenovirus Serotype 5 Vector Containing Reovirus σ1 and Adenovirus Serotype 3 Knob Fibers Increases Transduction in an Ovarian Cancer Ex vivo System via a Coxsackie and Adenovirus Receptor–Independent Pathway
Authors: Tsuruta Yuko , Pereboeva Larisa , Glasgow Joel N. , Rein Daniel T. , Kawakami Yosuke , Alvarez Ronald D. , Rocconi Rodney P. , Siegal Gene P. , Dent Paul , Fisher Paul B. , Curiel David T.
Published: May 2007

Purpose: Adenovirus serotype 5 (Ad5) has been used for gene therapy with limited success due to insufficient infectivity in cells with low expression of the primary receptor, the coxsackie and adenovirus receptor (CAR). Evidence that adenovirus serotype receptors other than CAR may be of use was presented in previous studies that showed that the Ad3 receptor is expressed at high levels in ovarian cancer cells. We hypothesized that combined use of unique chimeric fibers in the context of novel mosaic adenovirus vectors would enhance infectivity via non-CAR pathways in ovarian cancer cells.

Experimental Design: We constructed and characterized Ad5 vectors that use Ad3 knob and reovirus fibers to generate a mosaic fiber virion. Serotype 3 Dearing reovirus uses a fiber-like σ1 protein to infect cells expressing sialic acid and junction adhesion molecule 1. We therefore constructed a mosaic fiber Ad5 vector, designated Ad5/3-σ1, encoding two fibers: a σ1 chimeric fiber and the chimeric Ad5/3 fiber composed of an Ad3 knob.

Results: Functionally, Ad5/3-σ1 used sialic acid, junction adhesion molecule 1, and Ad3 receptor for cell transduction and achieved maximum infectivity enhancement in ovarian cancer cells with low CAR expression. Furthermore, Ad5/3-σ1 achieved infectivity enhancement in primary tissue slices of human ovarian tumor.

Conclusions: We have developed a new type of Ad5 vector with the novel tropism, possessing fibers from Ad3 and reovirus, which exhibits enhanced infectivity via CAR-independent pathway(s). In addition, the flexible genetic platform of vector allows different combination of fiber variants that can be incorporated within the same particle.
Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel Target for Prostate Cancer Inhibition in Transgenic Adenocarcinoma of Mouse Prostate Model Mediated by Nexrutine, a Phellodendron Amurense Bark Extract
Authors: Kumar Addanki P. , Bhaskaran Shylesh , Ganapathy Manonmani , Crosby Katherine , Davis Michael D. , Kochunov Peter , Schoolfield John , Yeh I-Tien , Troyer Dean A. , Ghosh Rita
Published: May 2007

Purpose: Development of prostate cancer prevention strategies is an important priority to overcome high incidence, morbidity, and mortality. Recently, we showed that Nexrutine, an herbal extract, inhibits prostate cancer cell proliferation through modulation of Akt and cAMP-responsive element binding protein (CREB)–mediated signaling pathways. However, it is unknown if Nexrutine can be developed as a dietary supplement for the prevention of prostate cancer. In this study, we used the transgenic adenocarcinoma of mouse prostate (TRAMP) model to examine the ability of Nexrutine to protect TRAMP mice from developing prostate cancer.

Experimental Design: Eight-week-old TRAMP mice were fed with pelleted diet containing 300 and 600 mg/kg Nexrutine for 20 weeks. Efficacy of Nexrutine was evaluated by magnetic resonance imaging at 18 and 28 weeks of progression and histologic analysis of prostate tumor or tissue at the termination of the experiment. Tumor tissue was analyzed for modulation of various signaling molecules.

Results: We show that Nexrutine significantly suppressed palpable tumors and progression of cancer in the TRAMP model. Expression of total and phosphorylated Akt, CREB, and cyclin D1 was significantly reduced in prostate tissue from Nexrutine intervention group compared with tumors from control animals. Nexrutine also inhibited cyclin D1 transcriptional activity in androgen-independent PC-3 cells. Overexpression of kinase dead Akt mutant or phosphorylation-defective CREB inhibited cyclin D1 transcriptional activity.

Conclusions: The current study shows that Nexrutine-mediated targeting of Akt/CREB–induced activation of cyclin D1 prevents the progression of prostate cancer. Expression of CREB and phosphorylated CREB increased in human prostate tumors compared with normal tissue, suggesting their potential use as prognostic markers.
Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene
Authors: Moss Arthur J. , Shimizu Wataru , Wilde Arthur A.M. , Towbin Jeffrey A. , Zareba Wojciech , Robinson Jennifer L. , Qi Ming , Vincent G. Michael , Ackerman Michael J. , Kaufman Elizabeth S. , Hofman Nynke , Seth Rahul , Kamakura Shiro , Miyamoto Yoshihiro , Goldenberg Ilan , Andrews Mark L. , McNitt Scott
Published: May 2007

Background—

Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded I
Ks
cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder.

Methods and Results—

We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing
I
Ks
potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06;
P
<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26;
P
<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors.

Conclusions—

This genotype–phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.
Heritability of Platelet Responsiveness to Aspirin in Activation Pathways Directly and Indirectly Related to Cyclooxygenase-1
Authors: Faraday Nauder , Yanek Lisa R. , Mathias Rasika , Herrera-Galeano J. Enrique , Vaidya Dhananjay , Moy Taryn F. , Fallin M. Daniele , Wilson Alexander F. , Bray Paul F. , Becker Lewis C. , Becker Diane M.
Published: May 2007

Background—

The inability of aspirin (acetylsalicylic acid [ASA]) to adequately suppress platelet function is associated with future risk of myocardial infarction, stroke, and cardiovascular death. Genetic variation is a proposed but unproved mechanism for insufficient ASA responsiveness.

Methods and Results—

We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age, 44±13 years; 58% women) recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet activation in pathways directly and indirectly related to cyclooxygenase-1, the enzyme inhibited by ASA. The proportion of phenotypic variance related to CHD risk factor covariates was determined by multivariable regression. Heritability of phenotypes was determined with the use of variance components models unadjusted and adjusted for covariates. ASA inhibited arachidonic acid–induced aggregation and thromboxane B
2
production by ≥99% (
P
<0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to cyclooxygenase-1 was less pronounced and more variable (inhibition of 0% to 100%). Measured covariates contributed modestly to variability in ASA response phenotypes (
r
2
=0.001 to 0.133). Phenotypes indirectly related to cyclooxygenase-1 were strongly and consistently heritable across races (h
2
=0.266 to 0.762;
P
<0.01), but direct cyclooxygenase-1 phenotypes were not.

Conclusions—

Heritable factors contribute prominently to variability in residual platelet function after ASA exposure. These data suggest a genetic basis for the adequacy of platelet suppression by ASA and potentially for differences in the clinical efficacy of ASA.
Exercise and Acute Cardiovascular Events
Authors:   In Collaboration With the American College of Sports Medicine, Thompson Paul D. , Franklin Barry A. , Balady Gary J. , Blair Steven N. , Corrado Domenico , Estes N.A. Mark , Fulton Janet E. , Gordon Neil F. , Haskell William L. , Link Mark S. , Maron Barry J. , Mittleman Murray A. , Pelliccia Antonio , Wenger Nanette K. , Willich Stefan N. , Costa Fernando
Published: April 2007

Habitual physical activity reduces coronary heart disease events, but vigorous activity can also acutely and transiently increase the risk of sudden cardiac death and acute myocardial infarction in susceptible persons. This scientific statement discusses the potential cardiovascular complications of exercise, their pathological substrate, and their incidence and suggests strategies to reduce these complications. Exercise-associated acute cardiac events generally occur in individuals with structural cardiac disease. Hereditary or congenital cardiovascular abnormalities are predominantly responsible for cardiac events among young individuals, whereas atherosclerotic disease is primarily responsible for these events in adults. The absolute rate of exercise-related sudden cardiac death varies with the prevalence of disease in the study population. The incidence of both acute myocardial infarction and sudden death is greatest in the habitually least physically active individuals. No strategies have been adequately studied to evaluate their ability to reduce exercise-related acute cardiovascular events. Maintaining physical fitness through regular physical activity may help to reduce events because a disproportionate number of events occur in least physically active subjects performing unaccustomed physical activity. Other strategies, such as screening patients before participation in exercise, excluding high-risk patients from certain activities, promptly evaluating possible prodromal symptoms, training fitness personnel for emergencies, and encouraging patients to avoid high-risk activities, appear prudent but have not been systematically evaluated.
Decreased Endogenous Levels of Ac-SDKP Promote Organ Fibrosis
Authors: Cavasin Maria A. , Liao Tang-Dong , Yang Xiao-Ping , Yang James J. , Carretero Oscar A.
Published: May 2007

There is convincing evidence that chronic treatment with N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a peptide normally found in tissues and biological fluids, reduces collagen deposition in the heart and kidneys of hypertensive rats and rats with myocardial infarction. However, it is not known whether endogenous Ac-SDKP at basal concentrations has any physiological function related to collagen deposition. Prolyl oligopeptidase is responsible for release of Ac-SDKP from its precursor thymosin-β
4
. When we treated rats with a specific oral rolyl oligopeptidase inhibitor, Ac-SDKP decreased significantly in the plasma, heart, and kidney. In the present study, we tested the hypothesis that endogenous Ac-SDKP at basal levels plays a physiological role, antagonizing and/or preventing excessive collagen deposition. We studied whether chronic blockade of Ac-SDKP promotes collagen accumulation and/or accelerates this process in the presence of a profibrotic stimulus such as angiotensin II. We found that decreased basal levels of Ac-SDKP increased cardiac and renal perivascular fibrosis and promoted glomerulosclerosis. Moreover, in the presence of angiotensin II decreasing basal levels of Ac-SDKP accelerated interstitial cardiac fibrosis attributable to an increase in cells that produce collagen. We concluded that Ac-SDKP participates in the regulation of collagen content under normal conditions. We believe this is the first study showing that this peptide plays a physiological role at basal concentrations, preventing organ collagen accumulation.
Central Pressor Actions of Aminopeptidase-Resistant Angiotensin II Analogs
Authors: Kokje Ranjita J. , Wilson Wendy L. , Brown Travis E. , Karamyan Vardan T. , Wright John W. , Speth Robert C.
Published: May 2007

Intracerebroventricular administration of angiotensins causes pronounced pressor and dipsogenic responses. The suggestion that angiotensin III rather than angiotensin II is the active peptide in the brain spawned what we call The Angiotensin III

Hypothesis.To test this hypothesis, 5 angiotensin II analogs containing zero or one position substitutions conferring resistance to aminopeptidases were administered intracerebroventricularly to determine their pressor and dipsogenic efficacies. Two aminopeptidase-resistant analogs caused significantly greater pressor responses than angiotensin II, whereas 3 analogs caused pressor responses similar to angiotensin II. Latency to cause a pressor response for 4 of the 5 aminopeptidase-resistant angiotensin II analogs was the same as for angiotensin II. There was no detectable formation of125I-angiotensin III from 1 of the intracerebroventricularly administered analogs,125I- N-Methyl-l-Asp1-angiotensin II, indicating its aminopeptidase resistance. Latency to drink also did not differ between the angiotensins. After the initial dipsogenic response, water was removed until 25 minutes after angiotensin administration to avoid interfering with the pressor response. The dipsogenic stimulus was sustained 25 minutes after intracerebroventricular injection of angiotensin II and its aminopeptidase-resistant analogs. Comparison of angiotensin III and angiotensin II showed equivalent pressor responses with similar latencies and durations. The latency to drink was similar for angiotensin III and angiotensin II. However, there was no dipsogenic response to angiotensin III 25 minutes after intracerebroventricular injection. These data do not support The Angiotensin III Hypothesis and suggest that conversion of exogenously applied angiotensin II to angiotensin III is not necessary to cause brain-mediated pressor or dipsogenic responses.
Transport and Entrainment in the Red Sea Outflow Plume
Authors: Matt Silvia , Johns William E.
Published: May 2007

The Red Sea outflow exhibits strong seasonal variability in outflow transport due to effects of monsoon winds and seasonal fluctuations in buoyancy forcing. As it descends the continental slope in the western Gulf of Aden, it entrains significantly less-dense near-surface water, which itself varies on seasonal time scales. High-resolution hydrographic and direct velocity data collected during the 2001 Red Sea Outflow Experiment (REDSOX) are used herein to characterize and quantify the pathways of the Red Sea Outflow Water (RSOW) and the associated entrainment of Gulf of Aden Water. The outflow transport exhibits a maximum in winter of about 0.29 Sv (Sv ≡ 106 m3 s−1) at the exit of the Bab-el-Mandeb and approximately doubles to 0.56 Sv as it descends into the Gulf of Aden and entrains ambient water. In summer, the outflow is much weaker, reaching about 0.06 Sv at the strait and about 0.18 Sv downstream. The outflow plume divides into three distinct branches in winter, consisting of descending branches along two bathymetrically confined channels (the “Northern” and “Southern” channels, respectively), and an adjusted intrusion layer at shallower depths in the water column. Estimates of transport of “pure” Red Sea Outflow Water through salt flux conservation show the general partitioning of the outflow between the individual plumes, where the Northern Channel (NC) accounts for 52% of Red Sea Outflow Water, the Southern Channel (SC) carries 31%, and the intrusion layer (IL) the remaining 17%. The results also indicate that the transport of Red Sea Outflow Water is subject to considerable synoptic temporal variability that is unresolved by the present study.
Distinct 17- and 33-Day Tropical Instability Waves in Subsurface Observations*
Authors: Lyman John M. , Johnson Gregory C. , Kessler William S.
Published: May 2007

Tropical instability waves (TIWs) within a half-degree of the equator in the Pacific Ocean have been consistently observed in meridional velocity with periods of around 20 days. On the other hand, near 5°N, TIWs have been observed in sea surface height (SSH), thermocline depth, and velocity to have periods near 30 days. Tropical Atmosphere–Ocean (TAO) Project moored equatorial velocity and temperature time series are used to investigate the spatial and temporal structure of TIWs during 3 years of La Niña conditions from 1998 through 2001. Along 140°W, where the TIW temperature and velocity variabilities are at their maxima, these variabilities include two distinct TIWs with periods of 17 and 33 days, rather than one broadbanded process. As predicted by modeling studies, the 17-day TIW variability is shown to occur not only in meridional velocity at the equator, but also in subsurface temperature at 2°N and 2°S, while the 33-day TIW variability is observed primarily in subsurface temperature at 5°N. These two TIWs, respectively, are shown to have characteristics similar to a Yanai wave/surface-trapped instability and an unstable first meridional mode Rossby wave. One implication of such a description is that the velocity variability on the equator is not directly associated with the dominant 33-day variability along 5°N.
Island Wakes in Deep Water
Authors: Dong Changming , McWilliams James C. , Shchepetkin Alexander F.
Published: May 2007

Density stratification and planetary rotation distinguish three-dimensional island wakes significantly from a classical fluid dynamical flow around an obstacle. A numerical model is used to study the formation and evolution of flow around an idealized island in deep water (i.e., with vertical island sides and surface-intensified stratification and upstream flow), focusing on wake instability, coherent vortex formation, and mesoscale and submesoscale eddy activity. In a baseline experiment with strong vorticity generation at the island, three types of instability are evident: centrifugal, barotropic, and baroclinic. Sensitivities are shown to three nondimensional parameters: the Reynolds number (Re), Rossby number (Ro), and Burger number (Bu). The dependence on Re is similar to the classical wake in its transition to turbulence, but in contrast the island wake contains coherent eddies no matter how large the Re value. When Re is large enough, the shear layer at the island is so narrow that the vertical component of vorticity is larger than the Coriolis frequency in the near wake, leading to centrifugal instability on the anticyclonic side. As Bu decreases the eddy size shrinks from the island breadth to the baroclinic deformation radius, and the eddy generation process shifts from barotropic to baroclinic instability. For small Ro values, the wake dynamics is symmetric with respect to cyclonic and anticyclonic eddies. At intermediate Ro and Bu values, the anticyclonic eddies are increasingly more robust than cyclonic ones as Ro/Bu increases, but for large Re and Ro values, centrifugal instability weakens the anticyclonic eddies while cyclonic eddies remain coherent.