bluuebunny/crossref_metadata_2025 huggingface dataset:
Antihypertensive therapy increases tetrahydrobiopterin levels and NO/cGMP signaling in small arteries of angiotensin II-infused hypertensive rats
Authors: Kang Kyu-Tae , Sullivan Jennifer C. , Spradley Frank T. , d'Uscio Livius V. , Katusic Zvonimir S. , Pollock Jennifer S.
Published: December 2010

We previously reported that small mesenteric arteries from hypertensive rats have increased NOS-derived H2O2 and reduced NO/cGMP signaling. We hypothesized that antihypertensive therapy lowers blood pressure through a tetrahydrobiopterin (BH4)-dependent mechanism restoring NO/cGMP signaling and endothelial NOS (NOS3; eNOS) phosphorylation in small arteries. To test this hypothesis, small mesenteric arteries from normotensive rats (NORM), angiotensin II-infused rats (ANG), ANG rats with triple therapy (reserperine, hydrochlorothiazide, and hydralazine), or ANG rats with oral BH4 therapy were studied. Both triple therapy and oral BH4 therapy attenuated the rise in systolic blood pressure in ANG rats and restored NO/cGMP signaling in small arteries similarly. Triple therapy significantly increased vascular BH4 levels and BH4-to-BH2 ratio similar to ANG rats with BH4 supplementation. Furthermore, triple therapy (but not oral BH4 therapy) significantly increased GTP cyclohydrolase I (GTPCH I) activity in small arteries without a change in expression. NOS3 phosphorylation at Ser1177 was reduced in small arteries from ANG compared with NORM, while NOS3 phosphorylation at Ser633 and Thr495 were similar in ANG and NORM. NOS3 phosphorylation at Ser1177 was restored with triple therapy or oral BH4 in ANG rats. In conclusion, antihypertensive therapy regulates NO/cGMP signaling in small arteries through increasing BH4 levels and NOS3 phosphorylation at Ser1177.
Vessel tortuousity and reduced vascularization in the fetoplacental arterial tree after maternal exposure to polycyclic aromatic hydrocarbons
Authors: Rennie Monique Y. , Detmar Jacqui , Whiteley Kathie J. , Yang Jian , Jurisicova Andrea , Adamson S. Lee , Sled John G.
Published: December 2010

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and the main toxicants found in cigarettes. Women are often exposed to PAHs before pregnancy, typically via prepregnancy smoking. To determine how prepregnancy exposure affects the fetoplacental vasculature of the placenta, we exposed female mice to PAHs before conception, perfused the fetoplacental arterial trees with X-ray contrast agent, and imaged the vasculature ex vivo by microcomputed tomography (micro-CT) at embryonic day 15.5. Automated vascular segmentation and flow calculations revealed that in control trees, <40 chorionic plate vessels (diameter >180 μm) gave rise to ∼1,300 intraplacental arteries (50–180 μm), predicting an arterial vascular resistance of 0.37 ± 0.04 mmHg·s·μl−1. PAH exposure increased vessel curvature of chorionic plate vessels and significantly increased the tortuousity ratio of the tree. Intraplacental arteries were reduced by 17%, primarily due to a 27% decrease in the number of arteriole-sized (50–100 μm) vessels. There were no changes in the number of chorionic vessels, the depth or span of the tree, the diameter scaling coefficient, or the segment length-to-diameter ratio. PAH exposure resulted in a tree with a similar size and dichotomous branching structure, but one that was comparatively sparse so that arterial vascular resistance was increased by 30%. Assuming the same pressure gradient, blood flow would be 19% lower. Low flow may contribute to the 23% reduction observed in fetal weight. New insights into the specific effects of PAH exposure on a developing arterial tree were achieved using micro-CT imaging and automated vascular segmentation analysis.
Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization
Authors: Nystoriak Matthew A. , O'Connor Kevin P. , Sonkusare Swapnil K. , Brayden Joseph E. , Nelson Mark T. , Wellman George C.
Published: December 2010

Intracerebral (parenchymal) arterioles are morphologically and physiologically unique compared with pial arteries and arterioles. The ability of subarachnoid hemorrhage (SAH) to induce vasospasm in large-diameter pial arteries has been extensively studied, although the contribution of this phenomenon to patient outcome is controversial. Currently, little is known regarding the impact of SAH on parenchymal arterioles, which are critical for regulation of local and global cerebral blood flow. Here diameter, smooth muscle intracellular Ca2+concentration ([Ca2+]i), and membrane potential measurements were used to assess the function of intact brain parenchymal arterioles isolated from unoperated (control), sham-operated, and SAH model rats. At low intravascular pressure (5 mmHg), membrane potential and [Ca2+]iwere not different in arterioles from control, sham-operated, and SAH animals. However, raising intravascular pressure caused significantly greater membrane potential depolarization, elevation in [Ca2+]i, and constriction in SAH arterioles. This SAH-induced increase in [Ca2+]iand tone occurred in the absence of the vascular endothelium and was abolished by the L-type voltage-dependent calcium channel (VDCC) inhibitor nimodipine. Arteriolar [Ca2+]iand tone were not different between groups when smooth muscle membrane potential was adjusted to the same value. Protein and mRNA levels of the L-type VDCC CaV1.2 were similar in parenchymal arterioles isolated from control and SAH animals, suggesting that SAH did not cause VDCC upregulation. We conclude that enhanced parenchymal arteriolar tone after SAH is driven by smooth muscle membrane potential depolarization, leading to increased L-type VDCC-mediated Ca2+influx.
Relative roles of doxycycline and cation chelation in endothelial glycan shedding and adhesion of leukocytes
Authors: Lipowsky Herbert H. , Sah Rachna , Lescanic Anne
Published: December 2010

Leukocyte [white blood cell (WBC)] adhesion and shedding of glycans from the endothelium [endothelial cells (ECs)] in response to the chemoattractant f-Met-Leu-Phe (fMLP) has been shown to be attenuated by topical inhibition of matrix metalloproteases (MMPs) with doxycycline (Doxy). Since Doxy also chelates divalent cations, these responses were studied to elucidate the relative roles of cation chelation and MMP inhibition. WBC-EC adhesion, WBC rolling flux, and WBC rolling velocity were studied in postcapillary venules in the rat mesentery during superfusion with the cation chelator EDTA or Doxy. Shedding and accumulation of glycans on ECs, with and without fMLP, were quantified by the surface concentration of lectin (BS-1)-coated fluorescently labeled microspheres (FLMs) during constant circulating concentration. Without fMLP, low concentrations of EDTA (1–3 mM) increased FLM-EC sequestration due to disruption of the permeability barrier with prolonged exposure. In contrast, with 0.5 μM Doxy alone, FLM adhesion remained constant (i.e., no change in glycan content) on ECs, and WBC adhesion increased with prolonged superfusion. Without fMLP, EDTA did not affect firm WBC-EC adhesion but reduced WBC rolling flux in a dose-dependent manner. With fMLP, EDTA did not inhibit WBC adhesion, whereas Doxy did during the first 20 min of superfusion. Thus, the inhibition by Doxy of glycan (FLM) shedding and WBC adhesion in response to fMLP results from MMP inhibition, in contrast to cation chelation. With either Doxy or the MMP inhibitor GM-6001, WBC rolling velocity decreased by 50%, as in the case with fMLP, suggesting that MMP inhibition reduces sheddase activity, which increases the adhesiveness of rolling WBCs. These events increase the effective leukocrit on the venular wall and increase firm WBC-EC adhesion. Thus, MMP inhibitors have both a proadhesion effect by reducing sheddase activity while exerting an antiadhesion effect by inhibiting glycocalyx shedding and subsequent exposure of adhesion molecules on the EC surface.
Effect of proteinS-glutathionylation on Ca2+homeostasis in cultured aortic endothelial cells
Authors: Lock Jeffrey T. , Sinkins William G. , Schilling William P.
Published: December 2010

Diamide is a membrane-permeable, thiol-oxidizing agent that rapidly and reversibly oxidizes glutathione to GSSG and promotes formation of protein-glutathione mixed disulfides. In the present study, the acute effect of diamide on free cytosolic Ca2+concentration ([Ca2+]i) was examined in fura-2-loaded bovine aortic endothelial cells. At low concentrations (50, 100 μM), diamide reversibly increased spontaneous, asynchronous Ca2+oscillations, whereas, at higher concentrations (250, 500 μM), diamide caused an immediate synchronized Ca2+oscillation in essentially all cells of the monolayer, followed by a time-dependent rise in basal [Ca2+]i. The effects of diamide on [Ca2+]idynamics were independent of extracellular Ca2+. Inhibition of phospholipase C by U-73122 prevented the observed changes in [Ca2+]i. Additionally, the diamide-induced oscillations, but not the rise in basal [Ca2+]i, were blocked by inhibition of the inositol-1,4,5-trisphosphate (IP3) receptor (IP3R) by 2-aminoethyl diphenyl borate. However, diamide failed to alter the plasmalemmal distribution of a green fluorescent protein-tagged phosphatidylinositol-4,5-bisphosphate binding protein, demonstrating that diamide does not activate phospholipase C. Inhibition of glutathione reductase by N, N′-bis(2-chloroethyl)- N-nitrosourea or depletion of glutathione by l-buthionine-sulfoximine enhanced the effects of diamide, which, under these conditions, could only be reversed by addition of dithiothreitol to the wash buffer. Biochemical assays showed that both the IP3R and the plasmalemmal Ca2+-ATPase pump could be reversibly glutathionylated in response to diamide. These results demonstrate that diamide promotes Ca2+release from IP3-sensitive internal Ca2+stores and elevates basal [Ca2+]iin the absence of extracellular Ca2+, effects that may be related to a diamide-induced glutathionylation of the IP3R and the plasmalemmal Ca2+-ATPase Ca2+pump, respectively.
Inhibition of apoptosis by 60% oxygen: a novel pathway contributing to lung injury in neonatal rats
Authors: Yi Man , Masood Azhar , Ziino Adrian , Johnson Ben-Hur , Belcastro Rosetta , Li Jun , Shek Samuel , Kantores Crystal , Jankov Robert P. , Keith Tanswell A.
Published: December 2010

During early postnatal alveolar formation, the lung tissue of rat pups undergoes a physiological remodeling involving apoptosis of distal lung cells. Exposure of neonatal rats to severe hyperoxia (≥95% O2) both arrests lung growth and results in increased lung cell apoptosis. In contrast, exposure to moderate hyperoxia (60% O2) for 14 days does not completely arrest lung cell proliferation and is associated with parenchymal thickening. On the basis of similarities in lung architecture observed following either exposure to 60% O2, or pharmacological inhibition of physiological apoptosis, we hypothesized that exposure to 60% O2would result in an inhibition of physiological lung cell apoptosis. Consistent with this hypothesis, we observed that the parenchymal thickening induced by exposure to 60% O2was associated with decreased numbers of apoptotic cells, increased expressions of the antiapoptotic regulator Bcl-xL, and the putative antiapoptotic protein survivin, and decreased expressions of the proapoptotic cleaved caspases-3 and -7. In summary, exposure of the neonatal rat lung to moderate hyperoxia results in an inhibition of physiological apoptosis, which contributes to the parenchymal thickening observed in the resultant lung injury.
Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite
Authors: Yadav Amit K. , Doran Stephen F. , Samal Andrey A. , Sharma Ruchita , Vedagiri Kokilavani , Postlethwait Edward M. , Squadrito Giuseppe L. , Fanucchi Michelle V. , Roberts L. Jackson , Patel Rakesh P. , Matalon Sadis
Published: December 2010

Nitrite (NO2−) has been shown to limit injury to the heart, liver, and kidneys in various models of ischemia-reperfusion injury. Potential protective effects of systemic NO2− in limiting lung injury or enhancing repair have not been documented. We assessed the efficacy and mechanisms by which postexposure intraperitoneal injections of NO2− mitigate chlorine (Cl2)-induced lung injury in rats. Rats were exposed to Cl2 (400 ppm) for 30 min and returned to room air. NO2− (1 mg/kg) or saline was administered intraperitoneally at 10 min and 2, 4, and 6 h after exposure. Rats were killed at 6 or 24 h. Injury to airway and alveolar epithelia was assessed by quantitative morphology, protein concentrations, number of cells in bronchoalveolar lavage (BAL), and wet-to-dry lung weight ratio. Lipid peroxidation was assessed by measurement of lung F2-isoprostanes. Rats developed severe, but transient, hypoxemia. A significant increase of protein concentration, neutrophil numbers, airway epithelia in the BAL, and lung wet-to-dry weight ratio was evident at 6 h after Cl2 exposure. Quantitative morphology revealed extensive lung injury in the upper airways. Airway epithelial cells stained positive for terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL), but not caspase-3. Administration of NO2− resulted in lower BAL protein levels, significant reduction in the intensity of the TUNEL-positive cells, and normal lung wet-to-dry weight ratios. F2-isoprostane levels increased at 6 and 24 h after Cl2 exposure in NO2−- and saline-injected rats. This is the first demonstration that systemic NO2− administration mitigates airway and epithelial injury.
Oncogenic Kras Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17
Authors: Van Schaeybroeck Sandra , Kyula Joan N. , Fenton Audrey , Fenning Catherine S. , Sasazuki Takehiko , Shirasawa Senji , Longley Daniel B. , Johnston Patrick G.
Published: December 2010

Oncogenic mutations in Kras occur in 40% to 45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17, resulting in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. In this study, we examined the role of mutant Kras in regulating growth factor shedding and ADAM17 activity, using isogenic Kras mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-α and VEGF were shed from KrasMT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk (phosphorylated extracellular signal regulated kinase)1/2 levels and ADAM17 activity. Inhibition of Kras, MEK (MAP/ERK kinase)1/2, or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-α shedding. Moreover, we found that these effects were not drug or cell line specific. In addition, MEK1/2 inhibition in KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, which correlated with dramatically attenuated tumor growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity. Cancer Res; 71(3); 1071–80. ©2010 AACR.
Src and Caveolin-1 Reciprocally Regulate Metastasis via a Common Downstream Signaling Pathway in Bladder Cancer
Authors: Thomas Shibu , Overdevest Jonathan B. , Nitz Matthew D. , Williams Paul D. , Owens Charles R. , Sanchez-Carbayo Marta , Frierson Henry F. , Schwartz Martin A. , Theodorescu Dan
Published: December 2010

In bladder cancer, increased caveolin-1 (Cav-1) expression and decreased Src expression and kinase activity correlate with tumor aggressiveness. Here, we investigate the clinical and functional significance, if any, of this reciprocal expression in bladder cancer metastasis. We evaluated the ability of tumor Cav-1 and Src RNA and protein expression to predict outcome following cystectomy in 257 patients enrolled in two independent clinical studies. In both, high Cav-1 and low Src levels were associated with metastasis development. We overexpressed or depleted Cav-1 and Src protein levels in UMUC-3 and RT4 human bladder cancer cells and evaluated the effect of this on actin stress fibers, migration using Transwells, and lung metastasis following tail vein inoculation. Cav-1 depletion or expression of active Src in metastatic UMUC-3 cells decreases actin stress fibers, cell migration, and metastasis, while Cav-1 overexpression or Src depletion increased the migration of nonmetastatic RT4 cells. Biochemical studies indicated that Cav-1 mediates these effects via its phosphorylated form (pY14), whereas Src effects are mediated through phosphorylation of p190RhoGAP and these pathways converge to reduce activity of RhoA, RhoC, and Rho effector ROCK1. Treatment with a ROCK inhibitor reduced UMUC-3 lung metastasis in vivo, phenocopying the effect of Cav-1 depletion or expression of active Src. Src suppresses whereas Cav-1 promotes metastasis of bladder cancer through a pharmacologically tractable common downstream signaling pathway. Clinical evaluation of personalized therapy to suppress metastasis development based on Cav-1 and Src profiles seems warranted. Cancer Res; 71(3); 832–41. ©2010 AACR.
Phase I Assessment of New Mechanism-Based Pharmacodynamic Biomarkers for MLN8054, a Small-Molecule Inhibitor of Aurora A Kinase
Authors: Chakravarty Arijit , Shinde Vaishali , Tabernero Josep , Cervantes Andres , Cohen Roger B. , Dees E. Claire , Burris Howard , Infante Jeffrey R. , Macarulla Teresa , Elez Elena , Andreu Jordi , Rodriguez-Braun Edith , Rosello Susana , von Mehren Margaret , Meropol Neal J. , Langer Corey J. , ONeil Bert , Bowman Douglas , Zhang Mengkun , Danaee Hadi , Faron-Yowe Laura , Gray Gary , Liu Hua , Pappas Jodi , Silverman Lee , Simpson Chris , Stringer Bradley , Tirrell Stephen , Veiby Ole Petter , Venkatakrishnan Karthik , Galvin Katherine , Manfredi Mark , Ecsedy Jeffrey A.
Published: December 2010

The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure–effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues. Cancer Res; 71(3); 675–85. ©2010 AACR.
Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
Authors: Viaud Sophie , Flament Caroline , Zoubir Mustapha , Pautier Patricia , LeCesne Axel , Ribrag Vincent , Soria Jean-Charles , Marty Virginie , Vielh Philippe , Robert Caroline , Chaput Nathalie , Zitvogel Laurence
Published: December 2010

Low doses of the alkylating agent cyclophosphamide (CTX) mediate antiangiogenic and immunostimulatory effects, leading to potent tumoricidal activity in association with various immunotherapeutic strategies. Here, we show in rodents and cancer patients that CTX markedly promotes the differentiation of CD4+ T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells. Because Th17 are potent inducers of tissue inflammation and autoimmunity, these results suggest impact on the clinical management of various types of malignancies treated with alkylating agents and a potential need to optimize CTX-based immunotherapy in patients. Cancer Res; 71(3); 661–5. ©2010 AACR.
The Novel Metastasis Promoter Merm1/Wbscr22 Enhances Tumor Cell Survival in the Vasculature by Suppressing Zac1/p53-Dependent Apoptosis
Authors: Nakazawa Youya , Arai Hiroyuki , Fujita Naoya
Published: December 2010

Understanding metastasis is integral to curative cancer treatments. Using a mouse genetic screening model, we identified Merm1/Wbscr22 as a novel metastasis promoter that includes a methyltransferase fold in its structure. Merm1 showed high levels of expression in invasive breast cancer. Ectopic expression of Merm1 in nonmetastatic cells enhanced metastasis formation without affecting cell growth and motility. The intact methyltransferase fold of Merm1 was required for metastasis formation. Interestingly, Merm1 expression promoted cell survival after entrapment in the lung microvasculature. Consistent with these results, knockdown of endogenous Merm1 in tumor cells reduced lung retention and metastasis formation. On the basis of comparative transcriptome analysis, Merm1 expression was negatively correlated with the expression of tumor suppressor Zac1. We confirmed that Merm1 suppressed Zac1 expression with histone H3 methylation at Lys9 in the Zac1 promoter region. Zac1 can induce apoptosis through its ability to transcriptionally coactivate p53, which regulates apoptosis in the vasculature and is often downregulated in metastasis. We found that Zac1 knockdown reduced the p53-dependent apoptosis that was enhanced by Merm1 knockdown, thereby increasing lung retention of metastatic cells. Our findings show that Merm1 enhances cancer cell survival in the vasculature by suppressing Zac1/p53-dependent apoptosis, thereby enhancing metastasis. Cancer Res; 71(3); 1146–55. ©2010 AACR.
ETV6-NTRK3–Mediated Breast Epithelial Cell Transformation Is Blocked by Targeting the IGF1R Signaling Pathway
Authors: Tognon Cristina E. , Somasiri Aruna M. , Evdokimova Valentina E. , Trigo Genny , Uy Evett E. , Melnyk Nataliya , Carboni Joan M. , Gottardis Marco M. , Roskelley Calvin D. , Pollak Michael , Sorensen Poul H.B.
Published: December 2010

The insulin-like growth factor (IGF) 1 receptor (IGF1R) is an important therapeutic target under study in many cancers. Here, we describe a breast cancer model based on expression of the ETV6-NTRK3 (EN) chimeric tyrosine kinase that suggests novel therapeutic applications of IGF1R inhibitors in secretory breast cancers. Originally discovered in congenital fibrosarcomas with t(12;15) translocations, EN was identified subsequently in secretory breast carcinoma (SBC) which represent a variant of invasive ductal carcinoma. Because fibroblast transformation by EN requires the IGF1R axis, we hypothesized a similar dependency may exist in mammary cells and, if so, that IGF1R inhibitors might be useful to block EN-driven breast oncogenesis. In this study, we analyzed EN expressing murine and human mammary epithelial cell lines for transformation properties. Various IGF1R signaling inhibitors, including the dual specificity IGF1R/insulin receptor (INSR) inhibitor BMS-536924, were then tested for effects on three-dimensional Matrigel cell growth, migration, and tumor formation. We found that EN expression increased acinar size and luminal filling in Matrigel cultures and promoted orthotopic tumor growth in mice. Tumors were well differentiated and nonmetastatic, similar to human SBC. The known EN effector pathway, PI3K-Akt, was activated in an IGF1- or insulin-dependent manner. BMS-536924 blocked EN transformation in vitro, whereas BMS-754807, another IGIFR/INSR kinase inhibitor currently in clinical trials, significantly reduced tumor growth in vivo. Importantly, EN model systems mimic the clinical phenotype observed in human SBC. Moreover, EN has a strict requirement for IGF1R or INSR in breast cell transformation. Thus, our findings strongly encourage the evaluation of IGF1R/INSR inhibitors to treat EN-driven breast cancers. Cancer Res; 71(3); 1060–70. ©2010 AACR.
Both Gene Amplification and Allelic Loss Occur at 14q13.3 in Lung Cancer
Authors: Harris Thomas , Pan Qiulu , Sironi Juan , Lutz Dionne , Tian Jianmin , Sapkar Jana , Perez-Soler Roman , Keller Steven , Locker Joseph
Published: December 2010

Purpose: Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer.

Experimental Design: NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines.

Results: Thirteen of forty-five (29%) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14−, 14+, or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells.

Conclusions: 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells. Clin Cancer Res; 17(4); 690–9. ©2010 AACR.
siRNA-Mediated Downregulation of MMP-9 and uPAR in Combination with Radiation Induces G2/M Cell-Cycle Arrest in Medulloblastoma
Authors: Ganji Purna Chandra Nagaraju , Nalla Arun Kumar , Gupta Reshu , Mohanam Sanjeeva , Gujrati Meena , Dinh Dzung H. , Rao Jasti S.
Published: December 2010

Our previous work and that of other investigators strongly suggest a relationship between the upregulation of metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator receptor (uPAR) in tumor angiogenesis and metastasis. In this study, we evaluated the role of MMP-9 and uPAR in medulloblastoma cancer cell resistance to ionizing irradiation (IR) and tested the antitumor efficacy of siRNA (short interfering RNA) against MMP-9 [plasmid siRNA vector for MMP-9 (pM)] and uPAR [plasmid vector for uPAR (pU)] either alone or in combination [plasmid siRNA vector for both uPAR and MMP-9 (pUM)]. Cell proliferation (BrdU assay), apoptosis (in situ TUNEL for DNA fragmentation), and cell-cycle (FACS) analyses were carried out to determine the effect of siRNA either alone or in combination with IR on G2/M cell-cycle arrest in medulloblastoma cells. IR upregulated MMP-9 and uPAR expression in medulloblastoma cells; pM, pU, and pUM in combination with IR effectively reduced both MMP-9 and uPAR expression, thereby leading to increased radiosensitivity of medulloblastoma cells. siRNA treatments (pM, pU, and pUM) also promoted IR-induced apoptosis and enhanced IR-induced G2/M arrest during cell-cycle progression. While IR induces G2/M cell-cycle arrest through inhibition of the pCdc2- and cyclin B–regulated signaling pathways involving p53, p21/WAF1, and Chk2 gene expression, siRNA (pM, pU, and pUM) alone or in combination with IR induced G2/M arrest mediated through inhibition of the pCdc2- and cyclin B1-regulated signaling pathways involving Chk1 and Cdc25A gene expression. Taken together, our data suggest that downregulation of MMP-9 and uPAR induces Chk1-mediated G2/M cell-cycle arrest, whereas the disruption caused by IR alone is dependent on p53- and Chk2-mediated G2/M cell-cycle arrest. Mol Cancer Res; 9(1); 51–66 ©2010 AACR.
Client Common Factors Represented by Client Motivation and Autonomy
Authors: Scheel Michael J.
Published: December 2010

Ryan and colleagues are applauded for elevating client factors in the form of motivation and autonomy to equal status with the alliance as common factors in psychotherapy. Next, client motivation and autonomy are explained to be inextricably linked with one promoting the other. Motivational methods are summarized for the major approaches, making the point that some motivational approaches are more related to the promotion of client autonomy. Change talk is explained as similar to solution talk. Both are social constructivist methods of motivating clients and overcoming impasse in therapy. Matching client beliefs, using client strengths, and providing compelling rationales are underscored as motivational techniques. Similarities between motivation and hope are drawn through Snyder’s hope theory and Frank and Frank’s contextual model of psychotherapy. Finally, motivation and the formation of the alliance are discussed as factors that overlap conceptually and interact as variables in research.
Establishing a Causal Relationship Between Intervention to Promote Self-Determination and Enhanced Student Self-Determination
Authors: Wehmeyer Michael L. , Palmer Susan B. , Shogren Karrie , Williams-Diehm Kendra , Soukup Jane H.
Published: December 2010

Promoting the self-determination of adolescents with disabilities has become best practice in secondary education and transition services, but to date there have been no studies establishing a causal relationship between efforts to promote self-determination and enhancement of the self-determination of youth with disabilities. This article reports a randomized trial placebo control group study of 371 high school students receiving special education services under the categorical areas of mental retardation or learning disabilities. Students were randomly assigned to an intervention or control group (by high school campus), with students in the intervention condition receiving multiple instructional components to promote self-determination. Latent growth curve analysis showed that although all students in the study showed improved self-determination over the 3 years of the study, students in the intervention group showed significantly greater growth, though specific intraindividual variables affected this growth. Implications for research and intervention are discussed.
Second Thoughts, Second Feelings: Attenuating the Impact of Threatening Narratives Through Rational Reappraisal
Authors: Berger Charles R. , Key Jung Lee
Published: December 2010

Two experiments tested hypotheses, derived from dual-process theory frameworks, concerning the attenuating effects of analytic system activation on emotion and cognitive judgments made after exposure to threatening narratives. In Experiment 1, after reading an emotionally intense news story, those whose rational system was activated by evaluating the story’s probative value reported less intense emotions than those whose rational system was not so activated. Reporting emotional responses to the story before or after making probative value judgments had no effect on the probative value judgments. In Experiment 2, rationally activated individuals reported less intense emotions than those who were activated experientially by listing emotions experienced by the story’s victim. Rational system activation also significantly reduced estimates of the problem’s seriousness and victimization risk relative to both those who were experientially activated and those who were not explicitly activated. The asymmetrical impact of the rational and experiential systems on affective and cognitive judgments is discussed in terms of the dynamic interaction between the two processing systems.
On the Nature and Strategies of Organized Interests in Health Care Policy Making
Authors: Contandriopoulos Damien
Published: December 2010

Relying on a sweeping review of the literature on interest group influence in health care policy making, we propose a basic definition and a typology of interest groups in provincial health care policy making. Then, using Milbrath’s communication framework, we analyze organized interests’ strategies for influencing policy making. This article is a modest attempt to cross-fertilize the group theory and resource dependency literature. This theoretical framework allows us to explore many of the recurring questions about groups’ origins and strategies from an original standpoint.
Connecting the Past With the Present
Authors: Newbold Stephanie P. , Schortgen Alicia C.
Published: December 2010

Moses Maimonides is widely regarded as one of the most important Jewish theologians. A careful examination of his life’s work, however, reveals that he also made important contributions to the history of Western political thought, law, statesmanship, public management, and civil society. His professional career illuminates important connections between the administration of innovative public programs and how the state benefits from the collective good associated with these initiatives. Such efforts provide public administration with a rare opportunity to explore the theoretical perspectives of a political philosopher whose ideas are as strikingly modern today as they were more than nine centuries ago.
Invited Editorial: Why Micro-Foundations for Resource-Based Theory Are Needed and What They May Look Like
Authors: Foss Nicolai J.
Published: December 2010

One of the important events in the development of resource-based theory (RBT) over the past decade has been the call for establishing micro-foundations for RBT. However, the micro-foundations project is still largely an unfulfilled promise. This article clarifies the nature of the micro-foundations project, discusses what it may add in terms of additional explanatory leverage, and specifically addresses micro-foundations in the context of knowledge-based value creation, a key theme in RBT.
Invited Editorial: A Natural-Resource-Based View of the Firm
Authors: Hart Stuart L. , Dowell Glen
Published: December 2010

The authors revisit Hart’s natural-resource-based view (NRBV) of the firm and summarize progress that has been made in testing elements of that theory and reevaluate the NRBV in light of a number of important developments that have emerged in recent years in both the resource-based view literature and in research on sustainable enterprise. First, the authors consider how the NRBV can both benefit from recent work in dynamic capabilities and can itself inform such work. Second, they review recent research in the areas of clean technology and business at the base of the pyramid and suggest how the NRBV can help inform research on the resources and capabilities needed to enter and succeed in these domains.
Social tags as news event detectors
Authors: Chua Alton Y.K. , Razikin Khasfariyati , Goh Dion H.
Published: December 2010

The objective of this study was to investigate the use of tags in iReport to detect breaking news in terms of coverage and immediacy. Coverage refers to the extent to which news reported in mainstream media can also be detected in iReport, while immediacy refers to the promptness of news reported in mainstream media vis-à-vis those detected in iReport. A total of 10 ground truth events were identified from mainstream media between 1 April 2008 and 31 December 2008. Additionally, 481,455 tags from 118,545 postings were drawn from iReport in the same period. Relative frequencies of the top 200 most frequently-used tags were analysed to check for spikes and bursts. Based on the results, four main findings emerged. First, the performance of using spikes and bursts to detect news events was found to be comparable. Next, news events detected via spikes and bursts were found to lag ranging from a few days to more than a week compared to the dates reported by mainstream media. Third, news events deemed to be significant by professional journalists did not always attract a high level of interest from iReport contributors. Finally, even though citizen journalism transcends national boundaries via the internet, news posted to iReport seemed to show a proclivity towards local context.
Multiple open access availability and citation impact
Authors: Jingfeng Xia  , Lynette Myers Rebekah , Kay Wilhoite Sara
Published: December 2010

This research examines the relationship between multiple open access (OA) availability of journal articles and the citation advantage by collecting data of OA copies and citation numbers in 20 top library and information science journals. We discover a correlation between the two variables; namely, multiple OA availability of an article has a positive impact on its citation count. The statistical analysis reveals that for every increase in the availability of OA articles, citation numbers increase by 2.348.
Youth Perspectives on Restrictive Mental Health Placement: Unearthing a Counter Narrative
Authors: Polvere Lauren
Published: December 2010

Though research has focused on clinical characteristics and behavioral problems of youth in out-of-home mental health placement settings, few studies have examined how adolescents and emerging adults (Arnett, 2000) experience and make sense of treatment. In this study, semistructured interviews regarding the experience of mental health placement were conducted with 12 adolescent and emerging adult participants with emotional and behavioral challenges, between the ages of 16 and 23. The participants were previously placed in residential mental health treatment centers, facilities, and inpatient hospitals. At the time of the interviews, all participants were involved in youth-run forums across New York State, through which they engage in peer-support initiatives and advocacy efforts aimed at reforming the children’s mental health system. Miles and Huberman’s suggestions for qualitative data coding (1994) were used to analyze the narratives. The participants identified salient conflicts when describing their experiences in restrictive mental health settings and also described the negative psychosocial ramifications of these experiences, including stigma and alienation. The findings suggest that by eliciting critical youth perspectives on mental health placement, a “counternarrative” emerges (Bamberg, 2004; Solis, 2004), which challenges and complicates clinically oriented discourses on youth with emotional and behavioral challenges. Implications for mental health reform and directions for future research are discussed.
Anchors of Religious Commitment in Adolescents
Authors: Layton Emily , Dollahite David C. , Hardy Sam A.
Published: December 2010

This study explores adolescent religious commitment using qualitative data from a religiously diverse (Jewish, Christian, Muslim) sample of 80 adolescents. A new construct, anchors of religious commitment, grounded in interview data, is proposed to describe what adolescents commit to as a part of their religious identity. Seven anchors of religious commitment are discussed: (a) religious traditions, rituals, and laws; (b) God; (c) faith traditions or denominations; (d) faith community members; (e) parents; (f) scriptures or sacred texts; and (g) religious leaders. The findings broaden the conceptual understanding of commitment as a relational construct and not just a behavioral or attitudinal construct. Implications for future research on adolescent religious commitment are discussed along with practical implications for parents and religious leaders.
Tarka® overdose in a young child
Authors: Doğan Murat , Basaranoglu Murat , Peker Erdal , Akbayram Sinan , Sahin Musa , Uner Abdurrahman , Caksen Huseyin
Published: December 2010

Tarka® is a combination antihypertensive medication composed of verapamil hydrochloride and trandolapril. A 3.5-year-old female was brought to our hospital due to a sleepy condition 7 hours after an accidental ingestion of six tablets of Tarka® containing 240 mg verapamil hydrochloride and 4 mg trandolapril in each tablet. Five hours after hospitalization, her condition deteriorated and arterial pressure progressively decreased despite the treatment. Finally, a temporary pacemaker was implanted, after which the vital findings began to return to normal values. The pacemaker was removed 13 hours after implantation as normal heart rhythm was observed. There are no reports of intoxication with fixed-dose combination products, especially Tarka®, in young children in the literature. Therefore, we believe that our report can provide an insight on the toxic dose of this drug in younger children. Clinicians should keep in mind that lethargy can be the first symptom of a possible clinical deterioration, even in normotensive and normorhythmic individuals.
Dietary safety evaluation of water hyacinth leaf protein concentrate
Authors: Wu Wenbiao , Sun Yanling
Published: December 2010

It has been shown that water hyacinth leaf protein concentrate (WHLPC) is nutritionally and economically available for applications in food and feed, such as biscuits or seasonings industries, but, its dietary safety has never been studied. The dietary safety of WHLPC was therefore evaluated by analyzing the contents of total alkaloids, phenolic compounds, and heavy metals, followed by laboratory animal feeding test. The total alkaloid and phenolic contents of WHLPC were 18.7 mg/kg and 5.2 mg/kg, respectively. WHLPC contained non-detectable Cd, 0.04 mg/kg Cr, 0.001 mg/kg Pb, 0.002 mg/kg Pt, 0.001 mg/kg Pd, 0.003 mg/kg Sn, 0.002 mg/kg Hg, 0.01 mg/kg Ba, 0.001 mg/kg Ag, 0.006 mg/kg Sd, and 0.03 mg/kg Al. The LD50 of WHLPC in mice was more than 20.5 g/kg body weight (bw). After feeding mice for 7, 30, 60 or 90 days, either on diet containing WHLPC or a control diet of equivalent protein content, there were no significant differences in absolute body weight or weight gain of WHLPC-treated mice. The results of haematological analysis, histopathological evaluation, general dissection, and investigations of internal organs did not show any adverse effects from diet containing WHLPC. It was concluded that WHLPC is not acutely toxic and does not show sub-chronic in mice.
Squamous cell carcinoma on the palate in a patient with systemic lupus erythematosus: case report and review of literature
Authors: Grimaldo-Carjevschi M , López-Labady J , Villarroel-Dorrego M
Published: December 2010

Squamous cell carcinoma is a rare consequence of lupus erythematosus and it is generally associated with skin lesions rather than with oral mucosa. This paper reports a patient diagnosed with systemic lupus erythematosus who developed a squamous cell carcinoma on the palate as an outcome of a persistent ulcer, a frequent lesion in patients with this disease and, in fact, clinical criterion for its diagnosis. A 38-year-old female patient diagnosed with systemic lupus erythematosus 12 years previously, who attended the dental school for routine dental control. The patient was being treated with prednisone 10 mg per day and cyclophosphamide 750 mg per month until 10 months prior to her diagnostic biopsy. She had, however, been previously treated with chloroquine. Oral lesions started 6 months before consultation as symptomatic multiple ulcers on the palate. After topical treatment with steroids for 1 month, the lesions regressed except for the central lesion, from which an incisional biopsy was taken and a well differentiated squamous cell carcinoma was diagnosed. The oncological phase consisted of partial palatectomy. To date, 3 years after surgery, the patient is free from malignant lesions. Lupus erythematosus is considered a potentially malignant disorder, although the cause for neoplasic transformation in these patients is still not clear, but cyclophosphamide consumption may be implicated; the case emphasizes the importance of periodical oral evaluation of such patients. Repeated biopsies should be performed if there is failure to respond to conventional therapy.
Systemic lupus erythematosus in a 3-month old male presenting as thrombocytopenia
Authors: Dang Do AN , Umoren RA , Tarvin SE , Heilbrunn BR , Mahajerin A , Bowyer SL
Published: December 2010

We report a case of a 3-month old male infant, born to a mother with a known history of systemic lupus erythematosus (SLE). The infant initially presented with petechiae, anemia, and thrombocytopenia. His evaluation revealed antinuclear antibody (ANA) titer of 1 : 160, negative anti-SS-A/SS-B antibody, positive anti-Smith antibody, elevated anti-dsDNA titer, and a slightly low C4 level. His subsequent development of hematuria with nephrotic grade proteinuria fulfilled criteria for a diagnosis of SLE. His condition improved with corticosteroids, mycophenolate mofetil and low-dose aspirin. At 18 months of age, he is clinically well, off all immunosuppression with normal growth parameters and no detectable autoantibodies.
Systemic lupus erythematosus presenting as Stevens–Johnson syndrome and toxic epidermal necrolysis: a report of three cases
Authors: Lee H-Y , Tey H-L , Pang S-M , Thirumoorthy T
Published: December 2010

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening dermatological conditions that are characterized by mucositis, epidermal detachment and erosions. The underlying etiology in SJS and TEN is almost invariably secondary to drugs. Rarely, other causes such as systemic lupus erythematosus (SLE), infections and vaccinations have been implicated. This report describes three patients with SLE who presented with manifestations of SJS/TEN without a clear drug causality. All three patients presented with photodistributed macular exanthema, which evolved to target lesions, bullae, erosions or sheet-like detachment. This was associated with oral mucositis and conjunctivitis. The onset of the rash was insidious with a protracted clinical course. Ultraviolet exposure and steroid tapering appear to be precipitating factors. In two of the patients, SJS and TEN were the initial presentation of lupus. Although SJS and TEN are almost invariably due to medications, they may, rarely, be an initial presentation of lupus, particularly when associated with an initial photodistribution, absence of genital involvement and a prolonged clinical course.