bluuebunny/crossref_metadata_2025 huggingface dataset:
Frontal collapse during thrust propagation in mountain belts: a case study in the Lucania Apennines, Southern Italy
Authors: Bucci Francesco , Novellino Rocco , Tavarnelli Enrico , Prosser Giacomo , Guzzetti Fausto , Cardinali Mauro , Gueguen Erwan , Guglielmi Paola , Adurno Ivana
Published: May 2014

In thrust belts, low-angle tectonic contacts are common, and are associated with the stacking of tectonic units and the resulting regional shortening. The Southern Apennines of Italy, where basin and platform sediments are stacked along low-angle regional thrusts caused by the shortening of the Adria passive margin, are no exception. We studied a portion of a north–south-trending, low-angle regional thrust that separates Apennine platform sediments from Lagonegro basin rocks. To the east of the thrust, klippen composed of platform sediments overlying Lagonegro rocks along a low-angle tectonic contact are present. The klippen were first interpreted as remnants of the regional thrust. We performed a detailed structural analysis of the regional thrust, and we examined the structural setting of the klippen. Field evidence and analysis of map patterns revealed that emplacement of low-angle, foreland-propagating thrusts was followed by extensional deformation accommodated by regional east-dipping, low-angle normal faults. At the base of the klippen, we identified low-angle tectonic contacts with an extensional kinematics. We conclude that the klippen were the result of movements of platform sediments and Lagonegro rocks along low-angle normal faults, and not thrusts as previously interpreted. These faults are cut by more recent, high-angle normal faults associated with the opening of the Agri basin. Collectively, we show that evidence of changes in the tectonostratigraphic architecture, fault geometry and kinematics, and fabrics in the thrusts can reveal the presence of low-angle normal faults, the result of an extensional regime. We expect that our findings will contribute to the understanding of the deformation history of part of the Southern Apennines, and of other mountain belts. The results are also important to understand the transition from compression to extension in the Southern Apennines and in similar orogenic belts.
Ganderia–Laurentia collision in the Caledonides of Great Britain and Ireland
Authors: Waldron John W.F. , Schofield David I. , Dufrane S. Andrew , Floyd James D. , Crowley Quentin G. , Simonetti Antonio , Dokken Robert J. , Pothier Hayley D.
Published: May 2014

During terrane convergence, an influx of clastic sediment from an upper plate onto a lower plate is an early indication of terrane juxtaposition. In the Caledonides of Great Britain and Ireland, units accreted to Laurentia during the early Palaeozoic Era include peri-Gondwanan terrane assemblages that earlier separated from West Gondwana. However, the Southern Uplands Terrane contains detrital zircon populations apparently derived entirely from Laurentia, characterized by a large, asymmetric Mesoproterozoic peak and a scarcity of zircon at 600 Ma and 2.1 Ga. In contrast, Cambrian and Ordovician rocks from the Lake District and the Leinster Massif of Ireland show abundant grains with these ages, together with a range of Mesoproterozoic zircon. These characteristics are shared with the Monian terrane of Anglesey and with Ganderia in the Appalachians, indicating probable derivation from Amazonia in West Gondwana. Silurian sandstones from the Lake District show an influx of Laurentia-derived zircon, and lack the peri-Gondwanan signal. This indicates that in the Caledonides, Ganderia was not accreted to the Laurentian margin until
c
. 430 Ma, in contrast to the Ordovician accretion of Ganderian fragments recorded in the Appalachians, suggesting that the configuration of the closing Iapetus Ocean varied significantly along the strike of the orogen.

Supplementary material:

Details of sample coordinates, analytical procedure and U/Pb detrital zircon analytical data are available at
www.geolsoc.org.uk/SUP18739
.
Overexpression of angiotensin-converting enzyme 2 attenuates tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats
Authors: Wang Yang-Kai , Shen Du , Hao Qiang , Yu Qiang , Wu Zhao-Tang , Deng Yu , Chen Yan-Fang , Yuan Wen-Jun , Hu Qi-Kuan , Su Ding-Feng , Wang Wei-Zhong
Published: May 2014

The rostral ventrolateral medulla (RVLM) plays a key role in cardiovascular regulation. It has been reported that tonically active glutamatergic input to the RVLM is increased in hypertensive rats, whereas angiotensin-converting enzyme 2 (ACE2) in the brain has been suggested to be beneficial to hypertension. This study was designed to determine the effect of ACE2 gene transfer into the RVLM on tonically active glutamatergic input in spontaneously hypertensive rats (SHRs). Lentiviral particles containing enhanced green fluorescent protein (lenti-GFP) or ACE2 (lenti-ACE2) were injected bilaterally into the RVLM. Both protein expression and activity of ACE2 in the RVLM were increased in SHRs after overexpression of ACE2. A significant reduction in blood pressure and heart rate in SHRs was observed 6 wk after lenti-ACE2 injected into the RVLM. The concentration of glutamate in microdialysis fluid from the RVLM was significantly reduced by an average of 61% in SHRs with lenti-ACE2 compared with lenti-GFP. ACE2 overexpression significantly attenuated the decrease in blood pressure and renal sympathetic nerve activity evoked by bilateral injection of the glutamate receptor antagonist kynurenic acid (2.7 nmol in 100 nl) into the RVLM in SHRs. Therefore, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced tonically active glutamatergic input in SHRs, which may be an important mechanism underlying the beneficial effect of central ACE2 to hypertension.
TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury
Authors: Balakrishna Shrilatha , Song Weifeng , Achanta Satyanarayana , Doran Stephen F. , Liu Boyi , Kaelberer Melanie M. , Yu Zhihong , Sui Aiwei , Cheung Mui , Leishman Emma , Eidam Hilary S. , Ye Guosen , Willette Robert N. , Thorneloe Kevin S. , Bradshaw Heather B. , Matalon Sadis , Jordt Sven-Eric
Published: May 2014

The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function.
Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation
Authors: Zhang Yang , Liu Gongjian , Dull Randal O. , Schwartz David E. , Hu Guochang
Published: May 2014

The inflammatory response is a primary mechanism in the pathogenesis of ventilator-induced lung injury. Autophagy is an essential, homeostatic process by which cells break down their own components. We explored the role of autophagy in the mechanisms of mechanical ventilation-induced lung inflammatory injury. Mice were subjected to low (7 ml/kg) or high (28 ml/kg) tidal volume ventilation for 2 h. Bone marrow-derived macrophages transfected with a scrambled or autophagy-related protein 5 small interfering RNA were administered to alveolar macrophage-depleted mice via a jugular venous cannula 30 min before the start of the ventilation protocol. In some experiments, mice were ventilated in the absence and presence of autophagy inhibitors 3-methyladenine (15 mg/kg ip) or trichostatin A (1 mg/kg ip). Mechanical ventilation with a high tidal volume caused rapid (within minutes) activation of autophagy in the lung. Conventional transmission electron microscopic examination of lung sections showed that mechanical ventilation-induced autophagy activation mainly occurred in lung macrophages. Autophagy activation in the lungs during mechanical ventilation was dramatically attenuated in alveolar macrophage-depleted mice. Selective silencing of autophagy-related protein 5 in lung macrophages abolished mechanical ventilation-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and lung inflammatory injury. Pharmacological inhibition of autophagy also significantly attenuated the inflammatory responses caused by lung hyperinflation. The activation of autophagy in macrophages mediates early lung inflammation during mechanical ventilation via NLRP3 inflammasome signaling. Inhibition of autophagy activation in lung macrophages may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.
The polymorphic and contradictory aspects of intermittent hypoxia
Authors: Almendros Isaac , Wang Yang , Gozal David
Published: May 2014

Intermittent hypoxia (IH) has been extensively studied during the last decade, primarily as a surrogate model of sleep apnea. However, IH is a much more pervasive phenomenon in human disease, is viewed as a potential therapeutic approach, and has also been used in other disciplines, such as in competitive sports. In this context, adverse outcomes involving cardiovascular, cognitive, metabolic, and cancer problems have emerged in obstructive sleep apnea-based studies, whereas beneficial effects of IH have also been identified. Those a priori contradictory findings may not be as contradictory as initially thought. Indeed, the opposite outcomes triggered by IH can be explained by the specific characteristics of the large diversity of IH patterns applied in each study. The balance between benefits and injury appears to primarily depend on the ability of the organism to respond and activate adaptive mechanisms to IH. In this context, the adaptive or maladaptive responses can be generally predicted by the frequency, severity, and duration of IH. However, the presence of underlying conditions such as hypertension or obesity, as well as age, sex, or genotypic variance, may be important factors tilting the balance between an appropriate homeostatic response and decompensation. Here, the two possible facets of IH as derived from human and experimental animal settings will be reviewed.
Maternal stress during pregnancy increases neonatal allergy susceptibility: Role of glucocorticoids
Authors: Lim Robert , Fedulov Alexey V. , Kobzik Lester
Published: May 2014

We sought to test experimentally whether maternal stress can promote susceptibility to development of asthma-like allergic airways disease in offspring. Normal pregnant mice ( day 15) were subjected to a single restraint stress exposure. We subsequently tested their offspring for the development of airway hyperreactivity (AHR) and allergic airway inflammation (AI), after an intentionally suboptimal sensitization protocol. The offspring of stressed mothers showed levels of AI and enhanced airway responses to methacholine comparable to those seen in fully sensitized and challenged positive control animals; in contrast, minimal effects were seen in control offspring. Restraint stress caused a rapid and large increase in plasma corticosterone levels. Maternal treatment with dexamethasone on day 15 of pregnancy mimicked the stress effect and reproduced the AI and AHR outcomes, whereas blockade of the stress-induced corticosterone surge with metyrapone pretreatment of pregnant mice abrogated the effect. We conclude that stress-triggered glucocorticoids during pregnancy can increase susceptibility to allergy in offspring. Because inflammation typically includes a stress hormone response, the results also suggest a common pathway by which various injurious exposures during pregnancy might increase offspring susceptibility to asthma.
Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation
Authors: Kearns Mark T. , Barthel Lea , Bednarek Joseph M. , Yunt Zulma X. , Henson Peter M. , Janssen William J.
Published: May 2014

Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1−/−) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasL-dependent manner. Specifically, FasL-expressing CD8+T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8+T lymphocytes in the resolution of acute pulmonary inflammation.
EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production
Authors: Kalinowski April , Ueki Iris , Min-Oo Gundula , Ballon-Landa Eric , Knoff David , Galen Benjamin , Lanier Lewis L. , Nadel Jay A. , Koff Jonathan L.
Published: May 2014

Airway epithelial cells are the primary cell type involved in respiratory viral infection. Upon infection, airway epithelium plays a critical role in host defense against viral infection by contributing to innate and adaptive immune responses. Influenza A virus, rhinovirus, and respiratory syncytial virus (RSV) represent a broad range of human viral pathogens that cause viral pneumonia and induce exacerbations of asthma and chronic obstructive pulmonary disease. These respiratory viruses induce airway epithelial production of IL-8, which involves epidermal growth factor receptor (EGFR) activation. EGFR activation involves an integrated signaling pathway that includes NADPH oxidase activation of metalloproteinase, and EGFR proligand release that activates EGFR. Because respiratory viruses have been shown to activate EGFR via this signaling pathway in airway epithelium, we investigated the effect of virus-induced EGFR activation on airway epithelial antiviral responses. CXCL10, a chemokine produced by airway epithelial cells in response to respiratory viral infection, contributes to the recruitment of lymphocytes to target and kill virus-infected cells. While respiratory viruses activate EGFR, the interaction between CXCL10 and EGFR signaling pathways is unclear, and the potential for EGFR signaling to suppress CXCL10 has not been explored. Here, we report that respiratory virus-induced EGFR activation suppresses CXCL10 production. We found that influenza virus-, rhinovirus-, and RSV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-dependent CXCL10 production. In addition, inhibition of EGFR during viral infection augmented IRF1 and CXCL10. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.
Considering Patients’ Mental Capacity When Giving Them Bad News May Help Their Well-Being: A Case of Suicide Attempt after Being Informed of Lung Cancer Diagnosis
Authors: Kobayashi Toshiyuki , Kato Satoshi , Takeuchi Mitsuo
Published: May 2014

Mental capacity is a central determinant of patients’ ability to make autonomous decisions about their care and deal with bad news. Physicians should be cognizant of this when giving patients bad news in efforts to help them to cope with the illness and to avoid a deterioration of their mental well-being. To show the importance of this concept, a case of suicide attempt with lung cancer is exemplified. A 76-year-old woman attempted suicide after receiving a diagnosis of lung cancer. Her recent life had been emotionally turbulent and she did not have sufficient mental capacity to accept and cope with this truth. She developed depression before attempting suicide.
Redundant Vasodilator Pathways Underlying Radial Artery Flow-Mediated Dilation Are Preserved in Healthy Aging
Authors: Ballard Kevin D. , Tschakovsky Michael E. , Zaleski Amanda L. , Polk Donna M. , Thompson Paul D. , Kiernan Francis J. , Parker Beth A.
Published: May 2014

Background.Blocking nitric oxide (NO) and vasodilator prostanoids (PN) does not consistently reduce flow-mediated dilation (FMD) in young adults. The impact of aging on the contribution of NO and PG to FMD is unknown.Methods.FMD was measured in older adults (n=10,65±3 y) after arterial infusion of saline, N(G)-monomethyl-L-arginine (L-NMMA), and ketorolac + L-NMMA. Data were compared to published data in young adults.Results.L-NMMA reduced FMD in older adults (8.9±3.6to5.9±3.7%) although this was not statistically significant (P=0.08) and did not differ (P=0.74) from the reduction observed in young adults (10.0±3.8to7.6±4.7%;P=0.03). Blocking PN did not affect FMD in young or older adults. In older adults, L-NMMA reduced (n=6; range = 36–123% decrease), augmented (n=3; 10–122% increase), or did not change FMD (n=1; 0.4% increase). After PN blockade, FMD responses were reduced (n=2), augmented (n=6), or unaffected (n=1).Conclusions.NO or PN blockade did not consistently reduce FMD in healthy older adults, suggesting the existence of redundant vasodilator phenotypes as observed previously in young adults.
Nicotine and Carcinogen Exposure after Water Pipe Smoking in Hookah Bars
Authors: St. Helen Gideon , Benowitz Neal L. , Dains Katherine M. , Havel Christopher , Peng Margaret , Jacob Peyton
Published: May 2014

Background: Water pipe tobacco smoking is spreading globally and is increasingly becoming popular in the United States, particularly among young people. Although many perceive water pipe smoking to be relatively safe, clinical experimental studies indicate significant exposures to tobacco smoke carcinogens following water pipe use. We investigated biomarkers of nicotine intake and carcinogen exposure from water pipe smoking in the naturalistic setting of hookah bars.

Methods: Fifty-five experienced water pipe users were studied before and after smoking water pipe in their customary way in a hookah bar. Urine samples were analyzed for nicotine, cotinine, the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and mercapturic acid metabolites of volatile organic compounds (VOC).

Results: We found an average 73-fold increase in nicotine, 4-fold increase in cotinine, 2-fold increase in NNAL, and 14% to 91% increase in VOC mercapturic acid metabolites immediately following water pipe smoking. We saw moderate to high correlations between changes in tobacco-specific biomarkers (nicotine, cotinine, and NNAL) and several mercapturic acid metabolites of VOCs.

Conclusion: Water pipe smoking in a hookah bar is associated with significant nicotine intake and carcinogen exposure.

Impact: Given the significant intake of nicotine and carcinogens, chronic water pipe use could place users at increased risk of cancer and other chronic diseases. Cancer Epidemiol Biomarkers Prev; 23(6); 1055–66. ©2014 AACR.
PIK3R3 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Colorectal Cancer
Authors: Wang Guihua , Yang Xi , Li Chuan , Cao Xiaonian , Luo Xuelai , Hu Junbo
Published: May 2014

Class IA PI3K plays an essential role in the invasion and metastasis of cancer. However, the mechanisms and specific functions of PI3K isoforms in tumor invasion and metastasis are not fully understood. We evaluated the role of PIK3R3, a PI3K regulatory subunit encoded by the PIK3R3 gene, in colorectal cancer invasion and metastasis. Clinical specimens and cell lines data show that the expression level of PIK3R3 is associated with colorectal cancer metastasis. Overexpression of PIK3R3 increases tumor migration and invasion in vitro and promotes metastasis of colorectal cancers in vivo. Furthermore, we investigated that the overexpression of PIK3R3 depends on SNAI2, inducing significant epithelial-to-mesenchymal transition (EMT). Downregulation of PIK3R3 reverses this process, which possibly contributes to the enhanced invasive and metastasizing abilities of colorectal cancer cells. In this study, we found that PIK3R3 plays an important role in colorectal cancer metastasis and might be a potential and specific target for therapies against metastatic colorectal cancer. Mol Cancer Ther; 13(7); 1837–47. ©2014 AACR.
STAT3-Activated GM-CSFRα Translocates to the Nucleus and Protects CLL Cells from Apoptosis
Authors: Li Ping , Harris David , Liu Zhiming , Rozovski Uri , Ferrajoli Alessandra , Wang Yongtao , Bueso-Ramos Carlos , Hazan-Halevy Inbal , Grgurevic Srdana , Wierda William , Burger Jan , O'Brien Susan , Faderl Stefan , Keating Michael , Estrov Zeev
Published: May 2014

Here, it was determined that chronic lymphocytic leukemia (CLL) cells express the α subunit, but not the β subunit, of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR/CSF2R). GM-CSFRα was detected on the surface, in the cytosol, and in the nucleus of CLL cells via confocal microscopy, cell fractionation, and GM-CSFRα antibody epitope mapping. Because STAT3 is frequently activated in CLL and the GM-CSFRα promoter harbors putative STAT3 consensus binding sites, MM1 cells were transfected with truncated forms of the GM-CSFRα promoter, then stimulated with IL6 to activate STAT3 and to identify STAT3-binding sites. Chromatin immunoprecipitation (ChIP) and an electoromobility shift assay (EMSA) confirmed STAT3 occupancy to those promoter regions in both IL6-stimulated MM1 and CLL cells. Transfection of MM1 cells with STAT3-siRNA or CLL cells with STAT3-shRNA significantly downregulated GM-CSFRα mRNA and protein levels. RNA transcripts, involved in regulating cell survival pathways, and the proteins KAP1 (TRIM28) and ISG15 coimmunoprecipitated with GM-CSFRα. GM-CSFRα–bound KAP1 enhanced the transcriptional activity of STAT3, whereas GM-CSFRα-bound ISG15 inhibited the NF-κB pathway. Nevertheless, overexpression of GM-CSFRα protected MM1 cells from dexamethasone-induced apoptosis, and GM-CSFRα knockdown induced apoptosis in CLL cells, suggesting that GM-CSFRα provides a ligand-independent survival advantage.

Implications: Constitutively, activation of STAT3 induces the expression of GM-CSFRα that protects CLL cells from apoptosis, suggesting that inhibition of STAT3 or GM-CSFRα may benefit patients with CLL. Mol Cancer Res; 12(9); 1267–82. ©2014 AACR.
Inactivating Mutation in the Prostaglandin Transporter Gene, SLCO2A1, Associated with Familial Digital Clubbing, Colon Neoplasia, and NSAID Resistance
Authors: Guda Kishore , Fink Stephen P. , Milne Ginger L. , Molyneaux Neil , Ravi Lakshmeswari , Lewis Susan M. , Dannenberg Andrew J. , Montgomery Courtney G. , Zhang Shulin , Willis Joseph , Wiesner Georgia L. , Markowitz Sanford D.
Published: May 2014

HPGDand SLCO2A1 genes encode components of the prostaglandin catabolic pathway, with HPGD encoding the degradative enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and SLCO2A1 encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. HPGD-null mice show increased prostaglandin E2 (PGE2), marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by nonsteroidal anti-inflammatory drugs (NSAID). But in humans, HPGD and SLCO2A1 mutations have only been associated with familial digital clubbing. We, here, characterize a family with digital clubbing and early-onset colon neoplasia. Whole-exome sequencing identified a heterozygous nonsense mutation (G104X) in the SLCO2A1 gene segregating in 3 males with digital clubbing. Two of these males further demonstrated notably early-onset colon neoplasia, 1 with an early-onset colon cancer and another with an early-onset sessile serrated colon adenoma. Two females also carried the mutation, and both these women developed sessile serrated colon adenomas without any digital clubbing. Males with clubbing also showed marked elevations in the levels of urinary prostaglandin E2 metabolite, PGE-M, whereas, female mutation carriers were in the normal range. Furthermore, in the male proband, urinary PGE-M remained markedly elevated during NSAID treatment with either celecoxib or sulindac. Thus, in this human kindred, a null SLCO2A1 allele mimics the phenotype of the related HPGD-null mouse, with increased prostaglandin levels that cannot be normalized by NSAID therapy, plus with increased colon neoplasia. The development of early-onset colon neoplasia in male and female human SLCO2A1 mutation carriers suggests that disordered prostaglandin catabolism can mediate inherited susceptibility to colon neoplasia in man. Cancer Prev Res; 7(8); 805–12. ©2014 AACR.
PTEN-Deficient Tumors Depend on AKT2 for Maintenance and Survival
Authors: Chin Y. Rebecca , Yuan Xin , Balk Steven P. , Toker Alex
Published: May 2014

Loss of PTEN is a common event in many cancers and leads to hyperactivation of the PI3K–AKT signaling pathway. The mechanisms by which AKT isoforms mediate signaling to phenotypes associated with PTEN inactivation in cancer have not been defined. Here, we show that AKT2 is exclusively required for PTEN-deficient prostate tumor spheroid maintenance, whereas AKT1 is dispensable. shRNA silencing of AKT2 but not AKT1 promotes regression of prostate cancer xenografts. Mechanistically, we show that AKT2 silencing upregulates p21 and the proapoptotic protein BAX and downregulates the insulin-like growth factor receptor-1. We also show that p21 is an effector of AKT2 in mediating prostate tumor maintenance. Moreover, AKT2 is also exclusively required for the maintenance and survival of other PTEN-deficient solid tumors, including breast cancer and glioblastoma. These findings identify a specific function for AKT2 in mediating survival of PTEN-deficient tumors and provide a rationale for developing therapeutics targeting AKT2.

Significance: Depletion of AKT2, but not AKT1, induces potent tumor regression in PTEN-deficient prostate cancer xenografts, concomitant with upregulation of p21, which may serve as a potential biomarker for screening AKT2 activity in clinical samples. The specific role of AKT2 in tumor maintenance provides a rationale for the development of isoform-specific inhibitors for patients with PTEN-deficient cancers. Cancer Discov; 4(8); 942–55. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 855
Stretch–Activation of Angiotensin II Type 1
a
Receptors Contributes to the Myogenic Response of Mouse Mesenteric and Renal Arteries
Authors: Schleifenbaum Johanna , Kassmann Mario , Szijártó István András , Hercule Hantz C. , Tano Jean-Yves , Weinert Stefanie , Heidenreich Matthias , Pathan Asif R. , Anistan Yoland-Marie , Alenina Natalia , Rusch Nancy J. , Bader Michael , Jentsch Thomas J. , Gollasch Maik
Published: May 2014

Rationale
:

Vascular wall stretch is the major stimulus for the myogenic response of small arteries to pressure. The molecular mechanisms are elusive, but recent findings suggest that G protein–coupled receptors can elicit a stretch response.

Objective
:

To determine whether angiotensin II type 1 receptors (AT
1
R) in vascular smooth muscle cells exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction.

Methods and Results
:

We used mice deficient in AT
1
R signaling molecules and putative ion channel targets, namely AT
1
R, angiotensinogen, transient receptor potential channel 6 (TRPC6) channels, or several subtypes of the voltage-gated K
+
(K
v
7) gene family (KCNQ3, 4, or 5). We identified a mechanosensing mechanism in isolated mesenteric arteries and in the renal circulation that relies on coupling of the AT
1
R subtype a to a G
q/11
protein as a critical event to accomplish the myogenic response. Arterial mechanoactivation occurs after pharmacological block of AT
1
R and in the absence of angiotensinogen or TRPC6 channels. Activation of AT
1
R subtype a by osmotically induced membrane stretch suppresses an XE991-sensitive K
v
channel current in patch-clamped vascular smooth muscle cells, and similar concentrations of XE991 enhance mesenteric and renal myogenic tone. Although XE991-sensitive KCNQ3, 4, and 5 channels are expressed in vascular smooth muscle cells, XE991-sensitive K
+
current and myogenic contractions persist in arteries deficient in these channels.

Conclusions
:

Our results provide definitive evidence that myogenic responses of mouse mesenteric and renal arteries rely on ligand-independent, mechanoactivation of AT
1
R subtype a. The AT
1
R subtype a signal relies on an ion channel distinct from TRPC6 or KCNQ3, 4, or 5 to enact vascular smooth muscle cell activation and elevated vascular resistance.
Upregulation of Adenosine A1 Receptors Facilitates Sinoatrial Node Dysfunction in Chronic Canine Heart Failure by Exacerbating Nodal Conduction Abnormalities Revealed by Novel Dual-Sided Intramural Optical Mapping
Authors: Lou Qing , Hansen Brian J. , Fedorenko Olga , Csepe Thomas A. , Kalyanasundaram Anuradha , Li Ning , Hage Lori T. , Glukhov Alexey V. , Billman George E. , Weiss Raul , Mohler Peter J. , Györke Sándor , Biesiadecki Brandon J. , Carnes Cynthia A. , Fedorov Vadim V.
Published: May 2014

Background—

Although sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF.

Methods and Results—

We applied multiple approaches to characterize SAN structure, SAN function, and adenosine A1 receptor expression in control (n=17) and 4-month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10 μmol/L) markedly prolonged postpacing SAN conduction time in HF by 206±99 milliseconds (versus 66±21 milliseconds in controls;
P
=0.02). Adenosine induced SAN intranodal conduction block or microreentry in 6 of 8 dogs with HF versus 0 of 7 controls (
P
=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused postpacing atrial pauses in HF versus control dogs (17.1±28.9 versus 1.5±1.3 seconds;
P
<0.001). Furthermore, 10 μmol/L adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation in 6 of 7 HF versus 0 of 7 control dogs (
P
=0.002). Adenosine-induced SAN dysfunction and atrial fibrillation were abolished or prevented by adenosine A1 receptor antagonists (50 μmol/L theophylline/1 μmol/L 8-cyclopentyl-1,3-dipropylxanthine). Adenosine A1 receptor protein expression was significantly upregulated during HF in the SAN (by 47±19%) and surrounding atrial myocardium (by 90±40%). Interstitial fibrosis was significantly increased within the SAN in HF versus control dogs (38±4% versus 23±4%;
P
<0.001).

Conclusions—

In chronic HF, adenosine A1 receptor upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN, leading to SAN dysfunction, and potentiate atrial repolarization shortening, thereby facilitating atrial fibrillation. Atrial fibrillation may further depress SAN function and lead to tachy-brady arrhythmias in HF.
Association Between Antipsychotic Use and Risk of Acute Myocardial Infarction
Authors: Lin Shuai-Ting , Chen Cheng-Chung , Tsang Hin-Yeung , Lee Chee-Siong , Yang Pinchen , Cheng Kai-Da , Li Dian-Jeng , Wang Chin-Jen , Hsieh Yung-Chi , Yang Wei-Cheng
Published: May 2014

Background—

Antipsychotic medications have been increasingly and more widely prescribed despite continued uncertainty about their association with the incidence of acute myocardial infarction (AMI).

Methods and Results—

We investigated the risk of AMI associated with antipsychotic treatment in 56 910 patients with schizophrenia, mood disorders, or dementia first hospitalized or visiting an emergency room for AMI in 1999 to 2009. A case-crossover design was used to compare the distributions of antipsychotic exposure for the same patient across 1 to 30 and 91 to 120 days just before the AMI event. Adjustments were made for comedications and outpatient visits. The adjusted odds ratio of AMI risk was 2.52 (95% confidence interval, 2.37–2.68) for any antipsychotics, 2.32 (95% confidence interval, 2.17–2.47) for first-generation antipsychotics, and 2.74 (95% confidence interval, 2.49–3.02) for second-generation antipsychotics. The risk significantly increased (
P
<0.001) with elevations in dosage and in short-term use (≤30 days). Male patients, elderly patients, and patients with dementia were at significantly increased risk (all
P
<0.001). Physically healthier patients with no preexisting diabetes mellitus, hypertension, or dyslipidemia were at significantly greater risk (
P
<0.001), largely because they had been exposed to higher doses of antipsychotics (
P
<0.001). A study of the selected binding of antipsychotics to 14 neurotransmitter receptors revealed only dopamine type 3 receptor antagonism to be significantly associated with AMI risk (adjusted odds ratio, 2.59; 95% confidence interval, 2.43–2.75;
P
<0.0001).

Conclusions—

Antipsychotic use may be associated with a transient increase in risk for AMI, possibly mediated by dopamine type 3 receptor blockades. Further education on drug safety and research into the underlying biological mechanisms are needed.
Efficacy of Long Detection Interval Implantable Cardioverter-Defibrillator Settings in Secondary Prevention Population
Authors: Kloppe Axel , Proclemer Alessandro , Arenal Angel , Lunati Maurizio , Martìnez Ferrer José Bautista , Hersi Ahmad , Gulaj Marcin , Wijffels Maurits C.E.F. , Santi Elisabetta , Manotta Laura , Mangoni Lorenza , Gasparini Maurizio
Published: May 2014

Background—

Three trials demonstrated recently that a long detection window reduces implantable cardioverter-defibrillator (ICD) therapy in primary prevention patients. Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III (ADVANCE III) was the only trial that enrolled both primary and secondary prevention patients.

Methods and Results—

Of the 1902 patients enrolled in the ADVANCE III trial, 477 received a defibrillator for secondary prevention; 248 patients were randomly assigned to a long detection setting (30 of 40 intervals) and 229 to the nominal setting (18 of 24 intervals) for ventricular arrhythmias with cycle length ≤320 ms. Eight-five percent of patients were men, with a mean age of 65±12 years, a previous history of ventricular fibrillation in 37% of the cases, and a mean ejection fraction of 38±13%. The ICD device mix was 37% single chamber, 47% dual chamber, and 16% triple chamber. Over a median period of 12 months, the long detection period was associated with a 25% reduction in the number of overall therapies (115.6 versus 86.8 per 100 patient-years; incidence rate ratio, 0.75; 95% confidence interval, 0.61–0.93;
P
=0.008) and a 34% reduction in the number of shocks (rate per 100 patient-years, 51.2 versus 38.1; incidence rate ratio, 0.66; 95% confidence interval, 0.48–0.89;
P
=0.007). Appropriate therapies (89.7 versus 67.7; incidence rate ratio, 0.77; 95% confidence interval, 0.60–0.97;
P
=0.029) and appropriate shocks (37.1 versus 28.1; incidence rate ratio, 0.64; 95% confidence interval, 0.45–0.93;
P
=0.018) were also reduced.

Conclusions—

ADVANCE III is the first randomized trial to assess a long detection window setting in ICDs in both primary and secondary prevention populations and demonstrates a reduction of overall therapies and shocks in the subgroup of secondary prevention patients. These data suggest that even the secondary prevention population may benefit from programming that combines a long detection period with antitachycardia pacing during charging.

Clinical Trial Registration—

URL:
http://www/clinicaltrials.gov
. Unique identifier: NCT00617175.
Haptoglobin 2‐2 Genotype is Not Associated With Cardiovascular Risk in Subjects With Elevated Glycohemoglobin—Results From the Bruneck Study
Authors: Pechlaner Raimund , Kiechl Stefan , Willeit Peter , Demetz Egon , Haun Margot , Weger Siegfried , Oberhollenzer Friedrich , Kronenberg Florian , Bonora Enzo , Weiss Günter , Willeit Johann
Published: May 2014

Background

Haptoglobin (Hp) is an abundant plasma protein with antioxidant properties. The Hp 2‐2 genotype has previously been linked to coronary heart disease risk in individuals with elevated glycosylated hemoglobin (HbA
1c
). We investigated the association of Hp and HbA
1c
with cardiovascular disease (
CVD
) in the longitudinal, population‐based Bruneck Study.

Methods and Results

Hp genotype was determined by polymerase chain reaction according to standard procedures and HbA
1c
concentration by a Diabetes Control and Complications Trial‐aligned assay. HbA
1c
was measured in 1995, 2000, and 2005. Occurrence of the combined
CVD
endpoint of myocardial infarction or stroke was recorded between 1995 and 2010. Outcome analyses employed the Cox proportional hazards model with HbA
1c
category as time‐varying covariate. At baseline in 1995, 806 subjects (male sex, 49.3%; age, mean±standard deviation, 62.70±11.08 years) were included. During follow‐up, 123 subjects experienced at least 1
CVD
event (48 suffered myocardial infarction, 68 stroke, and 7 both). Among subjects with HbA
1c
≥6.5% (≥48 mmol/mol), those with the Hp 2‐2 genotype did not show an elevated risk of incident
CVD
compared with those with other genotypes (age‐ and sex‐adjusted hazard ratio [95%
CI
], 0.47 [0.19, 1.13],
P
=0.092) and a null association was also observed in subjects with HbA
1c
<6.5% (1.10 [0.75, 1.62],
P
=0.629) (
P
for interaction=0.082).

Conclusions

Subjects with the Hp 2‐2 genotype and elevated HbA
1c
compared with subjects with other Hp genotypes and elevated HbA
1c
did not show increased
CVD
risk.
Argonaute‐2 Promotes miR‐18a Entry in Human Brain Endothelial Cells
Authors: Ferreira Raquel , Santos Tiago , Amar Arun , Gong Alex , Chen Thomas C. , Tahara Stanley M. , Giannotta Steven L. , Hofman Florence M.
Published: May 2014

Background

Cerebral arteriovenous malformation (
AVM
) is a vascular disease exhibiting abnormal blood vessel morphology and function. miR‐18a ameliorates the abnormal characteristics of
AVM
‐derived brain endothelial cells (
AVM
‐
BEC
) without the use of transfection reagents. Hence, our aim was to identify the mechanisms by which miR‐18a is internalized by
AVM
‐
BEC
. Since
AVM
‐
BEC
overexpress
RNA
‐binding protein Argonaute‐2 (Ago‐2) we explored the clinical potential of Ago‐2 as a systemic mi
RNA
carrier.

Methods and Results

Primary cultures of
AVM
‐
BEC
were isolated from surgical specimens and tested for endogenous miR‐18a levels using
qPCR
. Conditioned media (
CM
) was derived from
AVM
‐
BEC
cultures (
AVM
‐
BEC
‐
CM
).
AVM
‐
BEC
‐
CM
significantly enhanced miR‐18a internalization. Ago‐2 was detected using western blotting and immunostaining techniques. Ago‐2 was highly expressed in
AVM
‐
BEC
; and siAgo‐2 decreased miR‐18a entry into brain‐derived endothelial cells. Only brain‐derived endothelial cells were responsive to the Ago‐2/miR‐18a complex and not other cell types tested. Secreted products (eg, thrombospondin‐1 [TSP‐1]) were tested using ELISA. Brain endothelial cells treated with the Ago‐2/miR‐18a complex in vitro increased TSP‐1 secretion. In the in vivo angiogenesis glioma model, animals were treated with miR‐18a in combination with Ago‐2. Plasma was obtained and tested for TSP‐1 and vascular endothelial growth factor (VEGF)‐A. In this angiogenesis model, the Ago‐2/miR‐18a complex caused a significant increase in TSP‐1 and decrease in VEGF‐A secretion in the plasma.

Conclusions

Ago‐2 facilitates miR‐18a entry into brain endothelial cells in vitro and in vivo. This study highlights the clinical potential of Ago‐2 as a mi
RNA
delivery platform for the treatment of brain vascular diseases.
Hybridity, Coproduction, and Third Sector Social Services in Europe
Authors: Pestoff Victor
Published: May 2014

This article analyzes hybridity in third sector organizations (TSOs) in relation to the coproduction of public services. It begins by discussing hybridity in terms of the overlap between the third sector and other social institutions like the state, market, and community, illustrated by the welfare triangle. Then, it briefly introduces three different public administration regimes. It argues that changing from one area of overlap to another may place TSOs in an unfamiliar, or even alien, environment, resulting in increased hybridity and complexity. After it turns to coproduction and notes, it can refer to a variety of phenomena at various levels that contribute to the growing hybridity and complexity for TSOs and their leaders. It concludes that TSOs can orient themselves toward one of two main kinds of hybridity. A number of hypotheses are presented and some preliminary conclusions about the importance of coproduction for the governance of hybrid organizations are reached at the end of the article.
Red Cell Distribution Width Predicts Contrast-Induced Nephropathy in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome
Authors: Kurtul Alparslan , Yarlioglues Mikail , Murat Sani Namik , Demircelik Muhammed Bora , Acikgoz Sadik Kadri , Ergun Gokhan , Duran Mustafa , Cetin Mustafa , Ornek Ender
Published: May 2014

We investigated the relationship between red cell distribution width (RDW) and contrast-induced nephropathy (CIN) in patients (aged 61 ± 12, 69% men) with acute coronary syndrome (ACS). Consecutive patients diagnosed with ACS (n = 662) who underwent percutaneous coronary intervention (PCI) were included in the study. Patients were divided into 2 groups: CIN and no CIN. Contrast-induced nephropathy was defined as an increase in serum creatinine level of ≥0.5 mg/dL or ≥25% above baseline within 72 hours after PCI. Contrast-induced nephropathy occurred in 81 (12.2%) patients. Red cell distribution width, creatinine, and high-sensitivity C-reactive protein levels were significantly higher in the CIN group than in the no-CIN group. Multivariate regression analysis revealed that baseline RDW level (odds ratio 1.379, 95% confidence interval 1.084-1.753, P = .009), age ( P = .025), creatinine ( P = .004), and left ventricular ejection fraction ( P = .011) were independent risk factors for the development of CIN. In conclusion, increased RDW levels are independently associated with a greater risk of CIN in patients undergoing PCI for ACS.
Neutrophil–Lymphocyte Ratio and Platelet–Lymphocyte Ratio Combination Can Predict Prognosis in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Çiçek Gökhan , Açıkgoz Sadık Kadri , Bozbay Mehmet , Altay Servet , Uğur Murat , Uluganyan Mahmut , Uyarel Huseyin
Published: May 2014

We assessed the effect of combination of neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) in predicting in-hospital and long-term mortality in patients (n = 2518) undergoing primary percutaneous coronary intervention (pPCI). Cutoff values for NLR and PLR were calculated with receiver–operating characteristic (ROC) curves. If both PLR and NLR were above the threshold, patients were classified as “high risk.” If either PLR or NLR was above the threshold individually, patients were classified as “intermediate risk.” High-risk (n = 693) and intermediate-risk (n = 545) groups had higher in-hospital and long-term mortality (7.2 4% vs 0.7%, P < .001; 14.1, 9.5% vs 4.5%, P < .001, respectively). Classifying patients into intermediate-risk group (hazards ratio [HR]: 1.492, 95% confidence interval [CI]: 1.022-2.178, P = .038) and high-risk group (HR: 1.845, 95% CI: 1.313-2.594, P < .001) was an independent predictor of in-hospital and long-term mortality. The combination of PLR and NLR can be useful for the prediction of in-hospital and long-term mortality in patients undergoing pPCI.
Real and Artificial Differential Item Functioning in Polytomous Items
Authors: Andrich David , Hagquist Curt
Published: May 2014

Differential item functioning (DIF) for an item between two groups is present if, for the same person location on a variable, persons from different groups have different expected values for their responses. Applying only to dichotomously scored items in the popular Mantel–Haenszel (MH) method for detecting DIF in which persons are classified by their total scores on an instrument, Andrich and Hagquist articulated the concept of artificial DIF and showed that as an artifact of the MH method, real DIF in one item favoring one group inevitably induces artificial DIF favoring the other group in all other items. Using the dichotomous Rasch model in which the total score for a person is a sufficient statistic, and therefore justifies classifying persons by their total scores, Andrich and Hagquist showed that to distinguish between real and artificial DIF in an item identified by the MH method, a sequential procedure for resolving items is implied. Using the polytomous Rasch model, this article generalizes the concept of artificial DIF to polytomous items, in which multiple item parameters play a role. The article shows that the same principle of resolving items sequentially as with dichotomous items applies also to distinguishing between real and artificial DIF with polytomous items. A real example and a small simulated example that parallels the real example are used illustratively.