bluuebunny/crossref_metadata_2025 huggingface dataset:
LBO-1.6 Efficacy of the quadrivalent HPV vaccine to prevent anal intraepithelial neoplasia among young men who have sex with men
Authors: Goldstone S
Published: July 2011

Introduction

Most anal cancers are associated with HPV, particularly HPV 16. The incidence of anal cancer is increased among men who have sex with men (MSM) compared with the general population. Screening and treatment of anal intraepithelial neoplasia (AIN), the anal cancer precursor, are not yet standard of care, and prevention efforts are needed to reduce the incidence of anal cancer. We tested the quadrivalent HPV vaccine to determine its ability to reduce the incidence of AIN/anal cancer.

Methods

598 MSM aged 16–26 years with five or fewer lifetime sex partners were randomised to receive vaccine or placebo at enrolment, month 2 and month 6. Subjects underwent detailed anogenital exams and HPV sampling from the penis, scrotum, perineal/perianal and anal canal at enrolment, month 7 and at 6-month intervals afterwards. Efficacy analyses were performed in a per-protocol (PPE) population (sero-negative and DNA-negative from day 1 through month 7 to the relevant vaccine HPV type) and in all enrolees in an intent-to treat (ITT) analysis. Median follow-up of the PPE population was 2.5 years (post-dose 3).

Results

Vaccine efficacy against HPV 6/11/16/18-related AIN and anal cancer in the PPE population was 77.5% (95% CI 39.6 to 93.3) (5 vaccine cases vs 24 placebo cases). Efficacy against high-grade AIN (AIN 2+) was 74.9% (95% CI 8.8 to 95.4). In the ITT population the efficacy was 50.3% (95% CI 25.7 to 67.2) and 54.2% (95% CI 18.0 to 75.3), respectively. No anal cancer was seen in either treatment group.

Conclusions

These results demonstrate that the quadrivalent HPV vaccine is efficacious in preventing AIN related to HPV 6/11/16/18 in MSM subjects naïve to vaccine HPV types at enrolment, as well as in an ITT population. The quadrivalent HPV vaccine may be a useful measure to reduce the incidence of anal disease in at-risk populations.
Antimicrobial susceptibility of Pseudomonas aeruginosa isolates from dogs with otitis externa
Authors: Mekić S. , Matanović K. , Šeol B.
Published: July 2011

Pseudomonas aeruginosa is a common cause of otitis externa in dogs, and treatment of these infections is becoming problematic because of the increasing number of multiresistant strains. The aim of the present study was to compare the in vitro activities of cefepime, ceftazidime, enrofloxacin, ciprofloxacin, gentamicin and ticarcillin/clavulanic acid against 104 strains of P aeruginosa isolated from dogs with otitis externa. Antimicrobial susceptibility and minimum inhibitory concentrations, in µg/ml, were evaluated by the E test (bioMérieux). The most active compound was ceftazidime, with 100 per cent efficiency. The majority of tested strains were susceptible to ticarcillin/clavulanic acid (89.4 per cent), followed by ciprofloxacin (88.5 per cent) and cefepime (60.6 per cent). The highest resistance was observed to enrofloxacin (51.9 per cent) and gentamicin (43.3 per cent). Large numbers of strains were intermediately susceptible to antibiotics registered for use in veterinary medicine in Croatia – enrofloxacin (47.1 per cent) and gentamicin (41.3 per cent).
ISOTROPIC CASES OF STATIC CHARGED FLUID SPHERES IN GENERAL RELATIVITY
Authors: DAS BASANTI , RAY PRATAP CHANDRA , RADINSCHI IRINA , RAHAMAN FAROOK , RAY SAIBAL
Published: July 2011

In this paper we study the isotropic cases of static charged fluid spheres in general relativity. For this purpose we consider two different specializations and under these we solve the Einstein–Maxwell field equations in isotropic coordinates. The analytical solutions thus obtained are matched to the exterior Reissner–Nordström solutions which concern the values for the metric coefficients eν and eμ. We derive the pressure, density and pressure-to-density ratio at the center of the charged fluid sphere and boundary R of the star. Our conclusion is that static charged fluid spheres provide a good connection to compact stars.
A UNIVERSAL BIPED WALKING GENERATOR FOR COMPLEX ENVIRONMENTS WITH PATTERN FEASIBILITY CHECKING
Authors: LIU JINSU , XUE FENG , CHEN XIAOPING
Published: July 2011

In this paper, we propose a universal biped walking generator that can plan smooth and flexible walking motions in complex environments, including stairs, slopes, and obstacles. In addition to generating collision-free patterns while keeping the balance of the robot, this generator also checks whether the patterns are achievable for the robot. Aiming at this goal, we introduce a simplified walking method to specify the complete biped motions with the unit of a walking step, instead of a time step of the robot's working time used in usual methods. The zero moment point sampling search is also proposed as an efficient method to determine the walking solution for a feasible footstep plan while simultaneously considering dynamic balance and feasibility. Furthermore, another sampling-based algorithm is proposed to revise unfeasible footstep plans to feasible ones. The feasibility and the efficiency of our proposed approach are demonstrated by experiments on simulated and real Nao robots.
Adenosine A2A and A2B receptors are both required for adenosine A1 receptor-mediated cardioprotection
Authors: Zhan Enbo , McIntosh Victoria J. , Lasley Robert D.
Published: July 2011

All four adenosine receptor subtypes have been shown to play a role in cardioprotection, and there is evidence that all four subtypes may be expressed in cardiomyocytes. There is also increasing evidence that optimal adenosine cardioprotection requires the activation of more than one receptor subtype. The purpose of this study was to determine whether adenosine A2A and/or A2B receptors modulate adenosine A1 receptor-mediated cardioprotection. Isolated perfused hearts of wild-type (WT), A2A knockout (KO), and A2BKO mice, perfused at constant pressure and constant heart rate, underwent 30 min of global ischemia and 60 min of reperfusion. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 200 nM) was administrated 10 min before ischemia and for the first 10 min of reperfusion. Treatment with CHA significantly improved postischemic left ventricular developed pressure (74 ± 4% vs. 44 ± 4% of preischemic left ventricular developed pressure at 60 min of reperfusion) and reduced infarct size (30 ± 2% with CHA vs. 52 ± 5% in control) in WT hearts, effects that were blocked by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM). Treatments with the A2A receptor agonist CGS-21680 (200 nM) and the A2B agonist BAY 60-6583 (200 nM) did not exert any beneficial effects. Deletion of adenosine A2A or A2B receptor subtypes did not alter ischemia-reperfusion injury, but CHA failed to exert a cardioprotective effect in hearts of mice from either KO group. These findings indicate that both adenosine A2A and A2B receptors are required for adenosine A1 receptor-mediated cardioprotection, implicating a role for interactions among receptor subtypes.
Effects of nicotine administration in a mouse model of familial hypertrophic cardiomyopathy, α-tropomyosin D175N
Authors: Gaffin Robert D. , Chowdhury Shamim A. K. , Alves Marco S. L. , Dias Fernando A. L. , Ribeiro Cibele T. D. , Fogaca Rosalvo T. H. , Wieczorek David F. , Wolska Beata M.
Published: July 2011

The effects of nicotine (NIC) on normal hearts are fairly well established, yet its effects on hearts displaying familial hypertrophic cardiomyopathy have not been tested. We studied both the acute and chronic effects of NIC on a transgenic (TG) mouse model of FHC caused by a mutation in α-tropomyosin (Tm; i.e., α-Tm D175N TG, or Tm175). For acute effects, intravenously injected NIC increased heart rate, left ventricular (LV) pressure, and the maximal rate of LV pressure increase (+dP/d t) in non-TG (NTG) and Tm175 mice; however, Tm175 showed a significantly smaller increase in the maximal rate of LV pressure decrease (−dP/ dt) compared with NTGs. Western blots revealed phosphorylation of phospholamban Ser16 and Thr17 residue increased in NTG mice following NIC injection but not in Tm175 mice. In contrast, phosphorylation of troponin I at serine residues 23 and 24 increased equally in both NTG and Tm175. Thus the attenuated increase in relaxation in Tm175 mice following acute NIC appears to result primarily from attenuated phospholamban phosphorylation. Chronic NIC administration (equivalent to smoking 2 packs of cigarettes/day for 4 mo) also increased +dP/dt in NTG and Tm175 mice compared with chronic saline. However, chronic NIC had little effect on heart rate, LV pressure, −dP/d t, LV wall and chamber dimensions, or collagen content for either group of mice.
Evidence for greater burden of peripheral arterial disease in lower extremity arteries of spinal cord-injured individuals
Authors: Bell Jeffrey W. , Chen David , Bahls Martin , Newcomer Sean C.
Published: July 2011

Spinal cord injury leads to increased risk for cardiovascular disease and results in greater risk of death. Subclinical markers of atherosclerosis have been reported in carotid arteries of spinal cord-injured individuals (SCI), but the development of lower extremity peripheral arterial disease (PAD) has not been investigated in this population. The purpose of this study was to determine the effect of spinal cord injury on ankle-brachial index (ABI) and intima-media thickness (IMT) of upper-body and lower-extremity arteries. We hypothesized that the aforementioned measures of lower-extremity PAD would be worsened in SCI compared with controls and that regular participation in endurance exercise would improve these in both groups. To test these hypotheses, ABI and IMT were determined in 105 SCI and compared with 156 able-bodied controls with groups further subdivided into physically active and sedentary. ABIs were significantly lower in SCI versus controls (0.96 ± 0.12 vs. 1.06 ± 0.07, P < 0.001), indicating a greater burden of lower-extremity PAD. Upper-body IMTs were similar for brachial and carotid arteries in controls versus SCI. Lower extremity IMTs revealed similar thicknesses for both superficial femoral and popliteal arteries, but when normalized for artery diameter, individuals with SCI had greater IMT than controls in the superficial femoral (0.094 ± 0.03 vs. 0.073 ± 0.02 mm/mm lumen diameter, P < 0.01) and popliteal (0.117 ± 0.04 vs. 0.091 ± 0.02 mm/mm lumen diameter, P < 0.01) arteries. The ABI and normalized IMT of SCI compared with controls indicate that subclinical measures of lower-extremity PAD are worsened in individuals with SCI. These findings should prompt physicians to consider using the ABI as a screening method to detect lower-extremity PAD in SCI.
Catecholaminergic-induced arrhythmias in failing cardiomyocytes associated with human HRCS96A variant overexpression
Authors: Han Peidong , Cai Wenfeng , Wang Yanru , Lam Chi Keung , Arvanitis Demetrios A. , Singh Vivek P. , Chen Shan , Zhang Huiliang , Zhang Rongli , Cheng Heping , Kranias Evangelia G.
Published: July 2011

The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers. In the present study, we assessed the molecular and cellular mechanisms underlying human arrhythmias by adenoviral expression of the human wild-type (HRCWT) or mutant HRC (HRCS96A) in adult rat ventricular cardiomyocytes. Total HRC protein was increased by ∼50% in both HRCWT- and HRCS96A-infected cells. The HRCS96A mutant exacerbated the inhibitory effects of HRCWT on the amplitude of Ca2+ transients, prolongation of Ca2+ decay time, and caffeine-induced sarcoplasmic reticulum Ca2+ release. Consistent with these findings, HRCS96A reduced maximal sarcoplasmic reticulum calcium uptake rate to a higher extent than HRCWT. Furthermore, the frequency of spontaneous Ca2+ sparks, which was reduced by HRCWT, was increased by mutant HRCS96A under resting conditions although there were no spontaneous Ca2+ waves under stress conditions. However, expression of the HRCS96A genetic variant in cardiomyocytes from a rat model of postmyocardial infarction heart failure induced dramatic disturbances of rhythmic Ca2+ transients. These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca2+ waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers.
Inflammation and matrix remodeling during repair of ventilator-induced lung injury
Authors: González-López Adrián , Astudillo Aurora , García-Prieto Emilio , Fernández-García María Soledad , López-Vázquez Antonio , Batalla-Solís Estefanía , Taboada Francisco , Fueyo Antonio , Albaiceta Guillermo M.
Published: July 2011

High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.
The oncogeneTrop2regulates fetal lung cell proliferation
Authors: McDougall Annie R. A. , Hooper Stuart B. , Zahra Valerie A. , Sozo Foula , Lo Camden Y. , Cole Timothy J. , Doran Tim , Wallace Megan J.
Published: July 2011

The factors regulating growth of the developing lung are poorly understood, although the degree of fetal lung expansion is critical. The oncogene Trop2 (trophoblast antigen 2) is upregulated during accelerated fetal lung growth, and we hypothesized that it may regulate normal fetal lung growth. We investigated Trop2 expression in the fetal and neonatal sheep lung during accelerated and delayed lung growth induced by alterations in fetal lung expansion, as well as in response to glucocorticoids. Trop2 expression was measured using real-time PCR and localized spatially using in situ hybridization and immunofluorescence. During normal lung development, Trop2 expression was higher at 90 days gestational age (GA; 4.0 ± 0.8) than at 128 days GA (1.0 ± 0.1), decreased to 0.5 ± 0.1 at 142 days GA (full term ∼147 days GA), and was positively correlated to lung cell proliferation rates ( r = 0.953, P < 0.005). Trop2 expression was regulated by fetal lung expansion, but not by glucocorticoids. It was increased nearly threefold by 36 h of increased fetal lung expansion ( P < 0.05) and was reduced to ∼55% of control levels by reduced fetal lung expansion ( P < 0.05). Trop2 expression was associated with lung cell proliferation during normal and altered lung growth, and the TROP2 protein colocalized with Ki-67-positive cells in the fetal lung. TROP2 was predominantly localized to fibroblasts and type II alveolar epithelial cells. Trop2 small interfering RNA decreased Trop2 expression by ∼75% in cultured fetal rat lung fibroblasts and decreased their proliferation by ∼50%. Cell viability was not affected. This study demonstrates that TROP2 regulates lung cell proliferation during development.
Enhancement of alveolar epithelial sodium channel activity with decreased cystic fibrosis transmembrane conductance regulator expression in mouse lung
Authors: Lazrak Ahmed , Jurkuvenaite Asta , Chen Lan , Keeling Kim M. , Collawn James F. , Bedwell David M. , Matalon Sadis
Published: July 2011

We sought to establish whether the cystic fibrosis transmembrane conductance regulator (CFTR) regulates the activity of amiloride-sensitive sodium channels (ENaC) in alveolar epithelial cells of wild-type, heterozygous ( Cftr+/−), knockout ( Cftr−/−), and ΔF508-expressing mice in situ. RT-PCR studies confirmed the presence of CFTR message in freshly isolated alveolar type II (ATII) cells from wild-type mice. We patched alveolar type I (ATI) and ATII cells in freshly prepared lung slices from these mice and demonstrated the presence of 4-pS ENaC channels with the following basal open probabilities (Po): wild-type=0.21 ± 0.015: Cftr+/−=0.4 ± 0.03; ΔF508=0.55 ± 0.01; and Cftr−/−=and 0.81 ± 0.016 (means ± SE; n ≥ 9). Forskolin (5 μM) or trypsin (2 μM), applied in the pipette solution, increased the Poand number of channels in ATII cells of wild-type, Cftr+/−, and ΔF508, but not in Cftr−/−mice, suggesting that the latter were maximally activated. Western blot analysis showed that lungs of all groups of mice had similar levels of α-ENaC; however, lungs of Cftr+/−and Cftr−/−mice had significantly higher levels of an α-ENaC proteolytic fragment (65 kDa) that is associated with active ENaC channels. Our results indicate that ENaC activity is inversely correlated to predicted CFTR levels and that CFTR heterozygous and homozygous mice have higher levels of proteolytically processed ENaC fragments in their lungs. This is the first demonstration of functional ENaC-CFTR interactions in alveolar epithelial cells in situ.
Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis
Authors: Redente Elizabeth F. , Jacobsen Kristen M. , Solomon Joshua J. , Lara Abigail R. , Faubel Sarah , Keith Rebecca C. , Henson Peter M. , Downey Gregory P. , Riches David W. H.
Published: July 2011

Fibrotic interstitial pneumonias are more prevalent in males of advancing age, although little is known about the underlying mechanisms. To evaluate the contributions of age and sex to the development of pulmonary fibrosis, we intratracheally instilled young (8–12 wk) and aged (52–54 wk) male and female mice with bleomycin and assessed the development and severity of fibrotic lung disease by measurements of lung collagen levels, static compliance, leukocyte infiltration, and stereological quantification of fibrotic areas in histological sections. We also quantified proinflammatory and profibrotic chemokine and cytokine levels in the bronchoalveolar lavage fluid. Aged male mice developed more severe lung disease, indicated by increased mortality, increased collagen deposition, and neutrophilic alveolitis compared with aged female mice or young mice of either sex. Aged male mice also exhibited increased levels of transforming growth factor-β, IL-17A, and CXCL1 in their bronchoalveolar lavage fluid. Young male mice developed a more fibrotic disease after bleomycin instillation compared with female mice, regardless of age. There was no difference in fibrosis between young and aged female mice. Taken together, these findings suggest that the variables of advanced age and male sex contribute to the severity of pulmonary fibrosis in this model. Our findings also emphasize the importance of stratifying experimental groups on the basis of age and sex in experimental and epidemiological studies of this nature.
Activation of MMP-9 by human lung epithelial cells in response to the cystic fibrosis-associated pathogen Burkholderia cenocepacia reduced wound healing in vitro
Authors: Wright Ciara , Pilkington Ruth , Callaghan Máire , McClean Siobhán
Published: July 2011

Burkholderia cepacia complex is a group of bacterial pathogens that cause opportunistic infections in cystic fibrosis (CF). The most virulent of these is Burkholderia cenocepacia . Matrix metalloproteinases (MMPs) are upregulated in CF patients. The aim of this work was to examine the role of MMPs in the pathogenesis of B. cepacia complex, which has not been explored to date. Real-time PCR analysis showed that B. cenocepacia infection upregulated MMP-2 and MMP-9 genes in the CF lung cell line CFBE41o− within 1 h, whereas MMP-2, -7, and -9 genes were upregulated in the non-CF lung cell line 16HBE14o−. Conditioned media from both cell lines showed increased MMP-9 activation following B. cenocepacia infection. Conditioned media from B. cenocepacia -infected cells significantly reduced the rate of wound healing in confluent lung epithelia ( P < 0.05), in contrast to conditioned media from Pseudomonas aeruginosa -infected cells, which showed predominant MMP-2 activation. Treatment of control conditioned media from both cell lines with the MMP activator 4-aminophenylmercuric acetate (APMA) also resulted in clear activation of MMP-9 and to a much lesser extent MMP-2. APMA treatment of control media also delayed the repair of wound healing in confluent epithelial cells. Furthermore, specific inhibition of MMP-9 in medium from cells exposed to B. cenocepacia completely reversed the delay in wound repair. These data suggest that MMP-9 plays a role in the reduced epithelial repair observed in response to B. cenocepacia infection and that its activation following B. cenocepacia infection contributes to the pathogenesis of this virulent pathogen.
Role of the Fas/FasL system in a model of RSV infection in mechanically ventilated mice
Authors: van den Berg Elske , van Woensel Job B. M. , Bos Albert P. , Bem Reinout A. , Altemeier William A. , Gill Sean E. , Martin Thomas R. , Matute-Bello Gustavo
Published: July 2011

Infection with respiratory syncytial virus (RSV) in children can progress to respiratory distress and acute lung injury necessitating mechanical ventilation (MV). MV enhances apoptosis and inflammation in mice infected with pneumonia virus of mice (PVM), a mouse pneumovirus that has been used as a model for severe RSV infection in mice. We hypothesized that the Fas/Fas ligand (FasL) system, a dual proapoptotic/proinflammatory system involved in other forms of lung injury, is required for enhanced lung injury in mechanically ventilated mice infected with PVM. C57BL/6 mice and Fas-deficient (“ lpr”) mice were inoculated intratracheally with PVM. Seven or eight days after PVM inoculation, the mice were subjected to 4 h of MV (tidal volume 10 ml/kg, fraction of inspired O2= 0.21, and positive end-expiratory pressure = 3 cm H2O). Seven days after PVM inoculation, exposure to MV resulted in less severe injury in lpr mice than in C57BL/6 mice, as evidenced by decreased numbers of polymorphonuclear neutrophils in the bronchoalveolar lavage (BAL), and lower concentrations of the proinflammatory chemokines KC, macrophage inflammatory protein (MIP)-1α, and MIP-2 in the lungs. However, when PVM infection was allowed to progress one additional day, all of the lpr mice (7/7) died unexpectedly between 0.5 and 3.5 h after the onset of ventilation compared with three of the seven ventilated C57BL/6 mice. Parameters of lung injury were similar in nonventilated mice, as was the viral content in the lungs and other organs. Thus, the Fas/FasL system was partly required for the lung inflammatory response in ventilated mice infected with PVM, but attenuation of lung inflammation did not prevent subsequent mortality.
Description of a Sulfitobacter Strain and Its Extracellular Cyclodipeptides
Authors: Long Cong , Lu Xiao-Ling , Gao Yun , Jiao Bing-Hua , Liu Xiao-Yu
Published: July 2011

A marine bacterium M44 was separated from 30 m deep seawater in the East China Sea (26° 28.3′ N 122° 29.0′ E) in 2006. 16S rDNA gene sequence comparison showed that the strain M44 was a member of the genus Sulfitobacter and highly similar to KMM 3554T. A series of experiments demonstrated that this strain M44 had many distinctive characteristics: its cells were gram‐negative and mesophilic; its colonies were slightly yellowish, round, convex, and smooth; and it could grow at 10–28°C, pH 6.0–10.0, and in the presence of 0–12.5% (w/v) NaCl; the optimum growth conditions were 25°C and pH 7.0, and the optimum Na+ concentration was 2.5%. In addition, strain M44 contained 18 : 1 ω7c, 11 methyl 18 : 1 ω7c and 16 : 0 fatty acids as major fatty acids, and the genomic DNA G+C content was 58.04 mol%. According to our results of the secondary metabolites, six cyclodipeptides were isolated from the strain M44, which were Cyclo (Val‐Leu), Cyclo (Phe‐Val), Cyclo (Phe‐Leu), Cyclo (Leu‐Ile), Cyclo (Phe‐Ile), and Cyclo (Trp‐Pro). It is the first study of secondary metabolites isolated from this genus.
CXCL12/CXCR4 Blockade Induces Multimodal Antitumor Effects That Prolong Survival in an Immunocompetent Mouse Model of Ovarian Cancer
Authors: Righi Elda , Kashiwagi Satoshi , Yuan Jianping , Santosuosso Michael , Leblanc Pierre , Ingraham Rachel , Forbes Benjamin , Edelblute Beth , Collette Brian , Xing Deyin , Kowalski Magdalena , Mingari Maria Cristina , Vianello Fabrizio , Birrer Michael , Orsulic Sandra , Dranoff Glenn , Poznansky Mark C.
Published: July 2011

The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1–derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3+ regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell–mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease. Cancer Res; 71(16); 5522–34. ©2011 AACR.
p53-Dependent Regulation of Mitochondrial Energy Production by the RelA Subunit of NF-κB
Authors: Johnson Renée F. , Witzel Ini-Isabée , Perkins Neil D.
Published: July 2011

Aberrant activity of the nuclear factor kappaB (NF-κB) transcription factor family, which regulates cellular responses to stress and infection, is associated with many human cancers. In this study, we define a function of NF-κB in regulation of cellular respiration that is dependent upon the tumor suppressor p53. Translocation of the NF-κB family member RelA to mitochondria was inhibited by p53 by blocking an essential interaction with the HSP Mortalin. However, in the absence of p53, RelA was transported into the mitochondria and recruited to the mitochondrial genome where it repressed mitochondrial gene expression, oxygen consumption, and cellular ATP levels. We found mitochondrial RelA function to be dependent on its conserved C-terminal transactivation domain and independent of its sequence-specific DNA-binding ability, suggesting that its function in this setting was mediated by direct interaction with mitochondrial transcription factors. Taken together, our findings uncover a new mechanism through which RelA can regulate mitochondrial function, with important implications for how NF-κB activity and loss of p53 can contribute to changes in tumor cell metabolism and energy production. Cancer Res; 71(16); 5588–97. ©2011 AACR.
Comparing Signaling Networks between Normal and Transformed Hepatocytes Using Discrete Logical Models
Authors: Saez-Rodriguez Julio , Alexopoulos Leonidas G. , Zhang MingSheng , Morris Melody K. , Lauffenburger Douglas A. , Sorger Peter K.
Published: July 2011

Substantial effort in recent years has been devoted to constructing and analyzing large-scale gene and protein networks on the basis of “omic” data and literature mining. These interaction graphs provide valuable insight into the topologies of complex biological networks but are rarely context specific and cannot be used to predict the responses of cell signaling proteins to specific ligands or drugs. Conversely, traditional approaches to analyzing cell signaling are narrow in scope and cannot easily make use of network-level data. Here, we combine network analysis and functional experimentation by using a hybrid approach in which graphs are converted into simple mathematical models that can be trained against biochemical data. Specifically, we created Boolean logic models of immediate-early signaling in liver cells by training a literature-based prior knowledge network against biochemical data obtained from primary human hepatocytes and 4 hepatocellular carcinoma cell lines exposed to combinations of cytokines and small-molecule kinase inhibitors. Distinct families of models were recovered for each cell type, and these families clustered topologically into normal and diseased sets. Cancer Res; 71(16); 5400–11. ©2011 AACR.
STK33 Kinase Activity Is Nonessential in KRAS-Dependent Cancer Cells
Authors: Babij Carol , Zhang Yihong , Kurzeja Robert J. , Munzli Anke , Shehabeldin Amro , Fernando Manory , Quon Kim , Kassner Paul D. , Ruefli-Brasse Astrid A. , Watson Vivienne J. , Fajardo Flordeliza , Jackson Angela , Zondlo James , Sun Yu , Ellison Aaron R. , Plewa Cherylene A. , San Miguel Tisha , Robinson John , McCarter John , Schwandner Ralf , Judd Ted , Carnahan Josette , Dussault Isabelle
Published: July 2011

Despite the prevalence of KRAS mutations in human cancers, there remain no targeted therapies for treatment. The serine–threonine kinase STK33 has been proposed to be required for the survival of mutant KRAS-dependent cell lines, suggesting that small molecule kinase inhibitors of STK33 may be useful to treat KRAS-dependent tumors. In this study, we investigated the role of STK33 in mutant KRAS human cancer cells using RNA interference, dominant mutant overexpression, and small molecule inhibitors. As expected, KRAS downregulation decreased the survival of KRAS-dependent cells. In contrast, STK33 downregulation or dominant mutant overexpression had no effect on KRAS signaling or survival of these cells. Similarly, a synthetic lethal siRNA screen conducted in a broad panel of KRAS wild-type or mutant cells identified KRAS but not STK33 as essential for survival. We also obtained similar negative results using small molecule inhibitors of the STK33 kinase identified by high-throughput screening. Taken together, our findings refute earlier proposals that STK33 inhibition may be a useful therapeutic approach to target human KRAS mutant tumors. Cancer Res; 71(17); 5818–26. ©2011 AACR.
Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer
Authors: Kayani Irfan , Avril Norbert , Bomanji Jamshed , Chowdhury Simon , Rockall Andrea , Sahdev Anju , Nathan Paul , Wilson Peter , Shamash Jonathan , Sharpe Kevin , Lim Louise , Dickson John , Ell Peter , Reynolds Andrew , Powles Thomas
Published: July 2011

Purpose: To test the hypothesis that sequential 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant.

Experimental Design: Forty-four untreated mRCC patients were enrolled into this prospective phase II study. 18F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUVmax) at 4 and 16 weeks with overall survival (OS).

Results: Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUVmax = 6.8, range: <2.5–18.4). In multivariate analysis, a high SUVmax and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36–8.45) and 3.67 (95% CI: 1.43–9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40–1.99) or OS (HR for responders = 0.80; 95% CI: 0.34–1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43–19.02) and HR = 12.13 (95% CI: 3.72–46.45), respectively].

Conclusions: Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant. Clin Cancer Res; 17(18); 6021–8. ©2011 AACR.
Robust Gene Expression Signature from Formalin-Fixed Paraffin-Embedded Samples Predicts Prognosis of Non–Small-Cell Lung Cancer Patients
Authors: Xie Yang , Xiao Guanghua , Coombes Kevin R. , Behrens Carmen , Solis Luisa M. , Raso Gabriela , Girard Luc , Erickson Heidi S. , Roth Jack , Heymach John V. , Moran Cesar , Danenberg Kathy , Minna John D. , Wistuba Ignacio I.
Published: July 2011

Purpose: The requirement of frozen tissues for microarray experiments limits the clinical usage of genome-wide expression profiling by using microarray technology. The goal of this study is to test the feasibility of developing lung cancer prognosis gene signatures by using genome-wide expression profiling of formalin-fixed paraffin-embedded (FFPE) samples, which are widely available and provide a valuable rich source for studying the association of molecular changes in cancer and associated clinical outcomes.

Experimental Design: We randomly selected 100 Non–Small-Cell lung cancer (NSCLC) FFPE samples with annotated clinical information from the UT-Lung SPORE Tissue Bank. We microdissected tumor area from FFPE specimens and used Affymetrix U133 plus 2.0 arrays to attain gene expression data. After strict quality control and analysis procedures, a supervised principal component analysis was used to develop a robust prognosis signature for NSCLC. Three independent published microarray datasets were used to validate the prognosis model.

Results: This study showed that the robust gene signature derived from genome-wide expression profiling of FFPE samples is strongly associated with lung cancer clinical outcomes and can be used to refine the prognosis for stage I lung cancer patients, and the prognostic signature is independent of clinical variables. This signature was validated in several independent studies and was refined to a 59-gene lung cancer prognosis signature.

Conclusions: We conclude that genome-wide profiling of FFPE lung cancer samples can identify a set of genes whose expression level provides prognostic information across different platforms and studies, which will allow its application in clinical settings. Clin Cancer Res; 17(17); 5705–14. ©2011 AACR.
Tumor Engraftment in Nude Mice and Enrichment in Stroma- Related Gene Pathways Predict Poor Survival and Resistance to Gemcitabine in Patients with Pancreatic Cancer
Authors: Garrido-Laguna Ignacio , Uson Maria , Rajeshkumar N.V. , Tan Aik Choon , de Oliveira Elizabeth , Karikari Collins , Villaroel Maria C. , Salomon Ana , Taylor Gretchen , Sharma Rajni , Hruban Ralph H. , Maitra Anirban , Laheru Daniel , Rubio-Viqueira Belén , Jimeno Antonio , Hidalgo Manuel
Published: July 2011

Purpose: The goal of this study was to evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts.

Experimental Design: Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells were determined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array. Patients were followed for progression and survival.

Results: A total of 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression for patients who received treatment with gemcitabine for metastatic disease (n = 7) was double in patients with xenografts sensitive to gemcitabine.

Conclusion: A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate. Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways. Clin Cancer Res; 17(17); 5793–800. ©2011 AACR.
Gene Set Enrichment Analysis Unveils the Mechanism for the Phosphodiesterase 4B Control of Glucocorticoid Response in B-cell Lymphoma
Authors: Kim Sang-Woo , Rai Deepak , Aguiar Ricardo C.T.
Published: July 2011

Purpose: Resistance to glucocorticoid (GC) is a significant problem in the clinical management of lymphoid malignancies. Addressing this issue via a mechanistic understanding of relevant signaling pathways is more likely to yield positive outcomes.

Experimental Design: We used gene set enrichment analysis (GSEA), multiple genetic models of gain and loss of function in B-cell lymphoma cell lines, in vitro and in vivo, and primary patient samples to characterize a novel relationship between the cyclic AMP/phosphodiesterase 4B (cAMP/PDE4B), AKT/mTOR activities, and GC responses.

Results: Starting from the GSEA, we found that overexpression of the PDE4B in diffuse large B-cell lymphoma (DLBCL) impinge on the same genes/pathways that are abnormally active in GC-resistant tumors. We used genetically modified cell lines to show that PDE4B modulates cAMP inhibitory activities toward the AKT/mTOR pathway and defines GC resistance in DLBCL. In agreement with these data, pharmacologic inhibition of PDE4 in a xenograft model of human lymphoma unleashed cAMP effects, inhibited AKT, and restored GC sensitivity. Finally, we used primary DLBCL samples to confirm the clinical relevance and biomarker potential of AKT/mTOR regulation by PDE4B.

Conclusions: Together, these data mechanistically elucidated how cAMP modulates GC responses in lymphocytes, defined AKT as the principal transducer of the growth inhibitory effects of cAMP in B cells, and allowed the formulation of genomics-guided clinical trials that test the ability of PDE4 inhibitors to restore GC sensitivity and improve the outcome of patients with B-cell malignancies. Clin Cancer Res; 17(21); 6723–32. ©2011 AACR.
Admission, Discharge, or Change in B-Type Natriuretic Peptide and Long-Term Outcomes
Authors: Kociol Robb D. , Horton John R. , Fonarow Gregg C. , Reyes Eric M. , Shaw Linda K. , O'Connor Christopher M. , Felker G. Michael , Hernandez Adrian F.
Published: July 2011

Background—

B-type natriuretic peptide (BNP) has been associated with short- and long-term postdischarge prognosis among hospitalized patients with heart failure. It is unknown if admission, discharge, or change from admission to discharge BNP measure is the most important predictor of long-term outcomes.

Methods and Results—

We linked patients ≥65 years of age from hospitals in Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) to Medicare claims. Among patients with recorded admission and discharge BNP, we compared Cox models predicting 1-year mortality and/or rehospitalization, including clinical variables and clinical variables plus BNP. We calculated the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) for the best-fit model for each outcome versus the model with clinical variables alone. Among 7039 patients in 220 hospitals, median (25th, 75th) admission and discharge BNP were 832 pg/mL (451, 1660) and 534 pg/mL (281, 1111). Observed 1-year mortality and 1-year mortality or rehospitalization rates were 35.2% and 79.4%. The discharge BNP model had the best performance and was the most important characteristic for predicting 1-year mortality (hazard ratio for log transformation, 1.34; 95% confidence interval, 1.28 to 1.40) and 1-year death or rehospitalization (hazard ratio, 1.15; 95% confidence interval, 1.12 to 1.18). Compared with a clinical variables only model, the discharge BNP model improved risk reclassification and discrimination in predicting each outcome (1-year mortality: NRI, 5.5%,
P
<0.0001; IDI, 0.023,
P
<0.0001; 1-year mortality or rehospitalization: NRI, 4.2%,
P
<0.0001; IDI, 0.010,
P
<0.0001).

Conclusions—

Discharge BNP best predicts 1-year mortality and/or rehospitalization among older patients hospitalized with heart failure. Discharge BNP plus clinical variables modestly improves risk classification and model discrimination for long-term outcomes.
The Readers Project: Procedural Agents and Literary Vectors
Authors: Howe Daniel C. , Cayley John
Published: July 2011

The Readers Project is an aesthetically oriented system of software entities designed to explore the culture of human reading. These entities, or “readers,” navigate texts according to specific reading strategies based upon linguistic feature analysis and real-time probability models harvested from search engines. As such, they function as autonomous text generators, writing machines that become visible within and beyond the typographic dimension of the texts on which they operate. Thus far the authors have deployed the system in a number of interactive art installations at which audience members can view the aggregate behavior of the readers on a large screen display and also subscribe, via mobile device, to individual reader outputs. As the structures on which these readers operate are culturally and aesthetically implicated, they shed critical light on a range of institutional practices - particularly those of reading and writing - and explore what it means to engage with the literary in digital media.
Summer Peak, Winter Minimum, and Growth in the Demand for Online Weather Services in Australia
Authors: Power Scott B. , Delage François
Published: July 2011

No abstract available.
Microskills, Trainee Competence, and Therapy Outcomes
Authors: Miville Marie L. , Redway Jorja A. K. , Hernandez Elizabeth
Published: July 2011

This article represents an invited reaction to the series of articles critiquing the microskills approach predominant in most counseling training programs as well as the new model of counseling competence presented in this issue. The authors note that the microskills approach has been a useful and well-researched framework in the field, although they were generally in agreement with the conclusions drawn regarding this approach. These authors suggest that the authors of the series of articles address how their new model intersects with the competency benchmarks model as well as provide feedback concerning the social justice applications of the model.
Islamic spirituality vis-à-vis Asia Pacific Muslim populations: A resource for Western social work practice
Authors: Hall Ronald E.
Published: July 2011

Among Asia Pacific Muslims who migrate West, spirituality is fundamental. The implications include the need for Western social workers when appropriate to apply Islamic-specific spiritual criteria. The dampening effects of Western social work absent Islamic spiritual resources will impair the potential of the profession. Effective social work practice involving Asia Pacific Muslim populations must necessarily incorporate knowledge of Islamic spirituality and if necessary apply it. The ability of Western social workers to accurately perceive, conceptualize, and interact therapeutically with Asia Pacific Muslim populations is a necessity where such populations have recently migrated West.
Social Capital and Community Development: An Analysis of Two Cases from India and Bangladesh
Authors: Bhuiyan Shahjahan H
Published: July 2011

This article explores the role of social capital in community development by focusing on two South Asian case studies drawn from India and Bangladesh. Both studies recognized social capital as a useful resource, which facilitates social interaction and promotes mutual support and cooperation and thus improves participants’ livelihood through income generation, better community governance and capacity building. An important observation is that social capital yields superior outcome if it is used in line with the local conditions of a given society. The findings suggest lessons for policy planners, donor agencies, development practitioners, non-governmental organizations (NGOs) and civil society to use social capital as a resource in order to achieve sustainable community development.
Religious Identification, Beliefs, and Practices Among Turkish Belgian and Moroccan Belgian Muslims
Authors: Güngör Derya , Fleischmann Fenella , Phalet Karen
Published: July 2011

In light of the religious vitality of Muslim immigrants in historically Christian and highly secularized West-European societies, this study addresses three related questions: (a) How does childhood religious transmission affect adult religiosity among second-generation Muslims? (b) How do acculturating groups as proximal acculturation contexts affect effective transmission? and (c) How do second-generation acculturation orientations affect the transmission process? Using the cross-cultural TIES (“The Integration of the European Second Generation”) surveys among adult community samples of Turkish and Moroccan Belgian Muslims in two cities ( Ns = 500 and 481), cross-cultural Structural Equation Models were tested in the four groups to estimate the paths from childhood religious transmission to adult religiosity and acculturation orientations as latent dependent variables. As expected, (a) religious transmission was generally effective for religious identification, beliefs, and practices across groups, yet (b) transmission was most effective in the Turkish Belgian groups as acculturation contexts with high collective cultural continuity. And finally (c) across groups and religious dimensions, individual orientations toward heritage culture maintenance strengthened effective transmission, and host culture adoption played a minor role. We conclude that the religious life of the second generation is part of a continued orientation toward the heritage culture in acculturating families and communities.