bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and Translational Studies of a Phase II Trial of the Novel Oral Akt Inhibitor Perifosine in Relapsed or Relapsed/Refractory Waldenström's Macroglobulinemia
Authors: Ghobrial Irene M. , Roccaro Aldo , Hong Fangxin , Weller Edie , Rubin Nancy , Leduc Renee , Rourke Meghan , Chuma Stacey , Sacco Antonio , Jia Xiaoying , Azab Feda , Azab Abdel Kareem , Rodig Scott , Warren Diane , Harris Brianna , Varticovski Lyuba , Sportelli Peter , Leleu Xavier , Anderson Kenneth C. , Richardson Paul G.
Published: January 2010

Background: Waldenström's macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM.

Patients and Methods: Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression.

Results: The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, β2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor κB activity.

Conclusion: Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM. Clin Cancer Res; 16(3); 1033–41
Serum Prognostic Markers in Head and Neck Cancer
Authors: Meyer François , Samson Élodie , Douville Pierre , Duchesne Thierry , Liu Geoffrey , Bairati Isabelle
Published: January 2010

Purpose: Recognized prognostic factors do not adequately predict outcomes of head and neck cancer (HNC) patients after their initial treatment. We identified from the literature nine potential serum prognostic markers and assessed whether they improve outcome prediction.

Experimental Design: A pretreatment serum sample was obtained from 527 of the 540 HNC patients who participated in a randomized controlled trial. During follow-up, 115 had a HNC recurrence, 110 had a second primary cancer (SPC), and 216 died. We measured nine potential serum prognostic markers: prolactin, soluble interleukin-2 (IL-2) receptor-α, vascular endothelial growth factor, IL-6, squamous cell carcinoma antigen, free β-human choriogonadotropin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and soluble epidermal growth factor receptor. Cox regression was used to identify a reference predictive model for (a) HNC recurrence, (b) SPC incidence, and (c) overall mortality. Each serum marker was added in turn to these reference models to determine by the likelihood ratio test whether it significantly improved outcome prediction. We controlled for the false discovery rate that results from multiple testing.

Results: IL-6 was the only serum marker that significantly improved outcome prediction. Higher levels of IL-6 were associated with a higher SPC incidence. The hazard ratio comparing the uppermost quartile to the lowest quartile of IL-6 was 2.68 (95% confidence interval, 1.49-4.08). IL-6 was also associated with SPC-specific mortality but not with mortality due to other causes. No marker improved outcome prediction for cancer recurrence or overall mortality.

Conclusions: IL-6 significantly improves outcome prediction for SPC in HNC patients. Clin Cancer Res; 16(3); 1008–15
Hepatitis C Virus Proteins Modulate MicroRNA Expression and Chemosensitivity in Malignant Hepatocytes
Authors: Braconi Chiara , Valeri Nicola , Gasparini Pierluigi , Huang Nianyuan , Taccioli Cristian , Nuovo Gerard , Suzuki Tetsuro , Croce Carlo Maria , Patel Tushar
Published: January 2010

Purpose: Hepatocellular cancer (HCC) is highly resistant to chemotherapy and is associated with poor prognosis. Chronic hepatitis C virus (HCV) infection is a major cause of HCC. However, the effect of viral proteins in mediating chemosensitivity in tumor cells is unknown. We postulated that HCV viral proteins could modulate therapeutic responses by altering host cell microRNA (miRNA) expression.

Experimental Design: HepG2 malignant hepatocytes were stably transfected with full-length HCV genome (Hep-394) or an empty vector (Hep-SWX). MiRNA profiling was done by using a custom microarray, and the expression of selected miRNAs was validated by real-time PCR. Protein expression was assessed by Western blotting, whereas caspase activation was assessed by a luminometric assay.

Results: The IC50 to sorafenib was lower in Hep-394 compared with Hep-SWX control cells. Alterations in miRNA expression occurred with 10 miRNAs downregulated >2-fold and 23 miRNAs upregulated >2-fold in Hep-394 cells compared with controls. Of these, miR-193b was overexpressed by 5-fold in Hep-394 cells. miR-193b was predicted to target Mcl-1, an antiapoptotic protein that can modulate the response to sorafenib. The expression of Mcl-1 was decreased, and basal caspase-3/7 activity and poly ADP ribose polymerase cleavage were increased in Hep-394 cells compared with controls. Moreover, transfection with precursors to miR-193b decreased both Mcl-1 expression and the IC50 to sorafenib.

Conclusions: Cellular expression of full-length HCV increases sensitivity to sorafenib by the miRNA-dependent modulation of Mcl-1 and apoptosis. Modulation of miRNA responses may be a useful strategy to enhance response to chemotherapy in HCC. Clin Cancer Res; 16(3); 957–66
Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases
Authors: Baldus Stephan E. , Schaefer Karl-L. , Engers Rainer , Hartleb Dinah , Stoecklein Nikolas H. , Gabbert Helmut E.
Published: January 2010

Purpose: Epidermal growth factor receptor (EGFR) antibody therapy is established in patients with wild-type KRAS colorectal carcinoma; however, up to 50% of these patients do not respond to this therapy. To identify the possible causes of this therapy failure, we searched for mutations in different EGFR-dependent signaling proteins and analyzed their distribution patterns in primary tumors and corresponding metastases.

Experimental Design: Tumor tissues, macrodissected from tumor centers, invasion fronts (n = 100), lymph nodes (n = 55), and distant metastases (n = 20), respectively, were subjected to DNA extraction and mutation analysis of KRAS, BRAF, and PIK3CA.

Results: Activating mutations were detected in 41% (KRAS), 7% (BRAF), and 21% (PIK3CA) of the primary tumors. By comparing tumor centers and invasion fronts, the intratumoral heterogeneity of KRAS, BRAF, and PIK3CA mutations was observed in 8%, 1%, and 5% of primary tumors, respectively. Heterogeneity between primary tumors and lymph node metastases was found in 31% (KRAS), 4% (BRAF), and 13% (PIK3CA) of the cases. Heterogeneity between primary tumors and distant metastases was present in two patients (10%) for KRAS and one patient for PIK3CA (5%), but not for BRAF. Discordant results between primary tumors and metastases could markedly be reduced by testing the additional tumor samples.

Conclusions: Failure of EGFR antibody therapy in patients with wild-type KRAS colorectal cancer may result from activating BRAF or PIK3CA mutations and false-negative sequencing results caused by intratumoral heterogeneity. Due to the particularly high rates of heterogeneity between primary tumors and lymph node metastases, the latter are least suitable for diagnostic mutation analysis. Clin Cancer Res; 16(3); 790–9
A Degenerate HLA-DR Epitope Pool of HER-2/neu Reveals a NovelIn vivoImmunodominant Epitope, HER-2/neu88-102
Authors: Karyampudi Lavakumar , Formicola Courtney , Erskine Courtney L. , Maurer Matthew J. , Ingle James N. , Krco Christopher J. , Wettstein Peter J. , Kalli Kimberly R. , Fikes John D. , Beebe Melanie , Hartmann Lynn C. , Disis Mary L. , Ferrone Soldano , Ishioka Glenn , Knutson Keith L.
Published: January 2010

Purpose: Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell–activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu–specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas.

Experimental Design: A combination of algorithms and HLA-DR–binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-γ enzyme-linked immunosorbent spot (ELIspot) assay.

Results: Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for ≥11 common HLA-DR molecules. A degenerate pool of four HLA-DR–restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which >58% of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in ∼84% of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu88-102 (p88).

Conclusion: The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu–targeting, immune-based therapies such as vaccines. Clin Cancer Res; 16(3); 825–34
The Antiangiogenic Activity in Xenograft Models of Brivanib, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Kinases
Authors: Bhide Rajeev S. , Lombardo Louis J. , Hunt John T. , Cai Zhen-wei , Barrish Joel C. , Galbraith Susan , Jeyaseelan Robert , Mortillo Steven , Wautlet Barri S. , Krishnan Bala , Kukral Daniel , Malone Harold , Lewin Anne C. , Henley Benjamin J. , Fargnoli Joseph
Published: January 2010

Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities. Mol Cancer Ther; 9(2); 369–78
Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation
Authors: Sinn Brigitte , Tallen Gesche , Schroeder Gisela , Grassl Birgit , Schulze Joern , Budach Volker , Tinhofer Inge
Published: January 2010

PTEN mutations are frequently found in malignant glioma and can result in activated phosphatidylinositol-3-kinase/Akt survival signaling associated with resistance to radiotherapy. Strategies to interfere with aberrant PI3K/Akt activity are therefore being developed to improve the therapeutic efficacy of radiotherapy in patients with malignant glioma. The methylxanthine caffeine has been described as a PI3K inhibitor and is also known to sensitize cells to ionizing radiation. However, a direct association between these two caffeine-mediated effects has not been reported yet. Therefore, we asked whether caffeine or its derivative pentoxifylline differentially affect the radiosensitivity of malignant gliomas with different PTEN status. As models, we used the radiosensitive EA14 malignant glioma cell line containing wild-type PTEN and the radioresistant U87MG malignant glioma cell line harboring mutant PTEN. Our study revealed that caffeine and pentoxifylline radiosensitized PTEN-deficient but not PTEN-proficient glioma cells. Radiosensitization of PTEN-deficient U87MG cells by caffeine was significantly correlated with the activation of the G1 DNA damage checkpoint that occurred independently of de novo synthesis of p53 and p21. The p53 independency was also confirmed by a significant caffeine-mediated radiosensitization of the glioma cell lines T98G and U373MG that are deficient for both PTEN and p53. Furthermore, caffeine-mediated radiosensitization was associated with the inhibition of Akt hyperphosphorylation in PTEN-deficient cells to a level comparable with PTEN-proficient cells. Our data suggest that the methylxanthine caffeine or its derivative pentoxifylline are promising candidate drugs for the radiosensitization of glioma cells particularly with PTEN mutations. Mol Cancer Ther; 9(2); 480–8
Human Mutations That Confer Paclitaxel Resistance
Authors: Yin Shanghua , Bhattacharya Rajat , Cabral Fernando
Published: January 2010

The involvement of tubulin mutations as a cause of clinical drug resistance has been intensely debated in recent years. In the studies described here, we used transfection to test whether β1-tubulin mutations and polymorphisms found in cancer patients are able to confer resistance to drugs that target microtubules. Three of four mutations (A185T, A248V, R306C, but not G437S) that we tested caused paclitaxel resistance, as indicated by the following observations: (a) essentially 100% of cells selected in paclitaxel contained transfected mutant tubulin; (b) paclitaxel resistance could be turned off using tetracycline to turn off transgene expression; (c) paclitaxel resistance increased as mutant tubulin production increased. All the paclitaxel resistance mutations disrupted microtubule assembly, conferred increased sensitivity to microtubule-disruptive drugs, and produced defects in mitosis. The results are consistent with a mechanism in which tubulin mutations alter microtubule stability in a way that counteracts drug action. These studies show that human tumor cells can acquire spontaneous mutations in β1-tubulin that cause resistance to paclitaxel, and suggest that patients with some polymorphisms in β1-tubulin may require higher drug concentrations for effective therapy. Mol Cancer Ther; 9(2); 327–35
Identification of a Novel Raf-1 Pathway Activator that Inhibits Gastrointestinal Carcinoid Cell Growth
Authors: Cook Mackenzie R. , Pinchot Scott N. , Jaskula-Sztul Renata , Luo Jie , Kunnimalaiyaan Muthusamy , Chen Herbert
Published: January 2010

Carcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration–approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal carcinoid cells and induce G2-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted carcinoid tumors confirms that LFN can inhibit NET growth in vivo. Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones. Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal–regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression. In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation. Mol Cancer Ther; 9(2); 429–37
Biological Activity of Celecoxib in the Bronchial Epithelium of Current and Former Smokers
Authors: Kim Edward S. , Hong Waun K. , Lee J. Jack , Mao Li , Morice Rodolfo C. , Liu Diane D. , Jimenez Carlos A. , Eapen Georgie A. , Lotan Reuben , Tang Ximing , Newman Robert A. , Wistuba Ignacio I. , Kurie Jonathan M.
Published: January 2010

Non–small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium. No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers—a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non–small cell lung cancer chemoprevention may be warranted. Cancer Prev Res; 3(2); 148–59
The Promise of Natural Products for Blocking Early Events in Skin Carcinogenesis
Authors: Clifford John L. , DiGiovanni John
Published: January 2010

This perspective on Stratton et al. (beginning on p. 160), Kowalczyk et al. (beginning on p. 170), and Katiyar et al. (beginning on p. 179) highlights the common theme of translational investigation of natural substances and their molecular effects and mechanisms in preventing skin squamous cell carcinoma, which has potentially severe clinical consequences. These studies comprise results of naturally occurring phytochemicals and green tea polyphenols in mouse models of UV-induced and chemically induced skin carcinogenesis and results of perillyl alcohol in a phase IIa clinical trial—all pointing to the great promise of this exciting approach for better understanding of and preventing skin cancer. Cancer Prev Res; 3(2); 132–5
Hypokalemia and Outcomes in Patients With Chronic Heart Failure and Chronic Kidney Disease
Authors: Bowling C. Barrett , Pitt Bertram , Ahmed Mustafa I. , Aban Inmaculada B. , Sanders Paul W. , Mujib Marjan , Campbell Ruth C. , Love Thomas E. , Aronow Wilbert S. , Allman Richard M. , Bakris George L. , Ahmed Ali
Published: January 2010

Background—

Little is known about the effects of hypokalemia on outcomes in patients with chronic heart failure (HF) and chronic kidney disease.

Methods and Results—

Of the 7788 patients with chronic HF in the Digitalis Investigation Group trial, 2793 had chronic kidney disease, defined as estimated glomerular filtration rate <60 mL/min per 1.73 m
2
. Of these, 527 had hypokalemia (serum potassium <4 mEq/L; mild) and 2266 had normokalemia (4 to 4.9 mEq/L). Propensity scores for hypokalemia were used to assemble a balanced cohort of 522 pairs of patients with hypokalemia and normokalemia. All-cause mortality occurred in 48% and 36% of patients with hypokalemia and normokalemia, respectively, during 57 months of follow-up (matched hazard ratio when hypokalemia was compared with normokalemia, 1.56; 95% CI, 1.25 to 1.95;
P
<0.0001). Matched hazard ratios (95% CIs) for cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations were 1.65 (1.29 to 2.11;
P
<0.0001), 1.82 (1.28 to 2.57;
P
<0.0001), 1.16 (1.00 to 1.35;
P
=0.036), 1.27 (1.08 to 1.50;
P
=0.004), and 1.29 (1.05 to 1.58;
P
=0.014), respectively. Among 453 pairs of balanced patients with HF and chronic kidney disease, all-cause mortality occurred in 47% and 38% of patients with mild hypokalemia (3.5 to 3.9 mEq/L) and normokalemia, respectively (matched hazard ratio, 1.31; 95% CI, 1.03 to 1.66;
P
=0.027). Among 169 pairs of balanced patients with estimated glomerular filtration rate <45 mL/min per 1.73 m
2
, all-cause mortality occurred in 57% and 47% of patients with hypokalemia (<4 mEq/L; mild) and normokalemia, respectively (matched hazard ratio, 1.53; 95% CI, 1.07 to 2.19;
P
=0.020).

Conclusions—

In patients with HF and chronic kidney disease, hypokalemia (serum potassium <4 mEq/L) is common and associated with increased mortality and hospitalization.
Circulating Rather Than Cardiac Angiotensin-(1-7) Stimulates Cardioprotection After Myocardial Infarction
Authors: Wang Yong , Qian Cheng , Roks Anton J.M. , Westermann Dirk , Schumacher Sarah-Mai , Escher Felicitas , Schoemaker Regien G. , Reudelhuber Timothy L. , van Gilst Wiek H. , Schultheiss Heinz-Peter , Tschöpe Carsten , Walther Thomas
Published: January 2010

Background—Angiotensin (Ang)-(1-7) attenuates the development of heart failure. In addition to its local effects on cardiovascular tissue, Ang-(1-7) also stimulates bone marrow, which harbors cells that might complement the therapeutic effect of Ang-(1-7). We studied the effects of Ang-(1-7) either produced locally in the heart or subcutaneously injected during the development of heart failure induced by myocardial infarction (MI) and explored the role of cardiovascular progenitor cells in promoting the effects of this heptapeptide.

Methods and Results—Effects of Ang-(1-7) on bone marrow–derived mononuclear cells in rodents, particularly endothelial progenitor cells, were investigated in vitro and in vivo in rats, in mice deficient for the putative Ang-(1-7) receptor Mas, and in mice overexpressing Ang-(1-7) exclusively in the heart. Three weeks after MI induction through permanent coronary artery occlusion, effects of Ang-(1-7) either produced locally in the heart or injected into the subcutaneous space were investigated. Ang-(1-7) stimulated proliferation of endothelial progenitor cells isolated from sham or infarcted rodents. The stimulation was blunted by A779, a Mas receptor blocker, or by Mas deficiency. Infusion of Ang-(1-7) after MI increased the number of c-kit– and vascular endothelial growth factor–positive cells in infarcted hearts, inhibited cardiac hypertrophy, and improved cardiac function 3 weeks after MI, whereas cardiomyocyte-derived Ang-(1-7) had no effect.

Conclusions—Our data suggest circulating rather than cardiac Ang-(1-7) to be beneficial after MI. This beneficial effect correlates with a stimulation of cardiac progenitor cells in vitro and in vivo. This characterizes the heptapeptide as a promising new tool in stimulating cardiovascular regeneration under pathophysiological conditions.
Long-Term Results of Carotid Artery Stents to Manage Symptomatic Carotid Artery Stenosis and Factors That Affect Outcome
Authors: Randall Marc S. , McKevitt Fiona M. , Kumar Sanjeev , Cleveland Trevor J. , Endean Keith , Venables Graham S. , Gaines Peter A.
Published: January 2010

Background—

Limited data are available about the long-term outcomes of the use of carotid artery stents in symptomatic patients and the impact of patient variables on the durability of endovascular carotid procedures. Outcome data previously reported from registry series mix symptomatic and asymptomatic patients. We present analysis of long-term follow-up, with independent neurological assessment, for patients with symptomatic high-grade carotid lesions undergoing stenting to identify patients at risk of recurrence.

Methods and Results—

Prospectively collected data on 563 carotid stenting procedures in a single center were analyzed. Univariate and multivariate techniques were used to identify risk groups and beneficial technical adaptations. Ipsilateral stroke rates for all patients were 4.8%, 7.0%, and 9.5% at 30 days, 1 year, and 4 years, respectively. The rates improved to 2.7%, 4.1%, and 4.5% when patients were treated with optimal therapy. Retinal events had a lower risk of long-term recurrent ipsilateral stroke (hazard ratio=0.228, CI=0.082 to 0.632,
P
=0.004) than cerebral events. A recurrent or residual stenosis of >50% had a statistically significant effect on long-term stroke recurrence in multivariate analysis (hazard ratio=2.187, CI=1.173 to 4.078,
P
=0.014).

Conclusions—

Patients with retinal presentations are a lower risk group to treat. Residual stenosis or restenosis >50% has a statistically significant trend to an increased risk of recurrence for ipsilateral stroke in the long term in this population. In our patients, a combination of procedural modifications and pharmacological changes seems to improve outcomes.
Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition than High Maintenance Dose Clopidogrel in Patients With Acute Myocardial Infarction
Authors: Jeong Young-Hoon , Hwang Jin-Yong , Kim In-Suk , Park Yongwhi , Hwang Seok-Jae , Lee Seung-Whan , Kwak Choong Hwan , Park Seong-Wook
Published: January 2010

Background—

Optimal platelet inhibition is an important therapeutic adjunct in patients acute myocardial infarction (AMI) undergoing coronary stenting. Whether adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) can inhibit enhanced platelet reactivity in patients with AMI yet has not been determined. The aim of this study was to assess the degree of platelet inhibition by triple antiplatelet therapy in patients with AMI.

Methods and Results—

Immediately after emergency room arrival, patients with AMI received clopidogrel (600-mg loading dose, followed by 75 mg daily) and aspirin (300-mg loading dose and 200 mg daily throughout the study period). After patients underwent coronary stenting (n=90), they were randomly assigned to 1 of 3 groups before discharge: standard group, clopidogrel of 75 mg daily (n=30); high maintenance dose (MD) group, clopidogrel of 150 mg daily (n=30); and triple group, adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily (n=30). Platelet reactivity was assessed at predischarge and 30-day follow-up by conventional aggregometry and the VerifyNow P2Y12 assay. Predischarge platelet reactivities were similar in the 3 groups. At 30-day follow-up, inhibition of maximal aggregation with 20 μM ADP stimuli was 6.0% in the standard group, 19.1% in the high-MD group, and 42.4% in the triple group (
P
<0.001), whereas inhibition of late aggregation with 20μM ADP stimuli was 10.8%, 38.1%, and 66.4%, respectively (
P
<0.001). Similar results were demonstrated when 5 μM ADP was used. Furthermore, percent changes of P2Y12 reaction unit were significantly different among regimens (10.6% in the standard group, 30.7% in the high-MD group, and 43.0% in the triple group;
P
<0.001). With respect to high-postclopidogrel platelet reactivity (prespecified as 20 μM ADP-induced maximal aggregation >50% of light transmission), fewer patients in the triple group (13.3%) met the criteria as compared with those in the standard (76.7%) and high-MD groups (56.7%) at 30-day follow-up (
P
<0.001). In the triple group, there were more potent and consistent platelet inhibitions by all parameters as compared with the high-MD group except for percent changes of P2Y12 reaction unit (
P
=0.071).

Conclusions—

Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect at 30 days as compared with a high-MD clopidogrel or standard dual antiplatelet therapy.
Paclitaxel-Eluting Versus Sirolimus-Eluting Stents in Diabetes Mellitus
Authors: Wolf William M. , Vlachos Helen A. , Marroquin Oscar C. , Lee Joon S. , Smith Conrad , Anderson William D. , Schindler John T. , Holper Elizabeth M. , Abbott J. Dawn , Williams David O. , Laskey Warren K. , Kip Kevin E. , Kelsey Sheryl F. , Mulukutla Suresh R.
Published: January 2010

Background—

Diabetes is a powerful predictor of adverse events in patients undergoing percutaneous coronary intervention. Drug-eluting stents reduce restenosis rates compared with bare metal stents; however, controversy remains regarding which drug-eluting stents provides greater benefit in patients with diabetes. Accordingly, we compared the safety and efficacy of sirolimus-eluting stents (SES) with paclitaxel-eluting stents (PES) among diabetic patients in a contemporary registry.

Methods and Results—

Using the National Heart, Lung, and Blood Institute Dynamic Registry, we evaluated 2-year outcomes of diabetic patients undergoing percutaneous coronary interventions with SES (
n
=677) and PES (
n
=328). Clinical and demographic characteristics, including age, body mass index, insulin use, left ventricular function, and aspirin/clopidogrel use postprocedure, did not differ significantly between the groups except that PES-treated patients had a greater frequency of hypertension and hyperlipidemia. At the 2-year follow-up, no significant differences were observed between PES and SES with regard to safety or efficacy end points. PES- and SES-treated patients had similar rates of death (10.7% versus 8.2%,
P
=0.20), death and myocardial infarction (14.9% versus 13.6%,
P
=0.55), repeat revascularization (14.8% versus 17.8%,
P
=0.36), and stent thrombosis (1.3% versus 1.3%,
P
=0.95). After adjustment, no significant differences between the 2 stent types in any outcome were observed.

Conclusions—

PES and SES are equally efficacious and have similar safety profiles in diabetic patients undergoing percutaneous coronary interventions in clinical practice.
Predictive Factors and Impact of No Reflow After Primary Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction
Authors: Ndrepepa Gjin , Tiroch Klaus , Keta Dritan , Fusaro Massimiliano , Seyfarth Melchior , Pache Jürgen , Mehilli Julinda , Schömig Albert , Kastrati Adnan
Published: January 2010

Background—

The investigation of no-reflow phenomenon after percutaneous coronary intervention (PCI) in patients with acute ST-segment–elevation myocardial infarction has therapeutic implications. We investigated the predictive factors, persistence in time, and impact of no reflow on myocardial salvage, ventricular function, and mortality.

Methods and Results—

The study included 1140 patients with ST-segment–elevation myocardial infarction undergoing primary PCI and paired scintigraphic examinations (before intervention and 7 to 14 days thereafter). After primary PCI, 108 patients had no reflow and 1032 patients had normal coronary flow. The median salvage index was 0.34 (interquartile range, 0.15, 0.49) in patients with no reflow versus 0.55 (interquartile range, 0.29, 0.81) in patients with normal flow (
P
<0.001). Left ventricular ejection fraction at 6 months after PCI was 47.7�13.1% in the no-reflow group versus 54.2�13.9% in the group with normal flow after PCI (
P
<0.001). In 80.3% of patients with no reflow, normalization of blood flow >6 months after PCI occurred and correlated with improvement in the left ventricular ejection fraction. Independent predictors of no reflow were residual flow in the infarct-related artery (
P
<0.001), initial perfusion defect (
P
=0.03), C-reactive protein (
P
<0.001), and previous myocardial infarction (
P
=0.013). Kaplan–Meier estimates of 1-year mortality were 16.7% (n=18) in patients with no reflow versus 5.5% (n=56) in patients with normal flow (hazard ratio, 3.35; 95% CI, 1.97 to 5.69;
P
<0.001).

Conclusions—

No reflow after primary PCI was associated with reduced myocardial salvage, larger infarct size, worse left ventricular ejection fraction at 6 months, and increased risk of 1-year mortality. In 4 of 5 patients with no reflow after PCI, restoration of normal flow occurred 6 months after reperfusion.
Adjunctive Thrombectomy for Acute Myocardial Infarction
Authors: Mongeon François-Pierre , Bélisle Patrick , Joseph Lawrence , Eisenberg Mark J. , Rinfret Stéphane
Published: January 2010

Background—

In available trials and meta-analyses, adjunctive thrombectomy in acute myocardial infarction (MI) improves markers of myocardial reperfusion but has limited effects on clinical outcomes. Thrombectomy devices simply aspirate thrombus or mechanically fragment it before aspiration. Simple aspiration thrombectomy may offer a distinct advantage.

Methods and Results—

We identified 21 eligible trials (16 that used a simple aspiration thrombectomy device) involving 4299 patients with ST-segment elevation MI randomized to reperfusion therapy by primary percutaneous coronary intervention with or without thrombectomy. By using Bayesian meta-analysis methods, we found that thrombectomy yielded substantially less no-reflow (odds ratio [OR], 0.39; 95% credible interval [CrI], 0.18 to 0.69), more ST-segment resolution ≥50% (OR, 2.22; 95% CrI, 1.60 to 3.23), and more thrombolysis in myocardial infarction/myocardial perfusion grade 3 (OR, 2.50; 95% CrI, 1.48 to 4.41). There was no evidence for a decrease in death (OR, 0.94; 95% CrI, 0.47 to 1.80), death, recurrent MI, or stroke (OR, 1.07; 95% CrI, 0.63 to 1.92) with thrombectomy. Restriction of the analysis to trials that used simple aspiration thrombectomy devices did not yield substantially different results, except for a positive effect on postprocedure thrombolysis in myocardial infarction grade 3 flow (OR, 1.49; 95% CrI, 1.14 to 1.99).

Conclusions—

In this Bayesian meta-analysis, adjunctive thrombectomy improves early markers of reperfusion but does not substantially effect 30-day post-MI mortality, reinfarction, and stroke. The use of aspiration thrombectomy devices is not associated with a reduction in post-MI clinical outcomes. Thrombectomy is one of the rare effective preventive measures against no-reflow.
Cardioprotective Effects of Ischemic Postconditioning in Patients Treated With Primary Percutaneous Coronary Intervention, Evaluated by Magnetic Resonance
Authors: Lønborg Jacob , Kelbæk Henning , Vejlstrup Niels , Jørgensen Erik , Helqvist Steffen , Saunamäki Kari , Clemmensen Peter , Holmvang Lene , Treiman Marek , Jensen Jan S. , Engstrøm Thomas
Published: January 2010

Background—

Postconditioning has been suggested to reduce myocardial damage during primary percutaneous coronary intervention (PPCI) in patients with ST-segment–elevation myocardial infarction. However, because clinical experience is limited, we examined the cardioprotective effects of postconditioning, using cardiac MRI in patients treated with PPCI.

Methods and Results—

One hundred eighteen patients with ST-segment–elevation myocardial infarction referred for PPCI were randomly assigned to have either conventional PPCI or PPCI with postconditioning. Postconditioning was performed immediately after obtained reperfusion with 4 balloon occlusions, each lasting 30 seconds, followed by 30 seconds of reperfusion. The primary end point was myocardial salvage after 3 months as judged by delayed enhancement cardiac MRI. We found a 19% relative reduction of infarct size in the postconditioning group (51�16% of total area at risk versus 63�17%,
P
<0.01), corresponding to a 31% increase in salvage ratio. The number of patients developing heart failure was significantly fewer in the postconditioning group (27% versus 46%,
P
=0.048). No significant evidence of interaction between the impact of postconditioning and the location of the culprit lesion or size of the myocardium at risk was detected (
P
=0.21 and
P
=0.71).

Conclusions—

Mechanical postconditioning reduces infarct size in patients with ST-segment–elevation myocardial infarction treated with PPCI. The impact of mechanical postconditioning seems to be independent of the size of myocardium at risk.

Clinical Trial Registration—

URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00507156.
Metamorphosis and Obedience: An Interpretation of Mark’s Account of the Transfiguration of Jesus
Authors: Knights Chris
Published: January 2010

This article offers the author’s interpretation of the account of the Transfiguration of Jesus in Mark 9.2-13, arguing that it is closely connected both with its immediate context in Mark and also with Mark 16.1-8. It suggests that two key themes in the Transfiguration in Mark are the metamorphosis of Jesus and of his followers, and the importance of obedience to Jesus.
Bishop Bell — The Man
Authors: Walker Peter K.
Published: January 2010

A personal reflection on the life and faith of Bishop Bell, remembering his commitment to peace and justice issues, and his sense of stillness.
Users as Innovators: A Review, Critique, and Future Research Directions
Authors: Bogers Marcel , Afuah Allan , Bastian Bettina
Published: January 2010

What role do users play during innovation? Ever since it was argued that users can also be the sources of innovation, the literature on the role of users during innovation has grown tremendously. In this article, the authors review this growing literature, critique it, and develop some of the research questions that could be explored to contribute to this literature and to the theoretical perspectives that underpin the literature.
Re-Discovering the New World
Authors: Singh Nitya
Published: January 2010

With an intensification of globalization a vast majority of the under-developed states are experiencing a high level of economic growth due to their economic relationship with the developed states. At the same time there has been a lack of significant economic relationships between the developing countries. Therefore, this article explores the potential of a South-South economic relationship by evaluating the case studies of India and Brazil. I initially identify the causal factors that bought about a structural change within the economies of these two nations. Post this, I evaluate the changes in the global economy that have made such an economic cooperation more important now than ever before. Finally, I identify the areas in which these two states can expand their economic relationship and conclude with the potential of such an economic relationship for the future of the South-South Cooperation initiative.
Ethnic Perspectives on Sibling Abuse in the United States
Authors: Rapoza Kimberly A. , Cook Kelley , Zaveri Tanvi , Malley-Morrison Kathleen
Published: January 2010

Sibling abuse has been studied much less extensively than other forms of family violence in the United States; moreover, research on how sibling abuse is viewed in different ethnic-minority groups has been rare. Convenience samples of Native American ( n = 25), Latino/Hispanic ( n = 45), African American ( n = 30), European American ( n = 78), Asian Pacific American ( n = 31), and South Asian American ( n = 29) participants responded to an open-ended survey requesting examples of extreme, moderate, and mild sibling abuse. Asian Pacific Americans listed proportionately more instances of physical aggression in their examples of mild abuse and of psychological aggression in their examples of severe abuse—an inverse of the pattern in the other groups. South Asian Americans mentioned beating and hitting significantly more often than other groups. In addition, European American participants gave the most instances of sexual abuse. Gender differences were found, with women mentioning physical aggression between siblings more often than men as extreme abuse.
Strategic misrepresentation in online dating: The effects of gender, self-monitoring, and personality traits
Authors: Hall Jeffrey A. , Park Namkee , Song Hayeon , Cody Michael J.
Published: January 2010

This study examines factors (including gender, self-monitoring, the big five personality traits, and demographic characteristics) that influence online dating service users’ strategic misrepresentation (i.e., the conscious and intentional misrepresentation of personal characteristics). Using data from a survey of online dating service users (N = 5,020), seven categories of misrepresentation — personal assets, relationship goals, personal interests, personal attributes, past relationships, weight, and age — were examined. The study found that men are more likely to misrepresent personal assets, relationship goals, personal interests, and personal attributes, whereas women are more likely to misrepresent weight. The study further discovered that self-monitoring (specifically other-directedness) was the strongest and most consistent predictor of misrepresentation in online dating. Agreeableness, conscientiousness, and openness also showed consistent relationships with misrepresentation.
Construct validity of the Capacity Profile in adolescents with cerebral palsy
Authors: Meester-Delver Anke , Beelen Anita , van Eck Mirjam , Voorman Jeanine , Dallmeijer Annet , Nollet Frans , Becher Jules
Published: January 2010

Objective: To establish construct validity of the Capacity Profile, a method to comprehensively classify additional care needs in five domains of body functions (physical health, motor, sensory, mental, voice and speech functions), in adolescents with non-progressive, permanent conditions such as cerebral palsy.

Design: Cross-sectional study.

Subjects: Ninety-four adolescents with cerebral palsy: 60 boys, 34 girls, median age 14.3, range 12—16 years, unilateral (n = 37), bilateral (n = 57), spastic (n = 76), ataxic (n = 4), dyskinetic (n = 5), mixed (dyskinetic and spastic, n =9), Gross Motor Function Classification System: level I (n = 50), level II (n = 6), level III (n = 10), level IV (n = 8), level V (n = 20).

Methods: Associations were calculated between Capacity Profile domains and Vineland Adaptive Behavior Scales (communication, daily activities, social and motor skills) and Gross Motor Function Classification System using Spearman’s rho. Furthermore, we explored the independent contribution of the Capacity Profile domains to activities and participation measured with the Vineland Adaptive Behavior Scales.

Results: All Capacity Profile domains were significantly associated with all domains of the Vineland Adaptive Behavior Scales and the Gross Motor Function Classification System (P<0.05). Multiple regression analysis showed that the Capacity Profile contributed 87% to variance in communication (Capacity Profile-voice 78%, mental 8% and physical 1%), 85% to daily activities (Capacity Profile-mental 75%, motor 8% and voice 2%), 60% to social skills (Capacity Profile-voice 56% and mental 4%), and 91% to motor skills (Capacity Profile-motor 87%, mental 3% and sensory 1%).

Conclusion: These findings support the construct validity of the Capacity Profile in adolescents with cerebral palsy. Construct validity in other medical conditions should be further investigated.
Ronidazole Toxicosis in 3 Society Finches (Lonchura striata)
Authors: Woods L. W. , Higgins R. J. , Joseph V. J. , Filigenzi M. S. , Puschner B.
Published: January 2010

A group of finches were accidentally overdosed with ronidazole, a 5-nitroimidazole used for treatment of trichomoniasis. Finches developed neurologic signs on the third day of treatment and were euthanized (or died). Three finches were submitted for necropsy. Focal necrosis of the cerebellar nucleus was seen in all 3 birds, as characterized by neuronal necrosis, vacuolation of the neuropil, gemistocytic astrocytosis, hemorrhage, and axonal swelling (spheroids) with demyelination. The liver from 1 finch was analyzed for ronidazole and its metabolite, 2-hydroxymethyl-1-methyl-5-nitroimidazole, by high-performance liquid chromatography–mass spectrometry. Ronidazole was detected in the liver tissue at 2,700 ng/g (wet weight), and 2-hydroxymethyl-1-methyl-5-nitroimidazole was detected at 140 ng/g (wet weight).
Focal Mastocytosis in Lymph Nodes From a Beagle Dog
Authors: Lund J. E. , Park J. F.
Published: January 2010

An 11-year-old Beagle dog had focal mastocytosis in the midtracheobronchial and left tracheobronchial lymph nodes. The cells were well-differentiated and were arranged in well-defined follicles. There were neither skin tumors nor mast-cell accumulations in other tissues.
The Ultrastructure of Bovine Peripheral Nerve Sheath Tumours
Authors: Canfield P.
Published: January 2010

Bovine peripheral nerve sheath tumours from 30 cattle were similar ultrastructurally to human schwannomas and neurofibromas. Bovine neurofibromatous tissue had large amounts of extracellular material, primarily collagen and electron lucent granular material. The principal cells had basal laminae and a disorganized proliferation of the plasmalemma. Axons were consistently seen and were surrounded by the plasmalemma of principal cells. The principal cells seemed to be Schwann cells or variants of them. Bovine schwannomas had areas similar to Antoni type A tissue with sparse extracellular material, few, if any, axons, and an apparent organized layering of cytoplasmic processes clad in a basal lamina. Cell nuclei often formed palisades. The principal cells in bovine schwannomas might be derived either from Schwann cells or perineurial cells. Bovine schwannomas appeared together with bovine neurofibromatous tissue in affected nerves.