bluuebunny/crossref_metadata_2025 huggingface dataset:
Origins and Prevalence of the American Founder Mutation of MSH2
Authors: Clendenning Mark , Baze Mark E. , Sun Shuying , Walsh Kyle , Liyanarachchi Sandya , Fix Dan , Schunemann Victoria , Comeras Ilene , Deacon Molly , Lynch Jane F. , Gong Gordon , Thomas Brittany C. , Thibodeau Stephen N. , Lynch Henry T. , Hampel Heather , de la Chapelle Albert
Published: April 2008

Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of ∼500 years (95% confidence interval, 425–625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted. [Cancer Res 2008;68(7):2145–53]
Signatures Associated with Rejection or Recurrence in HER-2/neu–Positive Mammary Tumors
Authors: Worschech Andrea , Kmieciak Maciej , Knutson Keith L. , Bear Harry D. , Szalay Aladar A. , Wang Ena , Marincola Francesco M. , Manjili Masoud H.
Published: April 2008

We have previously shown T-cell–mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-γ and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials. [Cancer Res 2008;68(7):2436–46]
Dissection of the APCCdh1-Skp2 Cascade in Breast Cancer
Authors: Fujita Takeo , Liu Weijun , Doihara Hiroyoshi , Date Hiroshi , Wan Yong
Published: April 2008

Purpose: Skp2 is a subunit of the SCF ubiquitin protein ligase, which plays a vital role in the control of tumorigenesis via its regulation of G1-S transition. Deregulation of Skp2 in various types of cancers correlates with aggressive clinical behavior and poor prognosis. Recent studies suggest that cell cycle–dependent fluctuation of Skp2 is governed by APCCdh1, another important E3 ligase, thereby preventing premature entry into S phase. To assess the potential role of APCCdh1 in tumorigenesis through proteolysis of Skp2, we have dissected the APCCdh1-Skp2 cascade.

Experimental Design: We manipulated the APCCdh1-Skp2 cascade and examined its cellular behavior using both breast cancer and normal breast epithelial cells. Furthermore, applying immunohistochemistry, we analyzed the clinicopathologic significance of these molecules in patients with breast cancer.

Results: Analysis of tissue arrays indicated that the percentage of samples positive for Cdh1 in breast cancer was significantly lower compared with normal breast tissues (P = 0.004). Conversely, the percentage of samples scored as positive for Skp2 in cancer was significantly higher than in normal tissues (P < 0.001). Moreover, prognostic studies revealed that relatively high levels of Cdh1 are associated with survivability in patients with breast cancer. In addition, depletion of Cdh1 by small interfering RNA in normal breast cells resulted in increased cellular proliferation, whereas knockdown of Skp2 significantly suppressed growth in breast cancer cells.

Conclusions: This study shows a correlation between Skp2 and APCCdh1 in breast cancer. Thus, Cdh1 may act as an important component in tumor suppression and could be considered as a novel biomarker in breast cancer.
Profiling of Genetic Variations in Inflammation Pathway Genes in Relation to Bladder Cancer Predisposition
Authors: Yang Hushan , Gu Jian , Lin Xin , Grossman H. Barton , Ye Yuanqing , Dinney Colin P. , Wu Xifeng
Published: April 2008

Purpose: Compelling evidence has indicated that inflammation plays an important role in cancer development. We sought to test the hypothesis that common sequence variants in the inflammation pathway modulate bladder cancer risk.

Experimental Design: We genotyped 59 potentially functional single nucleotide polymorphisms from 35 candidate inflammation genes in a case-control study including 635 Caucasian bladder cancer patients and 635 matched controls.

Results: The most significant finding was in the 3′-untranslated region of PTGS2 (exon10+837T>C, rs5275), which was associated with a significantly reduced risk (odds ratio, 0.68; 95% confidence interval, 0.54-0.87; P = 0.002) and remained significant after multiple comparison adjustment. Consistently, the most common PTGS2 haplotype containing the common allele of exon10+837T>C was associated with a significantly increased risk (odds ratio, 1.27; 95% confidence interval, 1.06-1.52; P = 0.008). In contrast, the haplotypes containing at least one variant allele of exon10+837T>C were all associated with a decreased risk. In a combined analysis to assess the cumulative effects of inflammation single nucleotide polymorphisms on bladder cancer risk, we found that in the anti-inflammation pathway, but not in the proinflammation pathway, when compared with individuals with a few adverse alleles, individuals with more adverse alleles had a significantly increased risk in a dose-dependent manner (Ptrend = 0.012). To further elucidate the functional mechanism of these associations, we redefined the adverse alleles based on literature-reported functional results and found that individuals with a higher number of inflammation-enhancing alleles in the anti-inflammation pathway exhibited a greater bladder cancer risk.

Conclusions: Our results strongly suggest that common variants in inflammation genes affect bladder cancer susceptibility individually and jointly.
Evaluation of d-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis
Authors: Vuyyuri Saleha B. , Hamstra Daniel A. , Khanna Divya , Hamilton Christin A. , Markwart Sonja M. , Campbell Kathleen C.M. , Sunkara Prasad , Ross Brian D. , Rehemtulla Alnawaz
Published: April 2008

Purpose: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. d-Methionine (d-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults.

Experimental Design: We evaluated if d-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice.

Results: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P < 0.05) whereas it did not confer a similar protection on transformed tumor cells. d-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6 ± 0.15). d-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by d-Met treatment. Pharmacokinetics following administration of a liquid suspension of d-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral d-Met doses between 200 and 500 mg/kg (P < 0.0003).

Conclusions: d-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of d-Met to protect from oral mucositis are warranted.
An In vivo Model of Met-Driven Lymphoma as a Tool to Explore the Therapeutic Potential of Met Inhibitors
Authors: Accornero Paolo , Lattanzio Giuseppe , Mangano Tony , Chiarle Roberto , Taulli Riccardo , Bersani Francesca , Forni Paolo E. , Miretti Silvia , Scuoppo Claudio , Dastrù Walter , Christensen James G. , Crepaldi Tiziana , Ponzetto Carola
Published: April 2008

Purpose: Met, the tyrosine kinase receptor for hepatocyte growth factor, is frequently deregulated in human cancer. Recent evidence indicates that Met amplification may confer resistance to treatments directed toward other receptor tyrosine kinases. Thus, there is a need to develop Met inhibitors into therapeutic tools, to be used alone or in combination with other molecularly targeted drugs. Preclinical validation of Met inhibitors has thus far been done in nude mice bearing cancer cells xenogratfs. A far superior model would be a transgenic line developing spontaneous Met-driven tumors with high penetrance and short latency.

Experimental Design: To this end, we introduced into the mouse genome TPR-MET, the oncogenic form of MET. The Tpr-Met protein ensures deregulation of Met signaling because dimerization motifs in the Tpr moiety cause ligand-independent activation of the Met kinase.

Results: Here, we describe a TPR-MET transgenic line that develops thymic T-cell lymphoma with full penetrance and very short latency. In the tumors, Tpr-Met and its effectors were phosphorylated. Treatment of tumor-derived T lymphocytes with the selective Met inhibitor PHA-665752 at nanomolar concentrations abolished phosphorylation of Met and downstream effectors and led to caspase-mediated apoptosis. I.v. administration of PHA-665752 to transgenic mice bearing lymphomas in exponential growth phase led to a significant decrease in tumor growth and, in some cases, to tumor regression.

Conclusions: Our transgenic line, which within 2 months reliably develops Tpr-Met–driven T-cell lymphoma, represents a valuable tool to explore the efficacy and therapeutic potential of Met kinase inhibitors as anticancer drugs.
Pilot Randomized Phase II Study of Celecoxib in Oral Premalignant Lesions
Authors: Papadimitrakopoulou Vassiliki A. , William William N. , Dannenberg Andrew J. , Lippman Scott M. , Lee J. Jack , Ondrey Frank G. , Peterson Douglas E. , Feng Lei , Atwell Anthea , El-Naggar Adel K. , Nathan Cherie-Ann , Helman Joseph I. , Du Baoheng , Yueh Bevan , Boyle Jay O.
Published: April 2008

Purpose: Cyclooxygenase-2 (COX-2)–specific inhibition suppresses carcinogenesis in preclinical models and is a promising strategy for preventing oral cancer. In this pilot randomized phase II study, we evaluated the efficacy and safety of the COX-2 inhibitor celecoxib in patients with oral premalignant lesions (OPL).

Experimental Design: Patients were randomly assigned to placebo (n = 18), celecoxib 100 mg twice daily (n = 17), or celecoxib 200 mg twice daily (n = 15) for 12 weeks. Six additional patients received celecoxib (400 mg twice daily) in an unblinded extension of the study. Biopsies were obtained at baseline and week 12. All patients entering the study were required to have at least one histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate to severe dysplasia) OPL.

Results: Forty-nine patients (46 of 50 randomized and 3 of 6 open label) were evaluable for efficacy analyses. There were no statistically significant differences between the response rates of the randomly assigned arms: placebo, 33.3% (6 of 18); celecoxib 100 mg twice daily, 41.2% (7 of 17); and celecoxib 200 mg twice daily, 20.0% (3 of 15). Two patients responded on celecoxib 400 mg twice daily. Celecoxib was generally well tolerated. Patients with higher baseline COX-2 mRNA levels had an increased risk of disease progression within 3 months.

Conclusions: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial. This result and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention. Better methods for identifying high-risk patients and more active interventions are needed for future oral cancer chemoprevention trials.
Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels
Authors: Brostjan Christine , Gebhardt Kristina , Gruenberger Birgit , Steinrueck Verena , Zommer Halina , Freudenthaler Harald , Roka Sebastian , Gruenberger Thomas
Published: April 2008

Purpose: Colorectal cancer patients receiving neoadjuvant treatment with bevacizumab, a monoclonal antibody neutralizing vascular endothelial growth factor (VEGF), may suffer from wound healing complications after surgery as the antibody persists in patient blood. We characterized the systemic angiogenic balance in the perioperative period to evaluate its effect on physiologic angiogenesis.

Experimental Design: Nineteen patients receiving combination chemotherapy and bevacizumab for six neoadjuvant cycles were compared with 14 patients receiving chemotherapy without bevacizumab. Plasma from perioperative days −1, +1, +7, and +21 was analyzed for VEGF, thrombospondin-1 (TSP-1), and PD-ECGF concentrations. The angiogenic capacity was further tested in an in vitro assay of endothelial cell proliferation and migration.

Results: On day +1, the onset of wound healing was reflected in a change of balance, i.e., an increase of proangiogenic factors VEGF and platelet-derived endothelial cell growth factor compared with low TSP-1 inhibitor levels in both treatment groups. Patients with bevacizumab therapy showed significantly higher blood levels of total VEGF throughout the evaluation period. However, most VEGF molecules were inactive, i.e., complexed with antibody. Nevertheless, the capacity to stimulate endothelial growth was higher for these plasma samples and was reflected in low TSP-1 levels and an altered TSP-1 sensitivity. When purified TSP-1 protein was added, plasma samples of the bevacizumab but not the chemotherapy group showed reduced endothelial growth.

Conclusions: Feedback mechanisms of bevacizumab therapy are not restricted to VEGF expression but seem to involve additional factors, such as TSP-1, which influences the systemic angiogenic balance and permits endothelial growth.
A Severe Combined Immunodeficient–hu In vivo Mouse Model of Human Primary Mantle Cell Lymphoma
Authors: Wang Michael , Zhang Liang , Han Xiaohong , Yang Jing , Qian Jianfei , Hong Sungyoul , Lin Pei , Shi Yuankai , Romaguera Jorge , Kwak Larry W. , Yi Qing
Published: April 2008

Purpose: To establish a severe combined immunodeficient (SCID)-hu in vivo mouse model of human primary mantle cell lymphoma (MCL) for the study of the biology and novel therapy of human MCL.

Experimental Design: Primary MCL cells were isolated from spleen, lymph node, bone marrow aspirates, or peripheral blood of six different patients and injected respectively into human bone chips, which had been s.c. implanted in SCID-hu. Circulating human β2-microglobulin in mouse serum was used to monitor the engraftment and growth of patient's MCL cells. H&E staining and immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies were used to confirm the tumor growth and migration.

Results: Increasing levels of circulating human β2-microglobulin in mouse serum indicated that the patient's MCL cells were engrafted successfully into human bone chip of SCID-hu mice. The engraftment and growth of patient's MCL cells were dependent on human bone marrow microenvironment. Immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies confirmed that patient's MCL cells were able to not only survive and propagate in the bone marrow microenvironment of the human fetal bone chips, but also similar to the human disease, migrate to lymph nodes, spleen, bone marrow, and gastrointestinal tract of host mice. Treatment of MCL-bearing SCID-hu mice with atiprimod, a novel antitumor compound against the protection of bone marrow stromal cells, induced tumor regression.

Conclusion: This is the first human primary MCL animal model that should be useful for the biological and therapeutic research on MCL.
Pharmacology of the Novel Antiangiogenic Peptide ATN-161 (Ac-PHSCN-NH2): Observation of a U-Shaped Dose-Response Curve in Several Preclinical Models of Angiogenesis and Tumor Growth
Authors: Doñate Fernando , Parry Graham C. , Shaked Yuval , Hensley Harvey , Guan Xiaojun , Beck Ivy , Tel-Tsur Ziva , Plunkett Marian L. , Manuia Mari , Shaw David E. , Kerbel Robert S. , Mazar Andrew P.
Published: April 2008

Purpose: ATN-161 (Ac-PHSCN-NH2) is an integrin-binding peptide that is currently in phase II trials in cancer patients. This peptide has been shown to have antitumor activity in a number of different preclinical models.

Experimental Design: In this study, we examined the binding, biodistribution, and dose and biomarker response of ATN-161 in several animal models.

Results: ATN-161 bound to the β subunit of a number of different integrins implicated in tumor growth and progression, which depended on its cysteine thiol. The peptide had antiangiogenic activity in the Matrigel plug model, and this activity could be reversed by inhibitors of protein kinase A, an effector of α5β1-dependent angiogenesis. A labeled analogue of ATN-161, ATN-453, localized to neovessels but not to preexisting vasculature in vivo. The half-life of the peptide when localized to a tumor was much longer than in plasma. Dose-response studies in the Matrigel plug model of angiogenesis or a Lewis lung carcinoma model of tumor growth showed a U-shaped dose-response curve with 1 to 10 mg/kg given thrice a week, being the optimal dose range of ATN-161. Two additional pharmacodynamic models of angiogenesis (dynamic contrast-enhanced magnetic resonance imaging and measurement of endothelial cell progenitors) also revealed U-shaped dose-response curves.

Conclusions: The presence of a U-shaped dose-response curve presents a significant challenge to identifying a biologically active dose of ATN-161. However, the identification of biomarkers of angiogenesis that also exhibit this same U-shaped response should allow the translation of those biomarkers to the clinic, allowing them to be used to identify the active dose of ATN-161 in phase II studies.
Impact of Smoking Cessation on Global Gene Expression in the Bronchial Epithelium of Chronic Smokers
Authors: Zhang Li , Lee J. Jack , Tang Hongli , Fan You-Hong , Xiao Lianchun , Ren Hening , Kurie Jonathan , Morice Rodolfo C. , Hong Waun Ki , Mao Li
Published: April 2008

Cigarette smoke is the major cause of lung cancer and can interact in complex ways with drugs for lung cancer prevention or therapy. Molecular genetic research promises to elucidate the biological mechanisms underlying divergent drug effects in smokers versus nonsmokers and to help in developing new approaches for controlling lung cancer. The present study compared global gene expression profiles (determined via Affymetrix microarray measurements in bronchial epithelial cells) between chronic smokers, former smokers, and never smokers. Smoking effects on global gene expression were determined from a combined analysis of three independent data sets. Differential expression between current and never smokers occurred in 591 of 13,902 measured genes (P < 0.01 and >2-fold change; pooled data)—a profound effect. In contrast, differential expression between current and former smokers occurred in only 145 of the measured genes (P < 0.01 and >2-fold change; pooled data). Nine of these 145 genes showed consistent and significant changes in each of the three data sets (P < 0.01 and >2-fold change), with eight being down-regulated in former smokers. Seven of the eight down-regulated genes, including CYP1B1 and three AKR genes, influence the metabolism of carcinogens and/or therapeutic/chemopreventive agents. Our data comparing former and current smokers allowed us to pinpoint the genes involved in smoking-drug interactions in lung cancer prevention and therapy. These findings have important implications for developing new targeted and dosing approaches for prevention and therapy in the lung and other sites, highlighting the importance of monitoring smoking status in patients receiving oncologic drug interventions.
Increased Susceptibility of Nrf2 Knockout Mice to Colitis-Associated Colorectal Cancer
Authors: Khor Tin Oo , Huang Mou-Tuan , Prawan Auemduan , Liu Yue , Hao Xingpei , Yu Siwang , Cheung William Ka Lung , Chan Jefferson Y. , Reddy Bandaru S. , Yang Chung S. , Kong Ah-Ng
Published: April 2008

The nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting various tissues against inflammation, which is a potential risk factor for colorectal and other cancers. Our previously published mouse model work showed that Nrf2 helps protect against dextran sulfate sodium (DSS)–induced colitis/inflammation, and others have shown that Nrf2 helps protect against inflammation-associated colorectal carcinogenesis (aberrant crypt foci). The present study extended these important earlier findings by exploring the role of Nrf2 in colitis-associated colorectal cancer in a mouse model involving azoxymethane/DSS–induced colorectal carcinogenesis in Nrf2 knockout mice. Azoxymethane/DSS–treated Nrf2 knockout mice had increased incidence, multiplicity, and size of all colorectal tumors, including adenomas, versus treated wild-type (WT) mice, and the proportion of tumors that were adenocarcinoma was much higher in knockout (80%) versus WT (29%) mice. Compared with WT mice, knockout mice also had increased markers of inflammation in tumor tissue (cyclooxygenase-2 and 5-lipoxygenase expressions and prostaglandin E2 and leukotriene B4 levels) and in inflamed colonic mucosa (nitrotyrosine expression), supporting the association of knockout mouse tumor formation with inflammation. The phase II detoxifying/antioxidant enzymes NAD(P)H-quinone reductase 1 and UDP-glucurosyltransferase 1A1 were elevated in the normal mucosa of WT, but not Nrf 2 knockout, mice treated with azoxymethane/DSS. Our findings show that Nrf2 plays a critical role in protecting against inflammation-associated colorectal cancer.
Effects of Left Bundle-Branch Block on Cardiac Structure, Function, Perfusion, and Perfusion Reserve
Authors: Hayat S.A. , Dwivedi G. , Jacobsen A. , Lim T.K. , Kinsey C. , Senior R.
Published: April 2008

Background—

We aimed to investigate the cardiac effects of left bundle-branch block (LBBB) using myocardial contrast echocardiography (MCE) to ascertain the value of MCE for detecting coronary artery disease (CAD) and to uncover the mechanism that affects the accuracy of single-photon emission computed tomography (SPECT) in these patients.

Methods and Results—

Sixty-three symptomatic LBBB patients (group A), 10 left ventricular ejection fraction–matched control subjects without LBBB and no CAD (group B), and 10 normal control subjects (group C) underwent resting echocardiography. Rest and vasodilator MCE and SPECT were undertaken in LBBB patients. Septal (SW) and posterior wall (PW) thickness, thickening, quantitative myocardial blood flow (MBF), and MBF reserve were measured. SW/PW thickness and percentage thickening ratios were lower (
P
<0.01 and
P
<0.05, respectively) in group A compared with both groups B and C, but resting SW/PW MBF and MBF reserve ratios were similar in all 3 groups. MBF reserve but not MBF was reduced in groups A and B (2.2±0.7 versus 2.2±0.2;
P
=0.98) compared with group C (3.1±0.5;
P
<0.01). SW thickness was an independent predictor (
P
=0.006) of SPECT perfusion defects in LBBB patients without CAD. MCE (92%) had a sensitivity similar to SPECT (92%); however, the specificity of MCE (95%) was superior (
P
<0.0001) to SPECT (47%) for the detection of CAD.

Conclusions—

Despite asymmetrical reduction in SW thickness and function, MBF is preserved and MBF reserve is homogeneously reduced in LBBB patients with left ventricular systolic dysfunction. Because of partial volume effects, the accuracy of SPECT for detecting CAD was significantly compromised compared with MCE in this patient cohort.
Complementary Roles for Biomarkers of Biomechanical Strain ST2 and N-Terminal Prohormone B-Type Natriuretic Peptide in Patients With ST-Elevation Myocardial Infarction
Authors: Sabatine Marc S. , Morrow David A. , Higgins Luke J. , MacGillivray Catherine , Guo Wei , Bode Christophe , Rifai Nader , Cannon Christopher P. , Gerszten Robert E. , Lee Richard T.
Published: April 2008

Background—

ST2 is a member of the interleukin-1 receptor family with a soluble form that is markedly upregulated on application of biomechanical strain to cardiac myocytes. Circulating ST2 levels are elevated in the setting of acute myocardial infarction, but the predictive value of ST2 independent of traditional clinical factors and of an established biomarker of biomechanical strain, N-terminal prohormone B-type natriuretic peptide (NT-proBNP), has not been established.

Methods and Results—

We measured ST2 at baseline in 1239 patients with ST-elevation myocardial infarction from the CLopidogrel as Adjunctive ReperfusIon TherapY–Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial. Per trial protocol, patients were to undergo coronary angiography after 2 to 8 days and were followed up for 30 days for clinical events. In contrast to NT-proBNP, ST2 levels were independent of clinical factors potentially related to chronic increased left ventricular wall stress, including age, hypertension, prior myocardial infarction, and prior heart failure; levels also were only modestly correlated with NT-proBNP (
r
=0.14). After adjustment for baseline characteristics and NT-proBNP levels, an ST2 level above the median was associated with a significantly greater risk of cardiovascular death or heart failure (third quartile: adjusted odds ratio, 1.42; 95% confidence interval, 0.68 to 3.57; fourth quartile: adjusted odds ratio, 3.57; 95% confidence interval, 1.87 to 6.81;
P
<0.0001 for trend). When both ST2 and NT-proBNP were added to a model containing traditional clinical predictors, the c statistic significantly improved from 0.82 (95% confidence interval, 0.77 to 0.87) to 0.86 (95% confidence interval, 0.81 to 0.90) (
P
=0.017).

Conclusions—

In ST-elevation myocardial infarction, high baseline ST2 levels are a significant predictor of cardiovascular death and heart failure independently of baseline characteristics and NT-proBNP, and the combination of ST2 and NT-proBNP significantly improves risk stratification. These data highlight the prognostic value of multiple, complementary biomarkers of biomechanical strain in ST-elevation myocardial infarction.
Left Ventricular Systolic Function and Outcome After In-Hospital Cardiac Arrest
Authors: Gonzalez Maria M. , Berg Robert A. , Nadkarni Vinay M. , Vianna Caio B. , Kern Karl B. , Timerman Sergio , Ramires Jose A.
Published: April 2008

Background—

The effect of prearrest left ventricular ejection fraction (LVEF) on outcome after cardiac arrest is unknown.

Methods and Results—

During a 26-month period, Utstein-style data were prospectively collected on 800 consecutive inpatient adult index cardiac arrests in an observational, single-center study at a tertiary cardiac care hospital. Prearrest echocardiograms were performed on 613 patients (77%) at 11±14 days before the cardiac arrest. Outcomes among patients with normal or nearly normal prearrest LVEF (≥45%) were compared with those of patients with moderate or severe dysfunction (LVEF <45%) by χ
2
and logistic regression analyses. Survival to discharge was 19% in patients with normal or nearly normal LVEF compared with 8% in those with moderate or severe dysfunction (adjusted odds ratio, 4.8; 95% confidence interval, 2.3 to 9.9;
P
<0.001) but did not differ with regard to sustained return of spontaneous circulation (59% versus 56%;
P
=0.468) or 24-hour survival (39% versus 36%;
P
=0.550). Postarrest echocardiograms were performed on 84 patients within 72 hours after the index cardiac arrest; the LVEF decreased 25% in those with normal or nearly normal prearrest LVEF (60±9% to 45±14%;
P
<0.001) and decreased 26% in those with moderate or severe dysfunction (31±7% to 23±6%,
P
<0.001). For all patients, prearrest β-blocker treatment was associated with higher survival to discharge (33% versus 8%; adjusted odds ratio, 3.9; 95% confidence interval, 1.8 to 8.2;
P
<0.001).

Conclusions—

Moderate and severe prearrest left ventricular systolic dysfunction was associated with substantially lower rates of survival to hospital discharge compared with normal or nearly normal function.
Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography
Authors: Ballantyne Christie M. , Raichlen Joel S. , Nicholls Stephen J. , Erbel Raimund , Tardif Jean-Claude , Brener Sorin J. , Cain Valerie A. , Nissen Steven E.
Published: April 2008

Background—

Previous studies using quantitative coronary angiography have demonstrated that statin therapy slows the progression of coronary stenoses in proportion to average low-density lipoprotein cholesterol levels during therapy. However, no major statin monotherapy study has demonstrated either halted progression or regression of angiographic disease. A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) assessed whether rosuvastatin could regress coronary atherosclerosis by intravascular ultrasound and quantitative coronary angiography. Intravascular ultrasound showed atheroma volume regression in a single coronary artery with <50% angiographic luminal narrowing.

Methods and Results—

ASTEROID treated 507 coronary disease patients with rosuvastatin 40 mg/d for 24 months. Blinded quantitative coronary angiography analyses of percent diameter stenosis and minimum lumen diameter were performed for up to 10 segments of coronary arteries and major branches with >25% diameter stenosis at baseline. For each patient, the mean of all matched lesions at baseline and study end was calculated. There were 292 patients with 613 matched stenoses. Rosuvastatin reduced low-density lipoprotein cholesterol by 53.3% to 61.1±20.3 mg/dL and increased high-density lipoprotein cholesterol by 13.8% to 48.3±12.4 mg/dL. Mean±SD percent diameter stenosis decreased from 37.3±8.4% (median, 35.7%; range, 26% to 73%) to 36.0±10.1% (median, 34.5%; range, 8% to 74%;
P
<0.001). Minimum lumen diameter increased from 1.65±0.36 mm (median, 1.62 mm; range, 0.56 to 2.65 mm) to 1.68±0.38 mm (median, 1.67 mm; range, 0.76 to 2.77 mm;
P
<0.001).

Conclusions—

Rosuvastatin treatment for 24 months to average low-density lipoprotein cholesterol levels well below 70 mg/dL, accompanied by significant increases in high-density lipoprotein cholesterol, produced regression by decreasing percent diameter stenosis and improving minimum lumen diameter as measured by quantitative coronary angiography in coronary disease patients.
Altered Release of Cytochrome P450 Metabolites of Arachidonic Acid in Renovascular Disease
Authors: Minuz Pietro , Jiang Houli , Fava Cristiano , Turolo Lucia , Tacconelli Stefania , Ricci Marco , Patrignani Paola , Morganti Alberto , Lechi Alessandro , McGiff John C.
Published: April 2008

The aim of the present cross-sectional study was to investigate whether activation of the renin-angiotensin system in renovascular disease affects the cytochrome P450 ω/ω-1 hydroxylase (20-hydroxyeicosatetraenoic acid [20-HETE]) and epoxygenase (epoxyeicosatrienoic acids [EETs]) pathways of arachidonic acid metabolism in vivo, each of which interacts with angiotensin II. Plasma concentration and urinary excretion of 20-HETE and EETs and their metabolites, dihydroxyeicosatrienoic acids, were measured in urine and plasma by mass spectrometry in 10 subjects with renovascular disease, 10 with essential hypertension, and 10 healthy normotensive subjects (control subjects), pair-matched for gender and age. Vascular and renal function were evaluated in all of the subjects. Plasma 20-HETE was highest in subjects with renovascular disease (median: 1.20 ng/mL; range: 0.42 to 1.92 ng/mL) compared with subjects with essential hypertension (median: 0.90 ng/mL; range: 0.40 to 2.17 ng/mL) and control subjects (median: 0.45 ng/mL; range: 0.14 to 1.70 ng/mL;
P
<0.05). Plasma 20-HETE significantly correlated with plasma renin activity in renovascular disease (
r
s
=0.67; n=10;
P
<0.05). The urinary excretion of 20-HETE was significantly lower in subjects with renovascular disease (median: 12.9 μg/g of creatinine; range: 4.4 to 24.9 μg/g of creatinine) than in control subjects (median: 31.0 μg/g of creatinine; range: 11.9 to 102.8 μg/g of creatinine;
P
<0.01) and essential hypertensive subjects (median: 35.9 μg/g of creatinine; range: 14.0 to 72.5 μg/g of creatinine;
P
<0.05). Total plasma EETs were lowest, as was the ratio of plasma EETs to plasma dihydroxyeicosatrienoic acids, an index of epoxide hydrolase activity, in renovascular disease (ratio: 2.4; range: 1.2 to 6.1) compared with essential hypertension (ratio: 3.4; range: 1.5 to 5.6) and control subjects (ratio: 6.8; range: 1.4 to 18.8;
P
<0.01). In conclusion, circulating levels of 20-HETE are increased and those of EETs are decreased in renovascular disease, whereas the urinary excretion of 20-HETE is reduced. Altered cytochrome P450 arachidonic acid metabolism may contribute to the vascular and tubular abnormalities of renovascular disease.
Analysis of Heart Period and Arterial Pressure Variability in Childhood Hypertension
Authors: Genovesi Simonetta , Pieruzzi Federico , Giussani Marco , Tono Valentina , Stella Andrea , Porta Alberto , Pagani Massimo , Lucini Daniela
Published: April 2008

In adults, initial stages of hypertension are associated with elevated sympathetic drive and significant alterations in indirect autonomic markers. There is growing evidence that children in the highest-pressure percentiles will be more likely to develop hypertension in adulthood, although mechanisms are not understood. We assessed whether computer analysis of RR interval and arterial blood pressure variability could detect early autonomic alterations in childhood hypertension, as assessed by noninvasive time and frequency domain measures of baroreflex regulation. We studied 75 children, subdivided in 3 subgroups of similar age (9.7±0.2 years): control subjects, prehypertensive children (ie, children with arterial pressure values >90th and <95th percentile for age, gender, and height), and children in the hypertensive range (ie, >95th percentile; systolic arterial pressure: 97±3/57±2, 121±5/70±1, and 128±2/80±2 mm Hg, respectively). We observed that hypertensive children demonstrate a significant impairment of the baroreflex as compared with control subjects (index α: 20±2 and 40±4 ms/mm Hg; spontaneous baroreflex slope: 20±2 and 37±5; ms/mm Hg;
P
<0.05 in both cases) and reduced RR variance. A similar baroreflex impairment is also observed in children whose arterial pressure falls short of this limit, ie, in the prehypertensive range. In conclusion, hypertensive children display a marked baroreflex impairment. A similar baroreflex impairment is also observed in the prehypertensive state. Baroreflex assessment could furnish additional information in the clinical assessment of pediatric hypertension.
How We Know Early Hadīth Critics Did Matn Criticism and Why It's So Hard to Find
Authors: Brown Jonathan
Published: March 2008

Western scholars generally agree that early hadīth critics limited their authentication of hadīths to examining isnāds. The argument that these critics took the matn into account has relied on material of dubious reliability or on works produced after the formative period of the Sunni hadīth tradition. By providing examples of matn criticism from the 3rd/9th and 4th/10th centuries, I prove that Sunni hadīth critics did in fact engage in matn criticism; and I argue that these critics consciously manufactured the image of exclusive focus on the isnād in an effort to ward off attacks by rationalist opponents. By demonstrating a high correlation between the hadīths found in early books of transmitter criticism and those found in later books of forged hadīth with explicit matn criticism, I show that early critics engaged in matn criticism far more often than appears to have been the case, disguising this activity in the language of isnād criticism.
The Students' Representative in the Law Colleges of 14th-Century Damascus
Authors: Stewart Devin
Published: March 2008

This study examines two fatwās issued by Taqī al-Dīn al-Subkī in the mid-14-century regarding the Shāmīyah Madrasah of Damascus. Both texts refer to the position of "representative of the law students" (nāib al-fuqahā) and state that the position had become customary at the Shāmīyah Madrasah and other madrasahs in Damascus during that period. The existence of the post, which has not been noted in scholarship on pre-modern Islamic education to date, shows that madrasah students were more organized in this context than has been realized and raises questions about the institutional character of the madrasah.
The Construction of Madhhab Authority: Ibn Taymiyya's Interpretation of Juristic Preference (Istihsān)
Authors: Opwis Felicitas
Published: March 2008

This essay analyzes Ibn Taymiyya's discussion of juristic preference (istihsān) as a valid method of law-finding. Ibn Taymiyya rejects the interpretation of leading Hanbalīs of juristic preference as contrary to analogy and explains it instead as specification of the ratio legis (takhsīs al-'illa). His changed understanding of juristic preference leads him to re-interpret several of Ibn Hanbal's rulings that are based on this legal principle. How Ibn Taymiyya does this is illustrated with Ibn Hanbal's ruling on usurpation of agricultural land. Ibn Taymiyya does not question the actual ruling but rather rejects the rationalization adduced for it by previous Hanbalīs, such as Abū Ya'lā and Ibn 'Aqīl. By attributing his own position to Ibn Hanbal, Ibn Taymiyya undermines the authority of earlier prominent Hanbalīs, increases the authority of the eponym of the school, and enhances his own position as the living heir of Ibn Hanbal.
A Statistical Portrait of the Resistance to Logic by Sunni Muslim Scholars Based on the Works of Jalāl al-Dīn al-Suyūtī (849-909/1448-1505)
Authors: Ali Mufti
Published: March 2008

On the basis of my analysis of four works composed by al-Suyūtī, I argue that hostility to logic was a predominant feature of Sunni scholarship, especially during the 13th, 14th, and 15th centuries. Logic was condemned by distinguished Sunni scholars in Valencia, Fez, Aleppo, Iraq, and Mecca, but especially in Egypt and Syria. This conclusion confirms Goldziher's argument that resistance to logic started already in the 2nd/8th century and increased in the 13th and 14th centuries; and disconfirms al-Rouayheb's argument that opposition to logic was never predominant among Muslim Sunni scholars.
(2 Sam. xiii 32): Lot (šiāmu/šâmu/šīmtu)?
Authors: Joo Samantha
Published: March 2008

Two distinct proposals have been suggested for the meaning of. The present author adopts an alternative reading based on an Akkadian cognate, šiāmu/šâmu/šīmtu, to capture the gravity of one's disposition in guiding one's actions.
The Answer of Psalm cxix 9
Authors: Reynolds Kent Aaron
Published: March 2008

The traditional reading of Ps. cxix 9 as a question and answer should be retained. Psalm cxix is not a lament psalm but rather uses elements of laments for a different purpose.
Ezekiel, P, and the Priestly School
Authors: Haran Menahem
Published: March 2008

Seeing that Ezekiel, with his law code of chaps. xl-xlviii, is connected with P in many characteristics, while, at the same time, they contradict each other in almost any tangible aspect, it is the author's contention that the two are independent manifestation of the same school, of which P is its authentic expression whereas Ezekiel is its loose and later extension. It is out of the question to argue, as was done recently, that Ezekiel saw P and modified it at will. The relationship between P and Ezekiel comprises two aspects, the first of which is the common literary language they share, which in itself calls for explanation. The lack of agreement between the two is the second aspect demanding an explanation, but only if it is assumed that, when formulating his code, Ezekiel had direct access to P. Since Ezekiel used the priestly style as his own, he should have acquired it, after the practice of the Ancient Near East, over the course of many years of training, beginning in childhood and ending up in maturity. This implies that Ezekiel received his training in Jerusalem, while upon his arrival in Babylonia he was already a qualified priestly scribe, and it was there that he became a prophet. It is a vexed question whether the P scrolls were obtainable at all in Tel Abib by the river Chebar.
Das Tag YHWHs-Verständnis von Zephanja iii
Authors: Beck Martin
Published: March 2008

Zeph. iii 6-8ab proclaims anew, in post-exilic times, the Day of YHWH as a disastrous event for Jerusalem. Various updatings in Zeph. iii 14-20 add to this image the idea of a forgiving God whose primary will aims at the wellbeing of his people. The Day of YHWH is understood in the sense of a comprehensive final judgment (iii 8b). Zeph. iii 11-13 points to a distinction between pious people and sinners in Jerusalem as a means of salvation, whereas iii 9-10 the nations (seen as a rest) are presented as taking part in the salvation.
Pain and Production in Eden: Some Philological Reflections on Genesis iii 16
Authors: Novick Tzvi
Published: March 2008

Genesis iii 16, which describes the unhappy consequences for Eve of her decision to eat from the forbidden fruit, is one of the most historically and theologically significant verses in the Hebrew Bible. Scholars have long debated certain cruces in the verse, among them the meaning of the phrase. I review various positions on the latter and then offer a new proposal.
The Ryukyu Islands Feng Shui Village Landscape
Authors: Chen Bixia , Kurima Gengi , Nakama Yuei
Published: March 2008

In a typical Ryukyu "Feng Shui" village, a forest belt, known as village Ho:go, was planted to curve in the front and extend to the east and the west to embrace the village along with preserved forest on the rear hill. Lines of Fukugi trees (Garcinia subelliptica) were planted to embrace the houses. Compared to the more symbolic existence of Feng Shui trees in China and other regions in East Asia, tree planting on a large scale was used as a practical means to repair defective topography with little protection from the strict natural condition on Ryuku's flat islands. This study focuses on village layout, forest composition in the front forest belt, habitat embracing trees, and forest plantations on the back hill. Garcinia subelliptica and Calophyllum inophyllum are the predominant species in the upper storey in the forest belt. A large number of species are also found in the under storey vegetation in the preserved forest. Thus, a Ryukyu Feng Shui village landscape, which embodies a symbiosis of the nature and human intervention, provides an ideal village landscape pattern in the Ryukyu Islands.
The Anonymity of the New Testament History Books: A Stylistic Device in the Context of Greco-Roman and Ancient Near Eastern Literature
Authors: Baum Armin
Published: April 2008

The anonymity of the NT historical books should not be regarded as peculiar to early Christian literature nor should it be interpreted in the context of Greco-Roman historiography. The striking fact that the NT Gospels and Acts do not mention their authors' names has its literary counterpart in the anonymity of the OT history books, whereas OT anonymity itself is rooted in the literary conventions of the Ancient Near East. Just as in the OT, where the authors of books that belonged to the genre of wisdom and prophetic literature were usually named while historical works were written anonymously, only the NT letters and the Apocalypse were published under their authors' names while the narrative literature of the NT remained anonymous. The authorial intent of the Gospels' anonymity can also be deduced from its ancient Near Eastern and OT background. Unlike the Greek or Roman historian who, among other things, wanted to earn praise and glory for his literary achievements from both his contemporaries and posterity, the history writer in the Ancient Near East sought to disappear as much as possible behind the material he presented and to become its invisible mouthpiece. By adopting the stylistic device of anonymity from OT historiography the Evangelists of the NT implied that they regarded themselves as comparatively insignificant mediators of a subject matter that deserved the full attention of the readers. The anonymity of the Gospels is thus rooted in a deep conviction concerning the ultimate priority of their subject matter.