bluuebunny/crossref_metadata_2025 huggingface dataset:
UCHL‐1 is not a Parkinson's disease susceptibility gene
Authors: Healy Daniel G. , Abou‐Sleiman Patrick M. , Casas Juan P. , Ahmadi Kourosh R. , Lynch Timothy , Gandhi Sonia , Muqit Miratul M. K. , Foltynie Thomas , Barker Roger , Bhatia Kailash P. , Quinn Niall P. , Lees Andrew J. , Gibson J. Mark , Holton Janice L. , Revesz Tamas , Goldstein David B. , Wood Nicholas W.
Published: January 2006

Objective

The UCHL‐1 gene is widely cited as a susceptibility factor for sporadic Parkinson's disease (PD). The strongest evidence comes from a meta‐analysis of small studies that reported the S18Y polymorphism as protective against PD, after pooling studies of white and Asian subjects. Here, we present data that challenge this association.

Methods

In a new large case–control study in white individuals (3,023 subjects), the S18Y variant was not protective against PD under any genetic model of inheritance. Similarly, a more powerful haplotype‐tagging approach did not detect other associated variants.

Results

Finally, in an updated S18Y‐PD meta‐analysis (6,594 subjects), no significant association was observed under additive, recessive, or dominant models (odds ratio = 1.00 [95% confidence interval: 0.74–1.33]; odds ratio = 1.01 [95% confidence interval: 0.76–1.35]; and odds ratio = 0.96 [95% confidence interval: 0.86–1.08], respectively), and a cumulative meta‐analysis showed a trend toward a null effect.

Interpretation

Based on the current evidence, the UCHL‐1 gene does not exhibit a protective effect in PD. Ann Neurol 2006
Suppression of cortical spreading depression in migraine prophylaxis
Authors: Ayata Cenk , Jin Hongwei , Kudo Chiho , Dalkara Turgay , Moskowitz Michael A.
Published: January 2006

Objective

Topiramate, valproate, propranolol, amitriptyline, and methysergide have been widely prescribed for migraine prophylaxis, but their mechanism or site of action is uncertain. Cortical spreading depression (CSD) has been implicated in migraine and as a headache trigger and can be evoked in experimental animals by electrical or chemical stimulation. We hypothesized that migraine prophylactic agents suppress CSD as a common mechanism of action.

Methods

Rats were treated either acutely or chronically over weeks and months, with one of the above migraine prophylactic drugs, vehicle, orD‐propranolol, a clinically ineffective drug. The impact of treatment was determined on the frequency of evoked CSDs after topical potassium application or on the incremental cathodal stimulation threshold to evoke CSD.

Results

Chronic daily administration of migraine prophylactic drugs dose‐dependently suppressed CSD frequency by 40 to 80% and increased the cathodal stimulation threshold, whereas acute treatment was ineffective. Longer treatment durations produced stronger CSD suppression. ChronicD‐propranolol treatment did not differ from saline control.

Interpretation

Our data suggest that CSD provides a common therapeutic target for widely prescribed migraine prophylactic drugs. Assessing CSD threshold may prove useful for developing new prophylactic drugs and improving upon existing ones. Ann Neurol 2006
Topographic cellular active contour techniques: theory, implementations and comparisons
Authors: Hillier Dániel , Binzberger Viktor , Vilariño David Lopez , Rekeczky Csaba
Published: January 2006

This paper overviews some massively parallel topographic cellular computational approaches proposed for contour localization and tracking. When implemented on a focal plane cellular array microprocessor, these algorithms offer real‐time object contour localization and tracking—even at very high frame rates. Three specific methods (Constrained Wave Computing, Pixel Level Snakes and Moving Patch Method) will be described and compared along with their associated hardware–software architectures. Computational complexity, implementation, and performance related issues are discussed on a common platform (ACE‐BOX with the ACEx CNN‐UM chips). In conclusion, a novel architecture is proposed incorporating the best solutions learned from this comparative study. Copyright © 2006 John Wiley & Sons, Ltd.
Synthesis of a New Family of N‐Aryl Lactams Active on Chemesthesis and Taste
Authors: Bassoli Angela , Borgonovo Gigliola , Busnelli Gilberto , Morini Gabriella
Published: January 2006

A new class of synthetic compounds with chemesthetic activity has been identified. They have been designed ex‐novo by structural similarity with known cooling compounds such as menthol, icilin and cyclic ketoenamines. 19 new derivatives have been obtained easily and in high yields by Goldberg arylation or lactam ring closure on the appropriate phenol or benzoic acid derivative. The synthetic procedures are suitable for gram‐scale preparation, and the products are stable and easy to purify. 17 new compounds were submitted to preliminary sensory evaluation, and 3 of them showed cooling activity and, in some cases, tingling sensation in the oral cavity. These N‐aryl lactams seem to be an interesting class of compounds to be enlarged in order to derive structure‐activity relationships. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Measuring the effect of husband's health on wife's labor supply
Authors: Siegel Michele J.
Published: January 2006

A sizable proportion of women remain married well into late life and an increasing proportion of them participate in the labor force. Since women tend to marry men older than themselves and men tend to experience serious illnesses at younger ages than women, women frequently witness declining health in their husbands. This is likely to affect a wife's labor–leisure trade‐off in offsetting ways. Prior studies have not sought to disentangle the effect of a husband's poor health on his wife's reservation wage from the income effect of his ill health. We argue that, if we control for husband's earnings, the coefficient of husband's health in models of his wife's labor force participation (and hours of work) will reflect, in part, her preference over whether to decrease her labor supply to provide health care for her husband or whether to instead increase it to purchase this care in the market. However, husband's earnings are likely to be endogenous in these models due to unobserved characteristics common to husbands and wives. We find that the estimated effect of husband's health depends on whether we instrument for husband's earnings and on the health measure used. This is indicative of the importance of using a variety of health measures and controlling for husband's earnings, and their endogeneity, in future research on the effect of husband's health on wife's labor supply. Copyright © 2006 John Wiley & Sons, Ltd.
Natural History of Chronic Hepatitis B Virus Infection: What We Knew in 1981 and What We Know in 2005
Authors: Yim Hyung Joon , Lok Anna Suk-Fong
Published: January 2006

Remarkable progress has been made in our understanding of the natural history of chronic hepatitis B virus (HBV) infection in the past 25 years. Availability of sensitive HBV DNA assays and application of sophisticated immunological techniques led to the recognition that HBV replication persists throughout the course of chronic HBV infection, and host immune response plays a pivotal role in HBV-related liver disease. Knowledge of the HBV genome organization and replication cycle led to the unraveling of HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. The natural course of chronic HBV infection is now perceived as consisting of 4 phases: immune tolerance, immune clearance [hepatitis B e antigen (HBeAg)-positive chronic hepatitis], inactive carrier state, and reactivation (HBeAg-negative chronic hepatitis B). Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers and underscores the need for long-term monitoring. Accumulating evidence indicates that antiviral therapy can prevent progression of HBV-related liver disease, particularly among patients with sustained response. Newer antiviral therapies with improved efficacy and decreased risk of resistance may lead to a complete revision of the chapter on the natural history of chronic HBV infection on the occasion of the golden jubilee of HEPATOLOGY.
Liver Regeneration
Authors: Fausto Nelson , Campbell Jean S. , Riehle Kimberly J.
Published: January 2006

During liver regeneration after partial hepatectomy, normally quiescent hepatocytes undergo one or two rounds of replication to restore the liver mass by a process of compensatory hyperplasia. A large number of genes are involved in liver regeneration, but the essential circuitry required for the process may be categorized into three networks: cytokine, growth factor and metabolic. There is much redundancy within each network, and intricate interactions exist between them. Thus, loss of function from a single gene rarely leads to complete blockage of liver regeneration. The innate immune system plays an important role in the initiation of liver regeneration after partial hepatectomy, and new cytokines and receptors that participate in initiation mechanisms have been identified. Hepatocytes primed by these agents readily respond to growth factors and enter the cell cycle. Presumably, the increased metabolic demands placed on hepatocytes of the regenerating liver are linked to the machinery needed for hepatocyte replication, and may function as a sensor that calibrates the regenerative response according to body demands. In contrast to the regenerative process after partial hepatectomy, which is driven by the replication of existing hepatocytes, liver repopulation after acute liver failure depends on the differentiation of progenitor cells. Such cells are also present in chronic liver diseases, but their contribution to the production of hepatocytes in those conditions is unknown. Most of the new knowledge about the molecular and cellular mechanisms of liver regeneration is both conceptually important and directly relevant to clinical problems. (Hepatology 2006;43:S45-S53.)
Nonalcoholic Fatty Liver Disease: From Steatosis to Cirrhosis
Authors: Farrell Geoffrey C. , Larter Claire Z.
Published: January 2006

Nonalcoholic steatohepatitis (NASH), the lynchpin between steatosis and cirrhosis in the spectrum of nonalcoholic fatty liver disorders (NAFLD), was barely recognized in 1981. NAFLD is now present in 17% to 33% of Americans, has a worldwide distribution, and parallels the frequency of central adiposity, obesity, insulin resistance, metabolic syndrome and type 2 diabetes. NASH could be present in one third of NAFLD cases. Age, activity of steatohepatitis, and established fibrosis predispose to cirrhosis, which has a 7- to 10-year liver-related mortality of 12% to 25%. Many cases of cryptogenic cirrhosis are likely endstage NASH. While endstage NAFLD currently accounts for 4% to 10% of liver transplants, this may soon rise. Pathogenic concepts for NAFLD/NASH must account for the strong links with overnutrition and underactivity, insulin resistance, and genetic factors. Lipotoxicity, oxidative stress, cytokines, and other proinflammatory mediators may each play a role in transition of steatosis to NASH. The present “gold standard” management of NASH is modest weight reduction, particularly correction of central obesity achieved by combining dietary measures with increased physical activity. Whether achieved by “lifestyle adjustment” or anti-obesity surgery, this improves insulin resistance and reverses steatosis, hepatocellular injury, inflammation, and fibrosis. The same potential for “unwinding” fibrotic NASH is indicated by studies of the peroxisome proliferation activator receptor (PPAR)-
γ

agonist “glitazones,” but these agents may improve liver disease at the expense of worsening obesity. Future challenges are to approach NAFLD as a preventive public health initiative and to motivate affected persons to adopt a healthier lifestyle. (Hepatology 2006;43:S99-S112.)
The Hyperdynamic Circulation of Chronic Liver Diseases: From the Patient to the Molecule
Authors: Iwakiri Yasuko , Groszmann Roberto J.
Published: January 2006

The hyperdynamic circulatory syndrome observed in chronic liver diseases is a great example of research that originated from clinical observations and progressed in the last 50 years from the patient to the experimental laboratory. Our knowledge has evolved from the patient to the molecule, using experimental models that serve as a source for understanding the complex pathophysiological mechanisms that govern this complex syndrome. We now know that progressive vasodilatation is central to the detrimental effects observed in multiple organs. Although nitric oxide has been shown to be the primary vasodilator molecule in these effects, other molecules also participate in the complex mechanisms of vasodilatation. This review summarizes three major areas: first, clinical observation in patients; second, experimental models used to study the hyperdynamic circulatory syndrome; and third, the vasodilator molecules that play roles in vascular abnormalities observed in portal hypertension.
Liver Stem Cells and Prospects for Liver Reconstitution by Transplanted Cells
Authors: Shafritz David A. , Oertel Michael , Menthena Anuradha , Nierhoff Dirk , Dabeva Mariana D.
Published: January 2006

Although it was proposed almost 60 years ago that the adult mammalian liver contains hepatic stem cells, this issue remains controversial. Part of the problem is that no specific marker gene unique to the adult hepatic stem cell has yet been identified, and regeneration of the liver after acute injury is achieved through proliferation of adult hepatocytes and does not require activation or proliferation of stem cells. Also, there are differences in the expected properties of stem versus progenitor cells, and we attempt to use specific criteria to distinguish between these cell types. We review the evidence for each of these cell types in the adult versus embryonic/fetal liver, where tissue-specific stem cells are known to exist and to be involved in organ development. This review is limited to studies directed toward identification of hepatic epithelial stem cells and does not address the controversial issue of whether stem cells derived from the bone marrow have hepatocytic potential, a topic that has been covered extensively in other recent reviews.
Autoimmune Hepatitis, From Mechanisms to Therapy
Authors: Manns Michael P. , Vogel Arndt
Published: January 2006

In 1950, Waldenström was the first to describe a chronic form of hepatitis in young women. Subsequently, the disease was found to be associated with other autoimmune syndromes and was later termed “lupoid hepatitis” because of the presence of antinuclear antibodies. In 1965, it became designated by Mackay et al. as “autoimmune hepatitis” at an international meeting, at which the general concept of autoimmunity was endorsed by the scientific community. In the early 1960s and 1970s, the value of immunosuppressive therapy with glucocorticoids and/or azathioprine was well documented in several studies. The original association of autoimmune hepatitis (AIH) and HLA alleles, which has remarkably stood the test of time, was published in 1972. In the 1970s and 1980s, several autoantibodies were identified in patients withautoimmunehepatitis directed against proteins of the endoplasmatic reticulum expressed in liver and kidney and against soluble liver antigens. Subsequently, the molecular targets of these antibodies were identified and more precisely characterized. In the last two decades many additional pieces of the AIH puzzle have been collected leading to the identification of additional antibodies and genes associated with AIH and to the emergence of new therapeutic agents. Meanwhile, the immunoserological and genetic heterogeneity of AIH is well established and it has become obvious that clinical manifestations, disease behavior, and treatment outcome may vary by racial groups, geographical regions and genetic predisposition. Currently, the International Autoimmune hepatitis group is endorsing multi-center collaborative studies to more precisely define the features at disease presentation and to define prognostic indices and appropriate treatment algorithms. Given the importance of serological testing, the IAHG is also working on guidelines and procedures for more reliable and standardized testing of autoantibodies.
The Liver as an Immunological Organ
Authors: Racanelli Vito , Rehermann Barbara
Published: January 2006

The liver is a unique anatomical and immunological site in which antigen-rich blood from the gastrointestinal tract is pressed through a network of sinusoids and scanned by antigen-presenting cells and lymphocytes. The liver's lymphocyte population is selectively enriched in natural killer and natural killer T cells which play critical roles in first line immune defense against invading pathogens, modulation of liver injury and recruitment of circulating lymphocytes. Circulating lymphocytes come in close contact to antigens displayed by endothelial cells, Kupffer cells and liver resident dendritic cells in the sinusoids. Circulating lymphocytes can also contact hepatocytes directly, because the sinusoidal endothelium is fenestrated and lacks a basement membrane. This unique anatomy of the liver may facilitate direct or indirect priming of lymphocytes, modulate the immune response to hepatotrophic pathogens and contribute to some of the unique immunological properties of this organ, particularly its capacity to induce antigen-specific tolerance.
Apoptosis and Necrosis in the Liver: A Tale of Two Deaths?
Authors: Malhi Harmeet , Gores Gregory J. , Lemasters John J.
Published: January 2006

Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for transplantation and drug/toxicant-induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug-induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP-dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease.
Functional Genomics of Hepatocellular Carcinoma
Authors: Thorgeirsson Snorri S. , Lee Ju-Seog , Grisham Joe W.
Published: January 2006

The majority of DNA-microarray based gene expression profiling studies on human hepatocellular carcinoma (HCC) has focused on identifying genes associated with clinicopathological features of HCC patients. Although notable success has been achieved, this approach still faces significant challenges due to the heterogeneous nature of HCC (and other cancers) as well as the many confounding factors embedded in gene expression profile data. However, these limitations are being overcome by improved bioinformatics and sophisticated analyses. Also, application of cross comparison of multiple gene expression data sets from human tumors and animal models are facilitating the identification of critical regulatory modules in the expression profiles. The success of this new experimental approach, comparative functional genomics, suggests that integration of independent data sets will enhance our ability to identify key regulatory elements in tumor development. Furthermore, integrating gene expression profiles with data from DNA sequence information in promoters, array-based CGH, and expression of non-coding genes (

i.e.

, microRNAs) will further increase the reliability and significance of the biological and clinical inferences drawn from the data. The pace of current progress in the cancer profiling field, combined with the advances in highthroughput technologies in genomics and proteomics, as well as in bioinformatics, promises to yield unprecedented biological insights from the integrative (or systems) analysis of the combined cancer genomics database. The predicted beneficial impact of this “new integrative biology” on diagnosis, treatment and prevention of liver cancer and indeed cancer in general is enormous.
Sialyltransferase STX (ST8SiaII): A novel molecular marker of metastatic neuroblastoma
Authors: Cheung Irene Y. , Vickers Andrew , Cheung Nai‐Kong V.
Published: January 2006

Polysialic acid (PSA) is highly expressed in many human cancers, including neuroblastoma (NB), and is critical for cellular adhesion, neuronal migration and tumor metastasis. The key enzyme responsible for PSA synthesis is sialyltransferase STX (ST8SiaII). Using quantitative RT‐PCR we (i) studied STX expression in 39 NB tumors and 8 cell lines and (ii) examined its potential clinical utility as an early response marker in the bone marrows of the entire cohort of 136 high‐risk NB patients treated with an immunotherapy protocol utilizing anti‐GD2 antibody 3F8 and GM‐CSF. Based on the quantitation of 24 normal marrow and peripheral blood samples, a normalized STX transcript value below the mean + 2SD was defined as negative. Sensitivity of this assay was 1 NB cell in 106 normal mononuclear cells. STX expression was high among NB tumors of all stages, as well as NB cell lines of different phenotypes. Evaluation for early (2.5 months from protocol entry) marrow response by univariate Cox model indicated that STX marker status (positive versus negative) was strongly associated with both progression‐free and overall survival (p < 0.0005 for both). Similarly, the STX transcript level of posttreatment marrows was also highly prognostic of outcome (PFS, p = 0.001; OS, p < 0.0005). We conclude that STX mRNA has potential clinical utility as a molecular marker of metastatic NB. © 2006 Wiley‐Liss, Inc.
Is there a folate‐related gene‐environment interaction in the etiology of childhood acute lymphoblastic leukemia?
Authors: Milne Elizabeth , de Klerk Nicholas H. , van Bockxmeer Frank , Kees Ursula R. , Thompson Judith R. , Baker David , Armstrong Bruce K.
Published: January 2006

Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer in developed countries. Little is known about its causes, although its early age at diagnosis has focused interest on maternal and perinatal factors. We have previously observed a protective effect of maternal folate supplementation during pregnancy against ALL, and a number of studies have reported protective effects of some common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene. One study has suggested that the effect of MTHFR polymorphisms on risk of ALL may depend on folate status. This study aimed to look for evidence of an interaction between maternal folate supplementation and child's genotype among the cases from our previous study. Bone marrow specimens from 82 of 83 case children were available. DNA was extracted and genotyped for MTHFR C677T and A1298C using standard techniques. We used a case‐only analysis to estimate the case‐only odds ratio (COR) for MTHFR genotype and folate supplementation in association with ALL. None of the CORs indicated a significant departure from a multiplicative model. Adjustment for sex, age or genotype at the other locus had little effect on the results. Other studies of this gene and environment interaction in ALL and other cancers have produced contradictory results, perhaps because of varying definitions of folate exposure. Further research into the interaction of folate intake and genotype in causing ALL and other cancers is needed. We are specifically studying it in an Australian national case‐control study of genetic and environmental causes of ALL. © 2006 Wiley‐Liss, Inc.
Performance of clinical mammography: A nationwide study from Denmark
Authors: Jensen Allan , Vejborg Ilse , Severinsen Niels , Nielsen Susanne , Rank Fritz , Mikkelsen Gerd Just , Hilden Jørgen , Vistisen Dorte , Dyreborg Uffe , Lynge Elsebeth
Published: January 2006

Clinical mammography is the key tool for breast cancer diagnosis, but little is known about the impact of the organisational set‐up on the performance. We evaluated whether organisatorial factors influence the performance of clinical mammography. Clinical mammography data from all clinics in Denmark in the year 2000 were collected and linked to cancer outcome. Use of the National Institute of Radiation Hygiene register for identification of radiology clinics ensured comprehensive nationwide registration. We used the final mammographic assessment at the end of the imaging work‐up to determine sensitivity, specificity and accuracy, the latter using a receiver‐operating characteristics (ROC) analysis. In 96,534 clinical mammography examinations, sensitivity was 75% and specificity 99%. The presence of at least one high volume‐reading radiologist in the clinic increased accuracy (AUC = 0.91 for <1,000 examinations/year and 0.92 for >2,000 examinations/year, p = 0.017). The examination volume per clinic showed no clear effect on performance, as accuracy was significantly higher in clinics with a medium number of examinations (AUC = 0.93 for 2,000–4,000 examinations/year and 0.90 for >6,000 examinations/year, p = 0.003). Accuracy was significantly lower in regions with high annual utilisation rate of clinical mammography, which means the proportion of examined women in a region (AUC = 0.90 for 3.0–5.0% annual utilisation rate and AUC = 0.93 for 2.0–2.5% annual utilisation rate, and p = 0.001), indicating that clinical mammography worked best in patient populations of purely symptomatic women. Our data indicate that to increase the accuracy of clinical mammography at the community level, the presence of an experienced radiologist should be prioritised ahead of raising the clinic size. © 2006 Wiley‐Liss, Inc.
Molecular characterization of adenocarcinoma and squamous carcinoma of the uterine cervix using microarray analysis of gene expression
Authors: Chao Angel , Wang Tzu‐Hao , Lee Yun‐Shien , Hsueh Swei , Chao An‐Shine , Chang Ting‐Chang , Kung Wei‐Hsiang , Huang Shang‐Lang , Chao Fang‐Yu , Wei Min‐Li , Lai Chyong‐Huey
Published: January 2006

In an attempt to understand the molecular mechanisms for the different clinical features between adenocarcinoma/adenosquamous carcinoma (AC/ASC) and squamous carcinoma (SC) of the uterine cervix, we analyzed gene expression profiles of different histological subtypes of cervical cancer. Cancer specimens and the surrounding normal tissue counterparts were separately collected from cervical cancer patients undergoing type III radical hysterectomy. Paired total RNA (cancer and normal tissues) was isolated and analyzed with cDNA microarrays containing duplicate spots of 7 334 sequence‐verified human cDNA clones. Selected differentially expressed genes specific for AC or SC were further verified using real‐time quantitative polymerase chain reaction (RTQ‐PCR) and immunohistochemistry. Genes, including CEACAM5, TACSTD1, S100P and MSLN were upregulated in AC. Contrarily, genes involved in epidermal differentiation complex such as S100A9 and ANXA8 were upregulated in SC. Cross‐validation of the results using an independent but comparable group of patients with known long‐term outcomes (n = 63, median follow‐up 70.3 months; range, 4–208 months) showed that the correlation between the selected 6 differentially expressed genes and histology was highly significant. CEACAM5 (p < 0.0001) and TACSTD1 (p = 0.009) were significant prognostic factors by multivariate Cox proportional hazards regression analysis. The combination of cDNA microarray, RTQ‐PCR and immunohistochemical results of this study showed that it is possible to define different gene profiles for AC and SC. Moreover, TACSTD1 expression may be a novel poor prognostic factor. © 2006 Wiley‐Liss, Inc.
Regular aspirin use and esophageal cancer risk
Authors: Jayaprakash Vijayvel , Menezes Ravi J. , Javle Milind M. , McCann Susan E. , Baker Julie A. , Reid Mary E. , Natarajan Nachimuthu , Moysich Kirsten B.
Published: January 2006

Given the high mortality rate and the rapidly increasing incidence rate of esophageal carcinoma, chemopreventive agents are highly desirable. Aspirin has been shown to be associated with reduced risk of developing colorectal carcinoma and other cancers. Even though previous studies have shown reduced risk of esophageal cancer associated with aspirin use, results were inconsistent with respect to frequency and duration of use. In this hospital‐based case‐control study, 163 esophageal cancer cases were compared to 482 age‐ and sex‐matched hospital controls with nonneoplastic conditions. Participants were classified as regular aspirin users if they had taken the drug at least once a week for 6 months. Results suggest that esophageal cancer risk is significantly lower for regular aspirin users compared to nonusers [adjusted odds ratio (aOR) 0.54; 95% confidence interval (CI) 0.36–0.86]. Individuals who used an equivalent of at least 1 aspirin a day (≥7 tablets/week) were half as likely to have been diagnosed with esophageal carcinoma (aOR 0.47; 95% CI 0.26–0.85), and a linear trend was noted with increasing frequency of use (ptrend 0.007). Similar protective effects were noted with ≤20 years of use, whereas no risk reduction was noted with >20 years of use. Consistent reduction in risk associated with aspirin use was noted among both the major histological subtypes, but the protective effect appears to be more pronounced in adenocarcinoma compared to squamous cell carcinoma. Overall, results from the current study suggest that regular aspirin use may be associated with reduced risk of esophageal cancer. © 2006 Wiley‐Liss, Inc.
Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors
Authors: Heaphy Christopher M. , Bisoffi Marco , Fordyce Colleen A. , Haaland Christina M. , Hines William C. , Joste Nancy E. , Griffith Jeffrey K.
Published: January 2006

Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of “field cancerization” and “cancer field effect,” concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast‐sparing surgery. © 2006 Wiley‐Liss, Inc.
Cytoplasmic melanoma‐associated antigen (CYT‐MAA) serum level in patients with melanoma: A potential marker of response to immunotherapy?
Authors: Reynolds Sandra R. , Vergilis Irene J. , Szarek Michael , Ferrone Soldano , Bystryn Jean‐Claude
Published: January 2006

Simple, noninvasive methods are needed to follow effectiveness of new treatments in patients with melanoma. In our study, we examined cytoplasmic melanoma‐associated antigen (CYT‐MAA) serum level in melanoma patients during immunotherapy. Sera of 117 patients were assayed for CYT‐MAA by double‐sandwich ELISA before and during treatment with a polyvalent, shed antigen, melanoma vaccine. Vaccine‐treated patients included 30 with American Joint Committee on Cancer (AJCC) stage IIb or IIIa, 30 with stage IIc, IIIb or IIIc, 30 with resected stage IV and 27 with measurable stage IV disease. Prior to vaccine therapy, 63% of patients had elevated serum CYT‐MAA with high levels of antigen in all disease stages. After initiation of therapy, the level declined in more than 90% of the positive patients and fell below the positive cut‐off in 56% of these patients within 5 months. By contrast, there was no decline in CYT‐MAA serum level in 11 patients who served as untreated controls with melanoma. Multivariate analysis of the treated patients using accelerated failure time Weibull models adjusted for stage and age showed that patients whose CYT‐MAA serum level remained elevated during treatment were ∼3 times more likely to recur or progress than patients who were consistently below the positive cut‐off (hazard ratio = 3.42, 95% CI [1.38, 8.47], p = 0.0079). Measurement of CYT‐MAA serum level appears to show potential as an early marker of prognosis in patients with stages IIb to IV melanoma. Measurement of CYT‐MAA serum level during therapy could provide an intermediate marker of response in these patients. © 2006 Wiley‐Liss, Inc.
SAHA‐sensitized prostate cancer cells to TNFα‐related apoptosis‐inducing ligand (TRAIL): Mechanisms leading to synergistic apoptosis
Authors: Lakshmikanthan Vijayabaskar , Kaddour‐Djebbar Ismail , Lewis Ronald W. , Kumar M. Vijay
Published: January 2006

Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNFα‐Related Apoptosis‐Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined with even with the lowest dose SAHA. Treatment with caspase inhibitor confirmed that SAHA‐induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKKα, IKKβ and IKKγ, suggesting that SAHA treatment may reduce the activity of NFκB. However, assay for NFκB luciferase reporter activity showed highly significant increase in SAHA‐treated cells, supporting earlier suggestions that HDACi promotes NFκB transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NFκB activity at several regulatory steps. © 2006 Wiley‐Liss, Inc.
Optical diagnosis of cervical cancer by fluorescence spectroscopy technique
Authors: Chidananda Siddappa M. , Satyamoorthy Kapaettu , Rai Lavanya , Manjunath Attibele P. , Kartha Vasudevan B.
Published: January 2006

In the present work, we examine normal and malignant stage IIIB cervical tissue by laser induced fluorescence, with 2 different objectives. (i) Development of the fluorescence spectroscopy technique as a standard optical method for discrimination of normal and malignant tissue samples and, (ii) Optimization of the technique by the method of matching of a sample spectrum with calibration sets of spectra of pathologically certified samples. Laser‐induced fluorescence spectra were measured using samples from 62 subjects at different excitation wavelengths. Principal component analysis (PCA) of spectra and intensity ratios of curve‐resolved fluorescence peaks were tested for discrimination. It was found that PCA of total fluorescence at 325 nm excitation gives specificity and sensitivity over 95%. Use of calibration sets of spectra of histo‐pathologically certified samples combined with PCA for matching and pass/fail classification of test samples is shown to have high sensitivity/specificity for routine diagnostic purposes as well as for possible staging of the disease. Further, the multi‐component origin of the fluorescence spectra is illustrated by curve resolution and fluorescence spectra of separated proteins of tissue homogenates. © 2006 Wiley‐Liss, Inc.
Truncated APC is required for cell proliferation and DNA replication
Authors: Schneikert Jean , Behrens Jürgen
Published: January 2006

The tumour suppressor APC is truncated in most colon cancers, which leads to the stabilization of β‐catenin and to the constitutive activation of Wnt signalling. However, it is not clear why colon cancer cells retain the truncated APC fragment. Here, we show that a decrease of APC levels achieved by RNA interference impairs cell proliferation and DNA replication, not only in 293 cells that express a wild‐type protein, but also in SW480 colon cancer cells that express exclusively a truncated APC fragment. This correlates with a reduction of the levels of cyclin A, cyclin A‐dependent kinase activity, p27kip1 and the catalytic subunit of DNA polymerase δ. Thus, our data suggest that colon cancer cells retain a truncated APC fragment because it is essential for cell proliferation. © 2006 Wiley‐Liss, Inc.
Nocardia tartaricans cells immobilized in sodium alginate–cellulose sulfate–poly (methylene‐co‐guanidine)capsules: mechanical resistance and operational stability
Authors: Bučko Marek , Vikartovská Alica , Gemeiner Peter , Lacík Igor , Kolláriková Gabriela , Marison Ian W
Published: January 2006

The stereospecific hydrolysis of cis‐epoxysuccinate (CES) to L‐(+)‐tartrate, catalysed by the action of CES hydrolase activity in whole Nocardia tartaricans bacterial cells, has been chosen as a model biotransformation system. The performance of cells was studied by immobilization in polyelectrolyte complex (sodium alginate–cellulose sulfate–poly(methylene‐co‐guanidine, SA–CS/PMCG) capsules based on sodium alginate and cellulose sulfate as polyanions, poly(methylene‐co‐guanidine) as polycation, CaCl2 as gelling agent and NaCl as antigelling agent. The encapsulated cells showed a preservation of 80% of the initial catalytic activity in encapsulated cells compared with 15% of retained catalytic activity in free cells after 10 repeated biotransformation cycles. Uniformity of batches of capsules was achieved by the use of an air‐stripping extrusion device fitted with a multiloop reactor. The capsules produced using this device had narrow standard deviations for capsule diameter (<3%) and membrane thickness (<6%). Monodisperse capsules are essential to ensure constant properties, including mechanical resistance and diffusional characteristics. Storage of capsules under different conditions revealed an approximate three‐fold decrease in bursting force after long‐term exposure to the highly sequestering CES, compared with capsules stored in 0.9% (w/v) NaCl. The molecular weight cut‐off of the capsular membrane, determined by inverse size exclusion chromatography, is in the range of the size of CES hydrolase. Copyright © 2006 Society of Chemical Industry
Quantitative myocardial infarction on delayed enhancement MRI. Part I: Animal validation of an automated feature analysis and combined thresholding infarct sizing algorithm
Authors: Hsu Li‐Yueh , Natanzon Alex , Kellman Peter , Hirsch Glenn A. , Aletras Anthony H. , Arai Andrew E.
Published: January 2006

Purpose

To develop a computer algorithm to measure myocardial infarct size in gadolinium‐enhanced magnetic resonance (MR) imaging and to validate this method using a canine histopathological reference.

Materials and Methods

Delayed enhancement MR was performed in 11 dogs with myocardial infarction (MI) determined by triphenyltetrazolium chloride (TTC). Infarct size on in vivo and ex vivo images was measured by a computer algorithm based on automated feature analysis and combined thresholding (FACT). For comparison, infarct size by human manual contouring and simple intensity thresholding (based on two standard deviation [2SD] and full width at half maximum [FWHM]) were studied.

Results

Both in vivo and ex vivo MR infarct size measured by the FACT algorithm correlated well with TTC (R = 0.95–0.97) and showed no significant bias on Bland Altman analysis (P = not significant). Despite similar correlations (R = 0.91–0.97), human manual contouring overestimated in vivo MR infarct size by 5.4% of the left ventricular (LV) area (equivalent to 55.1% of the MI area) vs. TTC (P < 0.001). Infarct size measured by simple intensity thresholdings was less accurate than the proposed algorithm (P < 0.001 and P = 0.007).

Conclusion

The FACT algorithm accurately measured MI size on delayed enhancement MR imaging in vivo and ex vivo. The FACT algorithm was also more accurate than human manual contouring and simple intensity thresholding approaches. J. Magn. Reson. Imaging 2006. Published 2006 Wiley‐Liss, Inc.
HOXD10 M319K mutation in a family with isolated congenital vertical talus
Authors: Dobbs Matthew B. , Gurnett Christina A. , Pierce Brandon , Exner G. Ulrich , Robarge Jason , Morcuende Jose A. , Cole William G. , Templeton Peter A. , Foster Bruce , Bowcock Anne M.
Published: January 2006

Congenital vertical talus (CVT) is a primary dislocation of the talonavicular joint that often occurs in neuromusculoskeletal syndromes, but may also be seen as an isolated abnormality. Six families with isolated CVT were ascertained. DNA was isolated from 21 affected individuals and 17 unaffected individuals from these families, as well as from five sporadic patients with CVT. Variable expressivity was noted in three families, manifesting as clubfoot in three individuals. Genome‐wide linkage analysis generated a maximum two‐point logarithm of odds score on chromosome 2q with D2S1353 (Zmax = 1.43 at θmax = 0.1), 17 Mb from the HOXD gene cluster. DNA from one affected individual of each family was subjected to mutational analysis of the HOXD10 gene. A single missense mutation was identified (M319K, 956T > A) in the homeodomain recognition helix of the HOXD10 gene that segregated with disease in one large British family. This mutation was recently described in a family of Italian descent with CVT and Charcot‐Marie‐Tooth deformity HOXD10 gene mutations were not identified in any of the other families or sporadic patients with CVT, suggesting that genetic heterogeneity underlies this disorder. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:448–453, 2006
Particulate endocytosis mediates biological responses of human mesenchymal stem cells to titanium wear debris
Authors: Okafor Chukwuka C. , Haleem‐Smith Hana , Laqueriere Patrice , Manner Paul A. , Tuan Rocky S.
Published: January 2006

Continual loading and articulation cycles undergone by metallic (e.g., titanium) alloy arthroplasty prostheses lead to liberation of a large number of metallic debris particulates, which have long been implicated as a primary cause of periprosthetic osteolysis and postarthroplasty aseptic implant loosening. Long‐term stability of total joint replacement prostheses relies on proper integration between implant biomaterial and osseous tissue, and factors that interfere with this integration are likely to cause osteolysis. Because multipotent mesenchymal stem cells (MSCs) located adjacent to the implant have an osteoprogenitor function and are critical contributors to osseous tissue integrity, when their functions or activities are compromised, osteolysis will most likely occur. To date, it is not certain or sufficiently confirmed whether MSCs endocytose titanium particles, and if so, whether particulate endocytosis has any effect on cellular responses to wear debris. This study seeks to clarify the phenomenon of titanium endocytosis by human MSCs (hMSCs), and investigates the influence of endocytosis on their activities. hMSCs incubated with commercially pure titanium particles exhibited internalized particles, as observed by scanning electron microscopy and confocal laser scanning microscopy, with time‐dependent reduction in the number of extracellular particles. Particulate endocytosis was associated with reduced rates of cellular proliferation and cell–substrate adhesion, suppressed osteogenic differentiation, and increased rate of apoptosis. These cellular effects of exposure to titanium particles were reduced when endocytosis was inhibited by treatment with cytochalasin D, and no significant effect was seen when hMSCs were treated only with conditioned medium obtained from particulate‐treated cells. These findings strongly suggest that the biological responses of hMSCs to wear debris are triggered primarily by the direct endocytosis of titanium particulates, and not mediated by secreted soluble factors. In this manner, therapeutical approaches that suppress particle endocytosis could reduce the bioreactivity of hMSCs to particulates, and enhance long‐term orthopedic implant prognosis by minimizing wear‐debris periprosthethic osteolysis. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:461–473, 2006
Nitrogen metabolism in flag leaf and grain of wheat in response to irrigation regimes
Authors: Xu Zhen‐Zhu , Yu Zhen‐Wen
Published: January 2006

Although scarcity of irrigation water is one of the key limiting factors for wheat production in many regions of the world, by using partial irrigation at strategic times during the growing season, it might be possible to enhance productivity. We measured the changes in various parameters related to nitrogen (N) metabolism in flag leaf and grain of wheat (Triticum aestivum L.) plants (cv. Jinan 17 and Lumai 21), which were subjected to five irrigation regimes until physiological maturity. Severely deficient or excessive irrigation during grain filling decreased the photosynthetic rate (A), the concentrations of N, free amino acid, and soluble protein, as well as the activities of nitrate reductase (NR) and glutamine synthetase (GS) and increased malondialdehyde (MDA) accumulation and endopeptidase (EP) activity, though grain protein concentration might mainly depend on genotype. The activities of NR and GS were significantly positively correlated with A, but those of EP were significantly negatively correlated with A. The results indicate that while severe water stress aggravates the adverse effect on nitrogen metabolism, excessive soil moisture is also not useful during the grain‐filling stage, resulting in lower grain yield and quality. Our results suggest that applying an optimal irrigation regime in wheat fields still plays an important role in the improvement of grain yield and quality.