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Single-molecule genomicsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The term 'single-molecule genomics' (SMG) describes a group of molecular methods in which single molecules are detected or sequenced. The focus on the analysis of individual molecules distinguishes these techniques from more traditional methods, in which template DNA is cloned or PCR-amplified prior to analysis. Although technically challenging, the analysis of single molecules has the potential to play a major role in the delivery of truly personalized medicine. The two main subgroups of SMG methods are single-molecule digital PCR and single-molecule sequencing. Single-molecule PCR has a number of advantages over competin...
Source: The Journal of Pathology - November 20, 2009 Category: Pathology Authors: Frank McCaughan, Paul H Dear Source Type: journals

The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decadeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In the last decade, the development of microarrays and the ability to perform massively parallel gene expression analysis of human tumours were received with great excitement by the scientific community. The promise of microarrays was of apocalyptic dimensions, with some experts envisaging that it would be a matter of a few years for this technology to replace traditional clinicopathological markers in clinical practice and treatment decision-making. The replacement of histopathology by high-tech and more objective approaches to cancer diagnosis, prognostication and prediction was, at that time, a foregone conclusion. Ten ...
Source: The Journal of Pathology - November 19, 2009 Category: Pathology Authors: Britta Weigelt, Frederick L Baehner, Jorge S Reis-Filho Source Type: journals

The role of nuclear organization in cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The functional significance of changes in nuclear structure and organization in transformed cells remains one of the most enigmatic questions in cancer biology. In this review, we discuss relationships between nuclear organization and transcription in terms of the three-dimensional arrangement of genes in the interphase cancer nucleus and the regulatory functions of nuclear matrix proteins. We also analyse the role of nuclear topology in the generation of gene fusions. We speculate that this type of multi-layered analysis will one day provide a framework for a more comprehensive understanding of the genetic origins of canc...
Source: The Journal of Pathology - November 19, 2009 Category: Pathology Authors: Elliott Lever, Denise Sheer Source Type: journals

General lessons from large-scale studies to identify human cancer predisposition genesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
There are now about 100 genes known to cause Mendelian inherited cancer syndromes, but these only explain a minor part of the familial clustering of the common cancers. The increased familial relative risk of cancer in the general population must largely involve genes of low- or moderate-penetrance. Until recently, attempts to identify cancer predisposition genes with low penetrance had proved similarly unrewarding. However, in the past 2 years, developments in this area have been rapid. In particular, the 'common disease-common variant' model of predisposition has come to the fore. In this model, alleles of high frequency...
Source: The Journal of Pathology - November 19, 2009 Category: Pathology Authors: Jean-Baptiste Cazier, Ian Tomlinson Source Type: journals

Network-based drugs and biomarkersEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The structure and dynamics of protein signalling networks governs cell decision processes and the formation of tissue boundaries. Complex diseases such as cancer and diabetes are diseases of such networks. Therefore approaches that can give insight into how these networks change during disease progression are crucial for better understanding, detection and intervention. The era of network medicine has begun; however, there are fundamental principles associated with molecular networks that are essential to consider for this field to succeed. Here, we introduce network biology and some of its associated technologies. We then...
Source: The Journal of Pathology - November 18, 2009 Category: Pathology Authors: Janine T Erler, Rune Linding Source Type: journals

Fusion genes and chromosome translocations in the common epithelial cancersEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
It has been known for 25 years that fusion genes play a central role in leukaemias and sarcomas but they have been neglected in the common carcinomas, largely because of technical limitations of cytogenetics. In the last few years it has emerged that gene fusions, caused by chromosome translocations, inversions, deletions, etc., are important in the common epithelial cancers, such as prostate and lung carcinoma. Most prostate cancers, for example, have an androgen-regulated fusion of one of the ETS transcription factor gene family. Early results of genome-wide searches for gene fusions in breast and other epithelial cancer...
Source: The Journal of Pathology - November 17, 2009 Category: Pathology Authors: Paul AW Edwards Source Type: journals

Does massively parallel DNA resequencing signify the end of histopathology as we know it?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present an overview of the techniques involved and review early results from the resequencing of cancer genomes. The possible impacts of whole-genome and trancriptome resequencing in clinical cancer research and the practice of pathology are discussed. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)
Source: The Journal of Pathology - November 17, 2009 Category: Pathology Authors: Samuel AJR Aparicio, David G Huntsman Source Type: journals

The genetics of cardiovascular disease: new insights from emerging approachesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The prospect that sequencing the human genome would see rapid translation of a greater understanding of cardiovascular genetics into novel diagnostics and therapeutics has so far met with only limited success. However, diverse technological advances and exploitation of novel animal models of cardiovascular development and disease are providing ever more insight into cardiovascular diseases and development, and bring closer the prospect of 'post-genomic' diagnostics and therapies. Here we review some of these emerging approaches (genome wide association studies, deep sequencing, microRNA regulation, and zebrafish as a model...
Source: The Journal of Pathology - November 17, 2009 Category: Pathology Authors: Timothy JA Chico, Marta Milo, David C Crossman Source Type: journals

Massively regulated genes: the example of TP53Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Intensive study of the TP53 gene over the last three decades has revealed a highly complex network of factors that regulate its performance. The gene has several promoters, alternative splicing occurs and there are alternative translation initiation sites. Up to 10 p53 isoforms have been identified. At the post-translational level, p53 activity depends on its quantity in the cell and on qualitative changes in its structure, intracellular localization, DNA-binding activity and interactions with other proteins. Both accumulation and activation are regulated by an intricate pattern of post-translational modifications, includi...
Source: The Journal of Pathology - November 14, 2009 Category: Pathology Authors: Monica Hollstein, Pierre Hainaut Source Type: journals

Genetics and development of neural tube defectsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Congenital defects of neural tube closure (neural tube defects; NTDs) are among the commonest and most severe disorders of the fetus and newborn. Disturbance of any of the sequential events of embryonic neurulation produce NTDs, with the phenotype (eg anencephaly, spina bifida) varying depending on the region of neural tube that remains open. While mutation of > 200 genes is known to cause NTDs in mice, the pattern of occurrence in humans suggests a multifactorial polygenic or oligogenic aetiology. This emphasizes the importance of gene-gene and gene-environment interactions in the origins of these defects. A number of cel...
Source: The Journal of Pathology - November 13, 2009 Category: Pathology Authors: Andrew J Copp, Nicholas DE Greene Source Type: journals

Our changing view of the genomic landscape of cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Sporadic tumours, which account for the majority of all human cancers, arise from the acquisition of somatic, genetic and epigenetic alterations leading to changes in gene sequence, structure, copy number and expression. Within the last decade, the availability of a complete sequence-based map of the human genome, coupled with significant technological advances, has revolutionized the search for somatic alterations in tumour genomes. Recent landmark studies, which resequenced all coding exons within breast, colorectal, brain and pancreatic cancers, have shed new light on the genomic landscape of cancer. Within a given tumo...
Source: The Journal of Pathology - November 13, 2009 Category: Pathology Authors: Daphne W Bell Source Type: journals

The pathobiology of splicingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ninety-four percent of human genes are discontinuous, such that segments expressed as mRNA are contained within exons and separated by intervening segments, called introns. Following transcription, genes are expressed as precursor mRNAs (pre-mRNAs), which are spliced co-transcriptionally, and the flanking exons are joined together to form a continuous mRNA. One advantage of this architecture is that it allows alternative splicing by differential use of exons to generate multiple mRNAs from individual genes. Regulatory elements located within introns and exons guide the splicing complex, the spliceosome, and auxiliary RNA b...
Source: The Journal of Pathology - November 13, 2009 Category: Pathology Authors: Amanda J Ward, Thomas A Cooper Source Type: journals

Prognostic relevance of DNA copy number changes in colorectal cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In a study of 109 colorectal cancers, DNA copy number aberrations were identified by comparative genomic hybridization using a DNA microarray covering the entire genome at an average interval of less than 1 Mbase. Four patterns were revealed by unsupervised clustering analysis, one of them associated with significantly better prognosis than the others. This group contained tumours with short, dispersed, and relatively few regions of copy number gain or loss. The good prognosis of this group was not attributable to the presence of tumours showing microsatellite instability (MSI-H). Supervised methods were employed to determ...
Source: The Journal of Pathology - November 13, 2009 Category: Pathology Authors: George Poulogiannis, Koichi Ichimura, Rifat A Hamoudi, Feijun Luo, Suet Y Leung, Siu T Yuen, David J Harrison, Andrew H Wyllie, Mark J Arends Source Type: journals

Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumoursEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Malignant peripheral nerve sheath tumours (MPNSTs) are aggressive soft tissue tumours that occur either sporadically or in patients with neurofibromatosis type 1. The malignant transformation of the benign neurofibroma to MPNST is incompletely understood at the molecular level. We have determined the gene expression signature for benign and malignant PNSTs and found that the major trend in malignant transformation from neurofibroma to MPNST consists of the loss of expression of a large number of genes, rather than widespread increase in gene expression. Relatively few genes are expressed at higher levels in MPNSTs and thes...
Source: The Journal of Pathology - November 4, 2009 Category: Pathology Authors: Subbaya Subramanian, Venugopal Thayanithy, Robert B West, Cheng-Han Lee, Andrew H Beck, Shirley Zhu, Erinn Downs-Kelly, Kelli Montgomery, John R Goldblum, Pancras CW Hogendoorn, Christopher L Corless, Andre M Oliveira, Sarah M Dry, Torsten O Nielsen, Bria Source Type: journals

Genomic instability and the selection of treatments for cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A critical link exists between DNA mutation and chromosomal rearrangements (genomic instability) and cancer development. This genomic instability can manifest itself as small changes at the nucleotide level or as gross chromosomal alterations. Mutations in the genes that encode DNA damage response proteins are responsible for a variety of genomic instability syndromes including hereditary non-polyposis colorectal carcinoma, Bloom's syndrome, ataxia-telangiectasia, BRCA-associated breast and ovarian cancers and Fanconi anaemia. Similarly, epigenetic silencing of genes associated with the maintenance of genomic stability hav...
Source: The Journal of Pathology - November 3, 2009 Category: Pathology Authors: Sarah A Martin, Madeleine Hewish, Christopher J Lord, Alan Ashworth Source Type: journals

Wnts, bone and cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Wnt pathway plays vital roles in bone and in cancer. In this issue of The Journal of Pathology, Cai and colleagues report results that suggest that the Wnt pathway is inactivated in bone cancers, a finding that could have significant implications for the development of Wnt agonists as bone anabolic agents. While these findings are at odds with the prevailing view that the Wnt pathway is oncogenic in all systems studied to date, they remind us how complex and still poorly understood this important signalling pathway remains. At the very least, these findings should provoke debate and stimulate further research into the ...
Source: The Journal of Pathology - November 3, 2009 Category: Pathology Authors: David M Thomas Source Type: journals

Unravelling the genetic basis of renal diseases; from single gene to multifactorial disordersEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chronic kidney disease is common with up to 5% of the adult population reported to have an estimated glomerular filtration rate of < 60 ml/min/1.73 m2. A large number of pathogenic mutations have been identified that are responsible for 'single gene' renal disorders, such as autosomal dominant polycystic kidney disease and X-linked Alport syndrome. These single gene disorders account for < 15% of the burden of end-stage renal disease that requires dialysis or kidney transplantation. It has proved more difficult to identify the genetic susceptibility underlying common, complex, multifactorial kidney conditions, such as diab...
Source: The Journal of Pathology - October 31, 2009 Category: Pathology Authors: Amy J McKnight, Diane Currie, Alexander P Maxwell Source Type: journals

Non-coding RNAs: regulators of diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
For 50 years the term 'gene' has been synonymous with regions of the genome encoding mRNAs that are translated into protein. However, recent genome-wide studies have shown that the human genome is pervasively transcribed and produces many thousands of regulatory non-protein-coding RNAs (ncRNAs), including microRNAs, small interfering RNAs, PIWI-interacting RNAs and various classes of long ncRNAs. It is now clear that these RNAs fulfil critical roles as transcriptional and post-transcriptional regulators and as guides of chromatin-modifying complexes. Here we review the biology of ncRNAs, focusing on the fundamental mechani...
Source: The Journal of Pathology - October 30, 2009 Category: Pathology Authors: Ryan J Taft, Ken C Pang, Timothy R Mercer, Marcel Dinger, John S Mattick Source Type: journals

The molecular underpinning of lobular histological growth pattern: a genome-wide transcriptomic analysis of invasive lobular carcinomas and grade- and molecular subtype-matched invasive ductal carcinomas of no special typeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Invasive lobular carcinoma (ILC) is the most frequent special type of breast cancer. The majority of these tumours are of low histological grade, express hormone receptors, and lack HER2 expression. The pleomorphic variant of ILCs (PLCs) is characterized by atypical cells with pleomorphic nuclei and is reported to have an aggressive clinical behaviour. Expression profiling studies have demonstrated that classic ILCs preferentially display a luminal phenotype, whereas PLCs may be of luminal, HER2 or molecular apocrine subtypes. The aims of this study were two-fold: to determine the transcriptomic characteristics of lobular ...
Source: The Journal of Pathology - October 30, 2009 Category: Pathology Authors: Britta Weigelt, Felipe C Geyer, Rachael Natrajan, Maria A Lopez-Garcia, Amar S Ahmad, Kay Savage, Bas Kreike, Jorge S Reis-Filho Source Type: journals

A tissue reconstitution model to study cancer cell-intrinsic and -extrinsic factors in mammary tumourigenesisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The contribution of cancer cell-intrinsic and -extrinsic factors to metastatic breast cancer is still poorly understood, hampering development of novel therapeutic strategies that decrease breast cancer mortality. Cre/loxP-based conditional mouse models of breast cancer present unique opportunities to study sporadic tumour formation and progression in a controlled setting. Unfortunately, the generation of mouse strains carrying multiple mutant alleles needed for such studies is very time-consuming. Moreover, conditional mouse tumour models do not permit independent manipulation of tumour cell-intrinsic and -extrinsic facto...
Source: The Journal of Pathology - October 23, 2009 Category: Pathology Authors: Bastiaan Evers, Ewoud N Speksnijder, Eva Schut, Metamia Ciampricotti, Matthew J Smalley, Patrick WB Derksen, Jos Jonkers, Karin E de Visser Source Type: journals

The Journal of Pathology 2008 Jeremy Jass Prize for Research Excellence in PathologyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The first Jass Prize for Research Excellence has been awarded to a group from Hannover in Germany. These authors discovered the epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer and characterized its biological and clinical relevance. This frequent epigenetic silencing was found to occur early in the development of breast cancer, and illustrates another mechanism by which tumour development is influenced by genes that operate without expression as proteins. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)
Source: The Journal of Pathology - October 22, 2009 Category: Pathology Authors: Peter A Hall, Richard Poulsom, Philip J Coates, Ming-Qing Du, Pancras CW Hogendoorn, Louise J Jones, Marc Ladanyi, Graeme I Murray, Gerald Niedobitek Source Type: journals

Seladin-1 and testicular germ cell tumours: new insights into cisplatin responsivenessEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, we have demonstrated for the first time an important role for seladin-1 in the biology of TGCTs and provided new insights into cisplatin responsiveness of these tumours. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)
Source: The Journal of Pathology - October 19, 2009 Category: Pathology Authors: Francesca Nuti, Paola Luciani, Eliana Marinari, Edit Erdei, Mihaly Bak, Cristiana Deledda, Fabiana Rosati, Benedetta Mazzinghi, Giovanna Danza, Hans Stoop, Leendert HJ Looijenga, Alessandro Peri, Mario Serio, Csilla Krausz Source Type: journals

The Li-Fraumeni syndrome (LFS): a model for the initiation of p53 signatures in the distal Fallopian tubeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We examined tubes from women with pre-existing (germ-line) mutations in p53 [Li-Fraumeni syndrome (LFS)] for evidence of this precursor. Fallopian tubes from two cases of LFS were immunostained for p53, Ki-67 (proliferation) and H2AX (DNA damage response) and analysed for p53 mutations by laser capture microdissection (LCM) and p53 genomic sequencing (exons 2-11). A common single nucleotide repeat (snp) in exon 3 (rs1042522) and deletion sequencing chromatograms in exon 4 were examined in combination to estimate LOH in both LFS tubes and advanced serous carcinomas from the general population. LFS tubal epithelium contained...
Source: The Journal of Pathology - October 15, 2009 Category: Pathology Authors: Wa Xian, Alexander Miron, Michael Roh, Dana R Semmel, Yosuf Yassin, Judy Garber, Esther Oliva, Annekathryn Goodman, Karishma Mehra, Ross S Berkowitz, Christopher P Crum, Bradley J Quade Source Type: journals

Dysregulation of protein synthesis and diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The regulation of protein synthesis plays as important a role as transcriptional control in the control of gene expression. Once thought solely to act globally, translational control has now been shown to be able to control the expression of most genes specifically. Dysregulation of this process is associated with a range of pathological conditions, notably cancer and several neurological disorders, and can occur in many ways. These include alterations in the expression of canonical initiation factors, mutations in regulatory mRNA sequence elements in 5[prime] and 3[prime] untranslated regions (UTRs), such as upstream open...
Source: The Journal of Pathology - October 13, 2009 Category: Pathology Authors: John PC Le Quesne, Keith A Spriggs, Martin Bushell, Anne E Willis Source Type: journals

Dominance and gene dosage balance in health and disease: why levels matter!Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The classical concept of genetic dominance is a simplification of a more quantitative reality. This is clearly exemplified by aneuploid syndromes, of which the best known case is trisomy 21. Moreover, there is an increasing number of clinical conditions due to reduced dosage (haploinsufficiency) of genes encoding transcription factors and other proteins involved in signal transduction and macromolecular complexes. In such genetic diseases, a high degree of phenotypic variability is observed, which calls for an explanation. The sources of dominance are heterogeneous and difficult to cover in a brief review. Here, we will fo...
Source: The Journal of Pathology - October 12, 2009 Category: Pathology Authors: Reiner A. Veitia, James A. Birchler Source Type: journals

How does The Journal of Pathology deal with conflict of interest?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Here we outline the approach of The Journal of Pathology to the issue of conflict of interest. We aspire to have a fair and transparent review process where conflict of interest or prejudice does not influence the review and decision-making process, such that readers can be confident of the objectivity of peer-review and reliability of content. Transparency and openness from all involved is the cornerstone of this and our processes are intended to prevent, as far as is possible, financial, personal, intellectual, professional, political, religious, racial, gender-related or other conflicts of interest affecting our peer-re...
Source: The Journal of Pathology - October 12, 2009 Category: Pathology Authors: Peter A Hall, Richard Poulsom, Jo Wixon Source Type: journals

Impact of VEGF-dependent tumour micro-environment on EDB fibronectin expression by subcutaneous human tumour xenografts in nude miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Fibronectin (FN) is an extracellular matrix cell-adhesive glycoprotein. The alternative spliced isoform EDB-FN (extra domain B containing FN) is highly expressed in tumour blood vessels and stroma and represents a candidate for tumour targeting. To investigate the impact of different angiogenic micro-environments on EDB-FN expression, we used a tumour model in which human endometrial adenocarcinoma Tet-FGF2 cells overexpressing fibroblast growth factor-2 (FGF2) driven by the tetracycline-responsive promoter were further transfected with a VEGF antisense cDNA, generating AS-VEGF/Tet-FGF2 cells. In this model, the expression...
Source: The Journal of Pathology - October 12, 2009 Category: Pathology Authors: Daniela Coltrini, Roberto Ronca, Mirella Belleri, Luciano Zardi, Stefano Indraccolo, Valentina Scarlato, Raffaella Giavazzi, Marco Presta Source Type: journals

Reduced CRYL1 expression in hepatocellular carcinoma confers cell growth advantages and correlates with adverse patient prognosisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Homozygous deletion screening has been widely utilized to define tumour suppressor genes (TSGs) in cancers. Although these biallelic deletions are infrequent, their identification has facilitated the discovery of many important TSGs. We have systematically examined the genome of hepatocellular carcinoma (HCC), a highly malignant tumour that is rapidly fatal, for the presence of homozygous deletions. Array-CGH analysis on early passage of HCC cultures and cell lines led us to identify six homozygous deleted (HD) regions. A high concordance between array-CGH and expression of HD genes was demonstrated, where crystallin Lambd...
Source: The Journal of Pathology - October 12, 2009 Category: Pathology Authors: Ibis K-C Cheng, Arthur K-K Ching, Tsz-Choi Chan, Anthony W-H Chan, Chun-Kwok Wong, Kwong-Wai Choy, Man Kwan, Paul B-S Lai, Nathalie Wong Source Type: journals

Kidney injury molecule-1 in renal diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Kidney injury molecule-1 (KIM-1) is a marker for renal proximal tubular damage, the hallmark of virtually all proteinuric, toxic and ischaemic kidney diseases. KIM-1 has gained increasing interest because of its possible pathophysiological role in modulating tubular damage and repair. In this respect, it is interesting that the best biomarkers often turn out to be important in modulation of damage and some even become therapeutic targets. The emphasis of this review is on structural and biochemical aspects of KIM-1, its expression pattern and its pathophysiological role in renal disease. We also discuss the prognostic impa...
Source: The Journal of Pathology - October 9, 2009 Category: Pathology Authors: Femke Waanders, Mirjan M van Timmeren, Coen A Stegeman, Stephan JL Bakker, Harry van Goor Source Type: journals

PAX5 activates the transcription of the human telomerase reverse transcriptase gene in B cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA. Its activity is not detectable in most somatic cells but it is reactivated during tumorigenesis. In most cancers, the combination of hTERT hypermethylation and hypomethylation of a short promoter region is permissive for low-level hTERT transcription. Activated and malignant lymphocytes express high telomerase activity, through a mechanism that seems methylation-independent. The aim of this study was to determine which mechanism is involved in the enhanced expression of hTERT in lymphoid cells. Our data confirm that in B cells, some T cell lympho...
Source: The Journal of Pathology - October 5, 2009 Category: Pathology Authors: Stéphanie Bougel, Stéphanie Renaud, Richard Braunschweig, Dmitri Loukinov, Herbert C Morse III, Fred T. Bosman, Victor Lobanenkov, Jean Benhattar Source Type: journals

Chain reaction of amyloid fibril formation with induction of basement membrane in familial amyloidotic polyneuropathyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Familial amyloidotic polyneuropathy (FAP) is characterized by extracellular deposition of amyloid fibrils caused by a point mutation in the transthyretin (TTR) gene. Despite data from a number of in vitro studies of TTR amyloidogenesis, many questions, including where and how these fibrils form in vivo and what is the impact of amyloid deposition on tissues, remain unanswered. Here, we analysed the relationship between amyloid fibril formation and micro-environmental changes by using autopsy cardiac tissues from 11 patients with FAP and a smooth muscle cell line. Ultrastructural studies of cardiomyocytes and vascular smoot...
Source: The Journal of Pathology - September 30, 2009 Category: Pathology Authors: Yohei Misumi, Yukio Ando, Mitsuharu Ueda, Konen Obayashi, Hirofumi Jono, Yu Su, Taro Yamashita, Makoto Uchino Source Type: journals

The emerging role of the distal Fallopian tube and p53 in pelvic serous carcinogenesisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In their paper in this issue of the Journal, Xian et al have analysed in detail the Fallopian tubes from two patients with Li-Fraumeni syndrome (germline TP53 mutation) in order to investigate further the possible role of p53 signatures in the development of high-grade pelvic serous carcinoma. They find an increased frequency of p53 signatures, with associated evidence of DNA damage and loss of heterozygosity at the wild-type TP53 allele, but postulate, as Li-Fraumeni syndrome is not associated with an increased risk of pelvic serous carcinoma, that these events are not sufficient for the development of carcinoma. Rather, ...
Source: The Journal of Pathology - September 25, 2009 Category: Pathology Authors: C Simon Herrington, W Glenn McCluggage Source Type: journals

Inactive Wnt/[beta]-catenin pathway in conventional high-grade osteosarcomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Osteosarcoma is the most common malignant bone tumour, with a peak incidence in children and young adolescents, suggesting a role of rapid bone growth in its pathogenesis. The Wnt/[beta]-catenin pathway plays a crucial role in skeletal development and is indispensable for osteoblasts' lineage determination. Previous studies suggesting an oncogenic role for the Wnt/[beta]-catenin pathway in osteosarcoma were based on cytoplasmic staining of [beta]-catenin or the detection of one component of this pathway. However, those approaches are inappropriate to address whether the Wnt/[beta]-catenin pathway is functionally active. Th...
Source: The Journal of Pathology - September 24, 2009 Category: Pathology Authors: Yongping Cai, Alexander B Mohseny, Marcel Karperien, Pancras CW Hogendoorn, Gengyin Zhou, Anne-Marie Cleton-Jansen Source Type: journals

Fibril protein fragmentation pattern in systemic AL-amyloidosisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Immunoglobulin light chain (AL)-amyloidosis was one of the first types of amyloidosis discovered and still little is known about its pathogenic mechanisms. One major obstacle is the very heterogeneous condition; in fact, every patient could be considered to have their own disease since symptoms and outcome vary enormously. The reason for this is not known but intrinsic factors of the immunoglobulin light chain (LC) and the fact that every LC is unique seem to be important. Post-translational modifications such as glycosylation and proteolysis are most certainly involved. By using western blotting, we studied in detail the ...
Source: The Journal of Pathology - September 20, 2009 Category: Pathology Authors: Stina Enqvist, Knut Sletten, Per Westermark Source Type: journals

Increased expression and cellular localization of lipocalin-type prostaglandin D synthase in Helicobacter pylori-induced gastritisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Immunological responses in the host can result in different disease outcomes of Helicobacter pylori-induced gastritis. Prostaglandin E2 derived from cyclooxygenase (COX) and prostaglandin E synthase contribute to gastric protection. Recently, prostaglandin D2 was shown to be involved in host immunity by chemotactic activity through chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), but its role in H. pylori-induced gastritis has not been clarified. We determined the expression levels of mRNAs for haematopoietic PGD synthase (H-PGDS) and lipocalin-type PGDS (L-PGDS), MIP-1 alpha, IFN-gamma, IL-4, a...
Source: The Journal of Pathology - September 17, 2009 Category: Pathology Authors: Ryota Hokari, Nanae Nagata, Chie Kurihara, Chikako Watanabe, Shunsuke Komoto, Yoshikiyo Okada, Atsushi Kawaguchi, Shigeaki Nagao, Toshifumi Hibi, Kinya Nagata, Yoshihiro Urade, Soichiro Miura Source Type: journals

Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, 285 CRC cases were analysed for KRAS mutation by direct DNA sequencing followed by immunohistochemical analysis after validation with real-time PCR assay, to study the protein expression of KRAS4A and -4B isoforms. KRAS gene mutations were seen in 80/285 CRCs (28.1%) and of the mutated cases, the majority of the mutations were seen in codon 12 (81.2%) as opposed to codon 13 (18.8%). CRCs with KRAS mutations were associated with a poor overall survival (p = 0.0009). Furthermore, KRAS mutations at codon 12 were associated with a poor overall survival of 64.4% at 5 years compared with a 5-year overall survival ...
Source: The Journal of Pathology - September 16, 2009 Category: Pathology Authors: Jehad Abubaker, Prashant Bavi, Wael Al-Haqawi, Mehar Sultana, Sayer Al-Harbi, Nasser Al-Sanea, Alaa Abduljabbar, Luai H Ashari, Samar Alhomoud, Fouad Al-Dayel, Shahab Uddin, Khawla S Al-Kuraya Source Type: journals

Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Tumour metastasis is the result of a complex sequence of events, including migration of tumour cells through stroma, proteolytic degradation of stromal and vessel wall elements, intravasation, transport through the circulation, extravasation and outgrowth at compatible sites in the body (the 'seed and soil' hypothesis). However, the high incidence of metastasis from various tumour types in liver and lung may be explained by a stochastic process as well, based on the anatomical relationship of the primary tumour with the circulation and mechanical entrapment of metastatic tumour cells in capillary beds. We previously report...
Source: The Journal of Pathology - September 2, 2009 Category: Pathology Authors: Gursah Kats-Ugurlu, Ilse Roodink, Mirjam de Weijert, Dorien Tiemessen, Cathy Maass, Kiek Verrijp, Jeroen van der Laak, Rob de Waal, Peter Mulders, Egbert Oosterwijk, William Leenders Source Type: journals

Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
High-grade osteosarcoma is characterized by extensive genetic instability, thereby hampering the identification of causative gene mutations and understanding of the underlying pathological processes. It lacks a benign precursor lesion and reports on associations with hereditary predisposition or germline mutations are uncommon, despite the early age of onset. Here we demonstrate a novel comprehensive approach for the study of premalignant stages of osteosarcoma development in a murine mesenchymal stem cell (MSC) system that formed osteosarcomas upon grafting. By parallel functional and phenotypic analysis of normal MSCs, t...
Source: The Journal of Pathology - August 28, 2009 Category: Pathology Authors: Alexander B Mohseny, Karoly Szuhai, Salvatore Romeo, Emilie P Buddingh, Inge Briaire-de Bruijn, Daniëlle de Jong, Melissa van Pel, Anne-Marie Cleton-Jansen, Pancras CW Hogendoorn Source Type: journals

Recent progress in understanding the pathology of malignant melanomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Recently, several important findings on melanoma development and progression have accelerated progress towards a molecular understanding of melanoma biology. Furthermore, the development of experimental tools, such as a wide range of cell lines and animal models of metastasis, has turned melanoma into a model for general tumour research. However, it has also become evident that melanoma is distinct from other tumours with regard to its cellular origin and pathophysiological mechanisms. This review focuses on important new findings that have contributed to a greater understanding of the molecular processes leading to melano...
Source: The Journal of Pathology - August 24, 2009 Category: Pathology Authors: Silke Kuphal, Anja Bosserhoff Source Type: journals

Frequent PIK3CA gene amplification and its clinical significance in colorectal cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Using a DNA microarray approach to screen for gene copy number changes in 20 colorectal (CR) carcinoma samples and filtering for high-level DNA copy number changes, we detected an amplicon at 3q26 containing the PIK3CA gene. Fluorescence in situ hybridization was employed for evaluation of PIK3CA amplification on a progression CR tissue microarray containing 448 CR carcinomas, normal mucosa, and adenomas with follow-up information. PIK3CA amplification (ratio PIK3CA/centromere 3[ge]2.0) was found in 38% of cancers, while another 19% of tumours had PIK3CA gains (ratio >1.0 but (Source: The Journal of Pathology)
Source: The Journal of Pathology - August 20, 2009 Category: Pathology Authors: Zeenath Jehan, Prashant Bavi, Mehar Sultana, Jehad Abubaker, Rong Bu, Azhar Hussain, Ghazi Alsbeih, Nasser Al-Sanea, Alaa Abduljabbar, Luai H Ashari, Samar Alhomoud, Fouad Al-Dayel, Shahab Uddin, Khawla S Al-Kuraya Source Type: journals

Up-regulation of autophagy in small intestine Paneth cells in response to total-body [gamma]-irradiationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Macroautophagy (mAG) is a lysosomal mechanism of degradation of cell self-constituents damaged due to variety of stress factors, including ionizing irradiation. Activation of mAG requires expression of mAG protein Atg8 (LC3) and conversion of its form I (LC3-I) to form II (LC3-II), mediated by redox-sensitive Atg4 protease. We have demonstrated upregulation of this pathway in the innate host defense Paneth cells of the small intestine (SI) due to ionizing irradiation and correlation of this effect with induction of pro-oxidant inducible nitric oxide synthase (iNOS). CD2F1 mice were exposed to 9.25 Gy [gamma]-ionizing irrad...
Source: The Journal of Pathology - August 13, 2009 Category: Pathology Authors: Nikolai V. Gorbunov, Juliann G. Kiang Source Type: journals

Localization- and mutation-dependent microRNA (miRNA) expression signatures in gastrointestinal stromal tumours (GISTs), with a cluster of co-expressed miRNAs located at 14q32.31Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The molecular biology and clinical behaviour of gastrointestinal stromal tumours (GISTs) are associated with their anatomical localization (stomach or intestine), and also with the mutation status of the receptor tyrosine kinases KIT and PDGFRA. Twelve GISTs were evaluated for differential miRNA expression signatures by use of microarrays representing 734 human miRNAs. Thirty-two miRNAs were found to be differentially expressed according to localization and mutation status. Differential expression was further analysed and confirmed for four miRNAs (miR-132, miR-221, miR-222, and miR-504) by qRT-PCR in 49 additional GISTs. ...
Source: The Journal of Pathology - August 10, 2009 Category: Pathology Authors: Florian Haller, Anja von Heydebreck, Jitao David Zhang, Bastian Gunawan, Claus Langer, Giuliano Ramadori, Stefan Wiemann, Özgür Sahin Source Type: journals

Müller cell-derived VEGF is a significant contributor to retinal neovascularizationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Vascular endothelial growth factor (VEGF-A) is a major pathogenic factor and a therapeutic target for age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. Despite intensive effort in the field, the cellular mechanisms of VEGF action remain virtually uninvestigated. This situation makes it difficult to design cellular target-based therapeutics for these diseases. In light of the recent finding that VEGF is a potential neurotrophic factor, revealing the cellular mechanisms of VEGF action becomes necessary to preserve its beneficial effect and inhibit its pathological function in long-term a...
Source: The Journal of Pathology - August 10, 2009 Category: Pathology Authors: Yanyan Bai, Jian-xing Ma, Junjing Guo, Juanjuan Wang, Meili Zhu, Ying Chen, Yun-Zheng Le Source Type: journals

Cholinergic switch associated with morphological differentiation in neuroblastomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study included three undifferentiated (UN), 20 poorly differentiated (PDN) and 11 differentiating (DN) neuroblastomas. These groups could be clearly separated using unsupervised clustering methods, which further enabled a major classification impact of genes involved in neural development, differentiation and function to be identified. UNs are characterized by high ASCL1, high PHOX2B, low GATA2, low TH and low DBH expressions. Most PDNs harbour a clear adrenergic phenotype, even in the presence of missense PHOX2B mutations. Finally, all DN tumours demonstrate cholinergic features. Depending upon their association with...
Source: The Journal of Pathology - August 10, 2009 Category: Pathology Authors: Franck Bourdeaut, Isabelle Janoueix-Lerosey, Carlo Lucchesi, Régine Paris, Agnès Ribeiro, Loïc de Pontual, Jeanne Amiel, Stanislas Lyonnet, Gaëlle Pierron, Jean Michon, Michel Peuchmaur, Olivier Delattre Source Type: journals

New evidence for tumour embolism as a mode of metastasisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The demonstration that a significant proportion of patients with renal carcinomas of the clear cell type have tumour cell clumps or aggregates in venous outflow from the kidney has interest from two viewpoints. Firstly, the association of this occurrence with high VEGF-A production by the cancer seems to suggest a novel mode of 'budding' invasion where nests of tumour cells enter the dilated and mechanically fragile new vessels supplying the cancerous growth. Secondly, with the association of fragment occurrence and metastatic development, the entrance of clumps into the circulation indicates that epithelial-mesenchymal tr...
Source: The Journal of Pathology - August 10, 2009 Category: Pathology Authors: Ian R Hart Source Type: journals

The p53-mediated sensitivity of cancer cells to chemotherapeutic agents is conditioned by the status of the retinoblastoma proteinEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Despite the well-established function of p53 in determining cell cycle arrest and/or apoptosis in response to cytostatic/cytotoxic stresses, the role of the p53 status in the response to chemotherapeutic agents in human cancers has been not clearly defined. We wondered whether this was due to the fact that the p53-mediated response to chemotherapy drugs might be conditioned by the status of the retinoblastoma protein (pRb), a downstream factor of the pathway activated by p53 stabilization, which is frequently disrupted in cancer. The dependence of p53-mediated chemosensitivity on pRb status was first investigated in a pros...
Source: The Journal of Pathology - August 10, 2009 Category: Pathology Authors: Massimo Derenzini, Elisa Brighenti, Giulio Donati, Manuela Vici, Claudio Ceccarelli, Donatella Santini, Mario Taffurelli, Lorenzo Montanaro, Davide Treré Source Type: journals

Activated macrophages in the tumour microenvironment - dancing to the tune of TLR and NF-[kappa]BEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A large number of variables have been identified which appear to influence macrophage phenotype within the tumour microenvironment. These include reciprocal chemical and physical interactions with tumour cells and with non-malignant cells of the tumour microenvironment, tissue oxygen tension, and the origin and prior experience of the particular macrophage population. In this review we outline the key evidence for these influences and consider how macrophage phenotype is acquired and the relevance of the TLR-NF-[kappa]B pathway. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & ...
Source: The Journal of Pathology - August 6, 2009 Category: Pathology Authors: Simon Hallam, Monica Escorcio-Correia, Robin Soper, Anne Schultheiss, Thorsten Hagemann Source Type: journals

Identification of a novel 12p13.3 amplicon in nasopharyngeal carcinomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, multiple regions of gain were consistently found at 1q21-q24, 7q11-12, 7q21-22., 11q13, 12p13, 12q13, 19p13 and 19q13. Importantly, a 2.1 Mb region at 12p13.31 was highly amplified in a NPC xenograft, xeno-2117. By FISH mapping, we have further delineated the amplicon to a 1.24 region flanked by RP11-319E16 and RP11-433J6. Copy number gains of this amplicon were confirmed in 21/41 (51%) primary tumours, while three cases (7.3%) showed high copy number amplification. Among the 13 genes within this amplicon, three candidate genes, lymphotoxin beta receptor (LT[beta]R), tumour necrosis factor receptor superfami...
Source: The Journal of Pathology - August 3, 2009 Category: Pathology Authors: Yvonne Y-Y Or, Grace T-Y Chung, Ka-Fai To, Chit Chow, Kwong-Wai Choy, Carol Y-K Tong, Alice W-C Leung, Angela B-Y Hui, Sai-Wah Tsao, Ho-Keung Ng, Timothy T-C Yip, Pierre Busson, Kwok-Wai Lo Source Type: journals

RNA splicing factors regulated by HPV16 during cervical tumour progressionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The most prevalent human papillomaviruses (HPVs) causing cervical disease are the 'high-risk' HPV types 16 and 18. All papillomaviruses express a transcription factor, E2, that can regulate viral and cellular gene expression. Recently, we demonstrated high-risk HPV E2-mediated transcriptional transactivation of SF2/ASF. This essential oncoprotein is a key member of a family of proteins, the SR proteins, that regulate constitutive and alternative splicing. Tight control of RNA splicing is necessary for the production of wild-type proteins. So, aberrant expression of SR proteins is involved in the aetiology of a range of hum...
Source: The Journal of Pathology - August 3, 2009 Category: Pathology Authors: Sarah Mole, Melanie McFarlane, Thanaporn Chuen-Im, Steven G Milligan, David Millan, Sheila V Graham Source Type: journals

Characterization of LMX-1A as a metastasis suppressor in cervical cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we characterized the function of this transcription factor by examining cell lines, animal models and human cervical neoplastic tissues, and found that over-expression of LMX-1A does not affect cell proliferation or the cell cycle of cervical cancer cell lines but significantly inhibits colony formation and invasion in vitro. Analysis of changes in epithelial-mesenchymal transition (EMT) markers, such as CDH1, CDH2, VIMENTIN, SNAIL, SLUG and TWIST, revealed involvement of the EMT in LMX-1A-mediated cancer invasion; this result was validated in a stable transfectant over-expressing LMX-1A with RNA interferenc...
Source: The Journal of Pathology - July 30, 2009 Category: Pathology Authors: Chin-Yu Liu, Tai-Kuang Chao, Po-Hsuan Su, Hsin-Yi Lee, Yu-Lueng Shih, Her-Young Su, Tang-Yuan Chu, Mu-Hsien Yu, Ya-Wen Lin, Hung-Cheng Lai Source Type: journals