The Journal of Pathology via MedWorm.com

Interleukin-2 induces NF-[kappa]B activation through BCL10 and affects its subcellular localization in natural killer lymphoma cells

The Journal of Pathology — Tue, 16 Mar 2010 00:00:00 +0100

Deregulation of nuclear factor (NF)-[kappa]B signalling is common in cancers and is essential for tumourigenesis. Constitutive NF-[kappa]B activation in extranodal natural killer (NK)-cell lymphoma, nasal type (ENKL) is known to be associated with aberrant nuclear translocation of BCL10. Here we investigated the mechanisms leading to NF-[kappa]B activation and BCL10 nuclear localization in ENKLs. Given that ENKLs are dependent on T-cell-derived interleukin-2 (IL2) for cytotoxicity and proliferation, we investigated whether IL2 modulates NF-[kappa]B activation and BCL10 subcellular localization in ENKLs. In the present study, IL2-activated NK lymphoma cells were found to induce NF-[kappa]B activation via the PI3K/Akt pathway, leading to an increase in the entry of G2/M phase and concomitant...

Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary

The Journal of Pathology — Sat, 13 Mar 2010 00:00:00 +0100

Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2-11 and intron-exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/12...

Genomic profiling of gastric carcinoma in situ and adenomas by array-based comparative genomic hybridization

The Journal of Pathology — Wed, 10 Mar 2010 00:00:00 +0100

In this study, we investigated CNAs of 20 gastric CISs (Vienna category 4.2) and 20 adenomas including seven low-grade adenomas (LGA; Vienna category 3) and 13 high-grade adenomas (HGA; Vienna category 4.1), using oligonucleotide-based array CGH. The most frequent aberrations in CIS were gains at 8q (85%) and 20q (50%), and losses at 5q (50%) and 17p (50%), suggesting that these CNAs are involved in the development of CIS. We found that the pattern of CNAs in HGA was quite different from that in LGA. The most frequent CNAs in HGA were gains at 8q (62%) and 7pq (54%), whereas those in LGA were gain at 7q21.3-q22.1 (57%) and loss at 5q (43%). Interestingly, gains at 8q and 7pq, both of which occurred most frequently in HGA, were not detected in any cases of LGA. Of note, 8q gain was detected...

Oncogenic KRAS is not necessary for Wnt signalling activation in APC-associated FAP adenomas

The Journal of Pathology — Tue, 02 Mar 2010 00:00:00 +0100

Recent studies have suggested that APC loss alone may be insufficient to promote aberrant Wnt/[beta]-catenin signalling. Our aim was to comprehensively characterize Wnt signalling components in a set of APC-associated familial adenomatous polyposis (FAP) tumours. Sixty adenomas from six FAP patients with known pathogenic APC mutations were included. Somatic APC and KRAS mutations, [beta]-catenin immunostaining, and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analysed. Array-comparative genomic hybridization (aCGH) was also assessed in 26 FAP adenomas and 24 paired adenoma-carcinoma samples. A somatic APC alteration was present in 15 adenomas (LOH in 11 and four point mutations). KRAS mutations were detected in 10% of the cases. APC mRNA was overexpressed in adenomas. MYC and AXIN2 were also ...

Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis

The Journal of Pathology — Sat, 27 Feb 2010 00:00:00 +0100

Interleukin-34 (IL-34) is a newly discovered regulator of myeloid lineage differentiation, proliferation, and survival, acting via the macrophage-colony stimulating factor receptor (M-CSF receptor, c-fms). M-CSF, the main ligand for c-fms, is required for osteoclastogenesis and has been already identified as a critical contributor of the pathogenesis of giant cell tumours of bone (GCTs), tumours rich in osteoclasts. According to the key role of M-CSF in osteoclastogenesis and GCTs, the expression of IL-34 in human GCTs was first assessed. Quantitative analysis of IL-34 mRNA expression in 14 human GCTs revealed expression of this cytokine in GCTs as well as M-CSF and c-fms. Immunohistochemistry demonstrated that osteoclast-like cells exhibited a huge immunostaining for IL-34 and that mononu...

The sour side of neurodegenerative disorders: the effects of protein glycation

The Journal of Pathology — Wed, 24 Feb 2010 00:00:00 +0100

Neurodegenerative diseases are associated with the misfolding and deposition of specific proteins, either intra- or extracellularly in the nervous system. Although familial mutations play an important role in protein misfolding and aggregation, the majority of cases of neurodegenerative diseases are sporadic, suggesting that other factors must contribute to the onset and progression of these disorders. Post-translational modifications are known to influence protein structure and function. Some of these modifications might affect proteins in detrimental ways and lead to their misfolding and accumulation. Reducing sugars play important roles in modifying proteins, forming advanced glycation end-products (AGEs) in a non-enzymatic process named glycation. Several proteins linked to neurodegene...

Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma

The Journal of Pathology — Sat, 06 Feb 2010 00:00:00 +0100

Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded ...

General lessons from large-scale studies to identify human cancer predisposition genes. J Pathol 2010; 220: 255-262

The Journal of Pathology — Thu, 04 Feb 2010 00:00:00 +0100

The original article to which this Erratum refers was published in The Journal of Pathology 2010; 220: 255-262 (Source: The Journal of Pathology)

Heparin binding epidermal growth factor in renal ischaemia/reperfusion injury

The Journal of Pathology — Wed, 03 Feb 2010 00:00:00 +0100

The epidermal growth factor (EGF) receptor and its ligands are crucially involved in the renal response to ischaemia. We studied the heparin binding-epidermal growth factor (HB-EGF), a major ligand for the EGF receptor, in experimental and human ischaemia/reperfusion injury (IRI). HB-EGF mRNA and protein expression was studied in rat kidneys and cultured human tubular (HK-2) cells that were subjected to IRI and in human donor kidneys during transplantation. The effect of EGF receptor inhibition was investigated in vivo and in vitro. Furthermore, urinary HB-EGF protein excretion was studied after renal transplantation. Finally, HB-EGF KO and WT mice were subjected to IRI to study the role of HB-EGF in renal injury. HB-EGF mRNA was significantly up-regulated in the early phase of IRI in rats...

Autophagy: assays and artifacts

The Journal of Pathology — Wed, 03 Feb 2010 00:00:00 +0100

Autophagy is a fundamental and phylogenetically conserved self-degradation process that is characterized by the formation of double-layered vesicles (autophagosomes) around intracellular cargo for delivery to lysosomes and proteolytic degradation. The increasing significance attached to autophagy in development and disease in higher eukaryotes has placed greater importance on the validation of reliable, meaningful and quantitative assays to monitor autophagy in live cells and in vivo in the animal. To date, the detection of processed LC3B-II by western blot or fluorescence studies, together with electron microscopy for autophagosome formation, have been the mainstays for autophagy detection. However, LC3 expression levels can vary markedly between different cell types and in response to di...

Functional expression of the chemokine receptor XCR1 on oral epithelial cells

The Journal of Pathology — Wed, 03 Feb 2010 00:00:00 +0100

Chemokines are chemoattractant cytokines which act on specific receptors and play an important role in leukocyte migration as well as physiological and pathological processes. We investigated the role of the chemokine receptor XCR1 and its ligand lymphotactin (Lptn/XCL1) in the regulation of oral epithelial cell behaviour. In vitro XCR1 mRNA and cell surface protein expression was detected in normal oral keratinocytes and oral squamous cell carcinoma cell lines. Lymphotactin mediated intracellular activation of the ERK1/2 signalling pathway and stimulated migration, invasion, and proliferation of all cells through XCR1. Oral cancer cells showed a greater response to lymphotactin than normal keratinocytes and a direct relationship between receptor expression and migration, invasion, and pro...

Autophagy: cellular and molecular mechanisms

The Journal of Pathology — Wed, 03 Feb 2010 00:00:00 +0100

Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damag...

Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis

The Journal of Pathology — Fri, 29 Jan 2010 00:00:00 +0100

Multiple genetic factors contribute to the clinical variability of spontaneous systemic lupus erythematosus (SLE) but their role in drug-induced SLE remain largely unknown. Hydrocarbon oil-induced SLE depends on mesothelial cell apoptosis and Toll-like receptor (TLR)-7-mediated induction of type I interferons. Hence, we hypothesized that TIR8/SIGIRR, an endogenous TLR inhibitor, prevents oil-induced SLE. Sigirr-deficient dendritic cells expressed higher TLR7 mRNA levels and TLR7 activation resulted in increased IL-12 production in vitro. In vivo, lack of SIGIRR increased surface CD40 expression on spleen CD11c+ dendritic cells and MX-1, TNF, IL-12, BAFF and BCL-2 mRNA expression 6 months after pristane injection. Spleen cell counts of CD4-/CD8- 'autoreactive' T cells and B220+ B cells were...

Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas

The Journal of Pathology — Sun, 24 Jan 2010 00:00:00 +0100

Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative g...

Release of inflammatory mediators by adipose tissue during acute pancreatitis

The Journal of Pathology — Thu, 21 Jan 2010 00:00:00 +0100

In this study, we have examined the role of white adipose tissue as a source of inflammatory mediators that can promote systemic inflammation during experimental taurocholate-induced acute pancreatitis in rats. The inflammatory status and the expression of TNF[alpha], iNOS, adiponectin and IL-10 were determined in necrotic and non-necrotic areas of adipose tissue. Samples of adipose tissue were also used to induce the activation of macrophages in vitro. Finally, the release of TNF[alpha] to mesenterial vessels surrounded by necrotic or non-necrotic fat was evaluated in ex vivo perfused mesenterium. A strong inflammatory infiltrate was observed in the border between necrotic and non-necrotic areas of adipose tissue. In these areas, high expression of TNF[alpha] and iNOS and a reduced expres...

Anaplastic plasmacytomas: relationships to normal memory B cells and plasma cell neoplasms of immunodeficient nd autoimmune mice

The Journal of Pathology — Thu, 21 Jan 2010 00:00:00 +0100

Anaplastic plasmacytomas (APCTs) from NFS.V+ congenic mice and pristane-induced plasmacytic PCTs from BALB/c mice were previously shown to be histologically and molecularly distinct subsets of plasma cell neoplasms (PCNs). Here we extended these comparisons, contrasting primary APCTs and PCTs by gene expression profiling in relation to the expression profiles of normal naïve, germinal centre, and memory B cells and plasma cells. We also sequenced immunoglobulin genes from APCT and APCT-derived cell lines and defined surface phenotypes and chromosomal features of the cell lines by flow cytometry and by spectral karyotyping and fluorescence in situ hybridization. The results indicate that APCTs share many features with normal memory cells and the plasma cell-related neoplasms (PLs) of FASL-...

The role of autocrine TGF[beta]1 in endothelial cell activation induced by phagocytosis of necrotic trophoblasts: a possible role in the pathogenesis of pre-eclampsia

The Journal of Pathology — Thu, 21 Jan 2010 00:00:00 +0100

Pre-eclampsia is a disorder of pregnancy characterized by hypertension and endothelial cell dysfunction. The causes of pre-eclampsia are unclear but it is proposed that a factor released from the placenta triggers the maternal symptoms. One possible triggering factor is dead trophoblasts that are shed from the placenta, then deported to become trapped in the maternal pulmonary capillaries. It is hypothesized that trophoblasts die by apoptosis in normal pregnancy, but by necrosis in pre-eclampsia. Deported trophoblasts may be phagocytosed by the pulmonary endothelial cells and we have previously shown that phagocytosis of necrotic trophoblasts leads to the activation of endothelial cells, accompanied by the release of interleukin-6 from these cells. However, the mechanistic pathway linking ...

K-ras exon 4A has a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation

The Journal of Pathology — Wed, 20 Jan 2010 00:00:00 +0100

In conclusion, following DMH treatment, K-ras exon 4A deletion promoted increased number and size of colonic adenomas showing increased K-ras 4B expression, increased proliferation, decreased apoptosis, and activation of MapKinase and Akt pathways, in the absence of K-ras mutations. Therefore, K-ras 4A expression had a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation, explaining the selective advantage of the altered K-ras 4A : 4B isoform ratio found in human colorectal cancer. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)

VHL and HIF signalling in renal cell carcinogenesis

The Journal of Pathology — Tue, 19 Jan 2010 00:00:00 +0100

Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2[alpha] appears to be more oncogenic than HIF-1[alpha], in that HIF-2[alpha] activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1[alpha], more than HIF-2[alpha], can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, ...

Mutational analysis of FOXL2 codon 134 in granulosa cell tumour of ovary and other human cancers

The Journal of Pathology — Tue, 19 Jan 2010 00:00:00 +0100

A missense somatic mutation in the FOXL2 gene affecting codon 134 has recently been reported in granulosa cell tumour (GCT) and thecoma of the ovary. Such a recurrent nature of the mutation strongly suggests that the FOXL2 mutation may play an important role in the development of ovarian sex cord-stromal tumours. The aim of this study was to characterize the FOXL2 mutation in human tumour tissues. We analysed 1353 tumour tissues from various origins, including ovarian tumours and other common cancers, by single-strand conformation polymorphism analysis. We found the FOXL2 codon 134 missense mutation in 53 of 56 adult GCTs (94.6%) and two of the 16 thecomas (12.5%), but none in other tumours. Histologically, FOXL2 mutation-negative adult GCT showed that GCT cells were admixed with fibrothec...

Androgen depletion up-regulates cadherin-11 expression in prostate cancer

The Journal of Pathology — Fri, 15 Jan 2010 00:00:00 +0100

Men with castration-resistant prostate cancer (PCa) frequently develop metastasis in bone. The reason for this association is unclear. We have previously shown that cadherin-11 (also known as OB-cadherin), a homophilic cell adhesion molecule that mediates osteoblast adhesion, plays a role in the metastasis of PCa to bone. Here, we report that androgen-deprivation therapy up-regulates cadherin-11 expression in PCa. In human PCa specimens, immunohistochemical staining showed that 22/26 (85%) primary PCa tumours from men with castration-resistant PCa expressed cadherin-11. In contrast, only 7/50 (14%) androgen-dependent PCa tumours expressed cadherin-11. In the MDA-PCa-2b xenograft animal model, cadherin-11 was expressed in the recurrent tumours following castration. In the PCa cell lines, th...

A five-gene signature as a potential predictor of metastasis and survival in colorectal cancer

The Journal of Pathology — Fri, 15 Jan 2010 00:00:00 +0100

To understand the molecular mechanisms of metastasis and prognosis of colorectal cancer (CRC), we isolated single cell-derived progenies (SCPs) from SW480 cells in vitro and compared their metastatic potential in an orthotopic CRC tumour model in vivo. Two groups of SCPs with the capability of high and low metastasis, respectively, were obtained. By analysing the gene expression profiles of high (SCP51), low (SCP58) metastatic SCPs, and their parental cell line (SW480/EGFP), we demonstrated that 143 genes were differentially expressed either between SCP51 and SCP58 or between SCP58 and SW480/EGFP. Gene-annotation enrichment analysis of DAVID revealed 80 genes in the top ten clusters of the analysis (gene enrichment score > 1). Of the 80-gene set, 32 genes are potentially involved in metast...

Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers

The Journal of Pathology — Fri, 08 Jan 2010 00:00:00 +0100

Mounting evidence indicates that deregulation of microRNAs (miRNAs) are involved in development of many human diseases, including cancers. Regulation of miRNA is a complicated process and some components in the regulation are known to be altered in human cancers. Among the miRNA regulation-related genes, we found that AGO1, AGO2, TNRC6A, TNRC6C, TARBP2 and EXPORTIN5 genes have mononucleotide repeats in their coding sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analysed the mononucleotide repeats in 27 gastric cancers (GCs) with high MSI (MSI-H), 18 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 41 colorectal cancers (CRCs) with MSI-H, 14 CRCs with MSI-L and 45 CRCs with stable MSI (MSS) by single-strand conformation polymorphi...

p53 transcriptional pathways in breast cancer: the good, the bad and the complex

The Journal of Pathology — Fri, 01 Jan 2010 00:00:00 +0100

A p53 network immunohistochemically-based signature to discriminate between good and poor prognosis breast cancer would have clinical relevance, given the key role of p53 in malignancy and response to therapy. Utilizing a five-protein signature of p53/mdm2/mdm4/bcl2/p21 discriminates good-prognosis and poor-prognosis patient groups, based on the functionality of the p53 network. However, the relationship of this five-protein signature to p53 mutation, the wide range of breast cancer therapies now in use and the over-70 age group remain uncertain. Nonetheless, confirmation of the signature in two independent series suggests that this approach should be considered in further case series and in the context of clinical trials. Copyright © 2009 Pathological Society of Great Britain and Ireland...

Transcriptional regulation of pro-apoptotic Par-4 by NF-[kappa]B/p65 and its function in controlling cell kinetics during early events in endometrial tumourigenesis

The Journal of Pathology — Thu, 31 Dec 2009 00:00:00 +0100

Prostatic apoptosis response-4 (Par-4) was first identified in prostatic cancer cells that were induced to undergo apoptosis. Recently, Par-4 has been suggested to be a tumour suppressor gene that plays a role in the development of endometrial carcinomas (ECs), but the exact mechanism remains to be clarified. Here we examined gene activation signalling cascades and influence on cell kinetics during endometrial tumourigenesis. In normal endometrium, constitutively high levels of Par-4 expression were observed in epithelial cells through the menstrual cycle, in contrast to the transient up-regulation in stromal components in the menstrual stage, correlated positively with the phospho-p65 (pp65) status and apoptosis. In contrast, most ECs exhibited significant down-regulation as compared to n...

Plasmin induces apoptosis of aortic valvular myofibroblasts

The Journal of Pathology — Thu, 31 Dec 2009 00:00:00 +0100

In conclusion, various proteins of the fibrinolytic system are synthesized in vitro by cultured myofibroblasts from aortic valves, leading to plasmin-dependent cell detachment-induced apoptosis, a biological process named anoikis. The presence of plasminogen in aortic valves suggests that this process may be operating in vivo and may participate in valvular tissue remodelling, as also suggested by the finding of apoptotic cells in valvular tissue. This is the first demonstration of the presence and potential role of enzymes of the fibrinolytic system in aortic valves. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)

Targeted therapy in haematological malignancies

The Journal of Pathology — Wed, 30 Dec 2009 00:00:00 +0100

The recent and rapid development of molecularly targeted therapy is best illustrated by advances in the management of haematological malignancy. In myeloid diseases we have seen dramatic improvements in the overall survival and quality of life for patients with chronic myeloid leukaemia treated with ABL and Src/ABL kinase inhibitors and we are poised to discover whether JAK2 inhibitors may offer similar benefit in myeloproliferative diseases. For acute myeloid leukaemia, the introduction of ATRA and myelotarg have had major impacts on the design of therapy regimens and many novel targeted agents, including farnesyl transferase, FLT3 and histone deacetylase inhibitors, are now in clinical trial. In lymphoid malignancies the highlight has been the introduction of rituximab, with significant ...

Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD)

The Journal of Pathology — Tue, 22 Dec 2009 00:00:00 +0100

We examined 48 patients with SM-AHNMD for the presence of mutant KIT in the SM and AHNMD components of the disease. Mast cells and AHNMD cells were obtained from immunostained bone marrow sections by laser microdissection and examined by melting point analysis of nested-PCR products. KITD816V was found in AHNMD cells in the vast majority of patients with SM-chronic myelomonocytic leukaemia (CMML, 89%). Unexpectedly, KITD816V was far less frequently detectable in AHNMD cells in patients with SM-myeloproliferative neoplasm (MPN, 20%) and SM-acute myeloid leukaemia (AML, 30%). None of the patients with lymphoproliferative AHNMDs displayed KIT codon 816 mutations in AHNMD cells (0/8). In FIP1L1/PDGFRA-positive chronic eosinophilic leukaemia (CEL), neither the SM nor the CEL component of the di...

Differential expression of interleukin-17 family cytokines in intact and complicated human atherosclerotic plaques

The Journal of Pathology — Sat, 19 Dec 2009 00:00:00 +0100

In addition to the classical TH1 and TH2 cytokines, members of the recently identified IL-17 cytokine family play an important role in regulating cellular and humoral immune responses. At present nothing is known about the role of these cytokines in atherosclerosis. Expression of IL-17A, -E and -F was investigated in atherosclerotic tissue by rtPCR and immunohistochemistry. IL-17E and its receptor were further studied in cultured smooth muscle cells and endothelial cells, using rtPCR and western blot. rtPCR showed that IL-17A, -E and -F were expressed in the majority of plaques under investigation. IL-17A/F was expressed by mast cells in all stages of plaque development. IL-17A/F+ neutrophils were always observed in complicated plaques, but hardly in intact lesions. IL-17A/F+ Tcells ('TH17...

Lung adenocarcinoma cells floating in lymphatic vessels resist anoikis by expressing phosphorylated Src

The Journal of Pathology — Fri, 18 Dec 2009 00:00:00 +0100

We examined 20 human lung adenocarcinoma tissues with lymphatic permeation and nine cell lines to investigate whether intralymphatic floating carcinoma cells in the tissues, used as an in vivo model of anoikis resistance, actually suppressed anoikis and whether cell lines in suspension culture, an in vitro model of anoikis resistance, survived through Src activation. We observed that the intralymphatic carcinoma cells aggregated tightly to form nests expressing E-cadherin and phosphorylated Src (p-Src). The apoptotic indices of these cells were comparable to those of extracellular matrix adhesive cells in all tissues, indicating that the intralymphatic cells actually evaded anoikis. Next, we found that the nine cell lines in suspension aggregated loosely (five cell lines) or tightly (four ...

The role of the polyol pathway in acute kidney injury caused by hindlimb ischaemia in mice

The Journal of Pathology — Fri, 11 Dec 2009 00:00:00 +0100

In this study, we explored the role of the polyol pathway in acute kidney injury (AKI), a life-threatening condition, caused by hindlimb ischaemia, and determined if inhibition of the polyol pathway by aldose reductase (AR) inhibitor is beneficial for this serious disorder. Mice 8 weeks of age rendered hindlimb ischaemic for 3 h by the clipping of major supporting arteries revealed marked muscle necrosis with accumulation of sorbitol and fructose in ischaemic muscles. Serum concentrations of blood urea nitrogen (BUN), creatinine phosphokinase (CPK), creatinine, tumour necrosis factor (TNF)-[alpha] as well as interleukin (IL)-6 were all elevated in these mice. Treatment with AR inhibitor (ARI) effectively suppressed muscle necrosis and accompanying inflammatory reactions and prevented renal...

Molecular targeted therapies for diffuse large B-cell lymphoma based on apoptosis profiles

The Journal of Pathology — Fri, 11 Dec 2009 00:00:00 +0100

Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult non-Hodgkin lymphoma and is treated with chemotherapy in combination with rituximab. Despite this aggressive therapy, the disease is fatal in 30-40% of patients. Inhibition of the apoptosis signalling pathways is strongly related to response to chemotherapy and eventual clinical outcome. In order to survive, lymphoma cells depend on disruption of the apoptosis pathway by mutations in apoptosis inducing genes or by continuous expression of anti-apoptotic proteins. The development of molecules targeting these apoptosis inhibitors provides a very promising opportunity to specifically target tumour cells without toxicity to non-malignant cells in DLBCL patients. Sensitivity for most of these antagonists can be predicted bas...

Up-regulation of L1CAM is linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas

The Journal of Pathology — Fri, 11 Dec 2009 00:00:00 +0100

Endometrial carcinomas (ECs) are classified into type 1 (less aggressive) and type 2 (aggressive) tumours that differ in genetic alterations. So far, reliable immunohistochemical markers that can identify patients with high risk for recurrence are rare. We have defined the expression of L1 cell adhesion molecule (L1CAM), a biomarker previously identified for EC, and compared its expression to oestrogen receptor (ER)/progesterone receptor (PR) and E-cadherin. We found that L1CAM was absent in normal endometrium and the vast majority of endometrioid ECs (type 1) but was strongly expressed in serous and clear-cell ECs, considered as type 2. 78/272 cases were identified as L1CAM-positive endometrioid ECs that were correlated with a poor prognosis. Strikingly, we observed an inverse relationshi...

Oncogenic function of microtubule end-binding protein 1 in breast cancer

The Journal of Pathology — Sat, 05 Dec 2009 00:00:00 +0100

Microtubule end-binding protein 1 (EB1) is an evolutionarily conserved protein that regulates microtubule dynamics and participates in diverse cell activities. Here, we demonstrate that EB1 expression is up-regulated in human breast cancer specimens and cell lines. The level of EB1 correlates with clinicopathological parameters indicating the malignancy of breast cancer, including higher histological grade, higher pathological tumour node metastasis (pTNM) stage, and higher incidence of lymph node metastasis. Knockdown of EB1 expression remarkably inhibits cancer cell proliferation, and conversely, elevation of its expression promotes cell proliferation. Our data further show that EB1 promotes colony formation and enhances tumour growth in nude mice. In addition, EB1 stimulates Aurora-B ac...

Prognostic significance of Dicer expression in ovarian cancer - link to global microRNA changes and oestrogen receptor expression

The Journal of Pathology — Fri, 04 Dec 2009 00:00:00 +0100

MicroRNA (miRNA) deregulation is a hallmark of human cancer. However, the mechanisms underlying miRNA alteration and the specific role of proteins involved in miRNA processing remains to be elucidated. Dicer is a key enzyme in the miRNA processing pathway that is essential for the production of mature miRNAs from their precursors. We tested the hypothesis that Dicer has biological and clinical relevance in ovarian cancer, using a range of methods including in vitro manipulation of Dicer expression. We observed down-regulation of Dicer in a subgroup of ovarian carcinomas, and found that decreased Dicer expression correlates significantly with reduced patient survival in serous cancers and advanced disease stages. Moreover, microarray and functional analysis suggest that reduced Dicer expres...

Nephrin - signature molecule of the glomerular podocyte?

The Journal of Pathology — Tue, 01 Dec 2009 00:00:00 +0100

In recent years there has been an explosion of interest in the glomerular podocyte, which plays a central role in control of glomerular filtration. A host of new molecules have been identified as playing essential roles in the maintenance of podocyte integrity in both humans and mouse models. Of all of these, arguably the most pivotal is nephrin, a transmembrane receptor molecule located at the specialized podocyte cell-cell junction, termed the slit diaphragm. Mutations in this gene cause the most severe form of congenital nephrotic syndrome, and many interacting proteins have now been described to form a large multiprotein complex with complex dynamics. There is little evidence of functional nephrin expression outside the glomerulus, and there are accumulating data that nephrin is essent...

Splenic marginal zone lymphoma: characterization of 7q deletion and its value in diagnosis

The Journal of Pathology — Mon, 30 Nov 2009 00:00:00 +0100

In conclusion, 7q32 deletion is a characteristic feature of SMZL, albeit seen in isolated cases of splenic B-cell lymphoma/leukaemia unclassifiable, and its detection may help the differential diagnosis of splenic B-cell lymphomas. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)

Selective blockade of endothelial NF-[kappa]B pathway differentially affects systemic inflammation and multiple organ dysfunction and injury in septic mice

The Journal of Pathology — Mon, 30 Nov 2009 00:00:00 +0100

This study addresses the relative contribution of endothelial activation to systemic inflammation and multiple organ dysfunction and injury (MOD/I) in an E. coli peritonitis model of sepsis. We prevented endothelial activation using transgenic (TG) mice that conditionally overexpress a mutant I-[kappa]B[alpha], a NF-[kappa]B inhibitor, selectively on endothelium. TG mice and their transgene negative littermates (WT) were injected with saline or E. coli (108 CFU per mouse). At 7 h after E. coli infection, markers of systemic inflammation, endothelial activation, and MOD/I were assessed. WT-E. coli mice showed significantly increased serum levels of TNF-[alpha], IL-1[beta], IFN-[gamma], IL-6, KC, and MCP-1; tissue levels of TNF-[alpha], IL-6, KC, MCP-1, ICAM-1, and VCAM-1; endothelial leakag...

Single-molecule genomics

The Journal of Pathology — Fri, 20 Nov 2009 00:00:00 +0100

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 competing technologies, including improved detection of rare genetic variants and more precise analysis of copy-number variation, and is more easily adapted to the often small am...

The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade

The Journal of Pathology — Thu, 19 Nov 2009 00:00:00 +0100

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 years after the initial publications of translational research studies using microarrays, one cannot deny that this technology has changed the way breast cancer is percei...

The role of nuclear organization in cancer

The Journal of Pathology — Thu, 19 Nov 2009 00:00:00 +0100

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 cancer and the identification of new therapeutic targets. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: T...

General lessons from large-scale studies to identify human cancer predisposition genes

The Journal of Pathology — Thu, 19 Nov 2009 00:00:00 +0100

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 (typically > 10%) and low penetrance (typically < two-fold increased lifetime risk) contribute substantially to susceptibility to the common human diseases, including ca...

Network-based drugs and biomarkers

The Journal of Pathology — Wed, 18 Nov 2009 00:00:00 +0100

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 focus on the multivariate nature of cellular networks and how this has implications for biomarker and drug discovery using cancer metastasis as an example. Copyright © ...

The biological, clinical and prognostic implications of p53 transcriptional pathways in breast cancers