Insulin‐like growth factor‐1 receptor is associated with better prognosis in classical Hodgkin's lymphoma: Correlation with MET expression

The purpose of this study was to examine the prognostic significance of insulin‐like growth factor‐1 receptor (IGF‐1R) expression alone and in relation to the expression of the MET‐ receptor and the MET‐homologous receptor RON, in classical Hodgkin's lymphoma (cHL). Tumour samples from patients with cHL (n = 202; median age 37.5 years) were analysed retrospectively for IGF‐R1, MET or RON expression by immunohistochemistry using tissue microarrays. The median follow‐up time was 3.7 years (range, 0.1–20 years). Twenty‐nine patients (14.3%) expressed IGF‐1R protein in Hodgkin/Reed–Sternberg (HRS) cells, which was associated with a better overall survival (OS) (P = 0.036). IGF‐1R expression was closely associated with MET receptor expression and low level of lactate dehydrogenase. In patients with cHL receiving doxorubicin, bleomycin, vinblastine and dacarbazine, those expressing IGF‐1R showed a trend towards better OS and event‐free survival than IGF‐1R‐negative patients (P = 0.129 and P = 0.115 respectively), but statistical significance was not reached. This study suggests that IGF‐1R expression could be associated with better clinical outcome in cHL but is significantly associated with the expression of MET receptor.     

The use of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology

The histologic distinction between reactive processes and malignant neoplasms and between low-grade and high-grade tumors is not always straightforward and is sometimes extremely challenging. This is especially the case when the diagnostic material is a small biopsy specimen or a cytology specimen with scant cellularity. In addition, suboptimal processing and crush artifact may limit accurate diagnosis. A reliable diagnostic biomarker that preferentially highlights malignant processes and high-grade tumors would be very valuable in segregating these entities from reactive processes and low-grade lesions. Recent extensive studies have shown that an oncoprotein, insulin like-growth factor II messenger RNA binding protein-3, is not only a prognostic biomarker but also a diagnostic molecule. This review focuses on discussing the value of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology, with a focus on utilization of insulin like-growth factor II messenger RNA binding protein-3 in the discrimination of benign effusions from malignant effusions, malignant mesothelioma from mesothelial hyperplasia, carcinoids from high-grade neuroendocrine carcinomas, low-grade dysplasia from high-grade dysplasia, hepatocellular carcinoma from hepatic adenoma, cholangiocarcinoma and metastatic pancreatic ductal carcinoma from benign bile duct lesions, melanoma from nevi, and follicular thyroid carcinoma from follicular adenoma of the thyroid, as well as examining insulin like-growth factor II messenger RNA binding protein-3 expression in lymphomas of germinal center origin.     

Insulin‐like growth factor binding protein‐2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis

Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus. Invasive renal biopsy remains the gold standard for the diagnosis and management of LN. The objective of this study is to validate serum insulin‐like growth factor binding protein‐2 (IGFBP‐2) as a novel biomarker for clinical disease and renal pathology in LN. Eighty‐five biopsy‐proven lupus nephritis patients, 18 chronic kidney disease (CKD) patients and 20 healthy controls were recruited for enzyme‐linked immunosorbent assay (ELISA) testing of serum IGFBP‐2 levels. Compared to CKD patients of origins other than lupus or healthy controls, serum IGFBP‐2 levels were elevated significantly in LN patients. Serum IGFBP‐2 was able to discriminate LN patients from the other two groups of patients [area under the curve (AUC) = 0·65, 95% confidence interval (CI) = 0·52–0·78; P = 0·043 for LN versus CKD; 0·97, 95% CI = 0·93–1·00; P < 0·0001 for LN versus healthy controls]. Serum IGFBP‐2 was a potential indicator of both global disease activity and renal disease activity in LN patients, correlated with serum creatinine levels (r = 0·658, P < 0·001, n = 85) and urine protein‐to‐creatinine levels (r = 0·397, P < 0·001, n = 85). More importantly, in 19 concurrent patient samples, serum IGFBP‐2 correlated with the chronicity index of renal pathology (r = 0·576, P = 0·01, n = 19) but not renal pathological classification. In conclusion, serum IGFBP‐2 is a promising biomarker for lupus nephritis, reflective of disease activity and chronicity changes in renal pathology.     

Plasma membrane Toll‐like receptor activation increases bacterial uptake but abrogates endosomal Lactobacillus acidophilus induction of interferon‐β

Lactobacillus acidophilus induces a potent interferon‐β (IFN‐β) response in dendritic cells (DCs) by a Toll‐like receptor 2 (TLR2) ‐dependent mechanism, in turn leading to strong interleukin‐12 (IL‐12) production. In the present study, we investigated the involvement of different types of endocytosis in the L. acidophilus‐induced IFN‐β and IL‐12 responses and how TLR2 or TLR4 ligation by lipopolysaccharide and Pam3/4CSK4 influenced endocytosis of L. acidophilus and the induced IFN‐β and IL‐12 production. Lactobacillus acidophilus was endocytosed by constitutive macropinocytosis taking place in the immature cells as well as by spleen tyrosine kinase (Syk) ‐dependent phagocytosis but without involvement of plasma membrane TLR2. Stimulation with TLR2 or TLR4 ligands increased macropinocytosis in a Syk‐independent manner. As a consequence, incubation of DCs with TLR ligands before incubation with L. acidophilus enhanced the uptake of the bacteria. However, in these experimental conditions, induction of IFN‐β and IL‐12 was strongly inhibited. As L. acidophilus‐induced IFN‐β depends on endocytosis and endosomal degradation before signalling and as TLR stimulation from the plasma membrane leading to increased macropinocytosis abrogates IFN‐β induction we conclude that plasma membrane TLR stimulation leading to increased macropinocytosis decreases endosomal induction of IFN‐β and speculate that this is due to competition between compartments for molecules involved in the signal pathways. In summary, endosomal signalling by L. acidophilus that leads to IFN‐β and IL‐12 production is inhibited by TLR stimulation from the plasma membrane.     

Insulin‐like growth factor‐II is produced by,signals to and is an important survival factor for the mature podocyte in man and mouse

Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro‐survival mechanisms are critically important. Insulin‐like growth factor‐II (IGF‐II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF‐II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF‐II; it signals to this cell via the IGF‐I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF‐II transgenic mouse that produces approximately 60% of IGF‐II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF‐II in the mature podocyte for glomerular health across mammalian species. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

SPINK5 is associated with early‐onset and CHI3L1 with late‐onset atopic dermatitis

We have recently showed that filaggrin (FLG) mutations are associated only with early‐onset of AD, but not with late‐onset of AD. Consequently, other susceptibility genes should receive attention, especially in patients with late‐onset of AD. Our aim was to assess the associations between development of AD and the polymorphisms rs2303067 in SPINK5 and rs490928 in CHI3L1. A study population of 241 AD patients and 164 healthy controls was genotyped for two polymorphisms (rs2303067 in SPINK5 and rs490928 in CHI3L1). Rs2303067 in SPINK5 was significantly associated with early‐onset AD (≤8 years: p = .003; OR = 2.57) and was characterized by the need for hospitalization (p = .006; OR = 2.76), prolonged duration (≥10 years; p = .008; OR = 2.32) and more body parts affected (p = .015; OR = 2.01). In contrast, rs490928 in CHI3L1 was associated with late‐onset AD (>8 years: p = .048; OR = 1.65) and was characterized by no need for hospitalization (p = .049; OR = 1.59), shorter duration (<10 years; p = .017; OR = 1.94) and fewer body parts affected (p = .049; OR = 1.75). Our results confirmed that different AD phenotypes, specifically early‐ and late‐onset AD, have different genetic backgrounds. Early‐onset AD was associated with rs2303067 in SPINK5, which is involved in skin barrier functioning, and late‐onset was associated with rs4950928 in CHI3L1, which is involved in the immune response. Future studies should examine the early‐ versus late‐onset subgrouping more closely.     

Survival in the environment is a possible key factor for the expansion of Escherichia coli strains producing extended‐spectrum β‐lactamases

Acquired resistance to cephalosporins in Enterobacteriaceae is a global problem. After an outbreak at Uppsala University Hospital of extended‐spectrum β‐lactamase (ESBL)‐positive Klebsiella pneumoniae producing CTX‐M‐15, there was a shift from AmpC to ESBL production among Escherichia coli isolates. To explore the basis for this epidemiological shift, 46 E. coli isolates (ESBLs, n = 23; AmpC, n = 23) were characterized with regard to genetic relatedness, β‐lactamase, replicon and integron types, antibiotic resistance profiles, and genes encoding virulence factors. In addition, the survival in the environment and on hospital‐associated materials was analysed. CTX‐M‐15 was the most frequent ESBL (78%). Only three (13%) of the AmpC enzymes were harboured on plasmids (CMY‐2, DHA‐1). Independent of plasmid‐mediated beta‐lactamase, IncF plasmids predominated and only class I integrons were detected. The ESBL producers carried more virulence genes (p = 0.04), exhibited a broader resistance phenotype (p = 0.01) and survived significantly longer (p = 0.03) on different materials than the AmpC‐producing isolates. In conclusion, ESBL‐producing isolates had properties which are likely to augment their competitiveness. Apart from antibiotic resistance and virulence factors, extended survival in the environment could be a selective trait for successful ESBL‐producing E. coli strains.     

Molecular alterations of Ras‐Raf‐mitogen‐activated protein kinase and phosphatidylinositol 3‐kinase‐Akt signaling pathways in colorectal cancers from a tertiary hospital at Kuala Lumpur,Malaysia

Molecular alterations in KRAS, BRAF, PIK3CA, and PTEN have been implicated in designing targeted therapy for colorectal cancer (CRC). The present study aimed to determine the status of these molecular alterations in Malaysian CRCs as such data are not available in the literature. We investigated the mutations of KRAS, BRAF, and PTEN, the gene amplification of PIK3CA, and the protein expression of PTEN and phosphatidylinositol 3‐kinase (PI3K) catalytic subunit (p110α) by direct DNA sequencing, quantitative real‐time PCR, and immunohistochemistry, respectively, in 49 CRC samples. The frequency of KRAS (codons 12, 13, and 61), BRAF (V600E), and PTEN mutations, and PIK3CA amplification was 25.0% (11/44), 2.3% (1/43), 0.0% (0/43), and 76.7% (33/43), respectively. Immunohistochemical staining demonstrated loss of PTEN protein in 54.5% (24/44) of CRCs and no significant difference in PI3K p110α expression between CRCs and the adjacent normal colonic mucosa (p = 0.380). PIK3CA amplification was not associated with PI3K p110α expression level, but associated with male cases (100% of male cases vs 56% of female cases harbored amplified PIK3CA, p = 0.002). PI3K p110α expression was significantly higher (p = 0.041) in poorly/moderately differentiated carcinoma compared with well‐differentiated carcinoma. KRAS mutation, PIK3CA amplification, PTEN loss, and PI3K p110α expression did not correlate with Akt phosphorylation or Ki‐67 expression. KRAS mutation, PIK3CA amplification, and PTEN loss were not mutually exclusive. This is the first report on CRC in Malaysia showing comparable frequency of KRAS mutation and PTEN loss, lower BRAF mutation rate, higher PIK3CA amplification frequency, and rare PTEN mutation, as compared with published reports.