RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF(V600E) point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF(V600E) mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P(trend) = 0.002). In contrast, BRAF(V600E) mutation was less frequent in cases exposed to higher radiation dose (P(trend) < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF(V600E) mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis.     

Role of interleukin‐15 in the development of mouse olfactory nerve

Interleukin (IL)‐15 interacts with components of the IL‐2 receptor (R) and exhibits T cell‐stimulating activity similar to that of IL‐2. In addition, IL‐15 is widely expressed in many cell types and tissues, including the central nervous system. We provide evidence of a novel role of IL‐15 in olfactory neurogenesis. Both IL‐15 and IL‐15Rα were expressed in neuronal precursor cells of the developing olfactory epithelium in mice. Adult IL‐15Rα knockout mice had fewer mature olfactory neurons and proliferating cells than wild‐type. Our results suggest that IL‐15 plays an important role in regulating cell proliferation in olfactory neurogenesis.     

Effect of sample size for normal database on diagnostic performance of brain FDG PET for the detection of Alzheimer's disease using automated image analysis

OBJECTIVE: To investigate the relationship between the sample size for a normal database (NDB) and diagnostic performance of FDG PET using three-dimensional stereotactic surface projection for the detection of Alzheimer's disease. METHODS: We generated nine NDB sets consisting of 4, 6, 8, 10, 20, 30, 40, 50 and 60 normal subjects. In order to assess the diagnostic performance using these NDBs to distinguish Alzheimer's disease patients from normal subjects, we recruited 52 patients with probable Alzheimer's disease (25 males, 27 females; mean age, 66.8+/-8.1 years) and 50 normal subjects (24 males, 26 females; mean age, 65.7+/-9.4 years). A receiver operating characteristic (ROC) analysis was performed for comparison of diagnostic accuracy among NDB sets. RESULTS: Small NDBs (n< or =10) yielded poor quality of mean and SD images as compared with large NDBs (n> or =20). The ROC curves of the smaller group varied inconsistently, whereas those of the larger group were nearly superimposable. The area under the ROC curve (AUC) of the NDBs with sample size 6 (0.911) or 8 (0.929) was significantly smaller than that of the largest NDB (n=60, 0.956). The AUCs of the larger group did not fall below 0.950, whereas AUCs of the smaller subgroup never exceeded 0.950. CONCLUSIONS: Our data indicate that the sample size for an NDB affects the diagnostic performance of FDG PET using automated statistical approach, and that inclusion of at least 10 subjects is recommended, and 20 seems to be preferable for generating NDBs, although even a small NDB may provide clinically relevant results.     

Bilateral single ectopic ureters with hypoplastic bladder: How should we treat these challenging entities?

Bilateral single ectopic ureters with hypoplastic bladder are rare and difficult to treat. Urinary diversion (e.g. by ileal conduit) is usually performed because of small bladder capacity. We report a case treated by staged operation without urinary diversion or bladder augmentation. The outcome shows that ureterovesicostomy between the dilated ureter and the bladder is a feasible method to increase capacity for bilateral single ectopic ureters with hypoplastic bladder.     

Increased expression of TRAIL receptor 3 on eosinophils in Churg‐Strauss syndrome

Objective

Prolonged survival of eosinophils plays an important role in the pathogenesis of Churg‐Strauss syndrome (CSS); however, its detailed molecular mechanism is still unclear. TRAIL and its receptors are expressed on a variety of cells, including eosinophils. In this study, we examined the expression of TRAIL receptors on eosinophils from patients with CSS.

Methods

TRAIL receptor expression was assessed on eosinophils from healthy volunteers, patients with CSS, patients with asthma, and patients with hypereosinophilia due to parasitic infection. TRAIL‐induced apoptosis of eosinophils was compared between the patients with CSS and patients with asthma. RNA interference was used to assess the effects of suppression of TRAIL receptor 3.

Results

Expression of TRAIL receptor 3, a decoy receptor that acts as an antiapoptotic receptor, on eosinophils from patients with CSS was significantly higher than that in the other subjects. Moreover, in CSS, serum TRAIL receptor 3 levels showed a significant positive correlation with peripheral eosinophil counts, tissue‐infiltrating eosinophils stained positive for this receptor, and peripheral T cells expressed TRAIL on their surface. Compared with asthma patients, eosinophils from CSS patients showed a significantly lower percentage of recombinant TRAIL, less autologous T cell–induced apoptosis, and decreased level of active caspase 3. Suppression of TRAIL receptor 3 through RNA interference significantly increased the recombinant TRAIL–induced apoptosis of eosinophils from CSS patients.

Conclusion

Increased expression of TRAIL receptor 3 on eosinophils from patients with CSS was observed. These alterations in TRAIL receptor 3 expression might be involved in the molecular pathogenesis of CSS eosinophilia.

     

In situ identification of genes regulated specifically in fibroblasts of human basal cell carcinoma

Basal cell carcinoma (BCC) is characterized by slow growth, virtual absence of metastases, and strong stroma-dependency. Cancer-associated fibroblasts (CAFs) in the tumor stroma influence tumor growth, invasion, and metastasis. To comprehensively characterize CAFs of BCC in their in situ cancer environment, laser capture microdissection, linear gene amplification, microarray analysis, and quantitative real-time PCR (qRT-PCR) were combined. Pair-wise comparison of gene expression of microdissected CAFs and corresponding normal perifollicular fibroblasts identified 65 genes that were significantly upregulated in at least two of three different patients. Among the annotated genes, as many as 13 genes encoded secreted proteins, of which six were previously implicated as CAF-associated proteins in various tumor types. Four of the seven novel CAF genes--matrix Gla-protein, secreted frizzled-related protein 2, angiopoietin-related protein-2, and platelet-derived growth factor receptor-like protein--were selected for further analyses by qRT-PCR and were found to be frequently upregulated in CAFs of three independent BCC tissues. Analyses of CAFs from squamous cell cancer, prostate cancer, and colon cancer did not indicate that these genes were upregulated in these cancers. This study thus validates a novel approach for comprehensive characterization CAFs in their in situ environment of BCC. The results suggest a specific expression profile of CAFs in BCC possibly accounting for disease-specific pathological roles.