Challenging Metastatic Melanoma to the Lung With p40 Expression: A Diagnostic Pitfall, Case Report.

p40 immunohistochemistry is a cornerstone of histopathological examination for non-small cell lung carcinoma. p40 is an isoform of p63 and is reported to be highly specific for the diagnosis of squamous cell carcinoma. Very rare pitfalls are reported for this antibody, and p40 is typically negative in melanoma. A 66-year-old patient was admitted for multiple hemorrhagic brain tumors evocative of secondary tumors. On imaging, a 26 mm lung tumor was detected, and a biopsy of the lung tumor was performed. The tumor was stained by melanic markers and diffusely stained by p40 and p63. Molecular analysis found a somatic p.Asn581Ser (c.1742A>G) point mutation in exon 15 of BRAF and a p.Arg80Ter (c.238C>T) germline variant of CDKN2A , a predisposing mutation to melanoma. This case report highlights the importance of clinical, pathologic, and molecular correlation.

Positional cloning of zinc finger domain transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL.

Polygenic type 2 diabetes in mouse models is associated with obesity and results from a combination of adipogenic and diabetogenic alleles. Here we report the identification of a candidate gene for the diabetogenic effect of a QTL (Nidd/SJL, Nidd1) contributed by the SJL, NON, and NZB strains in outcross populations with New Zealand Obese (NZO) mice. A critical interval of distal chromosome 4 (2.1 Mbp) conferring the diabetic phenotype was identified by interval-specific congenic introgression of SJL into diabetes-resistant C57BL/6J, and subsequent reporter cross with NZO. Analysis of the 10 genes in the critical interval by sequencing, qRT-PCR, and RACE-PCR revealed a striking allelic variance of Zfp69 encoding zinc finger domain transcription factor 69. In NZO and C57BL/6J, a retrotransposon (IAPLTR1a) in intron 3 disrupted the gene by formation of a truncated mRNA that lacked the coding sequence for the KRAB (Krüppel-associated box) and Znf-C2H2 domains of Zfp69, whereas the diabetogenic SJL, NON, and NZB alleles generated a normal mRNA. When combined with the B6.V-Lep(ob) background, the diabetogenic Zfp69(SJL) allele produced hyperglycaemia, reduced gonadal fat, and increased plasma and liver triglycerides. mRNA levels of the human orthologue of Zfp69, ZNF642, were significantly increased in adipose tissue from patients with type 2 diabetes. We conclude that Zfp69 is the most likely candidate for the diabetogenic effect of Nidd/SJL, and that retrotransposon IAPLTR1a contributes substantially to the genetic heterogeneity of mouse strains. Expression of the transcription factor in adipose tissue may play a role in the pathogenesis of type 2 diabetes.

Expression of Zif268 in the granule cell layer of the adult mouse olfactory bulb is modulated by experience.

Behavioral and physiological evidence indicates that odor processing in the main olfactory bulb is influenced by olfactory experience. At the cellular level, changes in inhibitory influence exerted by granular interneurons may contribute to restructuring odor representations. To assess experience-dependent modulation in the responsiveness of granule cells, we measured the level and spatial distribution of odor-induced expression of the immediate-early gene Zif268 in the granule cell layer of adult mice submitted or not to olfactory discrimination conditioning. We first show that stimulation by the reinforced odorant in conditioned animals did not induce any increase in Zif268 expression in contrast to stimulation with an unfamiliar odorant which induced an odor-specific three-fold increase in Zif268 expression. The same lack of Zif268 induction was observed in animals exposed to odorants without learning, indicating that familiarity to the odorant with or without conditioning similarly reduced responsiveness of granule cells to odorant stimulation. Second, conditioning induced a spatial reorganization of Zif268-positive cells leading to higher contrast and significant enlargement of their distribution pattern. The latter effect was also present in animals exposed to the odorants without conditioning but was significantly weaker. Taken together, these data indicate that distinct populations of granule cells are solicited by odorant processing, depending on its familiarity or behavioral significance. Finally, we report that the expression pattern of Zif268 in the granule cell layer is constrained by anteroposterior and dorsolateral gradients in cell density, pointing to anatomical and possibly functional disparity within the layer.

Characterization of Nob3, a major quantitative trait locus for obesity and hyperglycemia on mouse chromosome 1.

New Zealand obese (NZO) mice present a metabolic syndrome of obesity, insulin resistance, and diabetes. To identify chromosomal segments associated with these traits, we intercrossed NZO mice with the lean and diabetes-resistant C57BL/6J (B6) strain. Obesity and hyperglycemia in the (NZO x B6)F2 intercross population were predominantly due to a broad quantitative trait locus (QTL) on chromosome 1 (Nob3; logarithm of the odds score 16.1, 16.0, 4.0 for body weight, body fat, and blood glucose, respectively), producing a difference between genotypes of 12.7 or 5.2 g of body weight and 12.0 or 4.0 g of body fat in females or males, respectively. In addition, significant QTL on chromosomes 3 and 13 and suggestive QTL on chromosomes 4, 6, 9, 12, 14, and 19 contributed to the obese phenotype. Distal chromosome 5 was significantly linked with plasma cholesterol (LOD score 10.7). Introgression of two segments of Nob3 into B6 confirmed the adipogenic effect of the QTL and suggested the presence of at least one causal gene. Haplotype mapping reduced the critical region of the distal part of the QTL to 31 Mbp containing the potential candidates Nr1i3, Apoa2, Atp1a2, Prox1, and Hsd11b1. We conclude that obesity and hyperglycemia of NZO is to a large part caused by variant genes located in Nob3 on chromosome 1. Since these exert robust effects on a B6 background, the QTL Nob3 is a prime target for identification of a novel diabesity gene.