Pulmonary adenofibroma: Cytologic and clinicopathologic features of a rare benign primary lung lesion

We report a case of pulmonary adenofibroma in a 29‐year‐old female found by CT scan during work‐up for midline chest pain. To our knowledge, the cytological features of this entity have not been previously reported. Cytology demonstrated bland epithelial and stromal cells of varying size without karyorrhexis, pyknosis, or necrosis and with very rare mitoses. Stromal cells were present as either naked bipolar nuclei, as spindle cells with fragile eosinophilic cytoplasm, or as rare larger carrot shaped nuclei. Epithelial cells were present as small loosely cohesive groups with smooth round nuclei and moderate amounts of cytoplasm. Histologically, this lesion consisted of a leaf‐like fibroepithelial pattern in which the clefts were lined by a single layer of cuboidal epithelium reminiscent of adenofibroma occurring in the female genital tract. Immunohistochemical analysis demonstrated epithelium that stained positively for pan‐cytokeratin and TTF‐1. The stroma stained positively for vimentin and desmin, and was weakly positive for SMA‐1. The lesion was confirmed to be pulmonary adenofibroma with a smooth muscle component. The differential diagnosis for this lesion includes, but is not limited to, pulmonary hamartoma, pulmonary blastoma, adenomyofibroma, synovial sarcoma, and visceral metastases. It is important for cytopathologists to be aware of this benign entity because it can be encountered on lung FNA specimens. Considering this benign lesion in the differential diagnosis may help plan for minimal lung resection. Confirmatory intraoperative frozen section is a reasonable option. Diagn. Cytopathol. 2013;41:991–996. © 2012 Wiley Periodicals, Inc.     

NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes

Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.     

Genes that are differentially expressed in rat vibrissa follicle germinative epithelium in vivo show altered expression patterns after extended organ culture

Hair growth depends on maintenance of signalling between the dermal papilla and the germinative epithelium (GE), from which the differentiated layers of the hair fibre originate. Because no molecular studies have been reported which concentrate specifically on GE cells either in vivo or in vitro, we prepared a cDNA library enriched for messages which were highly expressed in GE cells to identify genes that may be involved in hair growth control. Of 35 subtracted library clones sequenced, 23 shared extensive homology with previously determined cDNA sequences, including LEF-1 and id4. Hair follicle organ culture models are often used to investigate the molecular basis of hair growth, although hair growth arrest occurs relatively rapidly in vitro. As an indicator of their role in follicle activities, we compared the expression of GE-specific clones in different regions of freshly isolated vibrissa follicles, with the corresponding regions of growth arrested, cultured follicles. Changes in the expression of some of these clones indicates that they could be related to fundamental cellular activities in the follicle. A library enriched for GE-specific clones therefore provides a useful source of candidate molecules for studies of follicular epithelial cell behaviour, both in vivo and in vitro.     

Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel

A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.     

The influence of pulsed low-intensity ultrasound on matrix production of chondrocytes at different stages of differentiation: an explant study

The proximal and distal parts of sterna of chick embryos represent cartilage undergoing endochondral ossification and hyaline cartilage, respectively. Cartilage explants from both regions were exposed for 20 min to pulsed low-intensity ultrasound (PLIUS) with an intensity of 30 mW. cm(-2) (spatial average-temporal average) at a frequency of 1.5 MHz, with a pulse burst frequency of 1 kHz and burst duration of 200 micros. Histological and immunohistochemical analysis was performed on days 1, 3, 5 and 7 after treatment. An anabolic effect of PLIUS on matrix production was shown by an increase of up to 10% to 20% in quantitative immunohistochemical staining for type II collagen and aggrecan in the two parts of the sternum. PLIUS also increased type X collagen staining by up to 10% in certain regions of the proximal part of the sternum. Staining for type X collagen was negative in the distal part of the sternum in both PLIUS and control groups. These results suggest that PLIUS may stimulate bone formation by increasing hypertrophy of chondrocytes directed to terminal differentiation. However, PLIUS did not induce hypertrophy in hyaline cartilage; moreover, increased matrix synthesis indicates a potential role in cartilage repair.     

Increases in quantities consumed in drinking occasions in New Zealand 1995-2004

Introduction and Aims. Significant changes have occurred in the alcohol environment in New Zealand recently and there has been debate about how trends in alcohol consumption may currently look. This paper reports trends in drinking over three general population samples in New Zealand. Design and Methods. Three nationally representative comparable surveys were analysed for trends in: prevalence of drinking, typical occasion quantity, annual frequency and heavier drinking (5+ drinks). Analyses assessed the mean difference of the measures at each year point. Adjustments for multiple comparisons were made. Analysis was undertaken for age and separately for gender. Results. Increases in quantities consumed on a typical occasion occurred for the majority of age groups between 1995 and 2000. Women were as likely as men to increase the quantities they consumed. Observing differences between age groups found that young people tended to show the greatest increases in quantity (including heavier drinking) and frequency of consumption between 1995 and 2000. Drinking levels remained relatively stable between 2000 and 2004 with the exception of increases in abstention for some of the younger groups and increases in quantities consumed and heavier drinking among some of the older men. Discussion and Conclusions. Increases in quantities consumed per occasion have occurred almost across the board between 1995 and 2000 in New Zealand. Women were as likely as men to increase the quantities they consumed. Young people tended to show the greatest increases in quantity (including heavier drinking) and frequency of consumption between 1995 and 2000. Drinking remained relatively stable between 2000 and 2004.[Huckle T, You RQ, Casswell S. Increases in quantities consumed in drinking occasions in New Zealand 1995–2004. Drug Alcohol Rev 2011;30:366–371]     

Comparison of hydrocarbon - DNA adducts formed in mouse skin in vivo and in organ culture in vitro following treatment with benzo[a]pyrene

Species differences in the metabolism of toxic chemicals canconfound the extrapolation of experimentally determined riskdata to man. However, it is often difficult to obtain reliableinformation on human metabolism, particularly of genotoxic agents.In this study, comparisons of chromatographic pro-flies of DNAadducts formed in vivo and in vitro have been applied to developand validate in vitro systems as models for the bioactivationof precursor genotoxic agents in vivo. Reversed phase h.p.l.c.analysis showed that the DNA adducts obtained from the skin(epidermal and dermal) of mice (CD₁, CF₁ and athymic nude mice)treated topically with [³H] or [¹⁴C]benzo[a]pyrene (BP) werequalitatively very similar to those formed in mouse (CD₁) skinexplant cultures. In each case the principal product was theN²-deoxyguanosine adduct, (+)-N²-(7R, 8S, 9R-trihydroxy-7, 8,9, 10-tetrahydrobenzo[a]-pyren-10S-yl)-2'-deoxyguanosine, derivedfrom (+)-7R, 8S,9R-trihydroxy-9R, 10R-epoxy-7, 8, 9, 10-tetrahydrobenzo[a]pyrene.The use of [¹⁴C]BP has provided an accurate reference profileof BP - DNA adducts formed in mouse skin in vivo. These findingsshow that mouse skin explants maintained in organ culture effectivelymimic the bioactivation of BP and the binding of the productsto the DNA of mouse skin in vivo. Such culture techniques arereadily transferable to human skin thus permitting the indirectdetermination of bioactivation pathways in human skin in vivofor comparison with those of mouse skin and other models usedto determine the human hazard. In principle, this approach tovalidate in vitro bioactivation systems may be applied to allhuman tissues.     

Protein kinase C inhibits epidermal growth factor-dependent tyrosine phosphorylation of phospholipase C gamma and activation of phosphoinositide hydrolysis.

Recent studies have shown that the receptor for epidermal growth factor (EGF) can associate with and tyrosine-phosphorylate the gamma-isozyme of phosphoinositide (PtdIns)-specific phospholipase C (PLC gamma), suggesting a possible mechanism for activation of PtdIns hydrolysis by EGF. In the present study, the coupling between PtdIns hydrolysis and PLC gamma tyrosine phosphorylation in WB liver epithelial cells was examined. Peak levels of [P-Tyr]PLC gamma, measured by anti-P-Tyr immunoblotting, occurred at 0.5-2 min of EGF treatment and coincided with the onset of [3H]inositol phosphate production. The termination of PtdIns hydrolysis after EGF stimulation was accompanied by return of [P-Tyr]PLC gamma to near-basal levels. Activation of protein kinase C (PKC) with a phorbol ester inhibited (IC50 = 3-10 nM) both EGF-dependent PtdIns hydrolysis and PLC gamma phosphorylation by more than 90%. Both EGF-stimulated responses were potentiated in cells depleted of PKC by prolonged phorbol ester treatment. At physiological ionic strength, monoclonal antibodies to PLC gamma specifically precipitated (in addition to PLC gamma) the EGF receptor and at least six other [P-Tyr]proteins from extracts of EGF-treated cells. PKC activation had differential effects on the tyrosine phosphorylation of these coprecipitating proteins, i.e. the relative abundance of certain [P-Tyr] proteins decreased, whereas that of another protein increased. In conclusion, EGF-stimulated tyrosine phosphorylation of PLC gamma is broadly correlated with stimulation of PtdIns hydrolysis, consistent with a role for tyrosine phosphorylation in PLC activation. The attendant diacylglycerol release and activation of PKC may terminate PLC gamma activation, in part by inhibiting PLC gamma phosphorylation by the EGF receptor. Our results suggest further that PKC may exert regulatory effects by altering the relationship of PLC gamma to its associated [P-Tyr]proteins.