Design,synthesis, docking,Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein from Staphylococcus aureus

It is of interest to document the design, synthesis, docking, Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein (PDB ID: 3VOB) from Staphylococcus aureus for antimicrobial applications. We report the quantitative structure function data in this context.     

Cytologic and histologic findings in multiple renal hybrid oncocytic tumors in a patient with Birt-Hogg-Dubé syndrome: a case report

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant neoplastic syndrome characterized by multiple skin lesions, lung cysts and renal tumors. A variety of histologic types of renal tumors have been reported, including clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, oncocytoma and a recently described hybrid oncocytic tumor, which is thought to be highly associated with BHD. CASE: We report a case of a 48-year-old woman with BHD who initially presented to our institution with spontaneous pneumothorax and was found to have multiple lung cysts and renal tumors on computed tomography. We describe the fine needle aspiration findings of one of the renal tumors, which was suggestive of so-called hybrid oncocytic tumor. We also describe the gross and histologic findings of the multiple kidney tumors that the patient subsequently had excised. CONCLUSION: When multiple kidney tumors from a single patient appear oncycytic on fine needle aspiration, especially when focal clear cells are present, the possibility of oncocytomas and hybrid tumors associated with BHD must be entertained.     

Application of alpha-methylacyl coenzyme A racemase immunohistochemistry in the diagnosis of prostate cancer: a review

Alpha-methylacyl coenzyme A racemase (AMACR) is a recently discovered enzyme protein that has been shown to be increased at both the mRNA and protein levels in prostatic adenocarcinoma as compared with normal prostatic tissues. Since its discovery, AMACR has gained wide acceptance for use in the diagnosis of prostatic adenocarcinoma in conjunction with morphology and immunohistochemical staining for basal cell markers. Numerous studies have consistently shown high sensitivity and specificity of AMACR for prostate cancer. This review focuses on AMACR expression in prostate cancer and its morphologic variants, high grade prostatic intraepithelial neoplasia, adenosis and benign conditions of the prostate. In addition, we discuss AMACR expression in other tumors. We also focus on the utility and technical aspects of the now-popular "triple stain" immunohistochemical antibody cocktail, consisting of antibodies to high-molecular-weight keratin, p63 and AMACR. Finally, we emphasize diagnostic pitfalls in the application of AMACR to small, atypical foci of glands seen on prostate needle core biopsy and project future diagnostic as well as clinical applications for the protein.     

Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid

Valproic acid (VPA) is used to treat epilepsy and bipolar disorder and to prevent migraine. It is also undergoing trials for cancer therapy. However, the biochemical and molecular biological actions of VPA are poorly understood. Using the social amoeba Dictyostelium discoideum, we show that an acute effect of VPA is the inhibition of chemotactic cell movement, a process partially dependent upon phospholipid signaling. Analysis of this process shows that VPA attenuates the signal-induced translocation of PH(Crac)-green fluorescent protein from cytosol to membrane, suggesting the inhibition of phosphatidylinositol-(3,4,5)-trisphosphate (PIP(3)) production. Direct labeling of lipids in vivo also shows a reduction in PIP and PIP(2) phosphorylation following VPA treatment. We further show that VPA acutely reduces endocytosis and exocytosis-processes previously shown to be dependent upon PIP(3) production. These results suggest that in Dictyostelium, VPA rapidly attenuates phospholipid signaling to reduce endocytic trafficking. To examine this effect in a mammalian model, we also tested depolarization-dependent neurotransmitter release in rat nerve terminals, and we show that this process is also suppressed upon application of VPA and an inhibitor of phosphatidylinositol 3-kinase. Although a more comprehensive analysis of the effect of VPA on lipid signaling will be necessary in mammalian systems, these results suggest that VPA may function to reduce phospholipid signaling processes and thus may provide a novel therapeutic effect for this drug.     

Irish public perceptions and attitudes to modern biotechnology: an overview with a focus on GM foods

This article summarizes the current situation pertaining to modern biotechnology in Ireland, with a particular focus on genetically modified (GM) crops. It briefly examines some important results of the major national surveys carried out in Ireland since 1989, highlights the recent upsurge in media (newspaper) coverage of GM related stories in three Irish opinion leader publications and it allows for an insight into the Irish public's relationship with modern biotechnology.     

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone, (HDMP) to prevent ‘trafficking’ of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the ‘blood brain barrier (BBB)’. Three men with newly diagnosed PCNSL, ages 62, 76 and 78 y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin’s lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70 y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.     

Novel Tn4371-ICE like element in Ralstonia pickettii and Genome mining for comparative elements

Background  

Integrative Conjugative Elements (ICEs) are important factors in the plasticity of microbial genomes. An element related to the ICE Tn4371 was discovered during a bioinformatic search of the Ralstonia pickettii 12J genome. This element was analysed and further searches carried out for additional elements.     

The neuroprotective agent, valproic acid, regulates the mitogen-activated protein kinase pathway through modulation of protein kinase A signalling in Dictyostelium discoideum

Activation of the mitogen-activated protein kinase (MAPK) cascade gives rise to a neuroprotective effect in a variety of cell types. The bipolar disorder treatment, valproic acid (VPA), increases the activity of this pathway by modulating extracellular signal-regulated kinase 2 (ERK2) phosphorylation through an unknown mechanism. To investigate the molecular basis of this effect, we have used the biomedical model system Dictyostelium discoideum to dissect this signalling pathway. We find that, similar to mammalian systems, VPA causes a transient increase in the activation of the MAPK signalling pathway, as shown by ERK2 phosphorylation. We show that the MAP kinase and phosphatase, protein kinase A (PKA) and glycogen synthase kinase signalling pathways all function in controlling the levels of phospho-ERK2 (pERK2). We find that VPA induces elevated pERK2 levels through attenuation of the PKA signalling pathway. Interestingly, pERK2 levels are also controlled by another bipolar disorder drug, lithium, providing a common effect of these two drugs. This work therefore suggests a conserved pathway in eukaryotes that is targeted by neuroprotective and bipolar disorder drugs and allows us to propose a model for this neuroprotective effect.     

Diagnostic value of cytokeratin 7 and parvalbumin in differentiating chromophobe renal cell carcinoma from renal oncocytoma

OBJECTIVE: To investigate the diagnostic value of cytokeratin 7 (CK7) and parvalbumin at mRNA and protein levels. STUDY DESIGN: CK7 and parvalbumin mRNA expression levels in 23 oncocytomas and 32 chromophobe renal cell carcinomas (RCCs) were examined using gene expression microarrays. Immunohistochemistry was performed using monoclonal antibodies specific for CK7 or parvalbumin in 41 chromophobe RCCs and 55 oncocytomas. RESULTS: CK7 mRNA was overexpressed in 18 of 32 chromophobe RCCs but only 3 of 23 oncocytomas. Parvalbumin mRNA was overexpressed in 15 of 32 chromophobe RCCs and only 4 of 23 oncocytomas. In contrast, CK7 mRNA underexpression was noted in 13 of 23 oncocytomas and only 6 of 32 chromophobe RCCs, while parvalbumin underexpression was seen in 14 of 23 oncocytomas but only 6 of 32 chromophobe RCCs. By immunohistochemistry, 27 of 41 (66%) chromophobe RCCs expressed CK7 diffusely compared to only 3 of 55 (5%) oncocytomas. Diffuse parvalbumin expression was seen in all 41 of 41 (100%) chromophobe RCCs and only in 26 of 55 (47%) oncocytomas. CONCLUSION: Both mRNA and protein expression levels of CK7 appear significantly higher in chromophobe RCC compared to oncocytoma (p < 0.001). Parvalbumin expression is less specific but often displays a patchy pattern in oncocytomas. Our study provides further evidence that CK7 and parvalbumin immunostains may be useful in differentiating oncocytoma from chromophobe RCC in problematic cases. Negative or patchy staining (< 50% cells) for CK7 and/or parvalbumin strongly favors the diagnosis of oncocytoma.