Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG)

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65?years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.     

Lkb1 regulates organogenesis and early oncogenesis along AMPK-dependent and -independent pathways

The tumor suppressor Lkb1/STK11/Par-4 is a key regulator of cellular energy, proliferation, and polarity, yet its mechanisms of action remain poorly defined. We generated mice harboring a mutant Lkb1 knockin allele that allows for rapid inhibition of Lkb1 kinase. Culturing embryonic tissues, we show that acute loss of kinase activity perturbs epithelial morphogenesis without affecting cell polarity. In pancreas, cystic structures developed rapidly after Lkb1 inhibition. In lung, inhibition resulted in cell-autonomous branching defects. Although the lung phenotype was rescued by an activator of the Lkb1 target adenosine monophosphate–activated kinase (AMPK), pancreatic cyst development was independent of AMPK signaling. Remarkably, the pancreatic phenotype evolved to resemble precancerous lesions, demonstrating that loss of Lkb1 was sufficient to drive the initial steps of carcinogenesis ex vivo. A similar phenotype was induced by expression of mutant K-Ras with p16/p19 deletion. Combining culture of embryonic tissues with genetic manipulation and chemical genetics thus provides a powerful approach to unraveling developmental programs and understanding cancer initiation.     

Proteomic analysis of cell suspension cultures of Boesenbergia rotunda induced by phenylalanine: identification of proteins involved in flavonoid and phenylpropanoid biosynthesis pathways

Boesenbergia rotunda belongs to the Zingiberaceae family. It is widely found throughout Southeast Asia and is commonly used as a food ingredient and in folk medicine. Extracts from this plant contain a number of important bioactive compounds such as boesenbergin, cardamonin, pinostrobin, pinocembrin, panduratin A and 4-hydroxypanduratin A. These compounds have been shown to exhibit anti-HIV protease, anti-dengue NS2B/ NS3 protease, antibacterial, antifungal, anti-inflammatory, anticancer, and antioxidant activity. Here we report the use of proteomic approaches to identify proteins that may be involved in the biosynthesis of these compounds. Protein expressions of B. rotunda suspension cultures for phenylalanine-treated and normal callus were compared by two-dimensional gel electrophoresis. Following image analysis, protein spots whose expressions were found to be regulated were identified using Matrix Assisted Laser Desorption-Ionization tandem mass spectrometry. In all, thirty four proteins were identified. These proteins were categorized into nine functional categories??defence mechanism, protein biosynthesis, metabolism, terpenoid biosynthesis, cell division, cell organization, energy-related, signaling processes and proteins of unknown function. Eleven of the proteins involved in the phenylpropanoid biosynthetic pathway are related to the biosynthesis of cyclohexenyl chalcone derivatives.     

Regulation of neuronal bioenergy homeostasis by glutamate

Bioenergy homeostasis is crucial in maintaining normal cell function and survival and it is thus important to understand cellular mechanisms underlying its regulation. Neurons use a large amount of ATP to maintain membrane potential and synaptic communication, making the brain the most energy consuming organ in the body. Glutamate mediates a large majority of synaptic transmission which is responsible for the expression of neural plasticity and higher brain functions. Most of the energy cost is attributable to the glutamatergic system; under pathological conditions such as stroke and brain ischemia, neural energy depletion is accompanied by a massive release of glutamate. However, the specific cellular processes implicated in glutamate-dependent bioenergy dynamics are not well understood. We find that glutamate induces a rapid and dramatic reduction of ATP levels in neurons, through reduced ATP genesis and elevated consumption. ATP reduction depends on NMDA receptor activity, but is not a result of neuronal firing, gap junction-mediated leaking or intracellular signaling. Similar changes in ATP levels are also induced by synaptic glutamate accumulation following suppression of glutamate transporter activity. Furthermore, the glutamate-induced ATP down-regulation is blocked by the sodium pump inhibitor ouabain, suggesting the sodium pump as the primary energy consumer during glutamate stimulation. These data suggest the important role of glutamate in the control of cellular ATP homeostasis.     

S-Nitrosylation of platelet alphaIIbbeta3 as revealed by Raman spectroscopy

The exact mechanisms regulating conformational changes in the platelet-specific integrin alphaIIbbeta3 are not fully understood. However, a role exists for thiol/disulfide exchange in integrin conformational changes leading to altered disulfide bonding patterns, via its endogenous thiol isomerase activity. Nitric oxide (NO) accelerates this intrinsic enzymatic activity and, in doing so, reverses the activational state of the integrin on the platelet surface toward a more unactivated one. We propose that it is an S-nitrosylation-induced "shuffling" of thiol/disulfide exchange that regulates this reversal of the activated state of the integrin. In this study, we use Raman spectroscopy to explore S-nitrosylation of purified alphaIIbbeta3. Using S-nitrosoglutathione (GSNO) as a model system, we identify Raman markers which show a direct interaction between NO and the thiol groups of the integrin and reveal many of the structural changes that occur in alphaIIbbeta3 in the course of not only its activation but also its deactivation. Key conformational changes are detected within the integrin when treated with manganese (Mn2+), occurring mainly in the cysteine and disulfide regions of the protein, confirming the importance of thiol/disulfide exchange in integrin activation. These changes are subsequently shown to be reversed in the presence of NO.     

Mannose-resistant Proteus-like and P. mirabilis fimbriae have specific and additive roles in P. mirabilis urinary tract infections

Proteus mirabilis is an important uropathogen that can cause complicated urinary tract infections (UTI). It produces several types of fimbriae, including mannose-resistant Proteus-like (MR/P) fimbriae and P. mirabilis fimbriae (PMF). Previously, we determined that these fimbriae affect the ability of P. mirabilis to colonize the urinary tract. The objective of this study was to analyse the effect of the simultaneous lack of P. mirabilis MR/P and PMF fimbriae in UTI pathogenesis. A double mutant lacking both fimbriae was generated by allelic replacement mutagenesis. This mutant was characterized genetically and phenotypically, and tested using an in vitro uroepithelial cell adhesion assay and the ascending UTI murine model. In vitro adhesion to uroepithelial cells by the P. mirabilis pmfA/mrpA-D mutant was reduced when compared with the wild-type, although no significant differences were observed when it was compared with the single mrpA-D and pmfA mutants. However, in vivo assays showed that colonization of kidneys and bladders by the P. mirabilis pmfA/mrpA-D mutant was significantly reduced when compared with the wild-type and both single mutants. These results indicate that, although redundancy can occur, MR/P and PMF fimbriae have specific and additive roles in P. mirabilis UTI.     

Phloem phytochemistry and aphid responses to elevated CO2, nitrogen fertilization and endophyte infection

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Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial

Introduction

Calcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy.

Methods

Patients with CPPD arthropathy were randomized to receive either weekly subcutaneous injections of 15 mg/week of MTX or placebo (PBO) for three months, in a double-blind, crossover randomized controlled trial. Inclusion criteria comprised definite CPPD disease, recurrent arthritis or persistent polyarthritis, and an insufficient response to NSAIDs, glucocorticoids or colchicine. The primary outcome was an improvement in the disease activity scores based on 44 joints (DAS44). The analysis was performed on an intent-to-treat basis.

Results

We randomized 26 patients, and compared 25 treatment periods on MTX with 21 treatment periods on PBO. Baseline characteristics were balanced between the groups. The evolution of the DAS44 was not statistically significantly different between groups (median DAS44 decreased by −0.08 on MTX versus −0.13 on PBO, after three months, P = 0.44). Furthermore, pain levels remained stable in both groups (median change in VAS Pain −1 unit on MTX and 0 on PBO, P = 0.43), and none of the secondary outcomes was significantly different between the two groups. Minor adverse events (AE) did not differ in frequency between the groups, but the only serious AE occurred on MTX (bicytopenia).

Conclusions

The results of this trial with MTX in this older population with chronic or recurrent CPPD arthropathy suggest no strong effect of MTX on disease activity.

Trial registration

EudraCT No: 2007-003479-37. Registered 26 April 2008