Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer

BACKGROUND: Ras signalling is frequently aberrant in pancreatic cancer so that there is constitutive activation of the phosphatidylinositol 3-kinase (PI3K) and AKT/protein kinase B pathway, as well as the RAF/MEK/ERK pathway. AIMS: In the present study we investigated the role of the PI3K/AKT pathway in malignant transformation of pancreatic cancer cells. METHODS: A genetic approach was used to interfere with signal transduction in vitro and in vivo. RASN17, a dominant negative mutant of RAS, was applied to inhibit the PI3K/AKT pathway upstream of PI3K. The regulatory p85beta subunit of PI3K and the negative regulator PTEN were utilised to inhibit the pathway at the level of PI3K, and AAA-AKT, a dominant negative mutant of AKT was employed to interfere with PI3K/AKT signalling at the level of AKT. RESULTS: Antiproliferative, proapoptotic, and anticancer effects were documented, showing that inhibition of the PI3K pathway in these cell lines suppresses tumour cell growth in vitro and reduces growth in nude mice. CONCLUSIONS: The PI3K/AKT pathway represents a potential therapeutic target for pancreatic cancer, and gene therapy may be one approach to produce selective inhibition.     

Performance of the chronic kidney disease epidemiology collaboration equation to estimate glomerular filtration rate in diabetic patients

OBJECTIVE

The best method to estimate glomerular filtration rate (GFR) in diabetic patients is still largely debated. We compared the performance of creatinine-based formulas in a European diabetic population.

RESEARCH DESIGN AND METHODS

We compared the performance of Cockcroft and Gault, simplified Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equations in 246 diabetic patients by calculating the mean bias and the interquartile range (IQR) of the bias, 10% (P10) and 30% (P30) accuracies, and Bland-Altman plots. GFR was measured by inulin clearance.

RESULTS

For the whole population, the IQR was slightly lower for CKD-EPI, but the mean bias was lower and P10 and P30 were higher for MDRD. Similar results were observed in specific subgroups, including patients with mild renal insufficiency, obese patients, or type 2 diabetic patients.

CONCLUSIONS

In our population, the CKD-EPI formula does not exhibit better performance than the simplified MDRD formula for estimating GFR.Using a creatinine-based formula is the most common way to evaluate the glomerular filtration rate (GFR) in clinical practice. However, it can lead to an inaccurate evaluation, especially in patients with normal renal function (1). A new GFR formula, the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation, has recently been developed and has exhibited better performance than the other creatinine-based formulas in the general population (2). Therefore, we compared the performance of the CKD-EPI equation to Cockcroft and Gault (CG) and simplified Modification of Diet in Renal Disease (MDRD) equations in a population of diabetic patients.     

Lister vaccine strain of vaccinia virus armed with the endostatin-angiostatin fusion gene: an oncolytic virus superior to dl1520 (ONYX-015) for human head and neck cancer

Oncolytic viral therapy represents a promising strategy for the treatment of head and neck squamous cell carcinoma (HNSCC), with dl1520 (ONYX-015) the most widely used oncolytic adenovirus in clinical trials. This study aimed to determine the effectiveness of the Lister vaccine strain of vaccinia virus as well as a vaccinia virus armed with the endostatin-angiostatin fusion gene (VVhEA) as a novel therapy for HNSCC and to compare them with dl1520. The potency and replication of the Lister strain and VVhEA and the expression and function of the fusion protein were determined in human HNSCC cells in vitro and in vivo. Finally, the efficacy of VVhEA was compared with dl1520 in vivo in a human HNSCC model. The Lister vaccine strain of vaccinia virus was more effective than the adenovirus against all HNSCC cell lines tested in vitro. Although the potency of VVhEA was attenuated in vitro, the expression and function of the endostatin-angiostatin fusion protein was confirmed in HNSCC models both in vitro and in vivo. This novel vaccinia virus (VVhEA) demonstrated superior antitumor potency in vivo compared with both dl1520 and the control vaccinia virus. This study suggests that the Lister strain vaccinia virus armed with an endostatin-angiostatin fusion gene may be a potential therapeutic agent for HNSCC.     

Relaxant activity in rat aorta and trachea, conversion to a muscarinic receptor antagonist and structure-activity relationships of new K(ATP) activating 6-varied benzopyrans.

To characterize ATP-sensitive channels (K(ATP) channels) benzopyrans with different substituents at position 6 were synthesized as new K(ATP)-activators. Their relaxant potencies were determined in rat aorta and trachea. In aorta, pEC50-values (-log, M) ranged from 7.37 to 5.43; in trachea, pEC50-values were 0.3 to 0.8 log units lower. Functional data were compared with binding data obtained in calf tracheal cells using the cyanoguanidine [3H]P1075 (N-cyano-N'-1,1-dimethyl[2,3(n)-3H]propyl)-N11-(3-pyridinyl)guanidine) as radioligand. A high correlation (r = 0.96) between pEC50- and pKD-values indicated that tracheal relaxation produced by benzopyrans is mediated via K(ATP) channels without signal amplification. The permanently charged trimethylammonium derivative designed as a probe for the membrane site of action completely lost its affinity for K(ATP) channels, but converted to an antagonist for muscarinic acetylcholine receptors (pK(B) = 6.12+/-0.10), as confirmed in radioligand binding studies (pK(D) = 5.77+/-0.04). Structure-activity analyses revealed that the 6-substituent influences biological activity by a direct receptor interaction of its own and not indirectly by withdrawing electrons from the benzopyran nucleus. The variance of the biological activity is primarily determined by electrostatic properties, but desolvation energies additionally contribute.     

Si j’étais plus mince... ou les effets de la fée Rapidominceur!

Slim or stay fat... What have I got to lose, or to gain... And what if I lost everything... And what if I gained everything, including the realisation that I let those extra kilos ruin the first 40 years of my life... The arrival of the Fastslim Fairy in my life is making me think... And as usual, I have to weigh everything up... Including the advantages and disadvantages!     

Je suis gros(se), parce que... Paroles de personnes en surpoids

Far from the discussions of prominent professionals who study or care for them, here, we present the personal accounts of overweight people on the reasons they have gained weight. This provides an avenue for better understanding and, perhaps, better prevention and treatment of the condition.