HER2 mediates PSMA/mGluR1-driven resistance to the DS-7423 dual PI3K/mTOR inhibitor in PTEN wild-type prostate cancer models

Prostate cancer remains a major cause of male mortality. Genetic alteration of the PI3K/AKT/mTOR pathway is one of the key events in tumor development and progression in prostate cancer, with inactivation of the PTEN tumor suppressor being very common in this cancer type. Extensive evaluation has been performed on the therapeutic potential of PI3K/AKT/mTOR inhibitors and the resistance mechanisms arising in patients with PTEN-mutant background. However, in patients with a PTEN wild-type phenotype, PI3K/AKT/mTOR inhibitors have not demonstrated efficacy, and this remains an area of clinical unmet need. In this study, we have investigated the response of PTEN wild-type prostate cancer cell lines to the dual PI3K/mTOR inhibitor DS-7423 alone or in combination with HER2 inhibitors or mGluR1 inhibitors. Upon treatment with the dual PI3K/mTOR inhibitor DS-7423, PTEN wild-type prostate cancer CWR22/22RV1 cells upregulate expression of the proteins PSMA, mGluR1, and the tyrosine kinase receptor HER2, while PTEN-mutant LNCaP cells upregulate androgen receptor and HER3. PSMA, mGluR1, and HER2 exert control over one another in a positive feedback loop that allows cells to overcome treatment with DS-7423. Concomitant targeting of PI3K/mTOR with either HER2 or mGluR1 inhibitors results in decreased cell survival and tumor growth in xenograft studies. Our results suggest a novel therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors

Crater Formation and Deuterium Production in Laser Irradiation of Polymers with Implanted Nano-antennas

Recent validation experiments on laser irradiation of polymer foils with and without implanted golden nano-particles are discussed. First we analyze characteristics of craters, formed in the target after its interaction with laser beam. Preliminary experimental results show significant production of deuterons when both the energy of laser pulse and concentration of nano-particles are high enough. We consider the deuteron production via the nuclear transmutation reactions $p+C\rightarrow d+X$ where protons are accelerated by Coulomb field, generated in the target plasma. We argue that maximal proton energy can be above threshold values for these reactions and the deuteron yield may noticeably increase due to presence of nano-particles.Comment: 9 pages, 4 figure

Recent trends in publication of basic science and clinical research by United States investigators in anesthesia journals

<p>Abstract</p> <p>Background</p> <p>United States anesthesia research production declined sharply from 1980-2005. Whether this trend has continued despite recent calls to improve output is unknown. We conducted an observational internet analysis to quantify American basic science and clinical anesthesia research output in 14 anesthesia journals with impact factors greater than one at three-year intervals during the past decade.</p> <p>Results</p> <p>American investigators published 1,486 (21.7%) of the total of 6,845 research articles identified in anesthesia journals in 2001, 2004, 2007, and 2010. Approximately two-thirds of all US articles were published in <it>Anesthesiology </it>and <it>Anesthesia and Analgesia</it>. There was a significant correlation (r²= 0.316; P = 0.036) between the number of articles published by American authors in each anesthesia journal and the corresponding journal's impact factor in 2010. Significantly (P < 0.05; Pearson's Chi-square) fewer basic science articles were published in 2007 and 2010 compared with 2001. US clinical research output also declined in 2007 (201; 15.7%) compared with 2001 (266; 19.1%) and 2004, but an increase occurred in 2010 (279; 21.8%, P < 0.05 versus 2007).</p> <p>Conclusions</p> <p>The results indicate that US anesthesia research output continued to decrease from 2001 to 2007. An increase in clinical but not basic science research was observed in 2010 compared with 2007, suggesting that a modest recovery in clinical research production may have begun.</p

[Open-heart surgery in Jehovah's witnesses].

The religious community Jehovah's Witnesses was founded in 1870. They hold that blood transfusion is against God's law. Surgical treatment of a Jehova witness is a great challenge for every surgeon, especially for cardiac surgeons because blood transfusion is frequently needed during such operations. Authors have been trying to reduce the utilization of preserved blood for ten years. This study is about the experience with Jehovah's Witnesses who have undergone open heart surgery in Debrecen. Twenty-four patients underwent open heart surgery from 1989 till May 1999. 7 of them were males and 17 were females. The mean age was 53 years (40-70 yrs). Three patients had congenital heart disease, 11 had acquired valve disease and 7 had coronary stenosis. In 3 cases the patients had combined coronary and valve disease. Authors used a complete procedure for reducing blood loss during the operations. Two patients (8.3%) died during the early postoperative period. Preoperative mean haemoglobin level was 134.2 g/l (112-166) and haematocrit value varied between 36-50% (mean 38%). On the first postoperative day significant decrease was registrated in these values. From the second day a slow but significant increase of haemoglobin and haematocrit levels were detected. The mean follow up time was 37.6 months (2-144), and the NYHA classification of 21 longtime survivors improved from 3.06 to 1.62. At the Department of Cardiac Surgery in Debrecen as well as worldwide more and more operations are done without blood or preserved blood products, so it could be said that nowadays surgical treatment of Jehovah's Witnesses has lower risk than before