Cardiomyocyte-specific inactivation of thyroid hormone in pathologic ventricular hypertrophy: an adaptative response or part of the problem?

Recent studies in various rodent models of pathologic ventricular hypertrophy report the re-expression of deiodinase type 3 (D3) in cardiomyocytes. D3 inactivates thyroid hormone (T3) and is mainly expressed in tissues during development. The stimulation of D3 activity in ventricular hypertrophy and subsequent heart failure is associated with severe impairment of cardiac T3 signaling. Hypoxia-induced signaling appears to drive D3 expression in the hypertrophic cardiomyocyte, but other signaling cascades implicated in hypertrophy are also capable of stimulating transcription of the DIO3 gene. Many cardiac genes are transcriptionally regulated by T3 and impairment of T3 signaling will not only reduce energy turnover, but also lead to changes in gene expression that contribute to contractile dysfunction in pathologic remodeling. Whether stimulation of D3 activity and the ensuing local T3-deficiency is an adaptive response of the stressed heart or part of the pathologic signaling network leading to heart failure, remains to be established

Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control [Corrigendum]

Shen YA, Shyu IL, Lu M, et al. Int J Nanomedicine. 2015; 10:2485–2502.The authors advise that Figure 2B on page 2490 contains the incorrect image for the EP group. The correct Figure 2B image is shown below.Read the original articl

Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control

Yao An Shen,1,* Ing Luen Shyu,2,* Maggie Lu,3 Chun Lin He,4 Yen Mei Hsu,2 Hsiang Fa Liang,3 Chih Peng Liu,3 Ren Shyan Liu,5,6 Biing Jiun Shen,7 Yau Huei Wei,1 Chi Mu Chuang2,4 1Institute of Biochemistry and Molecular Biology, School of Life Sciences, 2Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, 3Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 4Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 5Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, 6National PET/Cyclotron Center, Taipei Veterans General Hospital, Taipei, Taiwan; 7Division of Psychology, Nanyang Technological University, Singapore *These authors contributed equally to the work Abstract: The current enhanced permeability and retention (EPR)-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil®, the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal) delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial-mesenchymal transition, angiogenesis signals, and multidrug resistance in the tumor microenvironment. Metastases to vital organs (eg, lung, liver, and lymphatic system) are also better controlled by intraperitoneal delivery of nanomedicine than by standard systemic delivery of the corresponding free drug. Moreover, the intraperitoneal delivery of nanomedicine has the potential to replace hyperthermic intraperitoneal chemotherapy because it shows equal efficacy and lower toxicity. In terms of efficacy, exploiting the EPR effect may not be the best approach for developing a nanomedicine. Because intraperitoneal chemotherapy is a type of regional chemotherapy, the pharmaceutical industry might consider the regional delivery of nanomedicine as a valid alternative pathway to develop their nanomedicine(s) with the goal of better tumor control in the future. Keywords: enhanced permeability and retention effect, liposome, paclitaxel, ovarian cancer&nbsp