Drug and Alcohol Rehabilitation: Modeling of Lamin A/C Mutation Premature Cardiac Aging Using Patient?Specific Induced Pluripotent Stem Cells.

Modeling of lamin A/C mutation premature cardiac aging using patient?specific induced pluripotent stem cells.

Filed under: Drug and Alcohol Rehabilitation

Aging (Albany NY). 2012 Nov; 4(11): 803-822
Siu CW, Lee YK, Ho JC, Lai WH, Chan YC, Ng KM, Wong LY, Au KW, Lau YM, Zhang J, Lay KW, Colman A, Tse HF

We identified an autosomal dominant non?sense mutation (R225X) in exon 4 of the lamin A/C (LMNA) gene in a Chinese family spanning 3 generations with familial dilated cardiomyopathy (DCM). In present study, we aim to generate induced pluripotent stem cells derived cardiomyocytes (iPSC?CMs) from an affected patient with R225X and another patient bearing LMNA frame?shift mutation for drug screening. METHODS andHigher prevalence of nuclear bleb formation and micronucleation was present in LMNA(R225X/WT) and LMNA(Framshift/WT) iPSC?CMs. Under field electrical stimulation, percentage of LMNA?mutated iPSC?CMs exhibiting nuclear senescence and cellular apoptosis markedly increased. shRNA knockdown of LMNA replicated those phenotypes of the mutated LMNA field electrical stress. Pharmacological blockade of ERK1/2 pathway with MEK1/2 inhibitors, U0126 and selumetinib (AZD6244) significantly attenuated the pro?apoptotic effects of field electric stimulation on the mutated LMNA iPSC?CMs.LMNA?related DCM was modeled in?vitro using patient?specific iPSC?CMs. Our results demonstrated that haploinsufficiency due to R225X LMNA non?sense mutation was associated with accelerated nuclear senescence and apoptosis of iPSC? CMs under electrical stimulation, which can be significantly attenuated by therapeutic blockade of stress?related ERK1/2 pathway.
HubMed – drug

 

2012 in review – Part I: The year’s new drugs & biologics.

Filed under: Drug and Alcohol Rehabilitation

Drugs Today (Barc). 2013 Jan; 49(1): 33-68
Graul AI, Lupone B, Cruces E, Stringer M

Thirty-seven new launches are considered in the first part of this annual review article, including 36 drugs and biologics that reached their first markets worldwide in 2012 and one additional drug that was launched at the end of December 2011. In addition, 26 significant new line extensions (new indications, new formulations and new combinations of existing drugs) that were launched for the first time in 2012 are discussed in this review. Also included are new drugs and biologics and new line extensions that were approved for the first time between January and December 2012, although they were not launched before the end of the year.
HubMed – drug

 

Enzalutamide for the treatment of castration-resistant prostate cancer.

Filed under: Drug and Alcohol Rehabilitation

Drugs Today (Barc). 2013 Jan; 49(1): 7-13
Ha YS, Goodin S, Dipaola RS, Kim IY

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, given the mechanistic heterogeneity due to a complex signal transduction network. Enzalutamide (MDV-3100), recently approved by the U.S. Food and Drug Administration (FDA) at a dose of 160 mg/day for the treatment of CRPC, blocks androgen signaling by directly binding to the androgen receptor (AR) and inhibiting nuclear translocation and coactivator recruitment of the ligand-receptor complex. In preclinical studies, enzalutamide has been shown to block the binding of AR to DNA, resulting in apoptosis and retardation of tumor growth. Clinically, a phase I/II study (N = 140) revealed that enzalutamide had an optimal safety profile and significant antitumor activity in patients with CRPC regardless of prior chemotherapy. In the AFFIRM phase III trial (N = 1,199), oral enzalutamide significantly improved survival in men with metastatic CRPC after chemotherapy. Currently, a phase III trial (PREVAIL) is under way to determine the effectiveness of enzalutamide in patients who have not received prior docetaxel chemotherapy.
HubMed – drug

 

Male osteoporosis: A review.

Filed under: Drug and Alcohol Rehabilitation

World J Orthop. 2012 Dec 18; 3(12): 223-34
Herrera A, Lobo-Escolar A, Mateo J, Gil J, Ibarz E, Gracia L

Osteoporosis in men is a heterogeneous disease that has received little attention. However, one third of worldwide hip fractures occur in the male population. This problem is more prevalent in people over 70 years of age. The etiology can be idiopathic or secondary to hypogonadism, vitamin D deficiency and inadequate calcium intake, hormonal treatments for prostate cancer, use of toxic and every disease or drug use that alters bone metabolism.Risk factors such as a previous history of fragility fracture should be assessed for the diagnosis. However, risk factors in men are very heterogeneous. There are significant differences in the pharmacological treatment of osteoporosis between men and women fundamentally due to the level of evidence in published trials supporting each treatment. New treatments will offer new therapeutic prospects. The goal of this work is a revision of the present status knowledge about male osteoporosis.
HubMed – drug

 

Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.

Filed under: Drug and Alcohol Rehabilitation

Sci Rep. 2013; 3: 1160
Yamaki T, Suenaga Y, Iuchi T, Alagu J, Takatori A, Itami M, Araki A, Ohira M, Inoue M, Kageyama H, Yokoi S, Saeki N, Nakagawara A

Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was an indicator of favourable prognosis. In human GBM cells, TMZ-induced TAp63 directly repressed MYC transcription. Activation of this TAp63-MYC pathway by TMZ inhibited human GBM progression both in vitro and in vivo. Furthermore, downregulation of MYC mRNA levels in recurrent GBMs after TMZ treatment correlated with better patient survival. Therefore, our results suggest that the TAp63-mediated transcriptional repression of MYC is a novel pathway regulating TMZ efficacy in GBM.
HubMed – drug

 

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