ALK is a serine/threonine-specific protein kinase that directly or indirectly stimulates PI3K/AKT/mTOR, Ras GTPase, ERKs, Janus kinase, STAT proteins, and other cell signaling elements. Activation of these elements stimulates cell growth, proliferation, survival, and other tumor-promoting behaviors. As an example of this chromosomal translocation, the ALK gene located on the short or "p" arm of chromosome 2 at position 23 (notated as 2p23) merges with the CLTC gene on the long, i.e. "q" arm of chromosome 17 at position 13 (notated 17q23) to form a chimeric gene notated as t(2;17)(p23;q23). This chimeric gene makes a CLTC-ALK fusion protein with uncontrolled ALK serine/threonine-specific protein kinase activity. Other genes that fuse with AKT found in IMT include: TFG, DCTN1, EML4, TPM3, TPM4, ATIC RANBP2 (most if not all RAMB2-ALK chimeric genes occur in the EMIS form of IMT), CARS1, and SEC31L1. IMT cases may express other chimeric genes in which the active parts of ROS1 (found in 10% of IFT cases and coding for a tyrosine kinase which promotes cell growth), PDGFRB (coding for a protein that may promote the development of cancer), and NTRK (coding for a receptor tyrosine kinase that may promote the development of cancer) merge with other genes. The fusion protein products of these chimeric genes, like those of ALK fusion proteins, are overproduced, overactive, and thereby may contribute to the development of IMT. Diagnosis
Histopathologic examination of the tumors in IMT generally reveals myofibroblastic spindle cell sheets in a myxoid background (i.e.
By the end of the study, candesartan had significantly reduced the risk of hypertension, by more than 15%. Serious adverse effects were more common among participants receiving placebo than in those given candesartan. Prevention of atrial fibrillation
Results from a meta-analysis completed in 2005 demonstrated a reduction in atrial fibrillation in patients with systolic left ventricular dysfunction treated with candesartan, another angiotensin receptor blocker or an angiotensin converting enzyme inhibitor. Evidence for the use of candesartan specifically is also supported by an analysis of the CHARM study which demonstrated a reduction in atrial fibrillation in patients with systolic left ventricular dysfunction. While these studies have demonstrated a potential additional benefit for candesartan when used in patients with systolic left ventricular dysfunction, additional studies are required to further elucidate the role of candesartan in the prevention of atrial fibrillation in other population groups. Diabetic retinopathy
Use of antihypertensive drugs has been demonstrated to slow the progression of diabetic retinopathy; the role of candesartan specifically in reducing progression in type 1 and type 2 diabetes is still up for debate. Results from a 2008 study on patients with type 1 diabetes showed there was no benefit in using candesartan to reduce progression of diabetic retinopathy when compared to placebo. Candesartan has been demonstrated to reverse the severity (cause regression) of mild to moderate diabetic retinopathy in patients with type 2 diabetes.