Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox) homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS). A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II binds with equal affinity to two main angiotensin receptors—type 1 (AT1R) and type 2 (AT2R). The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS). This Ang II-AT1R–NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell. AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a) report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b) discuss the effect of age-related activation of RAS on generation of free radicals.
Radiation therapy represents a vital component in the multidisciplinary management of soft tissue sarcomas. Combined with limb-preserving surgery, radiation therapy represents a standard of care treatment option for patients with high-grade sarcomas. Radiation therapy for soft tissue sarcoma continues to evolve with changes in timing, techniques, and targets. Over the past 2 decades, increasing data have supported the role of preoperative radiotherapy with the potential for lower total doses of radiation and improved long-term function coming at the cost of increased wound complications for certain locations. Retroperitoneal sarcomas represent a location where preoperative treatment is becoming the standard of care based on anatomic constraints and challenges with delivering postoperative radiotherapy. Multiple radiation therapy techniques exist to deliver treatment; currently both 3-dimensional conformal radiotherapy and intensity-modulated radiation therapy (IMRT) are appropriate options, although increasing data support the role of IMRT in reducing dose to critical structures (bone, bowel, kidneys, vessels) while maintaining target coverage. Traditional target volumes have included larger fields; however, recent prospective data have demonstrated that image guidance in conjunction with smaller treatment volumes may reduce toxicity while not increasing marginal failures, although follow-up is short. Because of the toxicity associated with treatment, novel radiotherapy strategies are being used such as stereotactic radiotherapy as well as the use of tumor genetics to identify patients most likely to benefit most from radiotherapy.
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