Ataxia Telangiectasia Mutated Protein Kinase: A Potential Master Puppeteer of Oxidative Stress-Induced Metabolic Recycling.

Ataxia Telangiectasia Mutated protein kinase (ATM) has recently come to the fore as a regulatory protein fulfilling many roles in the fine balancing act of metabolic homeostasis. Best known for its role as a transducer of DNA damage repair, the activity of ATM in the cytosol is enjoying increasing attention, where it plays a central role in general cellular recycling (macroautophagy) as well as the targeted clearance (selective autophagy) of damaged mitochondria and peroxisomes in response to oxidative stress, independently of the DNA damage response. The importance of ATM activation by oxidative stress has also recently been highlighted in the clearance of protein aggregates, where the expression of a functional ATM construct that cannot be activated by oxidative stress resulted in widespread accumulation of protein aggregates. This review will discuss the role of ATM in general autophagy, mitophagy, and pexophagy as well as aggrephagy and crosstalk between oxidative stress as an activator of ATM and its potential role as a master regulator of these processes.

HPV8 Field Cancerization in a Transgenic Mouse Model Is due to Lrig1+ Keratinocyte Stem Cell Expansion.

ß-Human papillomaviruses (HPVs) cause near ubiquitous latent skin infection within long-lived hair follicle (HF) keratinocyte stem cells. In patients with epidermodysplasia verruciformis, ß-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma. To determine the role of HF keratinocyte stem cells in ß-HPV-induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison with wild-type littermates consistent with a hyperproliferative epidermis. HF keratinocyte proliferation was evident within the Lrig1+ keratinocyte stem cell population (69 vs. 55%, P < 0.01, n = 7), and not in the CD34+, LGR5+, and LGR6+ keratinocyte stem cell populations. This was associated with a 2.8-fold expansion in Lrig1+ keratinocytes and 3.8-fold increased colony-forming efficiency. Consistent with this, we observed nuclear p63 expression throughout this population and the HF infundibulum and adjoining interfollicular epidermis, associated with a switch from p63 transcriptional activation isoforms to ΔNp63 isoforms in HPV8tg skin. Epidermodysplasia verruciformis keratosis and in some cases actinic keratoses demonstrated similar histology associated with ß-HPV reactivation and nuclear p63 expression within the HF infundibulum and perifollicular epidermis. These findings would suggest that ß-HPV field cancerization arises from the HF junctional zone and predispose to squamous cell carcinoma.

Access flow in arteriovenous accesses by optodilutional and ultrasound dilution methods.

BACKGROUND: Most large studies evaluating the diagnostic properties of access blood flow (Qa) in arteriovenous (AV) accesses have used the Transonic HD01 (Transonic Systems Inc, Ithaca, NY) device, and recommended thresholds for angiography are based on data from these studies. There has been little exploration of how the use of other devices might affect the feasibility or performance of screening in AV accesses. METHODS: We compared 2 devices for measuring Qa: the Transonic HD01 and the Crit-Line TQA III (Hemametrics, Salt Lake City, UT). We studied 124 adults with end-stage renal disease and a functioning AV access (fistula or graft). Qa was measured with both devices in immediate succession during a single dialysis treatment. The primary outcome was the technical feasibility of the Qa measurement. We also compared mean Qa values measured by the Crit-Line III and Transonic devices. RESULTS: Qa measurements were less likely to be technically feasible when the Crit-Line III device was used compared with the Transonic device (86.3% versus 100%; P < 0.001). In patients with valid measurements, mean Qa measured using the Crit-Line III was significantly less than that measured using the Transonic HD01 device (886 +/- 557 versus 1,148 +/- 685 mL/min; P < 0.001). The mean difference was 261 mL/min (95% confidence interval [CI], 117 to 405) and was greater at higher levels of Qa. On average, Qa measured by means of the Crit-Line III device was 73% as high as that measured using the Transonic device (95% CI, 63 to 84). There was poor agreement between devices about whether criteria for angiography were met (kappa < 0.1). The proportion of patients for whom angiography was indicated (based on results from the Crit-Line device) was significantly greater than when only results from the Transonic device were considered (40.3% versus 7.3%; P < 0.001). CONCLUSION: Consideration should be given to device-specific Qa thresholds for angiography or, alternatively, standardization of Qa results between manufacturers. Clinicians should be aware that Qa results cannot be compared directly between different devices, and access monitoring should be performed using a single technique in any given patient. Additional studies are required before the Crit-Line TQA device can be recommended for widespread use.