Salt at Dawn, Salt in my Veins

A contemplation on expanded time, over generations along my maternal lineage; on being on the borders, embodying homeland; on inheritance and shared labor; occupying a void that is dense; looking towards dawn

Nanog, Oct4 and Tet1 interplay in establishing pluripotency

A few central transcription factors inside mouse embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are believed to control the cells’ pluripotency. Characterizations of pluripotent state were put forward on both transcription factor and epigenetic levels. Whereas core players have been identified, it is desirable to map out gene regulatory networks which govern the reprogramming of somatic cells as well as the early developmental decisions. Here we propose a multiple level model where the regulatory network of Oct4, Nanog and Tet1 includes positive feedback loops involving DNA-demethylation around the promoters of Oct4 and Tet1. We put forward a mechanistic understanding of the regulatory dynamics which account for i) Oct4 overexpression is sufficient to induce pluripotency in somatic cell types expressing the other Yamanaka reprogramming factors endogenously; ii) Tet1 can replace Oct4 in reprogramming cocktail; iii) Nanog is not necessary for reprogramming however its over-expression leads to enhanced self-renewal; iv) DNA methylation is the key to the regulation of pluripotency genes; v) Lif withdrawal leads to loss of pluripotency. Overall, our paper proposes a novel framework combining transcription regulation with DNA methylation modifications which, takes into account the multi-layer nature of regulatory mechanisms governing pluripotency acquisition through reprogramming

Changes in Tear Cytokines Following a Short Period of Daily and Overnight Silicone Hydrogel Lens Wear

Background and Objective: To investigate changes in ocular surface inflammatory markers after daily and overnight silicone hydrogel contact lens wear in healthy wearers.
 Material and Methods: Twenty-six experienced soft contact lens subjects were evaluated at baseline, after 1-day of silicone hydrogel lens wear, and after 1-night of wear. Basal tears were collected at each visit and tear cytokine concentrations were quantified using multiplex [interleukin (IL)-1β, IL-6, IL-10, IL-12(p70), IL-17A and tumor necrosis factor (TNF)-α] or ELISA (IL-8) kits. A historical control group of 27 non-contact lens wearers was used to compare absolute concentrations and diurnal variations in tear cytokine concentrations. Changes in cytokine concentrations were analyzed using linear mixed models. Linear regression with bootstrapping was used to assess whether changes in IL-1β concentrations were associated with changes in other cytokines.
 Results: IL-8 concentrations decreased after 1 day of silicone hydrogel contact lens wear and returned to baseline levels the next morning (p=0.04). This same diurnal fluctuation was seen in non-contact lens wearers (p=0.03). With daily contact lens wear, there was a significant positive correlation between the changes in IL-1β and IL-8, TNF-α, IL-10 and IL-12(p70) (all p<0.03). With overnight contact lens wear, there were significant positive correlations between the changes in IL-1β and IL-6, IL-17A and TNF-α (all p<0.01).
 Conclusion: A short period of daily and overnight silicone hydrogel lens wear does not significantly alter the inflammatory status in adapted soft contact lens wearers

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer.

Tumors adapt to an unfavorable microenvironment by controlling the balance between cell proliferation and cell motility, but the regulators of this process are largely unknown. Here, we show that an alternatively spliced isoform of syntaphilin (SNPH), a cytoskeletal regulator of mitochondrial movements in neurons, is directed to mitochondria of tumor cells. Mitochondrial SNPH buffers oxidative stress and maintains complex II-dependent bioenergetics, sustaining local tumor growth while restricting mitochondrial redistribution to the cortical cytoskeleton and tumor cell motility. Conversely, introduction of stress stimuli to the microenvironment, including hypoxia, acutely lowered SNPH levels, resulting in bioenergetics defects and increased superoxide production. In turn, this suppressed tumor cell proliferation but increased tumor cell invasion via greater mitochondrial trafficking to the cortical cytoskeleton. Loss of SNPH or expression of an SNPH mutant lacking the mitochondrial localization sequence resulted in increased metastatic dissemination in xenograft or syngeneic tumor models in vivo. Accordingly, tumor cells that acquired the ability to metastasize in vivo constitutively downregulated SNPH and exhibited higher oxidative stress, reduced cell proliferation, and increased cell motility. Therefore, SNPH is a stress-regulated mitochondrial switch of the cell proliferation-motility balance in cancer, and its pathway may represent a therapeutic target

Contemporary analysis of Reexcision and Conversion to Mastectomy Rates and associated Healthcare Costs For Women Undergoing Breast-Conserving Surgery

PURPOSE: This study was designed to provide a comprehensive and up-to-date understanding of population-level reoperation rates and incremental healthcare costs associated with reoperation for patients who underwent breast-conserving surgery (BCS). METHODS: This is a retrospective cohort study using Merative™ MarketScan RESULTS: The commercial cohort included 17,129 women with a median age of 55 (interquartile range [IQR] 49-59) years, and the Medicare cohort included 6977 women with a median age of 73 (IQR 69-78) years. Overall reoperation rates were 21.1% (95% confidence interval [CI] 20.5-21.8%) for the commercial cohort and 14.9% (95% CI 14.1-15.7%) for the Medicare cohort. In both cohorts, reoperation rates decreased as age increased, and conversion to mastectomy was more prevalent among younger women in the commercial cohort. The mean healthcare costs during 1 year of follow-up from the initial BCS were $95,165 for the commercial cohort and$36,313 for the Medicare cohort. Reoperations were associated with 24% higher costs in both the commercial and Medicare cohorts, which translated into $21,607 and$8559 incremental costs, respectively. CONCLUSIONS: The rates of reoperation after BCS have remained high and have contributed to increased healthcare costs. Continuing efforts to reduce reoperation need more attention