13 research outputs found
Neuro4Neuro: A neural network approach for neural tract segmentation using large-scale population-based diffusion imaging
Subtle changes in white matter (WM) microstructure have been associated with
normal aging and neurodegeneration. To study these associations in more detail,
it is highly important that the WM tracts can be accurately and reproducibly
characterized from brain diffusion MRI. In addition, to enable analysis of WM
tracts in large datasets and in clinical practice it is essential to have
methodology that is fast and easy to apply. This work therefore presents a new
approach for WM tract segmentation: Neuro4Neuro, that is capable of direct
extraction of WM tracts from diffusion tensor images using convolutional neural
network (CNN). This 3D end-to-end method is trained to segment 25 WM tracts in
aging individuals from a large population-based study (N=9752, 1.5T MRI). The
proposed method showed good segmentation performance and high reproducibility,
i.e., a high spatial agreement (Cohen's kappa, k = 0.72 ~ 0.83) and a low
scan-rescan error in tract-specific diffusion measures (e.g., fractional
anisotropy: error = 1% ~ 5%). The reproducibility of the proposed method was
higher than that of a tractography-based segmentation algorithm, while being
orders of magnitude faster (0.5s to segment one tract). In addition, we showed
that the method successfully generalizes to diffusion scans from an external
dementia dataset (N=58, 3T MRI). In two proof-of-principle experiments, we
associated WM microstructure obtained using the proposed method with age in a
normal elderly population, and with disease subtypes in a dementia cohort. In
concordance with the literature, results showed a widespread reduction of
microstructural organization with aging and substantial group-wise
microstructure differences between dementia subtypes. In conclusion, we
presented a highly reproducible and fast method for WM tract segmentation that
has the potential of being used in large-scale studies and clinical practice.Comment: Preprint to be published in NeuroImag
Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer
In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.R35 GM118173 - NIGMS NIH HHS; U01 TR002625 - NCATS NIH HHS; P30 CA008748 - NCI NIH HHS; FC010144 - Cancer Research UK; FC010144 - Medical Research Council; FC010144 - Wellcome TrustPublished versio
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy
BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years
Envolvimento de canais de K+ sensíveis ao ATP (K+ ATP) na ação da testosterona sobre o potencial de membrana das células de Sertoli
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Efeito de bloqueadores de canais de Ca++ sobre a acão da testosterona no potencial de membrana das células de Sertoli
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Efeito de bloqueadores de canais de Ca++ sobre a acão da testosterona no potencial de membrana das células de Sertoli
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