Synthesis and preliminary assessment of the anticancer and Wnt/β-catenin inhibitory activity of small amide libraries of fenamates and profens

As part of an ongoing program to study the anticancer activity of non-steroidal anti-inflammatory drugs (NSAIDs) through generating diversity libraries of multiple NSAID scaffolds, we synthesized a series of NSAID amide derivatives and screened these sets against three cancer cell lines (prostate, colon and breast) and Wnt/β-catenin signaling. The evaluated amide analog libraries show significant anticancer activity/cell proliferation inhibition, and specific members of the sets show inhibition of Wnt/β-catenin signaling.</p

Die Thrombozytenaggregation nach vaginaler Hysterektomie unter kombinierter Thromboembolieprophylaxe mit Macrodex&lt;sup&gt;®&lt;/sup&gt; 6 % und Sintrom&lt;sup&gt;®&lt;/sup&gt;

Bei 25 wegen Descensus vaginae et uteri vaginal hysterektomierten und kolporrhaphierten Frauen wurde unter Frühund Spätthromboembolieprophylaxe (Macrodex® 6% 500 ml intraoperativ und Sintrom® ab dem 1. postoperativen Tag) die ADP- und Kollagen-induzierte Thrombozytenaggregation untersucht und statistisch überprüft. Die Aggregabilität der Thrombozyten nimmt unabhängig von der Konzentration und der Art des im Aggregationstest zugefügten Agens nach Dextran-60-.Gabe um die Hälfte 2 Stunden postoperativ ab und halt bis zum 1. postoperativen Tag an. Die Ausgangswerte werden um den 4. postoperativen Tag wieder erreicht. Die Desaggregationsge-schwindigkeit und -stärke weisen ein umgekehrtes Verhalten auf. Eine Abhängigkeit vom Alter und von der Zyklusphase (Proliferationsphase, Sekretionsphase und Postmenopause) lieβ sich nicht finden. Bei der Durchführung dieser kombinierten Thromboembolieprophylaxe erscheint ein ausreichender Schutz sowohl der intraals auch der postoperativen Gefährdungsphase gegeben.</jats:p

Microbial Mat Compositional and Functional Sensitivity to Environmental Disturbance

The ability of ecosystems to adapt to environmental perturbations depends on the duration and intensity of change and the overall biological diversity of the system. While studies have indicated that rare microbial taxa may provide a biological reservoir that supports long-term ecosystem stability, how this dynamic population is influenced by environmental parameters remains unclear. In this study, a microbial mat ecosystem located on San Salvador Island, The Bahamas was used as a model to examine how environmental disturbance affects the protein synthesis potential (PSP) of rare and abundant archaeal and bacterial communities and how these changes impact potential biogeochemical processes. This ecosystem experienced a large shift in salinity (230 to 65 g kg(-1)) during 2011–2012 following the landfall of Hurricane Irene on San Salvador Island. High throughput sequencing and analysis of 16S rRNA and rRNA genes from samples before and after the pulse disturbance showed significant changes in the diversity and PSP of abundant and rare taxa, suggesting overall compositional and functional sensitivity to environmental change. In both archaeal and bacterial communities, while the majority of taxa showed low PSP across conditions, the overall community PSP increased post-disturbance, with significant shifts occurring among abundant and rare taxa across and within phyla. Broadly, following the post-disturbance reduction in salinity, taxa within Halobacteria decreased while those within Crenarchaeota, Thaumarchaeota, Thermoplasmata, Cyanobacteria, and Proteobacteria, increased in abundance and PSP. Quantitative PCR of genes and transcripts involved in nitrogen and sulfur cycling showed concomitant shifts in biogeochemical cycling potential. Post-disturbance conditions increased the expression of genes involved in N-fixation, nitrification, denitrification, and sulfate reduction. Together, our findings show complex community adaptation to environmental change and help elucidate factors connecting disturbance, biodiversity, and ecosystem function that may enhance ecosystem models

Diffusion MRI in peripheral nerves: Optimized <em>b</em> values and the role of non-Gaussian diffusion.

Background Diffusion-weighted imaging (DWI) provides specific in vivo information about tissue microstructure, which is increasingly recognized for various applications outside the central nervous system. However, standard sequence parameters are commonly adopted from optimized central nervous system protocols, thus potentially neglecting differences in tissue-specific diffusional behavior. Purpose To characterize the optimal tissue-specific diffusion imaging weighting scheme over the b domain in peripheral nerves under physiologic and pathologic conditions. Materials and Methods In this prospective cross-sectional study, 3-T MR neurography of the sciatic nerve was performed in healthy volunteers (n = 16) and participants with type 2 diabetes (n = 12). For DWI, 16 b values in the range of 0-1500 sec/mm2 were acquired in axial and radial diffusion directions of the nerve. With a region of interest-based approach, diffusion-weighted signal behavior as a function of b was estimated using standard monoexponential, biexponential, and kurtosis fitting. Goodness of fit was assessed to determine the optimal b value for two-point DWI/diffusion tensor imaging (DTI). Results Non-Gaussian diffusional behavior was observed beyond b values of 600 sec/mm2 in the axial and 800 sec/mm2 in the radial diffusion direction in both participants with diabetes and healthy volunteers. Accordingly, the biexponential and kurtosis models achieved a better curve fit compared with the standard monoexponential model (Akaike information criterion &gt;99.9% in all models), but the kurtosis model was preferred in the majority of cases. Significant differences between healthy volunteers and participants with diabetes were found in the kurtosis-derived parameters Dk and K. The results suggest an upper bound b value of approximately 700 sec/mm2 for optimal standard DWI/DTI in peripheral nerve applications. Conclusion In MR neurography, an ideal standard diffusion-weighted imaging/diffusion tensor imaging protocol with b = 700 sec/mm2 is suggested. This is substantially lower than in the central nervous system due to early-occurring non-Gaussian diffusion behavior and emphasizes the need for tissue-specific b value optimization. Including higher b values, kurtosis-derived parameters may represent promising novel imaging markers of peripheral nerve disease. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Jang and Du in this issue

Structural nerve remodeling at 3-t mr neurography differs between painful and painless diabetic polyneuropathy in type 1 or 2 diabetes.

Background: The pathophysiologic mechanisms underlying painful symptoms in diabetic polyneuropathy (DPN) are poorly understood.They may be associated with MRI characteristics, which have not yet been investigated.Purpose: To investigate correlations between nerve structure, load and spatial distribution of nerve lesions, and pain in patients with DPN.Materials and Methods: In this prospective single-center cross-sectional study, participants with type 1 or 2 diabetes volunteered between June 2015 and March 2018. Participants underwent 3-T MR neurography of the sciatic nerve with a T2-weighed fat-suppressed sequence, which was preceded by clinical and electrophysiologic tests. For group comparisons, analysis of variance or the Kruskal-Wall is test was performed depending on Gaussian or non-Gaussian distribution of data. Spearman correlation coefficients were calculated for correlation analysis.Results: A total of 131 participants (mean age, 62 years +/- 11 [standard deviation]; 82 men) with either type 1 (n = 45) or type 2 (n = 86) diabetes were evaluated with painful (n = 64), painless (n = 37), or no (n = 30) DPN. Participants who had painful diabetic neuropathy had a higher percentage of nerve lesions in the full nerve volume (15.2% +/- 1.6) than did participants with nonpainful DPN (10.4% +/- 1.7, P = .03) or no DPN (8.3% +/- 1.7; P&lt;.001). The amount and extension of T2-weighted hyperintense nerve lesions correlated positively with the neuropathy disability score (r = 0.37; 95% confidence interval [CI]: 0.21, 0.52; r = 0.37; 95% CI: 0.20, 0.52, respectively) and the neuropathy symptom score (r = 0.41; 95% CI: 0.25, 0.55; r = 0.34; 95% CI: 0.17,0.49, respectively). Negative correlations were found for the tibial nerve conduction velocity (r = -0.23; 95% CI: -0.44, -0.01; r = 20.37; 95% CI: 20.55, 20.15, respectively). The cross-sectional area of the nerve was positively correlated with the neuropathy disability score (r = 0.23; 95% CI: 0.03, 0.36). Negative correlations were found for the tibial nerve conduction velocity (r = 20.24; 95% CI: -0.45, -0.01).Conclusion: The amount and extension of T2-weighted hyperintense fascicular nerve lesions were greater in patients with painful diabetic neuropathy than in those with painless diabetic neuropathy. These results suggest that proximal fascicular damage is associated with the evolution of painful sensory symptoms in diabetic polyneuropathy