Annular Lichen Planus with Central Clearing

Annular lichen planus is an uncommon clinical variant of lichen planus. Characteristics include an annular configuration associated with a narrow rim of erythema and inflammation and a depressed center. There is a tendency toward central clearing. We present an illustrative case of annular lichen planus in an 82-year-old woma

Formation of Galactic Disks II: the Physical Drivers of Disk Spin-up

Using a representative sample of Milky Way (MW)-like galaxies from the TNG50 cosmological-volume simulation, we investigate physical processes driving the formation of galactic disks. A disk forms as a result of the interplay between inflow and outflow carrying angular momentum in and out of the galaxy. Interestingly, the inflow and outflow have remarkably similar distributions of angular momentum, suggesting an exchange of angular momentum and/or outflow recycling, leading to continuous feeding of pre-aligned material from the co-rotating circumgalactic medium. We show that disk formation in TNG50 is correlated with stellar bulge formation, in qualitative agreement with a recent theoretical model of disk formation facilitated by steep gravitational potentials. Disk formation is also correlated with the formation of a hot circumgalactic halo with a significant fraction of the inflow occurring at sub- and transonic velocities. In the context of recent theoretical works connecting disk settling and hot halo formation, our results imply that the subsonic part of the inflow may settle into a disk while the remaining supersonic inflow will perturb this disk via the chaotic cold accretion. We find that disks tend to form when the host halos become more massive than $\sim (1-2) \times 10^{11} M_\odot$, consistent with previous theoretical findings and observational estimates of the pre-disk protogalaxy remnant in the MW. Our results do not prove that either co-rotating outflow recycling, gravitational potential steepening, or hot halo formation cause disk formation but they show that all these processes occur concurrently and may play an important role in disk growth.Comment: 22 pages, 15 figures; submitted to ApJ; comments are welcom

Formation of Galactic Disks I: Why did the Milky Way's Disk Form Unusually Early?

Recent results from spectroscopic and astrometric surveys of nearby stars suggest that the stellar disk of our Milky Way (MW) was formed quite early, within the first few billion years of its evolution. Chemo-kinematic signatures of disk formation in cosmological zoom-in simulations appear to be in tension with these data, suggesting that MW-like disk formation is delayed in simulations. We investigate the formation of galactic disks using a representative sample of MW-like galaxies from the cosmological-volume simulation TNG50. We find that on average MW-mass disks indeed form later than the local data suggest. However, their formation time and metallicity exhibit a substantial scatter, such that $\sim$10% of MW-mass galaxies form disks early, similar to the MW. Thus, although the MW is unusual, it is consistent with the overall population of MW-mass disk galaxies. The direct MW analogs assemble most of their mass early, $\gtrsim 10$ Gyr ago, and are not affected by destructive mergers after that. In addition, these galaxies form their disks during the early enrichment stage when the ISM metallicity increases rapidly, with only $\sim$25% of early-forming disks being as metal-poor as the MW was at the onset of disk formation, [Fe/H] $\approx -1.0$. In contrast, most MW-mass galaxies either form disks from already enriched material or experience late destructive mergers that reset the signatures of galactic disk formation to later times and higher metallicities. Finally, we also show that the earlier disk formation leads to more dominant rotationally-supported stellar disks at redshift zero.Comment: 18 pages, 13 figures + appendix; submitted to ApJ; comments are welcom

HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma

Indexación: Web of ScienceBackground: Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. Methods: Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2 alpha knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student's T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. Results: Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2 alpha is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ER alpha) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated alpha-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. Conclusions: Taking together, these results suggest that HDAC1 and HDAC6 may play a role in ccRCC biology and could represent rational therapeutic targets.http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2604-

Dll4 Blockade Potentiates the Anti-Tumor Effects of VEGF Inhibition in Renal Cell Carcinoma Patient-Derived Xenografts

<div><p>Background</p><p>The Notch ligand Delta-like 4 (Dll4) is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF) and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC).</p><p>Methods and Results</p><p>Severe combined immunodeficiency (SCID) mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI) examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36–62%) that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38–54%) and ziv-aflibercept (46%). Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72–80% growth inhibition), including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.</p><p>Conclusions</p><p>Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.</p></div

Effects of REGN1035 and/or ziv-aflibercept on tumor cell proliferation in RP-R-01 ccRCC xenograft.

<p>Mice were treated with vehicle, ziv-aflibercept and/or REGN1035. Tumors were harvested, processed, and tissue sections were stained for differential expression of Ki67. (A) Representative images. (B) Quantitative analysis was done in a blinded manner. Results are expressed as mean percentage positive nuclei ± S.E. *<i>p</i><0.05 using adjusted t-test analysis.</p

Effect of REGN1035 and/or anti-VEGF (sunitinib or ziv-aflibercept) on (A, B) RP-R-01 and (C) RP-R-02 tumor vasculature.

<p>Tumors from treated mice were harvested, processed, and tissue sections were stained for the differential expression of CD31 (red) for visualization of endothelial cells (left panels). (D, E, F) Blinded quantitative analysis of CD31 (right panels). Results are expressed as mean percentage positive stained area ± S.E. *<i>p</i><0.05 using adjusted t-test analysis.</p

Vascular response of RP-R-01 tumors to combined DLL4-VEGF blockade.

<p>MRI-based estimates of relative blood volume estimates of RP-R-01 tumors at (A) 24 hours and (B) 2 weeks (C) Panel of images represent contrast enhancement maps of a representative tumor from each group 2 weeks post treatment. Three contiguous slices of the tumor are shown. All treatment groups showed significant reduction in rBV compared to controls. Combination treatment resulted in the greatest reduction in tumor perfusion. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001.</p