Potential redox-sensitive Akt activation by dopamine activates Bad and promotes cell death in melanocytes

Dopamine (DA) is a well known oxidative neurotoxin. In addition, Akt has been reported to deliver a survival signal that inhibits apoptosis. However, it has also been reported that chronic Akt activation leads to apoptosis in response to oxidative stress. The objective of the present study was to investigate the possible role of the Akt pathway in vitiligo and its possible relationship with DA-induced cell death using Mel-Ab cells. Cultured Mel-Ab cells were treated with DA with and without N-Acetyl-L-cysteine (NAC), which is known to have antioxidative properties. Cell viability was then assessed by a crystal violet assay and Annexin staining was performed. The changes in the expression of Akt were analyzed by western blot analysis. The cell viability was reduced by approximately 60% in response to treatment with 500 µM DA, and NAC effectively prevented this cytotoxic effect. Likewise, treatment with DA produced numerous Annexin positive cells, while treatment with NAC prevented this apoptotic cell death. Akt was slowly phosphorylated after treatment with DA, while NAC clearly inhibited the DA-induced Akt activation. Western blot analysis also showed that treatment with DA induced the activation of Bad. Finally, LY294002 exerted a protective effect against DA-induced apoptotic cell death. DA may induce redox-sensitive Akt activation and increase the level of Bad, which can promote cell death by heterodimerization with survival proteins. Moreover, NAC effectively protects against DA-induced melanocyte death via inhibition of DA-induced Akt activation

Effects of Murine Dermal Cells on the Regulation of Hair Growth Is Dependent on the Cell Number and Post-Natal Age of Newborn Mice

Dermal cells from neonatal mice can initiate the formation of hair follicles (HFs) when combined with adult mouse epidermal cells and transplanted subcutaneously into athymic mice. In the present study, the effects of dermal cells on HF formation were tested in terms of total cell number and the time course of cell harvest. Results demonstrated that the number of dermal cells is critical to the formation of HF. Furthermore, hair forming ability is rapidly decreasing as the neonatal mice age. To examine potential differences in gene expression, cDNA array was performed. Results demonstrate that numerous molecules which are directly involved in receptor and signaling correlated with decreased hair inductivity in early time points after delivery. It is reported that bone morphogenic protein (BMP)-6 and Wnt3a treatment increased hair inductivity of dermal papilla cells. But in our study, no changes were observed in the expression levels of BMP-6 and Wnt3a. However, several Wnt related genes demonstrate increased or decreased expression levels. Thus, our results suggest that co-ordinated regulation of these molecules will be important in hair neogenesis within our model system

Spectroscopic Interpretation of PAH-Spectra in Minerals and Its Possible Application to Soil Monitoring

In order to properly assess the feasibility of using Laser-Induced Fluorescence (LIF) spectroscopy for soil monitoring, the variation of fluorescence intensity due to the heterogeneity and complexity of soil media was investigated. Different soil minerals showed fluorescence spectral structures distinguishable from the contaminants, implying dissimilar interactions or the binding of contaminants on mineral surfaces. More interestingly, solvent and water addition showed different responses in the fluorescence spectral structure showing their effect on the interactions between contaminants and minerals. These results support the claim that the spectral structure contains information on contaminant-mineral interactions; therefore contaminants can be used as a fluorescence probe for these interactions

gene amplification in patients with metastatic cancer

Purpose Neurotropic tropomyosin receptor kinase (NTRK) fusions have been identified in a variety of cancers, and tyrosine kinase inhibitors targeting the tropomyosin receptor kinase (TRK) receptor are currently in clinical trials. However, no reports are available on the effects of NTRK gene amplification. Methods Samples from patients enrolled in the sequencing program were analyzed using a next-generation sequencing (NGS) cancer panel. For cases in which NTRK amplification (defined as ≥ 4.0 copies) was identified, panTRK immunohistochemical (IHC) staining of tissue microarrays was performed. Results A total of 1,250 tumor specimens collected between February 2014 and January 2016 were analyzed using the NGS cancer panel. NTRK amplification was detected in 28 cases of various types of cancer. Among 27 cases, only four were positive for pan-TRK IHC. These four cases were melanoma, sarcoma, lung cancer, and gastric cancer. We found that 2.2% of cancer patients showed NTRK amplification using NGS cancer panel and NTRK amplification resulted in protein overexpression in 14.8% of these patients. Conclusion Patients with NTRK amplification and increased TRK protein expression may be considered for inclusion in clinical trials for NTRK inhibitors

ODIN: Where Do Lyman-alpha Blobs Live? Contextualizing Blob Environments within the Large-Scale Structure

While many Lyman-alpha Blobs (LABs) are found in and around several well-known protoclusters at high redshift, how they trace the underlying large-scale structure is still poorly understood. In this work, we utilize 5,352 Lyman-alpha emitters (LAEs) and 129 LABs at z=3.1 identified over a $\sim$ 9.5 sq. degree area in early data from the ongoing One-hundred-deg$^2$ DECam Imaging in Narrowbands (ODIN) survey to investigate this question. Using LAEs as tracers of the underlying matter distribution, we identify overdense structures as galaxy groups, protoclusters, and filaments of the cosmic web. We find that LABs preferentially reside in regions of higher-than-average density and are located in closer proximity to overdense structures, which represent the sites of protoclusters and their substructures. Moreover, protoclusters hosting one or more LABs tend to have a higher descendant mass than those which do not. Blobs are also strongly associated with filaments of the cosmic web, with $\sim$ 70% of the population being within a projected distance of 2.4 pMpc from a filament. We show that the proximity of LABs to protoclusters is naturally explained by their association with filaments as large cosmic structures are where many filaments converge. The contiguous wide-field coverage of the ODIN survey allows us for the first time to firmly establish a connection between LABs as a population and their environment.Comment: 24 pages, 17 figures; submitted to Ap

YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment

Among cancer cells, indoleamine 2, 3-dioxygenase1 (IDO1) activity has been implicated in improving the proliferation and growth of cancer cells and suppressing immune cell activity. IDO1 is also responsible for the catabolism of tryptophan to kynurenine. Depletion of tryptophan and an increase in kynurenine exert important immunosuppressive functions by activating regulatory T cells and suppressing CD8+ T and natural killer (NK) cells. In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). YH29407 treatment alone and anti-PD-1 (aPD-1) combination treatment induced significant tumor suppression compared with competing drugs. In particular, combination treatment showed the best anti-tumor effects, with most tumors reduced and complete responses. Our observations suggest that improved anti-tumor effects were caused by an increase in T cell infiltration and activity after YH29407 treatment. Notably, an immune depletion assay confirmed that YH29407 is closely related to CD8+ T cells. RNA-seq results showed that treatment with YH29407 increased the expression of genes involved in T cell function and antigen presentation in tumors expressing ZAP70, LCK, NFATC2, B2M, and MYD88 genes. Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8+ T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1

Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ Signaling

Background & Aims: The liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought to determine the physiological role of CTCF in hepatic lipid metabolism. Methods: We generated liver-specific, CTCF-ablated and/or CD36 whole-body knockout mice. Overexpression or knockdown of peroxisome proliferator-activated receptor (PPAR)γ in the liver was achieved using adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA sequencing was performed to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27 acetylation, PPARγ, and CTCF were analyzed by chromatin immunoprecipitation sequencing. Genome-wide chromatin interactions were analyzed by in situ Hi-C. Results: Liver-specific, CTCF-deficient mice developed hepatic steatosis and inflammation when fed a standard chow diet. Global analysis of the transcriptome and enhancer landscape revealed that CTCF-depleted liver showed enhanced accumulation of PPARγ in the nucleus, which leads to increased expression of its downstream target genes, including fat storage-related gene CD36, which is involved in the lipid metabolic process. Hepatic steatosis developed in liver-specific, CTCF-deficient mice was ameliorated by repression of PPARγ via pharmacologic blockade or adenovirus-mediated knockdown, but hardly rescued by additional knockout of CD36. Conclusions: Our data indicate that liver-specific deletion of CTCF leads to hepatosteatosis through augmented PPARγ DNA-binding activity, which up-regulates its downstream target genes associated with the lipid metabolic process. © 2021 The Authors1

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Second-generation drug-eluting stents (DES) have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES) is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES). In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI). A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT)) was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS) patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT)) is used more commonly than doubling the dose of clopidogrel in high-risk patients.</p> <p>Methods</p> <p>In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES) and antiplatelet regimen (TAT vs DDAT). The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen.</p> <p>Discussion</p> <p>The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI.</p> <p>Trial registration</p> <p>ClincalTrials.gov number <a href="http://www.clinicaltrials.gov/ct2/show/NCT01267734">NCT01267734</a>.</p