Background The left internal mammary artery (LIMA) is protected from developing atherosclerosis. Perivascular inflammation, which is closely associated with atherosclerosis, can be measured by ...perivascular adipose tissue attenuation on computed tomography angiography. Whether the absence of atherosclerosis in LIMA is related to the lower level of perivascular inflammation is unknown. This study was performed to compare the level of perivascular inflammation between LIMA in situ and native coronary arteries in patients with coronary artery disease. Methods and Results A total of 573 patients who underwent both computed tomography angiography and optical coherence tomography imaging were included. The level of perivascular adipose tissue attenuation between LIMA in situ and coronary arteries was compared. Perivascular adipose tissue attenuation around LIMA in situ was significantly lower around the 3 coronary arteries (−82.9 −87.3 to −78.0 versus −70.8 −75.9 to −65.9; P <0.001), irrespective of the level of pericoronary inflammation or the number of vulnerable features on optical coherence tomography. When patients were divided into high and low pericoronary inflammation groups, those in the high inflammation group had more target vessel failure (hazard ratio, 2.97 95% CI, 1.16–7.59; P =0.017). Conclusions The current study demonstrated that perivascular adipose tissue attenuation was significantly lower around LIMA in situ than around native coronary arteries. The lower level of perivascular inflammation may be related to the low prevalence of atherosclerosis in LIMA. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT04523194.
【Purpose】The purpose of this study was to objectively evaluate the acceptable range of refraction regarding binocular summation in eyes with simulated monovision using visual evoked potential (VEPs). ...【Subjects and Methods】Participants included 27 healthy individuals (13 men, 14 women; mean age, 21.4 years). VEPs were measured using Neuropack X1 (NIHON KOHDEN). The subjects were asked to fixate on a 17-inch liquid crystal monitor at a distance of 127 cm during a VEP. The monitor displayed a checkered pattern-reversal stimulus with a check size of 15 arcmins at a frequency of 1 Hz. VEPs were measured under the following seven conditions: binocular viewing with the best correction (binocular summation), monocular viewing with the non-dominant eye occluded (non-binocular summation), and simulated monovision with plus lenses (＋0.50, ＋1.00, ＋1.50, ＋2.00, and ＋3.00D) added to the non-dominant eye. The VEP amplitudes (N1-P1) and latency (P1) were evaluated under all the conditions and compared. 【Results】The respective mean amplitudes under binocular and monocular viewing conditions were 12.8 and 9.4μV, which significantly differed (P＜0.001). The mean amplitudes under the simulated monovision conditions with ＋0.50, ＋1.00, ＋1.50, ＋2.00 and ＋3.00D addition were 12.0, 11.0, 9.8, 9.4, and 8.8μV, respectively. The mean amplitude with monocular viewing was significantly lower than those with binocular viewing and simulated monovision with ＋0.50 and ＋1.00D addition (P＜0.001). The mean amplitude in the binocular condition with bilateral refractive correction was not significantly different from that of monovision simulation with ＋0.50D addition to the non-dominant eye (P＞0.99). The mean latency time did not significantly differ among all the conditions. 【Conclusion】Our findings suggest that the monovision correction was less than 1.00D for maintaining binocular summation.
We identified TPX2 and AURAKA as novel co-regulators on the MYC pathway and proposed a new model of MYC-driven cancer. Co-amplification between 8q24 and 20q leads to co-overexpression of MYC and ...AURKA/TPX2, which cooperatively induce MYC downstream target genes. Based on this model, inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.
The MYC oncogene has long been established as a central driver in many types of human cancers including colorectal cancer. However, the realization of MYC-targeting therapies remains elusive; as a result, synthetic lethal therapeutic approaches are alternatively being explored. A synthetic lethal therapeutic approach aims to kill MYC-driven tumors by targeting a certain co-regulator on the MYC pathway.
We analyzed copy number and expression profiles from 130 colorectal cancer tumors together with publicly available datasets to identify co-regulators on the MYC pathway. Candidates were functionally tested by in vitro assays using colorectal cancer and normal fibroblast cell lines. Additionally, survival analyses were carried out on another 159 colorectal cancer patients and public datasets.
Our in silico screening identified two MYC co-regulator candidates, AURKA and TPX2, which are interacting mitotic regulators located on chromosome 20q. We found the two candidates showed frequent co-amplification with the MYC locus while expression levels of MYC and the two genes were positively correlated with those of MYC downstream target genes across multiple cancer types. In vitro, the aberrant expression of MYC AURKA and TPX2 resulted in more aggressive anchorage-independent growth in normal fibroblast cells. Furthermore, knockdown of AURKA or TPX2, or treatment with an AURKA-specific inhibitor effectively suppressed the proliferation of MYC-expressing colorectal cancer cells. Additionally, combined high expression of MYC AURKA and TPX2 proved to be a poor prognostic indicator of colorectal cancer patient survival.
Through bioinformatic analyses and experiments, we proposed TPX2 and AURKA as novel co-regulators on the MYC pathway. Inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.
It was recently reported that thin-cap fibroatheroma (TCFA) detected by optical coherence tomography was an independent predictor of future cardiac events in patients with diabetes. However, the ...clinical usefulness of this finding is limited by the invasive nature of optical coherence tomography. Computed tomography angiography (CTA) characteristics of TCFA have not been systematically studied. The aim of this study was to investigate CTA characteristics of TCFA in patients with diabetes.
Patients with diabetes who underwent preintervention CTA and optical coherence tomography were included. Qualitative and quantitative analyses were performed for plaques on CTA. TCFA was assessed by optical coherence tomography. Among 366 plaques in 145 patients with diabetes, 111 plaques had TCFA. The prevalence of positive remodeling (74.8% versus 50.6%,
<0.001), low attenuation plaque (63.1% versus 33.7%,
<0.001), napkin-ring sign (32.4% versus 11.0%,
<0.001), and spotty calcification (55.0% versus 34.9%,
<0.001) was significantly higher in TCFA than in non-TCFA. Low-density noncalcified plaque volume (25.4 versus 15.7 mm
,
<0.001) and remodeling index (1.30 versus 1.20,
=0.002) were higher in TCFA than in non-TCFA. The presence of napkin-ring sign, spotty calcification, high low-density noncalcified plaque volume, and high remodeling index were independent predictors of TCFA. When all 4 predictors were present, the probability of TCFA increased to 82.4%.
The combined qualitative and quantitative plaque analysis of CTA may be helpful in identifying TCFA in patients with diabetes.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.
Abstract
Mild cognitive impairment (MCI) is a clinical precursor of Alzheimer’s disease (AD). Recent genetic studies have reported on associations between AD risk genes and immunity. Here, we ...obtained samples and data from 317 AD, 432 MCI, and 107 cognitively normal (CN) subjects and investigated immune-cell type composition and immune clonal diversity of T-cell receptor (TRA, TRB, TRG, and TRD) and B-cell receptor (IGH, IGK, and IGL) repertoires through bulk RNA sequencing. We found the proportions of plasma cells, γδ T cells, neutrophils, and B cells were significantly different and the diversities of IGH, IGK, and TRA were significantly small with AD progression. We then identified a differentially expressed gene,
WDR37
, in terms of risk of MCI-to-AD conversion. Our prognosis prediction model using the potential blood-based biomarkers for early AD diagnosis, which combined two immune repertoires (IGK and TRA),
WDR37
, and clinical information, successfully classified MCI patients into two groups, low and high, in terms of risk of MCI-to-AD conversion (log-rank test
P
= 2.57e-3). It achieved a concordance index of 0.694 in a discovery cohort and of 0.643 in an independent validation cohort. We believe that further investigation, using larger sample sizes, will lead to practical clinical use in the near future.
The stability field of pargasitic amphibole in a model mantle composition (MORB pyrolite) has been experimentally determined for a fixed water content. A solidus for a pargasite-bearing lherzolite ...has been defined at pressures below the limit of amphibole stability of 30kbar at T=925 degree C. The maximum temperature for pargasitic amphibole in MORB pyrolite occurs at 1075 degree C between P=18 and 25kbar. This maximum lies between that determined for a fertile peridotite composition (Hawaiian pyrolite) and a depleted peridotite composition (Tinaquillo lherzolite). A comparison of the new results with those from earlier studies suggests that the stability for a particular bulk H sub(2)O content is mostly controlled by alkali content of the lherzolite composition. The systematic compositional variation of pargasitic amphibole as a function of pressure and temperature can be represented as an increase of the richterite component with increase in both pressure and temperature. For a given pressure the tschermakite component increases with increasing temperature. The compositions of coexisting clinopyroxenes also show a systematic variation with pressure and temperature. The phase relationships in MORB pyrolite combined with the modal abundance of coexisting phases show that the breakdown reactions of pargasitic amphibole occur continuously throughout the subsolidus region studied. The temperature stability limit of pargasitic amphibole coincides with the water-undersaturated solidus (amphibole-dehydration solidus) at pressures below 30kbar. The experimental results are applicable to pargasitic amphibole-bearing natural peridotites. Cooling and decompression paths and heating events observed in natural peridotites can be interpreted from changes in the composition of pargasitic amphibole. The data are also applicable to a model for peridotite melting and hydration process in the subduction environment.
One of the two X chromosomes in female mammals is inactivated by the noncoding Xist RNA. In mice, X chromosome inactivation (XCI) is regulated by the antisense RNA Tsix, which represses Xist on the ...active X chromosome. In the absence of Tsix, PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) is established over the Xist promoter. Simultaneous disruption of Tsix and PRC2 leads to derepression of Xist and in turn silencing of the single X chromosome in male embryonic stem cells. Here, we identified histone H3 lysine 36 trimethylation (H3K36me3) as a modification that is recruited by Tsix cotranscriptionally and extends over the Xist promoter. Reduction of H3K36me3 by expression of a mutated histone H3.3 with a substitution of methionine for lysine at position 36 causes a significant derepression of Xist. Moreover, depletion of the H3K36 methylase Setd2 leads to upregulation of Xist, suggesting H3K36me3 as a modification that contributes to the mechanism of Tsix function in regulating XCI. Furthermore, we found that reduction of H3K36me3 does not facilitate an increase in H3K27me3 over the Xist promoter, indicating that additional mechanisms exist by which Tsix blocks PRC2 recruitment to the Xist promoter.
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