Search

Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma‐to‐carcinoma sequence associated with specific molecular alterations, including the 5‐hydroxymethylcytosine (5hmC) signature in circulating cell‐free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome‐wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early‐stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC‐modified regions (DhMRs) were gathered into four clusters: Disease‐enriched, AD‐enriched, Disease‐lost, and AD‐lost, with no overlap. AD‐related clusters, AD‐enriched and AD‐lost, displayed the unique 5hmC signals in AD patients. Disease‐enriched and Disease‐lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD‐enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC‐modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease‐enriched and Disease‐lost DhMR clusters demonstrated similar epigenetic modifications, while AD‐enriched and AD‐lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, consistent with the 'parallel' evolution hypothesis in adenoma, either developed through the adenoma‐to‐carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early‐stage CRC and assess adenoma malignancy with large‐scale follow‐up studies in the future. [ABSTRACT FROM AUTHOR]

Administration of donor-derived immature dendritic cells (DC) can prolong the survival of MHC-mismatched cardiac allografts. Genetic modification of DC by immunosuppressive molecules can enhance their potential tolerogenicity. In this study bone marrow derived immature DC were genetically modified by transforming growth factor (TGF) β1 by recombinant Ad. TGF-β1 gene modified immature DC (TGF-β-DC) displayed a characteristic phenotype of immature DC, decreased ability to secrete interleukin 12, and reduced allostimulatory ability. TGF-β-DC induced alloantigen-specific T cell hyporesponsiveness in vitro and in vivo, and Th2 cytokine polarization. mRNA expression of donor MHC class II (Iab) and human TGF-β1 was detected in spleen and lymph nodes of the allogeneic recipients for 3 weeks after TGF-β-DC infusion, indicating that microchimerism of TGF-β-DC is exhibited in allogeneic recipients. In this murine cervical heterotopic heart transplantation model, the survival of the allograft in recipients intravenously infused with TGF-β-DC 7 days before transplantation was greatly prolonged, and about 67% of cardiac grafts survived more than 40 days. Histological analysis of the allografts showed that the normal myocardial architecture was well preserved, accompanied by very little necrotic cells, but interstitial fibrosis replaced myocytes, and moderate collagen suffused the whole cardiac allograft in the recipients infused with TGF-β-DC. mRNA expression of type III procollagen was markedly increased in the allografts of the recipients infused with TGF-β-DC. Our results suggest that infusion of TGF-β1 gene modified immature DC prolongs the survival of the allograft through the effective induction of donor-specific T cell hyporesponsiveness. However, TGF-β1 expressed by gene modified immature DC can cause the fibrosis of the allografts, which may limit the application of this approach in the allograft transplantation. [ABSTRACT FROM AUTHOR]

Background: Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism. Methods: Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway. Results: DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/β and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/β and p-NF-κB. Conclusions: Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC. [ABSTRACT FROM AUTHOR]

Intraspecific trait variation (ITV) is common feature of natural communities and has gained increasing attention due to its significant ecological effects on community dynamics and ecosystem functioning. However, the estimation of ITV per se has yet to receive much attention, despite the need for accurate ITV estimation for trait-based ecological inferences. It remains unclear if, and to what extent, current estimations of ITV are biased. The most common method used to quantify ITV is the coefficient of variation (CV), which is dimensionless and can therefore be compared across traits, species, and studies. Here, we asked which CV estimator and data normalization method are optimal for quantifying ITV, and further identified the minimum sample size required for ±5% accuracy assuming a completely random sample scheme. To these ends, we compared the performance of four existing CV estimators, together with new simple composite estimators, across different data normalizations, and sample sizes using both a simulated and empirical trait datasets from local to regional scales. Our results consistently showed that the most commonly used ITV estimator (CV 1= σsample / μsample), often underestimated ITV—in some cases by nearly 50%—and that underestimation varies largely among traits and species. The extent of this bias depends on the sample size, skewness and kurtosis of the trait value distribution. The bias in ITV can be substantially reduced by using log-transforming trait data and alternative CV estimators that take into consideration the above dependencies. We find that the CV4 estimator, also known as Bao's CV estimator, combined with log data normalization, exhibits the lowest bias and can reach ±5% accuracy with sample sizes greater than 20 for almost all examined traits and species. These results demonstrated that many previous ITV measurements may be substantially underestimated and, further, that these underestimations are not equal among species and traits even using the same sample size. These problems can be largely solved by log-transforming trait data first and then using the Bao's CV to quantify ITV. Together, our findings facilitate a more accurate understanding of ITV in community structures and dynamics, and may also benefit studies in other research areas that depend on accurate estimation of CV. [ABSTRACT FROM AUTHOR]

Since there is currently no method to selectively fabricate superhydrophobic regions on superhydrophilic surfaces of metal substrates, wettability patterns on metal substrates are prepared via the three-step technique including superhydrophilic, superhydrophobic and selectively superhydrophilic modifications. Here, an innovative method that can selectively lower surface energy of superhydrophilic surfaces, and thereby makes it more convenient to fabricate the wettability patterns, is proposed. Chemical etching is used to formulate micro/nanoscale rough structures and fabricate superhydrophilic aluminium (Al) surface, which is then covered by patterned mask whose main composition is siloxane. Removing the mask after 80°C water bath heating for 20 s, the covered Al surface has been modified to become superhydrophobic (contact angles >165°, sliding angles <1.5°), while the uncovered region is still superhydrophilic, and wettability patterns are therefore obtained. Fourier transform infrared spectrophotometer and Raman spectra indicate that the change of wettability is induced by hydrophobic groups on the modified surfaces. The superhydrophobic surfaces fabricated by this method have excellent high-temperature resistance. The method proposed is simple, rapid and environmental-friendly. [ABSTRACT FROM AUTHOR]

In this work, a way to achieve effective directional transport of water on superhydrophobic surface is presented. An aluminium (Al) superhydrophobic surface was prepared by chemical etching method. After being treated by cold nitrogen plasma jet, a superhydrophilic track pattern corresponding to the mask was then fabricated. The vein-like structure of the liquid transport platform was composed of a trunk and several branches, both having wedge angles. Driven by surface tension, water droplets at any location of the dripping area can be transported against gravity. This method is reusable and could be widely used in the directional transportation and water recycling. [ABSTRACT FROM AUTHOR]