Targeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially ...useful in early diagnosis.
We developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients’ outcomes.
Median methylation scores in plasma cfDNA samples from patients on therapy were lower than from patients off therapy (4.74 versus 85.29; P = 0.001). Of 68 plasma samples from patients off therapy, methylation scores detected the presence of cancer in 57 (83.8%), and methylation-based signatures accurately classified the underlying cancer type in 45 (78.9%) of these. Methylation scores were most accurate in detecting colorectal cancer (96.3%), followed by breast cancer (91.7%), melanoma (81.8%) and NSCLC (61.1%), and most accurate in classifying the underlying cancer type in colorectal cancer (88.5%), followed by NSCLC (81.8%), breast cancer (72.7%) and melanoma (55.6%). Low methylation scores versus high were associated with longer survival (10.4 versus 4.4 months, P < 0.001) and longer time-to-treatment failure (2.8 versus 1.6 months, P = 0.016).
Comprehensive targeted methylation sequencing of 9223 CpG sites in plasma cfDNA from patients with common advanced cancers detects the presence of cancer and underlying cancer type with high accuracy. Methylation scores in plasma cfDNA correspond with treatment outcomes.
Macrophages can be activated and regulated by high-mobility group box 1 (HMGB1), a highly conserved nuclear protein. Inflammatory functions of HMGB1 are mediated by binding to cell surface receptors, ...including the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, TLR4, and TLR9. Pyroptosis is a caspase-1-dependent programmed cell death, which features rapid plasma membrane rupture, DNA fragmentation, and release of proinflammatory intracellular contents. Pyroptosis can be triggered by various stimuli, however, the mechanism underlying pyroptosis remains unclear. In this study, we identify a novel pathway of HMGB1-induced macrophage pyroptosis. We demonstrate that HMGB1, acting through RAGE and dynamin-dependent signaling, initiates HMGB1endocytosis, which in turn induces cell pyroptosis. The endocytosis of HMGB1 triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. We further confirm that HMGB1-induced macrophage pyroptosis also occurs in vivo during endotoxemia, suggesting a pathophysiological significance for this form of pyroptosis in the development of inflammation. These findings shed light on the regulatory role of ligand-receptor internalization in directing cell fate, which may have an important role in the progress of inflammation following infection and injury.
Topological features--global properties not discernible locally--emerge in systems ranging from liquid crystals to magnets to fractional quantum Hall systems. A deeper understanding of the role of ...topology in physics has led to a new class of matter--topologically ordered systems. The best known examples are quantum Hall effects, where insensitivity to local properties manifests itself as conductance through edge states that is insensitive to defects and disorder. Current research into engineering topological order primarily focuses on analogies to quantum Hall systems, where the required magnetic field is synthesized in non-magnetic systems. Here, we realize synthetic magnetic fields for photons at room temperature, using linear silicon photonics. We observe, for the first time, topological edge states of light in a two-dimensional system and show their robustness against intrinsic and introduced disorder. Our experiment demonstrates the feasibility of using photonics to realize topological order in both non-interacting and many-body regimes.
Translocator protein (18 kDa) (TSPO) is a ubiquitous mitochondrial protein. Studies of its responses to drug and endogenous ligands have shown TSPO to be involved either directly or indirectly in ...numerous biological functions, including mitochondrial cholesterol transport and steroid hormone biosynthesis, porphyrin transport and heme synthesis, apoptosis, cell proliferation, and anion transport. Localised to the outer mitochondrial membrane of steroidogenic cells, TSPO has been shown to associate with cytosolic and mitochondrial proteins as part of a large multiprotein complex involved in mitochondrial cholesterol transport, the rate‐limiting step in steroidogenesis. There is general agreement as to the structure and pharmacology of TSPO. Stimulation of TSPO has been shown to have therapeutic use as anxiolytics by inducing allopregnanolone production in the brain, and also potentially for re‐establishing androgen levels in hypogonadal ageing animals. Until recently, there has been general agreement regarding the role of TSPO in steroidogenesis. However, recent studies involving genetic depletion of TSPO in mice have created controversy about the role of this protein in steroid and heme synthesis. We review the data on the structure and function of TSPO, as well as the recent results obtained using various genetic animal models. Taken together, these studies suggest that TSPO is a unique mitochondrial pharmacological target for diseases that involve increased mitochondrial activity, including steroidogenesis. Although there is no known mammalian species that lacks TSPO, it is likely that, because of the importance of this ancient protein in evolution and mitochondrial function, redundant mechanisms may exist to replace it under circumstances when it is removed.
The increasing severity of droughts/floods and worsening air quality from increasing aerosols in Asia monsoon regions are the two gravest threats facing over 60% of the world population living in ...Asian monsoon regions. These dual threats have fueled a large body of research in the last decade on the roles of aerosols in impacting Asian monsoon weather and climate. This paper provides a comprehensive review of studies on Asian aerosols, monsoons, and their interactions. The Asian monsoon region is a primary source of emissions of diverse species of aerosols from both anthropogenic and natural origins. The distributions of aerosol loading are strongly influenced by distinct weather and climatic regimes, which are, in turn, modulated by aerosol effects. On a continental scale, aerosols reduce surface insolation and weaken the land‐ocean thermal contrast, thus inhibiting the development of monsoons. Locally, aerosol radiative effects alter the thermodynamic stability and convective potential of the lower atmosphere leading to reduced temperatures, increased atmospheric stability, and weakened wind and atmospheric circulations. The atmospheric thermodynamic state, which determines the formation of clouds, convection, and precipitation, may also be altered by aerosols serving as cloud condensation nuclei or ice nuclei. Absorbing aerosols such as black carbon and desert dust in Asian monsoon regions may also induce dynamical feedback processes, leading to a strengthening of the early monsoon and affecting the subsequent evolution of the monsoon. Many mechanisms have been put forth regarding how aerosols modulate the amplitude, frequency, intensity, and phase of different monsoon climate variables. A wide range of theoretical, observational, and modeling findings on the Asian monsoon, aerosols, and their interactions are synthesized. A new paradigm is proposed on investigating aerosol‐monsoon interactions, in which natural aerosols such as desert dust, black carbon from biomass burning, and biogenic aerosols from vegetation are considered integral components of an intrinsic aerosol‐monsoon climate system, subject to external forcing of global warming, anthropogenic aerosols, and land use and change. Future research on aerosol‐monsoon interactions calls for an integrated approach and international collaborations based on long‐term sustained observations, process measurements, and improved models, as well as using observations to constrain model simulations and projections.
Key Points
The fast‐developing Asia has suffered severe air pollution problem
Aerosol affects the Asian monsoon
Aerosol‐monsoon interactions dictate the climate change in the region
Summary
Background
The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region.
Aim
To study factors ...associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy‐proven nonalcoholic fatty liver disease (NAFLD) patients.
Methods
Retrospective study of biopsy‐proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort.
Results
We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m2, diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%‐83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count <150 × 109/L, constituting the Asia‐Pacific NAFLD advanced fibrosis risk score. A low score has a negative predictive value of 95%‐96% for advanced fibrosis. Only 1.7% of patients were referred for structured lifestyle program, 4.2% were on vitamin E, and 2.4% were on pioglitazone.
Conclusions
More severe liver disease can be suspected or ruled out based on factors identified in this study. Utilisation of structured lifestyle program, vitamin E and pioglitazone was limited despite this being a cohort of biopsy‐proven NAFLD patients with majority of patients having NASH.
Linked ContentThis article is linked to Hardy and McPherson and Chan et al papers. To view these articles visit https://doi.org/10.1111/apt.14557 and https://doi.org/10.1111/apt.14572.
Summary
CircRNAs exert gene regulatory effects by sequestering target microRNAs (miRNAs) and play a vital role in the onset and development of disease. Until recently, little has been known about the ...expression, regulation and biological function of circRNAs in both health and chronic hepatitis B (CHB).To identify hepatic circRNAs associated with CHB, we performed RNA sequencing using liver biopsies from untreated CHB patients and controls. We then established a bioinformatics pipeline for identification of CHB‐associated circRNAs and in silico analysis of the circRNA‐miRNA‐mRNA pathways. We used quantitative reverse transcription polymerase chain reaction (qRT‐PCR) to confirm these results. The profiles of hepatic circRNA expression were significantly different in CHB compared with controls, with a total of 99 dysregulated circRNAs identified to be correlated with CHB. Computational analysis of the circRNA‐miRNA‐mRNA pathways revealed a large number of miRNAs (665), which were putatively targeted by the differentially expressed hepatic circRNAs. Interestingly, four of the predicted CHB‐related circRNA‐miRNA‐mRNA pathways were found to be involved in the pathogenesis of HBV infection and progression of HBV‐associated liver disease. Among these pathways, regression analysis of gene expression revealed a strong positive correlation between hsa_circ_0000650 and TGFβ2 and a negative correlation between hsa_circ_0000650 and miR‐6873‐3p, which hinted that hsa_circ_0000650 interacted with TGFβ2 mediated by miR‐6873‐3p. This study firstly demonstrates that patients with CHB present different profiles of hepatic circRNAs and circRNA/miRNA interactions. Thus, circRNAs have promise as novel mechanisms underlying the pathogenesis and progression of CHB.
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