Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by ...modulating miR-541-initiated microRNA-autophagy axis.
Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality.
The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment.
Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients' responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.
Recent studies have shown that the presence of systemic inflammation correlates with poor survival in various cancers. The aim of this study was to determinate the prognostic value of the neutrophil ...lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) in patients with esophageal squamous cell carcinoma (ESCC).
Preoperative NLR and PLR were evaluated in 483 patients undergoing esophagectomy for ESCC from January 2005 to December 2008. The prognostic significance of both markers was then determined by both uni- and multivariate analytical methods. Receiver operating characteristic (ROC) curves were also plotted to verify the accuracy of NLR and PLR for survival prediction.
High preoperative NLR (≥3.5 versus < 3.5, P = 0.039) and PLR (≥150 versus < 150, P < 0.001) were significantly associated with poor overall survival in multivariate analysis. However, our study demonstrated a better discrimination for the PLR in terms of hazard ratio(HR) than the NLR (HR = 1.840 versus HR = 1.339). Patients with NLR ≥3.5 had significantly poorer overall survival compared to NLR <3.5 (35.4% versus 57.7%, P < 0.001). Patients with PLR ≥150 also had significantly poorer overall survival compared to patients with PLR <150 (32.7% versus 63.5%, P < 0.001). The area under the curve (AUC) was 0.658 (95% confidence interval (CI): 0.610 to 0.706, P < 0.001) for NLR and 0.708 (95% CI: 0.662 to 0.754, P < 0.001) for PLR, indicating that PLR was superior to NLR as a predictive factor in ESCC.
Preoperative NLR and PLR were significant predictors of overall survival in patients with ESCC. However, PLR is superior to NLR as a predictive factor in patients with ESCC.
An optoelectronic material with a spatially varying bandgap that is tunable is highly desirable for use in photovoltaics, photocatalysis and photodetection. Elastic strain has the potential to be ...used to achieve rapid and reversible tuning of the bandgap. However, as a result of plasticity or fracture, conventional materials cannot sustain a high enough elastic strain to create sufficient changes in their physical properties. Recently, an emergent class of materials--named 'ultrastrength materials'--have been shown to avoid inelastic relaxation up to a significant fraction of their ideal strength. Here, we illustrate theoretically and computationally that elastic strain is a viable agent for creating a continuously varying bandgap profile in an initially homogeneous, atomically thin membrane. We propose that a photovoltaic device made from a strain-engineered MoS2 monolayer will capture a broad range of the solar spectrum and concentrate excitons or charge carriers.
Viral infection triggers host defenses through pattern-recognition receptor-mediated cytokine production, inflammasome activation, and apoptosis of the infected cells. Inflammasome-activated caspases ...are known to cleave cyclic GMP-AMP synthase (cGAS). Here, we found that apoptotic caspases are critically involved in regulating both DNA and RNA virus-triggered host defenses, in which activated caspase-3 cleaved cGAS, MAVS, and IRF3 to prevent cytokine overproduction. Caspase-3 was exclusively required in human cells, whereas caspase-7 was involved only in murine cells to inactivate cGAS, reflecting distinct regulatory mechanisms in different species. Caspase-mediated cGAS cleavage was enhanced in the presence of dsDNA. Alternative MAVS cleavage sites were used to ensure the inactivation of this critical protein. Elevated type I IFNs were detected in caspase-3-deficient cells without any infection. Casp3−/− mice consistently showed increased resistance to viral infection and experimental autoimmune encephalomyelitis. Our results demonstrate that apoptotic caspases control innate immunity and maintain immune homeostasis against viral infection.
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•Deficiency in apoptotic caspases leads to elevated IFN production by virus infection•Caspase-3 cleaves cGAS, MAVS, and IRF3 to keep apoptosis immunologically silent•Caspase-7 is differently involved in mouse and human cells to cleave cGAS and MAVS•MAVS is cleaved at alternative sites to ensure caspase-mediated negative regulation
Ning et al. find that caspase-3 cleaves and inactivates cGAS, MAVS, and IRF3 to suppress cytokine and type I IFN production. Their findings reveal a role for apoptotic caspases in controlling antiviral innate immunity and keeping apoptosis immunologically silent.
Lymphopenia is a useful predictive factor in several cancers. The aim of this study was to determine the prognostic value of lymphopenia in patients with esophageal squamous cell carcinoma (ESCC).A ...retrospective analysis of 307 consecutive patients who had undergone esophagectomy for ESCC was conducted. In our study, a lymphocyte count (LC) of fewer than 1.0 Giga/L was defined as lymphopenia. Kaplan-Meier method was used to calculate the cancer-specific survival (CSS). Cox regression analyses were performed to evaluate the prognostic factors. Receiver operating characteristic (ROC) curve was also plotted to verify the accuracy of LC for CSS prediction.The mean LC was 1.55 ± 0.64 Giga/L (range 0.4-3.7 Giga/L). The incidence of lymphopenia (LC < 1.0 Giga/L) was 16.6% (51/307). Patients with lymphopenia (LC < 1.0 Giga/L) had a significantly shorter 5-year CSS (21.6% vs 43.8%, P = 0.004). On multivariate analysis, lymphopenia (LC < 1.0 Giga/L) was an independent prognostic factor in patients with ESCC (P = 0.013). Lymphopenia had a hazard ratio (HR) of 1.579 95% confidence interval (CI): 1.100-2.265 for CSS. ROC curve demonstrated that lymphopenia (LC < 1.0 Giga/L) predicts survival with a sensitivity of 86.2% and a specificity of 27.2%. Lymphopenia (LC < 1.0 Giga/L) is still an independent predictive factor for long-term survival in patients with ESCC.
This article studies social optimal control of mean field linear-quadratic-Gaussian models with uncertainty. Specially, the uncertainty is represented by an uncertain drift, which is common for all ...agents. A robust optimization approach is applied by assuming all agents treat the uncertain drift as an adversarial player. In our model, both dynamics and costs of agents are coupled by mean field terms, and both finite- and infinite-time horizon cases are considered. By examining social functional variation and exploiting person-by-person optimality principle, we construct an auxiliary control problem for the generic agent via a class of forward-backward stochastic differential equation system. By solving the auxiliary problem and constructing consistent mean field approximation, a set of decentralized control strategies is designed and shown to be asymptotically optimal.
The human-specific gene
NOTCH2NLC
is primarily expressed in radial glial cells and plays an important role in neuronal differentiation and cortical neurogenesis. Increasing studies were conducted to ...verify the relationship between
NOTCH2NLC
gene and many neurological diseases, such as neuronal intranuclear inclusion disease, essential tremor, multiple system atrophy, Parkinson’s disease, Alzheimer’s disease, and even oculopharyngodistal myopathy. Thus, we support the concept,
NOTCH2NLC
-related GGC repeat expansion disorders (NRED), to summarize all diseases with the GGC repeat expansion in the 5’UTR of
NOTCH2NLC
gene, regardless of their various clinical phenotypes. Here, we discuss the reported cases to analyze the clinical features of
NOTCH2NL
C-related GGC repeat expansion disorders, including dementia, parkinsonism, peripheral neuropathy and myopathy, leukoencephalopathy, and essential tremor. In addition, we outline radiological and pathological manifestations of
NOTCH2NL
C-related GGC repeat expansion disorders, and then present possible mechanisms, such as toxic polyG protein, toxic repeat RNA, the GGC repeat size, and the size and types of trinucleotide interruption. Therefore, this review provides a systematic description of
NOTCH2NLC
-related GGC repeat expansion disorders and emphasizes the significance for understanding this type of repeat expansion disease.
Ophiolites commonly sample the uppermost parts (15–20 km) of fossil oceanic lithosphere. However, in recent years, the documentation of diamonds, super‐reducing (e.g., SiC), and other “unusual” ...minerals from several ophiolitic peridotites and chromitites (e.g., Tibet and the Polar Urals) has caused debate concerning their origin (i.e., deep vs. shallower upper mantle). Here we report on symplectite‐bearing lherzolites from the Purang ophiolite in Tibet, which preserve the first compelling evidence of garnet‐facies protoliths. These lherzolites were previously formed and stabilized at a depth of ~85–100 km, which is much deeper than generally suggested and approaches the depth (~120 km) required for stabilizing the diamonds. Combining with other key observations, we suggest the Purang garnet‐bearing peridotites may represent mixtures of oceanic lithosphere domains with diverse origins; they were rapidly exhumed at a variety of mantle depths within a subduction channel associated with oceanic slab retreat.
Plain Language Summary
Ophiolites are remnants of fossil ocean basins that have been emplaced on land and usually sample the upper 15–20 km of oceanic lithosphere. However, the discovery of diamonds, super‐reducing, and other “unusual” minerals from several ophiolitic peridotites suggests that these peridotites might originate in the deep upper mantle (>300 km), challenging conventional models of ophiolite formation. In this study, we show that symplectite‐bearing lherzolites from the Purang diamond‐bearing ophiolite (Tibet) were originally garnet‐bearing peridotites, with a previous equilibration depth of ~85–100 km. Our results suggest that the Purang peridotites may represent mixtures of oceanic lithosphere domains with different nature and origins, which were exhumed and mixed within an oceanic subduction channel associated with slab retreat.
Key Points
Symplectite‐bearing lherzolites from a Tibetan diamond‐bearing ophiolite formed from garnet peridotite protoliths
These lherzolites were previously formed and stabilized at a depth of ~85‐100 km, much deeper than previously suggested
An oceanic subduction channel model is suggested for exhumation of some of the Tibetan diamond‐bearing peridotites
DNA topoisomerase II (topo II) is an important enzyme involved in DNA replication, recombination, and repair. Despite the popular applications of topo II inhibitors in cancer therapy, there is still ...an urgent need to upgrade topo II inhibitors to cope with drug resistance and severe adverse effects. Accordingly, novel topo II catalytic or multitarget topo II inhibitors are gaining more attention and make it possible to ease the toxic limitations of topo II poisons. In this review, medicinal chemistry approaches are mainly discussed toward the development of potent topo II inhibitors with low toxicities.
This study uses geochemical mohometers to investigate the paleo‐crustal thickness and elevation of western Tibet through the Cretaceous to Eocene. The northern Lhasa Block and southern Qiangtang ...Block (QB) had a similar paleo‐crustal thickness of ∼55 km during the Late Cretaceous, but the latter had reached its present‐day thickness (∼70 km) and elevation (∼5.5 km) by the mid‐Eocene, which was not caused by underthrusting of Indian crust according to isotopic evidence. Our study demonstrates the western and central QB shared a similar early Paleogene tectonomagmatic evolution with the formation of a continues proto‐plateau in central Tibet, resulting from crustal shortening and subsequent lithospheric foundering. This in turn implies underthrusting of the Indian lithosphere beneath the western QB after Eocene, given the present‐day lithospheric difference between the western and central QB. Our reconstruction of paleo‐crustal thickness and elevation, however, suggests the Indian underthrusting caused minimal further crustal thickening and uplift.
Plain Language Summary
The Tibetan Plateau is a key locality to study large‐scale continental tectonics because of the well‐preserved Cenozoic geological records along with the validity of geophysical data. The western part of the Tibetan Plateau is not a simple extension of the central‐eastern part as demonstrated by numerous geophysical investigations on the lithospheric structure. The western Qiangtang Block (QB) in central Tibet is generally thought to be raised by the Miocene underthrusting of the Indian lithosphere, yet no palaeoaltimetry data are available to test this hypothesis. This provides the first quantitative constraint on the uplift history of the western QB. We use recently calibrated igneous geochemical proxies of continental thickness to investigate the paleo‐crustal thickness and elevation of western Tibet through the Early Cretaceous to Eocene. Our data demonstrate that the western Tibetan crust had reached its present‐day thickness (∼70 km) and elevation (∼5.5 km) by the Mid‐Eocene, as a result of crustal shortening and subsequent lithospheric foundering. Based on a synthesis of independent geological and seismic data, we contend that the post‐Eocene underthrusting of the Indian lithosphere beneath the western QB has caused minimal further crustal thickening and uplift.
Key Points
First quantitative constraint on the uplift history of the western Qiangtang Block (QB) in central Tibet
The western QB has reached its present‐day thickness and elevation by Eocene
Underthrusting of the Indian lithosphere caused minimal further thickening and uplift of the western Qiangtang crust
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