Background. The role of interleukin-12 (IL-12), interleukin-23 (IL-23), and interleukin-17 (IL-17) has been recognized in psoriasis pathogenesis, and new drugs targeting this axis have already been ...developed which may provide a new therapeutic approach for patients with moderate to severe psoriasis. Objective. To compare the direct and indirect evidences of the efficacy and safety of brodalumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and risankizumab in the short-term treatment of moderate to severe plaque psoriasis using network meta-analysis (NMA). Methods. A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for the available relevant studies. NMA was conducted by Stata 15.0 software using relative risks (RR) with 95% confidence interval to assess the clinical effectiveness and safety. Ranked the efficacy and safety for each drug accordance with the surface under the cumulative ranking curve (SUCRA). Results. This meta-analysis included 28 studies. All the interventions performed better than placebo in short-term achievement. Based on the result of SUCRA, ixekizumab 80 mg every 2 weeks ranked the highest in short-term achievement of PASI 75 (SUCRA = 93.0%). Brodalumab 210 mg ranked the highest in short-term achievement of PASI 100 (SUCRA = 85.0%). Secukinumab 300 mg ranked the highest in short-term achievement of sPGA 0/1 or IGA 0/1 or PGA 0/1 (SUCRA = 98.1%). In terms of having a risk of adverse events, the rates were higher in brodalumab, secukinumab, ixekizumab, and ustekinumab 45 mg compared with placebo. Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of adverse events during short-term treatment (SUCRA = 4.5%). Guselkumab 50 mg ranked the highest in the risk of serious adverse events during short-term treatment (SUCRA = 25.9%). Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of discontinuations due to adverse events during short-ter treatment (SUCRA = 10.7%). Conclusions. IL-17, IL-12/23, and IL-23 inhibitors had high efficacy in the achievement of PASI 75, PASI 100, and sPGA 0/1 or IGA 0/1 or PGA 0/1 in moderate to severe plaque psoriasis after 12 or 16 weeks of treatment. IL-17 inhibitors showed superior efficacy. However, its clinical safety was poor. Risankizumab appeared to have relatively high efficacy and low risk. The clinical tolerance of other biological agents needs to be further observed.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is, however, not a uniform state but with ...graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly up-regulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Finally, we found that a gene-expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The growing demand in the number of sensor–dependent applications and infotainment services in vehicles is pushing the limits of their on–board computing resources. Today, vehicles are increasingly ...being connected to the Internet and becoming a part of the Smart Internet–of–Things (IoT) paradigm. Leveraging such connectivity, the idea of vehicular cloud–computing, where computation for vehicular applications and services are offloaded to the cloud, becomes an attractive proposition. However, the large sensory data inputs, strict latency requirements, and dynamic wireless networking conditions make offloading of vehicular applications to the cloud very challenging. To address this challenge, we design a dynamic approach for offloading specific vehicular application components or modules. We develop heuristic mechanisms for placement and scheduling of these modules in the on–board unit versus the cloud. The highlight of the proposed design is the ability to offload computation to the cloud in an elastic manner through dynamic decisions during variable network conditions. Through an experimental evaluation using our prototype system we show the effectiveness of the design in reducing the response time for compute intensive applications across variable network conditions in two urban environments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
One crucial condition for the uniqueness of Nash equilibrium set in vaccination games is that the attack ratio monotonically decreases as the vaccine coverage level increasing. We consider several ...deterministic vaccination models in homogeneous mixing population and in heterogeneous mixing population. Based on the final size relations obtained from the deterministic epidemic models, we prove that the attack ratios can be expressed in terms of the vaccine coverage levels, and also prove that the attack ratios are decreasing functions of vaccine coverage levels. Some thresholds are presented, which depend on the vaccine efficacy. It is proved that for vaccination games in homogeneous mixing population, there is a unique Nash equilibrium for each game.
Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered ...by low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole-genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of small-cell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The potential of infrastructureless vehicular ad hoc networks for providing safety and nonsafety applications is quite significant. The topology of VANETs in urban, suburban, and rural areas can ...exhibit fully connected, fully disconnected, or sparsely connected behavior, depending on the time of day or the market penetration rate of wireless communication devices. In this article we focus on highway scenarios, and present the design and implementation of a new distributed vehicular multihop broadcast protocol, that can operate in all traffic regimes, including extreme scenarios such as dense and sparse traffic regimes. DV-CAST is a distributed broadcast protocol that relies only on local topology information for handling broadcast messages in VANETs. It is shown that the performance of the proposed DV-CAST protocol in terms of reliability, efficiency, and scalability is excellent.
Somatic mutations that accumulate in normal tissues are associated with ageing and disease.sup.1,2. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies ...of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
A nitrogen-doped carbon was synthesized through the pyrolysis of the well-known metal-organic framework ZIF-8, followed by a subsequent acid treatment, and has been applied as a catalyst in the ...electrochemical reduction of carbon dioxide. The resulting electrode shows Faradaic efficiencies to carbon monoxide as high as ∼78%, with hydrogen being the only byproduct. The pyrolysis temperature determines the amount and the accessibility of N species in the carbon electrode, in which pyridinic-N and quaternary-N species play key roles in the selective formation of carbon monoxide.
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IJS, KILJ, NUK, PNG, UL, UM
We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were ...more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.
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•We build the genomic and transcriptomic landscape of 465 primary TNBCs•Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype•Transcriptomic data classify TNBCs into four subtypes•Multi-omics profiling identifies potential targets within specific TNBC subtypes
Jiang et al. characterize primary Chinese triple-negative breast cancer (TNBC) and classify it into four subtypes. They find that these TNBCs have more frequent PIK3CA mutations and chromosome 22q11 copy-number gains than non-Asian TNBCs and that the LAR subtype has more ERBB2 somatic mutations and CDKN2A loss.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Circulating tumor cells (CTCs) are cancer cells discovered in cancer patients’ peripheral blood that successfully escape from the primary tumor site and/or metastases, struggle to survive in the ...bloodstream, and have potential for seeding metastases. Numerous methods have been proposed to capture CTCs. The value of CTCs as a means of understanding cancer metastasis and a major form of ‘liquid biopsy’ has been widely demonstrated. Recently, single-cell molecular analyses of CTCs have provided profound biological insights into tumor heterogeneity, mechanism of metastasis and tumor evolution. In addition, because CTC analysis is non-invasive, CTCs exhibit great potential as biomarkers for assessment of cancer prognosis and therapy response. In this review, we summarize modern technologies for CTC detection and isolation, single-cell genomic/transcriptomic characterization of CTCs, and prospective clinical applications of CTCs. We expect that, after further technical improvements in methods of detection and sequencing, CTC analyses will shed new light on the mechanisms driving cancer metastasis and benefit many cancer patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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