Background
The prognostic significance of wait time between definite diagnosis and initial radical radiotherapy is not well established in patients with locoregionally advanced nasopharyngeal ...carcinoma (LA‐NPC) receiving both induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT).
Methods
From 2010 to 2018, 648 patients with LA‐NPC treated with IC followed by CCRT were included.
Results
A total of 172 pairs of patients with LA‐NPC were selected by propensity score matching (PSM). Compared to patients with an acceptable wait time (≤75 days), patients with a prolonged wait time (>75 days) had a significant lower 5‐year DMFS rate (86.6% vs. 74.1%, p = 0.006). Subgroup analyses indicated that the unfavorable effects of longer waiting times were mainly seen among stage IVa patients.
Conclusions
A prolonged wait time (>75 days) between definite diagnosis and initial radical radiotherapy has negative prognostic effects on patients with LA‐NPC receiving IC plus CCRT, particularly those with IVa stage.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mitochondrial virus-induced signal adaptor (MAVS), also known as VISA, IPS-1, and Cardif, is a crucial adaptor protein in the RIG-I-like receptor (RLR) signaling pathway. Upon viral infection, RIG-I ...recognizes viral dsRNA and further transfers it to mitochondria, where it binds to MAVS through its CARD domain, generating a series of signal cascades. Transduction through this signaling cascade leads to phosphorylation and nuclear translocation of interferon regulatory factor 3/7 (IRF3/IRF7) and activation of NF-κB, which ultimately produces type I interferon (IFN) and proinflammatory cytokines. Here, our experiments demonstrated that overexpression of SRY-related high-mobility group protein 9 (SOX9) significantly inhibited Sendai virus (SeV)-induced and MAVS-mediated activation of the IFN-β promoter and ISRE. However, knocking out the expression of SOX9 in cells promoted SeV-induced IFN-β promoter and ISRE activation. Further studies have shown that SOX9 interacts with MAVS and targets MAVS to inhibit the association of MAVS-TRAF2, thereby inhibiting MAVS-mediated TRAF2 ubiquitination. Taken together, these results indicate that SOX9 downregulates IFN-β expression and antiviral signal transduction by targeting MAVS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Long-term use of morphine induces analgesic tolerance, which limits its clinical efficacy. Evidence indicated morphine-evoked neuroinflammation mediated by toll-like receptor 4 (TLR4) - NOD-like ...receptor protein 3 (NLRP3) inflammasome was important for morphine tolerance. In our study, we investigated whether other existing alternative pathways caused morphine-induced activation of TLR4 in microglia. We focused on heat shock protein 70 (HSP70), a damage-associated molecular pattern (DAMP), which was released from various cells upon stimulations under the control of K
channel and bound with TLR4-inducing inflammation. Glibenclamide, a classic K
channel blocker, can improve neuroinflammation by inhibiting the activation of NLRP3 inflammasome. Our present study investigated the effect and possible mechanism of glibenclamide in improving morphine tolerance via its specific inhibition on the release of HSP70 and activation of NLRP3 inflammasome induced by morphine.
CD-1 mice were used for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 and neural cell line SH-SY5Y were used to investigate the pharmacological effects and the mechanism of glibenclamide on morphine-induced neuroinflammation. The activation of microglia was accessed by immunofluorescence staining. Neuroinflammation-related cytokines were measured by western blot and real-time PCR. The level of HSP70 and related signaling pathway were evaluated by western blot and immunofluorescence staining.
Morphine induced the release of HSP70 from neurons. The released HSP70 activated microglia and triggered TLR4-mediated inflammatory response, leading to the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 and the activation of NLRP3 inflammasome. Moreover, anti-HSP70 neutralizing antibody partly attenuated chronic morphine tolerance. The secretion of HSP70 was under the control of MOR/AKT/K
/ERK signal pathway. Glibenclamide as a classic K
channel blocker markedly inhibited the release of HSP70 induced by morphine and suppressed HSP70-TLR4-NLRP3 inflammasome-mediated neuroinflammation, which consequently attenuated morphine tolerance.
Our study indicated that morphine-induced extracellular HSP70 was an alternative way for the activation of TLR4-NLRP3 in analgesic tolerance. The release of HSP70 was regulated by MOR/AKT/K
/ERK pathway. Our study suggested a promising target, K
channel and a new leading compound, glibenclamide, for treating morphine tolerance.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background and purpose
As endovascular thrombectomy (EVT) is time-dependent, it is crucial to refer patients promptly. Current referral modes include Mothership (MS), Drip and Ship (DS) and ...Drive the Doctor (DD). The purpose of this study was to investigate the influences of different referral modes on the clinical outcomes of patients with acute ischemic stroke after EVT.
Methods
A total of 349 patients from 15 hospitals between April 2017 and March 2020 were enrolled. The primary outcomes include poor outcome (modified Rankin Scale score of 3 to 6), symptomatic intracranial hemorrhage transformation (sICH), mortality and cost. Regression analysis was used to assess the association of referral modes with poor outcome, sICH, mortality and cost in acute ischemic stroke patients.
Results
Among the 349 patients, 83 were in DD group (23.78%), 85 in MS group (24.36%) and 181 in DS group (51.86%). There were statistically significant differences in intravenous thrombolysis, onset-to-door time, onset-to-puncture time, puncture-to-recanalization time, door-to-puncture time, door-to-recanalization time, and cost among the DD, MS, and DS groups (59.04% vs 35.29% vs 33.15%,
P
<0.001; 90 vs 166 vs 170 minutes,
P
<0.001; 230 vs 270 vs 270 minutes,
P
<0.001; 82 vs 54 vs 51 minutes,
P
<0.001; 110 vs 85 vs 96 minutes,
P
=0.004; 210 vs 146 vs 150 minutes,
P
<0.001; 64258 vs 80041 vs 70750 Chinese Yuan,
P
=0.018). In terms of sICH, mortality and poor outcome, there was no significant difference among the DD, MS, and DS groups (22.89% vs 18.82% vs 19.34%,
P
=0.758; 24.10% vs 24.71% vs 29.83%,
P
=0.521; 64.47% vs 64.71% vs 68.51%,
P
=0.827). The results of multiple regression analysis indicated that there was no independent correlation between different referral modes regarding sICH (
OR
MS
: 0.50, 95%CI: 0.18, 1.38,
P
=0.1830;
OR
DS
: 0.47, 95%CI: 0.19, 1.16,
P
=0.1000), mortality (
OR
MS
: 0.56, 95%CI: 0.19, 1.67,
P
=0.2993;
OR
DS
: 0.65, 95%CI: 0.25, 1.69,
P
=0.3744) and poor outcome (
OR
MS
: 0.61, 95%CI: 0.25, 1.47,
P
=0.2705;
OR
DS
: 0.53, 95%CI: 0.24, 1.18,
P
=0.1223). However, there was a correlation between MS group and cost (
β
=30449.73, 95%CI: 11022.18, 49877.29;
P=
0.0023). The multiple regression analysis on patients finally admitted in comprehensive stroke center (MS+DS) versus patients finally admitted in primary stroke center (DD) showed that DD mode was independently associated with lower costs (
β
=-19438.86, 95%CI: -35977.79, -2899.94;
P
=0.0219).
Conclusion
There was no independent correlation between three referral modes and sICH, mortality, poor outcome correspondingly. Different referral modes can be implemented in clinical practice according to the situations encountered. Compared to MS and DS modes, DD mode is more economical.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study was aiming at the differences in the aroma, flavor compounds, and bioactivities of essential oil of Coreopsis tinctoria flower (CTFEO) and essential oil of Chrysanthemum morifolium flower ...(CMFEO). Both essential oils were extracted by steam distillation. Their flavor compositions were determined by GC-MS and the antioxidant, antibacterial, and anti-inflammatory activities were also evaluated. It was found that CTFEO possessed a special medicinal herb odor, which was obviously stronger than those of CMFEO. A preferred condition for steam distillation was flower powder-water ratio of 7.5:100 and extraction for more than 3.0 h. Interestingly, the main flavor compounds of CTFEO were determined as D-limonene (34.54%), cis-carveol (5.49%), trans-α-bergamotene (4.44%), and α-pinene (3.90%), which were quite different from those of CMFEO. CTFEO showed better antioxidant activities with IC
50
value of 121.4 ± 9.8 μg/mL than those of CMFEO. It also exhibited stronger antibacterial effects than those of CMFEO, with minimal inhibitory concentrations (MICs) ranging from 0.183 to 1.412 mg/mL against six strains of bacteria. Moreover, CTFEO was also found to exhibit strong anti-inflammatory effects that reduced the LPS-induced RAW 264.7 cell mRNA expression of the cytokines IL-1β, IL-6, and TNF-α at a concentration of 10.0 μg/mL. All these results suggest that the aroma, flavor compounds, and bioactivities of the two essential oils were quite different and they could be used as tea, drink, and food additive in the food industry for further development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This study aimed to investigate the intoxication mechanism of golden pompano (Trachinotus ovatus) exposed to high ammonia levels and the effects on the immune and antioxidant mechanisms of gills. ...Juvenile golden pompano was exposed to ammonia (total ammonia: 26.9 mg/L) to induce 96 h of ammonia stress, and a 96 h recovery experiment was performed after poisoning. Then, we evaluated hematological parameters, the histological structure and the expression of related genes. In this experiment, continuous exposure to high levels of ammonia led to a significant increase in plasma alkaline phosphatase (ALP), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels (P < 0.05), and the levels of triiodothyronine (T3) and tetraiodothyronine (T4) were significantly reduced (P < 0.05). Moreover, the expression of antioxidant genes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) increased (P < 0.05). These results indicate that ammonia activates the active osmotic regulatory mechanism of fish gills and participates in defense and immune responses. However, with prolonged exposure to ammonia, the balance of the defense system is disrupted, leading to oxidative damage and inflammation of the gill tissue. This research not only helps elucidate the intoxication mechanism of golden pompano by ammonia at the molecular level but also provides a theoretical basis for further research on detoxification mechanisms.
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•Ammonia stress causes oxidative damage and inflammation in golden pompano gills.•Ammonia stress upregulates the mRNA expression levels of HIF-1α and NF-κb.•The HIF-1α/NF-κb signaling pathway regulates the expression and release of defense enzyme genes and inflammatory cytokines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The complex genetic architecture of quality traits has hindered efforts to modify seed nutrients in soybean. Genome-wide association studies were conducted for seed composition, including protein, ...oil, fatty acids, and amino acids, using 313 diverse soybean germplasm accessions genotyped with a high-density SNP array. A total of 87 chromosomal regions were identified to be associated with seed composition, explaining 8%–89% of genetic variances. The candidate genes GmSAT1, AK-HSDH, SACPD-C, and FAD3A of known function, and putative MtN21 nodulin, FATB, and steroid-5-α-reductase involved in N2 fixation, amino acid biosynthesis, and fatty acid metabolism were found at the major-effect loci. Further analysis of additional germplasm accessions indicated that these major-effect loci had been subjected to domestication or modern breeding selection, and the allelic variants and distributions were relevant to geographic regions. We also revealed that amino acid concentrations related to seed weight and to total protein had a different genetic basis. This helps uncover the in-depth genetic mechanism of the intricate relationships among the seed compounds. Thus, our study not only provides valuable genes and markers for soybean nutrient improvement, both quantitatively and qualitatively, but also offers insights into the alteration of soybean quality during domestication and breeding.
Molecular and genomic investigation helps to reveal the genetic architecture of complex traits. By a genome-wide association study, 138 quantitative trait loci associated with seed composition and many candidate genes were identified in soybean. The results also indicated a different genetic basis between seed-weight-based and total-protein-corrected amino acids and revealed a marked impact of soybean domestication and modern breeding selection on six major-effect loci.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Legume crops are grown in the world primarily for their grain seeds that are widely used for human and animal consumption or for the production of oils for industrial uses ...
Mitogen-activated protein kinase kinase kinase 3 (MAP3K3), a member of the serine/threonine protein kinase family, is ubiquitously expressed and acts as an oncogene. However, the expression and exact ...molecular mechanism of MAP3K3 in ovarian carcinoma (OC) remain unclear. Here, we found that MAP3K3 protein was highly expressed in 70.5% of high-grade serous ovarian carcinoma (HGSOC) samples. MAP3K3 overexpression was significantly associated with the FIGO stage and chemotherapy response. Additionally, MAP3K3 overexpression was associated with reduced disease-free survival and overall survival. In vitro experiments showed that MAP3K3 overexpression promoted cell proliferation, inhibited apoptosis, and enhanced the migration and invasion of OC cells. Moreover, in vivo tumourigenesis experiments confirmed that silencing MAP3K3 significantly reduced the growth rate and volume of transplanted tumours in nude mice. Drug sensitivity experiments demonstrated that differential expression of MAP3K3 in OC cell lines correlates with chemotherapy resistance. Functionally, the MAP3K3 gene regulated the malignant biological behaviour of OC cells by mediating NF-κB signalling pathways, affecting the downstream epithelial-mesenchymal transition and cytoskeletal protein expression. Our results unveiled the role of MAP3K3 in mediating NF-κB signalling to promote the proliferation, invasion, migration, and chemotherapeutic resistance of OC cells, highlighting a potential new therapeutic and prognostic target.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Microbially induced calcium carbonate precipitation (MICP) is an environmentally friendly technology that improves soil permeability resistance through biocementation. In this study, 2D microscopic ...analysis and 3D volume reconstruction were performed on river sand after 24 cycles of bio-treatment based on stacked images and computed tomography (CT) scanning data, respectively, to extract biocementation patterns between particles. Based on the mutual validation findings of the two techniques, three patterns in the biocemented sand were identified as G-C-G, G-C, and G-G. Specifically, 2D microscopic analysis showed that G-C-G featured multi-particle encapsulation and bridging, with a pore filling ratio of 81.2%; G-C was characterized by locally coated particle layers, with a pore filling ratio of 19.7%; and the G-G was marked by sporadic filling of interparticle pores, with a pore filling ratio of 11.7%. G-C-G had the best cementation effect and permeability resistance (effective sealing rate of 68.5%), whereas G-C (effective sealing rate of 2.4%) had a relatively minor contribution to pore-filling and flow sealing. 3D volume reconstruction showed that G-C-G had the highest pore filling rate, followed by G-G and G-C. The average filling ratios of area and volume for G-C-G were 83.979% and 77.257%, respectively; for G-G 20.360% and 23.600%; and for G-C 11.545% and 11.250%. The analysis of the representative element volume (REV) was conducted, and the feasibility and reliability of the micro-scale pattern extraction results were confirmed to guide the analysis of macro-scale characteristics. The exploration of the effectiveness of cementation patterns in fluid sealing provides valuable insights into effective biocementation at the pore scale of porous media, which may inspire future research.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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