Sevoflurane is the most commonly used anesthetic in clinical practice and exerts a protective effect on cerebral ischemia-reperfusion (I/R) injury. This study aims to elucidate the molecular ...mechanism by which sevoflurane postconditioning protects against cerebral I/R injury. Oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro and the middle cerebral artery occlusion (MCAO) model in vivo were established to simulate cerebral I/R injury. Sevoflurane postconditioning reduced neurological deficits, cerebral infarction, and ferroptosis after I/R injury. Interestingly, sevoflurane significantly inhibited specificity protein 1 (SP1) expression in MACO rats and HT22 cells exposed to OGD/R. SP1 overexpression attenuated the neuroprotective effects of sevoflurane on OGD/R-treated HT22 cells, evidenced by reduced cell viability, increased apoptosis, and cleaved caspase-3 expression. Furthermore, chromatin immunoprecipitation and luciferase experiments verified that SP1 bound directly to the ACSL4 promoter region to increase its expression. In addition, sevoflurane inhibited ferroptosis via SP1/ACSL4 axis. Generally, our study describes an anti-ferroptosis effect of sevoflurane against cerebral I/R injury via downregulating the SP1/ASCL4 axis. These findings suggest a novel sight for cerebral protection against cerebral I/R injury and indicate a potential therapeutic approach for a variety of cerebral diseases.
Graphical Abstract
Accumulating evidences indicate that circular RNAs (circRNAs), a class of non-coding RNAs, play important roles in tumorigenesis. However, the function of circRNAs in hepatocellular cancer (HCC) is ...largely unknown.
We performed circRNA microarrays to identify circRNAs that are aberrantly expressed in HCC tissues. Expression levels of a significantly upregulated circRNA, circFBLIM1, was detected by quantitative real-time PCR (qRT-PCR) in HCC cell lines and tissues. Then, we examined the functions of circFBLIM1 in HCC by cell proliferation, apoptosis, invasion and mouse xenograft assay. In addition, luciferase assay and RNA immunoprecipitation (RIP) assay were used to explore the miRNA sponge function of circFBLIM1 in HCC.
Microarray analysis and qRT-PCR verified a circRNA termed circFBLIM1 that was upregulated in HCC tissues and cell lines. Knockdown of circFBLIM1 inhibited proliferation, invasion and promoted apoptosis in HCC. Via luciferase reporter assays, circFBLIM1 and FBLIM1 were observed to directly bind to miR-346. Subsequent experiments showed that circFBLIM1 and FBLIM1 regulated the expression of each other by sponging miR-346.
Taken together, we conclude that circFBLIM1 may function as a competing endogenous RNA (ceRNA) to regulate FBLIM1 expression through sponging miR-346 to exert regulatory functions in HCC. circFBLIM1 may be a diagnostic biomarker and potential target for HCC therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Interventional hepatic arterial infusion chemotherapy of infusional fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) displayed an encouraging safety profile and antitumor activity in a previous ...phase II trial and a propensity-score-matching study involving patients with locally advanced hepatocellular carcinoma (HCC).
In this open-label, phase III trial, patients with advanced HCC, previously untreated with systemic therapy, were randomly assigned in a 1:1 ratio to receive HAIC-FO or sorafenib. The primary end point was overall survival (OS) in the intention-to-treat population. An exploratory model for predicting the efficacy of HAIC-FO on the basis of genomic sequencing was developed.
Between May 2017 and May 2020, 262 patients were randomly assigned. The median tumor size was 11.2 cm (interquartile range, 8.5-13.7 cm). Macrovascular invasion was present in 65.6%, and the percentage of patients with > 50% tumor volume involvement of the liver and/or Vp-4 portal vein tumor thrombosis was 49.2%. At data cutoff (October 31, 2020), median OS was 13.9 months for HAIC-FO and 8.2 for sorafenib (hazard ratio HR 0.408; 95% CI, 0.301 to 0.552;
< .001). Tumor downstaging occurred in 16 (12.3% of 130) patients receiving HAIC-FO, including 15 receiving curative surgery or ablation, and finally achieving a median OS of 20.8 months, with a 1-year OS rate of 93.8%. In high-risk subpopulations, OS was significantly longer with HAIC-FO than with sorafenib (10.8 months
5.7 months; HR 0.343; 95% CI, 0.219 to 0.538;
< .001). A newly developed 15-mutant-gene prediction model identified 83% of patients with response to HAIC-FO. HAIC-FO responders had longer OS than HAIC-FO nonresponders (19.3 months
10.6 months; HR 0.323; 95% CI, 0.186 to 0.560;
= .002).
HAIC-FO achieved better survival outcomes than sorafenib in advanced HCC, even in association with a high intrahepatic disease burden.
Covering: Up to March 2019
Secondary metabolites (SMs) are chemical entities produced by organisms in response to environmental stimuli and as a defense against biological warfare. The production of ...SMs is controlled by a hierarchical regulatory network involving core factors that orchestrate transcriptional activation of SM gene clusters. In the past few years, significant achievements have been made in the discovery of novel fungal natural products by genetic manipulations of various types of transcriptional regulators. In this review, we summarized the representative regulators for the activation of fungal secondary metabolism and focused on the strategies for the exploitation of these regulators and their application in finding novel structures.
This review covers diverse transcriptional regulators for the activation of secondary metabolism and novel natural product discovery in fungi.
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•Hepatic arterial infusion was proven to be an effective and safe treatment in advanced HCC.•Hepatic arterial infusion therapy was an independent factor for PFS and OS.•Hepatic ...arterial infusion therapy provided a potential benefit of survival in patients with advanced HCC.
To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib.
This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16–82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models.
The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months RECIST/7.4 vs. 3.6 months mRECIST, respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio HR 0.389 RECIST/0.402 mRECIST; p <0.001 for each) and OS (HR 0.129; p <0.001).
HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding.
We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Covering: Up to 2020
Artemisinin has made a significant contribution towards global malaria control since its initial discovery. Countless lives have been saved by this unique and miraculous ...molecule. In 2006, artemisinin-based combination therapies (ACTs) were recommended by the World Health Organization (WHO) as the first-line treatment for uncomplicated malaria infection and have since remained as the mainstays of the antimalarial treatment. Even so, substantial efforts to pursue better curative effects for the treatment of malaria have never ceased, particularly with regards to the circumstances surrounding the appearance of delayed clearance of malaria parasites by 3 day ACT treatments in South-East Asian countries. Strategies to further optimize artemisinin-based therapies, including synthesizing better artemisinin derivatives, developing advanced drug delivery systems, and diversifying artemisinin partner drugs, have been proposed over the past few years. Here, we provide an updated account of the continuous efforts in improving ACTs for better efficacy in curing malarial infection.
This highlight provides a brief history of artemisinin in its journey from being a natural product to drug, as well as the continuous efforts to improve ACTs with better efficacy against the parasites, which have prolonged life cycles.
Indoleamine 2,3‐dioxygenase 1 (IDO1) is a tryptophan‐metabolizing enzyme that is widely distributed in normal or malignant tissues and contributes to immunologic tolerance and immune escape. However, ...in hepatocellular carcinoma (HCC), the characteristics and mechanism of IDO1 expression have not been well defined. In this study, IDO1 expression in tumor cells (T‐IDO1) was frequently detected (109/112) by immunohistochemistry in formalin‐fixed paraffin‐embedded specimens from HCC patients, and the expression patterns were mostly focal (102/109). Expression of T‐IDO1 was significantly associated with the infiltration of CD8+ T cells (P = .043), as well as younger age (<50 years old, P = .02). It was also found that IDO1 had diffuse expression in inflammatory cells in all specimens, which were defined as antigen‐presenting cells. Significant correlations among IDO1, IFNG, and CD8A transcriptional levels were observed in freshly resected HCC specimens; moreover, no constitutive IDO1 expression was detected in HCC cell lines until stimulated by interferon‐γ through the JAK2‐STAT1 signaling pathway, but not type I interferon. Survival analyses showed that increased T‐IDO1 and CD8+ T cell infiltration were significantly associated with superior overall survival (OS) (T‐IDO1, P = .003; CD8+ T cells, P = .004), and T‐IDO1 expression is an independent prognosis factor in both OS and disease‐free survival (OS, P = .007; disease‐free survival, P = .044). These findings indicated that T‐IDO1 expression in HCC is common and is dominantly driven by the host antitumor immune response, which is a favorable prognostic factor in HCC.
Increased indoleamine 2,3‐dioxygenase 1 (IDO1) levels represented an adaptive immune resistance mechanism exerted by hepatocellular carcinoma cells in response to endogenous antitumor activity. Expression of IDO1 by either tumor cells or infiltrating inflammatory cells was a positive prognostic predictor in hepatocellular carcinoma.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Sparse signal recovery becomes extremely challenging for a variety of real-time applications. In this paper, we improve the orthogonal matching pursuit (OMP) algorithm based on parallel correlation ...indices selection mechanism in each iteration and Goldschmidt algorithm. Simulation results show that the improved OMP algorithm with a reduced number of iterations and low hardware complexity of matrix operations has higher success rate and recovery signal-to-noise-ratio (RSNR) for sparse signal recovery. This paper presents an efficient complex-valued system hardware architecture of the recovery algorithm for analog-to-information structure based on compressive sensing. The proposed architecture is implemented and validated on the Xilinx Virtex6 field-programmable gate array (FPGA) for signal reconstruction with <inline-formula> <tex-math notation="LaTeX">N = 1024 </tex-math></inline-formula>, <inline-formula> <tex-math notation="LaTeX">K = 36 </tex-math></inline-formula>, and <inline-formula> <tex-math notation="LaTeX">M = 256 </tex-math></inline-formula>. The implementation results showed that the improved OMP algorithm achieved a higher RSNR of 31.04 dB compared with the original OMP algorithm. This synthesized design consumes a few percentages of the hardware resources of the FPGA chip with the clock frequency of 135.4 MHZ and reconstruction time of <inline-formula> <tex-math notation="LaTeX">170~\mu \text{s} </tex-math></inline-formula>, which is faster than the existing design.
Timing skews among channels degrade seriously the time-interleaved analog-to-digital converter (TIADC) performance, which can be improved by the blind timing skew estimation (TSE) technique. In this ...paper, we proposed the all-phase fast Fourier transform (ApFFT) based on spectrum sparsity signal phase relationship blind TSE (ApFFT-SSPR-BLTSE) algorithm. The ApFFT-SSPR-BLTSE algorithm reduces computational complexity based on the phase relationship of the total output from TIADC and the corresponding reference channel output compared with the existing spectrum sparsity blind TSE (SS-BLTSE) algorithm. We also utilized the ApFFT technique to increase the accuracy of phase spectral estimation. Simulation results show that the proposed ApFFT-SSPR-BLTSE algorithm, which as a reduced number of fast Fourier transforms (FFTs) and low hardware complexity, has higher accuracy for blind TSE compared to the existing SS-BLTSE algorithm. In addition, this paper presents an efficient hardware architecture of the ApFFT-SSPR-BLTSE algorithm on the Xilinx Virtex-6 vlx550tff1759 field-programmable gate array (FPGA) chip for the blind TSE of the four-channel 400-MHz 14-bit TIADC real system. The validation results show that the proposed algorithm uses only a few percent of the hardware resources of the FPGA chip, and the mismatch spurs were suppressed to better than −81.54 dB.
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