Clinical advances of siRNA therapeutics Hu, Bo; Weng, Yuhua; Xia, Xin‐Hua ...
The journal of gene medicine,
July 2019, Letnik:
21, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Small interfering RNA (siRNA) enables efficient target gene silencing by employing a RNA interference (RNAi) mechanism, which can compromise gene expression and regulate gene activity by cleaving ...mRNA or repressing its translation. Twenty years after the discovery of RNAi in 1998, ONPATTRO™ (patisiran) (Alnylam Pharmaceuticals, Inc.), a lipid formulated siRNA modality, was approved for the first time by United States Food and Drug Administration and the European Commission in 2018. With this milestone achievement, siRNA therapeutics will soar in the coming years. Here, we review the discovery and the mechanisms of RNAi, briefly describe the delivery technologies of siRNA, and summarize recent clinical advances of siRNA therapeutics.
Kidney injury initiates metabolic reprogramming in tubule cells that contributes to the development of chronic kidney disease (CKD). Exercise has been associated with beneficial effects in patients ...with CKD. Here we show that the induction of a myokine, irisin, improves kidney energy metabolism and prevents kidney damage. In response to kidney injury, mice with muscle-specific PGC-1α overexpression (mPGC-1α) exhibit reduced kidney damage and fibrosis. Metabolomics analysis reveals increased ATP production and improved energy metabolism in injured kidneys from mPGC-1α mice. We identify irisin as a serum factor that mediates these metabolic effects during progressive kidney injury by inhibiting TGF-β type 1 receptor. Irisin depletion from serum blunts the induction of oxygen consumption rate observed in tubule cells treated with mPGC-1α serum. In mice, recombinant irisin administration attenuates kidney damage and fibrosis and improves kidney functions. We suggest that myokine-mediated muscle-kidney crosstalk can suppress metabolic reprograming and fibrogenesis during kidney disease.
The development of lightweight composites with desirable thermo‐mechanical properties is progressively increasing. Phthalonitrile (PN) based composites have shown great potential in this regard. ...However, the basic thermal properties of PN composites required for engineering design are not yet fully understood. In this work, we investigated the thermal stability, thermal expansion behavior and thermal conductivity of PN composites reinforced with carbon fiber (CF) and high silicon fiberglass (HSF) via combined experimental studies and numerical simulations. The results indicated that CF/PN performs better in thermostability than HSF/PN at temperatures below 500°C. Moreover, the incorporation of CF and HSF lowered the coefficient of thermal expansion (CTE) and thermal insulation of PN. At room temperature, the in‐plane CTE of CF/PN and HSF/PN were 1.97E‐6 and 9.24E‐6°C−1, respectively, while the out‐plane thermal conductivities of CF/PN and HSF/PN were 0.65 and 0.34 W/(m K). It is worth noting that an excessively high fiber volume fraction would lead to poor thermal insulation and lightweight properties of the PN composites, while a low fiber volume fraction would result in poor stiffness and thermal dimensional stability. Determined via TOPSIS model, a fiber volume fraction range of 50%–60% was ideal for both composites with comprehensive optimal properties, respectively.
Preparation and simulation of PN composites.
Background
The monitoring of immunotherapies is still based on changes in the tumor size in imaging, with a long evaluation period and low sensitivity.
Purpose
To investigate the effectiveness of ...diffusion kurtosis imaging (DKI) and dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in assessing the therapeutic efficacy of anti‐programmed death‐1 (PD‐1) therapy in a mouse triple negative breast cancer (TNBC) model.
Study Type
Prospective.
Animal Model
A total of 54 BALB/c mouse subcutaneous 4 T1 transplantation models of TNBC.
Field Strength/Sequence
A 3.0‐T; turbo spin echo (TSE) T2‐weighted imaging, DKI with seven b values (0, 500, 1000, 1500, 2000, 2500, and 3000 sec/mm2) and T1‐twist DCE acquisition series.
Assessment
DKI and DCE‐MRI parameters were evaluated by two radiologists independently. Regions of interest (ROIs) were drawn manually on the maximum cross‐sectional area of the lesion; care was taken to avoid necrotic areas. The tumor cell density, the CD45 and CD31 levels were analyzed by two pathologists.
Statistical Tests
The two‐tailed unpaired t‐test, Mann–Whitney U test, Fisher's exact test and Pearson correlation coefficient were performed. A P < 0.05 was considered statistically significant.
Results
The apparent diffusion coefficient (ADC), mean diffusivity (MD), Ktrans and Kep values were significantly different between the two groups at each time point after treatment. There were significant differences in the mean kurtosis (MK) and Ve values between the two groups at 5 and 10 days after treatment but no significant differences at 15 days (P = 0.317 and 0.183, respectively). The ADC and MD values were significantly correlated with tumor cell density (ADC, r = −0.833; MD, r = 0.890) and the CD45 level (ADC, r = 0.720; MD, r = 0.718). The Ktrans and Kep values were significantly correlated with the CD31 level (Ktrans, r = 0.820; Kep, r = 0.683).
Data Conclusion
DKI and DCE‐MRI could reflect the changes in tumor microstructure and tumor tissue vasculature after anti‐PD‐1 therapy, respectively.
Level of Evidence
1
Technical Efficacy
Stage 4.
A double functionalization approach was developed to create efficient bifunctional electrocatalysts for electrochemical overall water splitting. Uniform Ni3Co(CN)62·12H2O nanocubes were taken as the ...starting material to fabricate the bifunctional catalysts through ammonia carving, conformal polydopamine coating, precursor metal ion coordination, and thermal phosphorization. N-doped carbon carved hollow nanocubes were loaded with hydrogen evolution reaction (HER) active (Ni-Co) phosphides in the interior cyanide-derived carbon layers and oxygen evolution reaction (OER) active (Ni-Fe) phosphides on the exterior polydopaimne-derived carbon layers. The product catalyst exhibited excellent electrolytic performances, achieving overpotentials of 251 and 142 mV for the OER and HER, respectively and a working cell voltage of 1.63 V for the overall water splitting all at 10 mA/cm2. Holes of several tens nanometers in size located at the eight vertices of the hollow cube allow easy access of the electrolyte to and fast rejection of evolving gas bubbles from the interior of the cube. The N-doped carbon nanocubes, providing fast charge transport pathway, and the positive synergistic effects arising from the mixed metal phosphides, significantly enhanced catalytic performances of the product catalyst. Both quantity and quality of the active sites are largely improved with the doubly functionalized N-doped carbon carved hollow nanocubes, which is a superior catalyst design for all electrocatalytic applications.
Doubly functionalized carbon carved hollow nanocubes, C-(Fe-Ni)P@PC/(Ni-Co)P@CC, were developed and demonstrated as a high performance bifunctional catalyst for electrochemical water splitting. Display omitted
•Double functionalization approach developed for bifunctional electrocatalysts.•N-doped carbon carved hollow nanocube structure increases quantity of active sites.•Well mixed metal phosphides induces synergistic effects to improve quality of active sites.•Require 1.63 V@10 mA cm−2 for full water splitting.
Multiparameter spectrophotometry (MPS) provides a powerful and environmental-friendly tool for the characterization of turbid materials, including foods, without additives. The existing methods of ...MPS, however, lack either modeling accuracy or capacity for translation into ease-of-use instrument. We have developed a novel method of MPS to rapidly retrieve the spectral data of absorption coefficient, scattering coefficient, and anisotropy factor within the framework of radiative transfer (RT) theory without using integrating spheres. To demonstrate the feasibility of our MPS method for food analysis, the RT parameters have been determined between 500 and 1000 nm for four types of milk samples and skim milk samples spiked with either Lactobacillus acidophilus (L. acid.) or DH<inline-formula> <tex-math notation="LaTeX">5\alpha </tex-math></inline-formula> Escherichia coli (E. coli) bacteria. The spectral data have been shown to agree with the published results on milk composition. We have also found the threshold of number density for the detection of E. coli in skim milk to be about <inline-formula> <tex-math notation="LaTeX">2\times 10^{4} </tex-math></inline-formula> (mm−3). These results show clearly the potential of the presented method for the development of accurate, ease-of-use, and cost-effective instrument for routine analysis of turbid materials by MPS.
Background
As the second leading cause of cancer morbidity and death in women, cervical cancer remains an important public health problem worldwide. Novel biomarkers with high sensitivity and ...specificity for the early detection and diagnosis of cervical cancer are urgently needed. Increasing evidence shows that long noncoding RNAs (lncRNAs) are differentially expressed in cancer tissues and may serve as diagnostic markers. In multiple tumor types, exosomes harboring lncRNAs are actively released from tumor cells. In this study, we investigate the potential association of exosomal lncRNA expression with cervical cancer.
Methods
Cervicovaginal lavage specimens were collected from patients with cervical cancer and cancer‐free volunteers who are HPV‐positive or HPV‐negative. Exosomes in these specimens were isolated by ultracentrifugation and confirmed by transmission electron microscopy. The exosomal lncRNAs HOTAIR, MALAT1, and MEG3 were quantified by qRT‐PCR.
Results
Expression of HOTAIR, MALAT1 and MEG3 was predominantly observed in cervical cancer‐derived exosomes in cervicovaginal lavage samples. The expression levels of lncRNAs were significantly different in exosomes isolated from cervical cancer patients compared to normal controls.
Conclusions
Our data suggest that lncRNAs in exosomes isolated from cervicovaginal lavage are differentially expressed in cervical cancer patients and cancer‐free volunteers. Exosomal lncRNAs may have great potential to be used for the early detection and diagnosis of cervical cancer, and serve as convenient and noninvasive biomarkers.
Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the ...DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.
Bone metastasis is the leading cause of mortality and reduced quality of life in patients with metastatic prostate cancer (PCa). Long non-coding RNA activated by DNA damage (NORAD) has been observed ...to have an abnormal expression in various cancers. This article aimed to explore the molecular mechanism underlying the regulatory role of NORAD in bone metastasis of PCa.
NORAD expression in clinical PCa tissues and cell lines was detected with the application of qRT-PCR. Cancer cells were then transfected with plasmids expressing NORAD, after which Transwell assay and CCK-8 assay were carried out to detect proliferation, migration, and bone metastasis of PCa. NORAD downstream target molecules were screened through bioinformatics analysis, followed by further verification using dual luciferase assay. Extracellular vesicles (EVs) were labeled with PKH67 and interacted with bone marrow stromal cells. The gain- and loss-function method was applied to determine the internalization and secretion of PCa cells-derived EVs under the intervention of downstream target molecules or NORAD.
PCa tissues and cell lines were observed to have a high expression of NORAD, particularly in tissues with bone metastasis. NORAD knockdown resulted in reduced secretion and internalization of EVs, and suppressed proliferation, migration, and bone metastasis of PCa cells. It was indicated that NORAD interacted with miR-541-3p, leading to the upregulation of PKM2. Forced expression of PKM2 promoted the transfer of PKH67-labeled EVs to bone marrow stromal cells.
NORAD might serve as a ceRNA of miR-541-3p to promote PKM2 expression, thereby enhancing the development of bone metastasis in PCa by promoting internalization and transfer of EVs of cancer cells, providing an insight into a novel treatment for the disorder.
Objective
To systematically investigate the effect of imaging features at different DCE-MRI phases to optimise a radiomics model based on DCE-MRI for the prediction of tumour-infiltrating lymphocyte ...(TIL) levels in breast cancer.
Materials and methods
This study retrospectively collected 133 patients with pathologically proven breast cancer, including 73 patients with low TIL levels and 60 patients with high TIL levels. The volumes of breast cancer lesions were manually delineated on T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and each phase of DCE-MRI, followed by 6250 quantitative feature extractions. The least absolute shrinkage and selection operator (LASSO) method was used to select predictive feature sets for the classifiers. Four models were developed for predicting TILs: (1) single enhanced phase radiomics models; (2) fusion enhanced multi-phase radiomics models; (3) fusion multi-sequence radiomics models; and (4) a combined radiomics-based clinical model.
Results
Image features extracted from the delayed phase MRI, especially DCE_Phase 6 (DCE_P6), demonstrated dominant predictive performances over features from other phases. The fusion multi-sequence radiomics model and combined radiomics-based clinical model achieved the highest predictive performances with areas under the curve (AUCs) of 0.934 and 0.950, respectively; however, the differences were not statistically significant.
Conclusion
The DCE-MRI radiomics model, especially image features extracted from the delayed phases, can help improve the performance in predicting TILs. The radiomics nomogram is effective in predicting TILs in breast cancer.
Key Points
•
Radiomics features extracted from DCE-MRI, especially delayed phase images, help predict TIL levels in breast cancer.
•
We developed a nomogram based on MRI to predict TILs in breast cancer that achieved the highest AUC of 0.950.
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