Abstract:In the course of isolating the attenuated Japanese encephalitis vaccine SA14-14-2, two attenuated strains SA14-9-7 and SA14-5-3 were also obtained that elicited low antibody responses in humans (<10% and 62%, respectively) and exerted much weaker immune protection in animal challenge experiments. However, the reason for these differences remains unknown. In order to understand why SA14-14-2 is superior to SA14-9-7 and SA14-5-3, we employed a reverse genetics method to identify the key mutations in the virus ge… Show more
“…These factors primarily antagonize IGF actions and may serve as biomarkers for AKI. 90 Among these IGFBPs, IGFBP-7 is well studied, and emerging evidence shows that urinary IGFBP-7 and tissue inhibitor of metalloproteinase-2 (TIMP-2) can be applied as early diagnostic biomarkers for AKI following cardiac surgery, 91 sepsis, 92 and other renal insults of varied etiology. [93][94][95][96] These factors appear to be ideal biomarkers for moderate and severe AKI, and the US Food and Drug Administration already permitted marketing of Nephro-Check® (Astute Medical) to detect urinary [TIMP-2]*[IGFBP-7] in critically ill patients in 2014.…”
Section: Egf and The Egf Receptor In Akimentioning
Acute kidney injury (AKI) is defined as a rapid decline in renal function and is characterized by excessive renal inflammation and programmed death of resident cells. AKI shows high morbidity and mortality, and severe or repeated AKI can transition to chronic kidney disease (CKD) or even end-stage renal disease (ESRD); however, very few effective and specific therapies are available, except for supportive treatment. Growth factors, such as epidermal growth factor (EGF), insulin-like growth factor (IGF), and transforming growth factor-β (TGF-β), are significantly altered in AKI models and have been suggested to play critical roles in the repair process of AKI because of their roles in cell regeneration and renal repair. In recent years, a series of studies have shown evidence that growth factors, receptors, and downstream effectors may be highly involved in the mechanism of AKI and may function in the early stage of AKI in response to stimuli by regulating inflammation and programmed cell death. Moreover, certain growth factors or correlated proteins act as biomarkers for AKI due to their sensitivity and specificity. Furthermore, growth factors originating from mesenchymal stem cells (MSCs) via paracrine signaling or extracellular vesicles recruit leukocytes or repair intrinsic cells and may participate in AKI repair or the AKI-CKD transition. In addition, growth factor-modified MSCs show superior therapeutic potential compared to that of unmodified controls. In this review, we summarized the current therapeutic and diagnostic strategies targeting growth factors to treat AKI in clinical trials. We also evaluated the possibilities of other growth factorcorrelated molecules as therapeutic targets in the treatment of AKI and the AKI-CKD transition.
“…These factors primarily antagonize IGF actions and may serve as biomarkers for AKI. 90 Among these IGFBPs, IGFBP-7 is well studied, and emerging evidence shows that urinary IGFBP-7 and tissue inhibitor of metalloproteinase-2 (TIMP-2) can be applied as early diagnostic biomarkers for AKI following cardiac surgery, 91 sepsis, 92 and other renal insults of varied etiology. [93][94][95][96] These factors appear to be ideal biomarkers for moderate and severe AKI, and the US Food and Drug Administration already permitted marketing of Nephro-Check® (Astute Medical) to detect urinary [TIMP-2]*[IGFBP-7] in critically ill patients in 2014.…”
Section: Egf and The Egf Receptor In Akimentioning
Acute kidney injury (AKI) is defined as a rapid decline in renal function and is characterized by excessive renal inflammation and programmed death of resident cells. AKI shows high morbidity and mortality, and severe or repeated AKI can transition to chronic kidney disease (CKD) or even end-stage renal disease (ESRD); however, very few effective and specific therapies are available, except for supportive treatment. Growth factors, such as epidermal growth factor (EGF), insulin-like growth factor (IGF), and transforming growth factor-β (TGF-β), are significantly altered in AKI models and have been suggested to play critical roles in the repair process of AKI because of their roles in cell regeneration and renal repair. In recent years, a series of studies have shown evidence that growth factors, receptors, and downstream effectors may be highly involved in the mechanism of AKI and may function in the early stage of AKI in response to stimuli by regulating inflammation and programmed cell death. Moreover, certain growth factors or correlated proteins act as biomarkers for AKI due to their sensitivity and specificity. Furthermore, growth factors originating from mesenchymal stem cells (MSCs) via paracrine signaling or extracellular vesicles recruit leukocytes or repair intrinsic cells and may participate in AKI repair or the AKI-CKD transition. In addition, growth factor-modified MSCs show superior therapeutic potential compared to that of unmodified controls. In this review, we summarized the current therapeutic and diagnostic strategies targeting growth factors to treat AKI in clinical trials. We also evaluated the possibilities of other growth factorcorrelated molecules as therapeutic targets in the treatment of AKI and the AKI-CKD transition.
“…The genomic sequences of SA14-14-2 and SA14 have been published a number of times but the published sequences differ between groups, which makes determination of attenuating mutations difficult 7 – 12 . While one study reports that there are no genomic changes after passage of SA14-14-2 in cell culture, mice or mosquitoes 13 others report consensus changes after very few passages in similar substrates. These changes include three amino acid substitutions after passage in C6/36 cells, four amino acid substitutions after 22 passages in PHK cells, one amino acid substitution after passage in baby hamster kidney (BHK) cells, one amino acid substitution after passage in Vero cells, and four amino acid substitutions after passage in mouse brain 10 , 14 , 15 .…”
Section: Introductionmentioning
confidence: 99%
“…Strain SA14-5-3 was also derived from Clone12-1-7 following passage in mice and PHK cells but it was also over-attenuated with low immunogenicity in clinical trials 22 , 23 . Subsequently, SA14-5-3 was passaged in suckling mice and plaque purified, to derive SA14-14-2, which demonstrates enhanced immunogenicity while retaining an attenuated phenotype 6 , 13 , 23 , 24 . Fig.…”
Section: Introductionmentioning
confidence: 99%
“…The E protein is the major antigenic driver of the humoral immune response to the virus, thereby dictating the success of vaccine cross-protection. Studies have implicated substitutions in the E protein as the major determinants of attenuation of SA14-14-2 9 , 13 , 15 , 17 , 30 – 38 with the NS proteins, which constitute the replication complex, playing no or a very limited role 11 , 17 , 39 , 40 . In fact, a chimeric SA14 virus containing SA14-14-2 prM/E genes was completely attenuated in a 3-week-old Kumming mouse model, demonstrating the importance of E protein in attenuation 41 .…”
Section: Introductionmentioning
confidence: 99%
“…WT JEV infection has been modeled using adult and suckling mice, and multiple outbred and inbred strains 10 , 11 , 13 , 17 , 31 , 34 , 45 – 49 . In general, other than newborn mice, WT JEV strains only cause a lethal infection when given intracranially or by a peripheral route after the blood brain barrier has been perturbed whereas it has been shown that SA14-14-2 is avirulent in suckling mice by both intracranial and intraperitoneal routes (Yang, 2014).…”
Japanese encephalitis virus (JEV) is the etiological agent of Japanese encephalitis (JE). The most commonly used vaccine used to prevent JE is the live-attenuated strain SA14-14-2, which was generated by serial passage of the wild-type (WT) JEV strain SA14. Two other vaccine candidates, SA14-5-3 and SA14-2-8 were derived from SA14. Both were shown to be attenuated but lacked sufficient immunogenicity to be considered effective vaccines. To better contrast the SA14-14-2 vaccine with its less-immunogenic counterparts, genetic diversity, ribavirin sensitivity, mouse virulence and mouse immunogenicity of the three vaccines were investigated. Next generation sequencing demonstrated that SA14-14-2 was significantly more diverse than both SA14-5-3 and SA14-2-8, and was slightly less diverse than WT SA14. Notably, WT SA14 had unpredictable levels of diversity across its genome whereas SA14-14-2 is highly diverse, but genetic diversity is not random, rather the virus only tolerates variability at certain residues. Using Ribavirin sensitivity in vitro, it was found that SA14-14-2 has a lower fidelity replication complex compared to SA14-5-3 and SA14-2-8. Mouse virulence studies showed that SA14-2-8 was the most virulent of the three vaccine strains while SA14-14-2 had the most favorable combination of safety (virulence) and immunogenicity for all vaccines tested. SA14-14-2 contains genetic diversity and sensitivity to the antiviral Ribavirin similar to WT parent SA14, and this genetic diversity likely explains the (1) differences in genomic sequences reported for SA14-14-2 and (2) the encoding of major attenuation determinants by the viral E protein.
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