Biomembrane-wrapped gene delivery nanoparticles for cancer therapy

As a promising strategy, gene delivery for cancer treatment accepts encouraging progress due to its high efficacy, low toxicity, and exclusive selectivity. However, the delivery efficiency, specific biological distribution, targeted uptake, and biosafety of naked nucleic acid agents still face serious challenges, which limit further clinical application. To overcome the above bottleneck, safe and efficient functional nanovectors are developed to improve the delivery efficiency of nucleic acid agents. In recent years, emerging membrane-wrapped biomimetic nanoparticles (MBNPs) based on the concept of “imitating nature” are well known for their advantages, such as low immunogenicity and long cycle time, and especially play a crucial role in improving the overall efficiency of gene delivery and reducing adverse reactions. Therefore, combining MBNPs and gene delivery is an effective strategy to enhance tumor treatment efficiency. This review presents the mechanism of gene therapy and the current obstacles to gene delivery. Remarkably, the latest development of gene delivery MBNPs and the strategies to overcome these obstacles are summarized. Finally, the future challenges and prospects of gene delivery MBNPs toward clinical transformation are introduced. The principal purpose of this review is to discuss the biomedical potential of gene delivery MBNPs for cancer therapy and to provide guidance for further enhancing the efficiency of tumor gene therapy

Linear brain measurement: a new screening method for cognitive impairment in elderly patients with cerebral small vessel disease

BackgroundThe old adults have high incidence of cognitive impairment, especially in patients with cerebral small vessel disease (CSVD). Cognitive impairment is not easy to be detected in such populations. We aimed to develop clinical prediction models for different degrees of cognitive impairments in elderly CSVD patients based on conventional imaging and clinical data to determine the better indicators for assessing cognitive function in the CSVD elderly.Methods210 CSVD patients were screened out by the evaluation of Magnetic Resonance Imaging (MRI). Then, participants were divided into the following three groups according to the cognitive assessment results: control, mild cognitive impairment (MCI), and dementia groups. Clinical data were collected from all patients, including demographic data, biochemical indicators, carotid ultrasound, transcranial Doppler (TCD) indicators, and linear measurement parameters based on MRI.ResultsOur results showed that the brain atrophy and vascular lesions developed progressive worsening with increased degree of cognitive impairment. Crouse score and Interuncal distance/Bitemporal distance (IUD/BTD) were independent risk factors for MCI in CSVD patients, and independent risk factors for dementia in CSVD were Crouse Score, the pulsatility index of the middle cerebral artery (MCAPI), IUD/BTD, and Sylvian fissure ratio (SFR). Overall, the parameters with high performance were the IUD/BTD (OR 2.28; 95% CI 1.26–4.10) and SFR (OR 3.28; 95% CI 1.54–6.91), and the AUC (area under the curve) in distinguishing between CSVD older adults with MCI and with dementia was 0.675 and 0.724, respectively. Linear brain measurement parameters had larger observed effect than other indexes to identify cognitive impairments in CSVD patients.ConclusionThis study shows that IUD/BTD and SFR are good predictors of cognitive impairments in CSVD elderly. Linear brain measurement showed a good predictive power for identifying MCI and dementia in elderly subjects with CSVD. Linear brain measurement could be a more suitable and novel method for screening cognitive impairment in aged CSVD patients in primary healthcare facilities, and worth further promotion among the rural population

Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model

Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation

AAV9-mediated gene delivery to liver grafts during static cold storage in a rat liver transplant model

IntroductionRecombinant adeno-associated virus (rAAV) is a novel strategy used clinically for gene delivery, but has not been characterized in the context of organ transplantation. We sought to determine the efficacy of rAAV-mediated gene delivery during static cold storage (SCS) prior to liver transplantation.MethodsA triple-plasmid transfection protocol was used to produce rAAV subtype-9 vectors containing firefly luciferase genomes in HEK293 cells. Lewis rat liver grafts were flushed and stored in cold HTK solution. Three experimental groups received rAAV at different doses, administered via the portal vein as a bolus during SCS. A control group did not receive rAAV (N = 2). Recipients then underwent syngeneic liver transplantation. Bioluminescence imaging to quantify in vivo luciferase expression was performed on post-operative days 7, 14, 28, and 56.ResultsControl animals demonstrated no bioluminescent activity, while animals receiving rAAV-treated livers had increasing bioluminescence, peaking at four weeks but sustained to the eight-week endpoint. This result was confirmed by experimental endpoint tissue luciferase activity assay.DiscussionrAAV mediates gene transduction in liver grafts when administered during SCS and has potential for gene therapy applications in solid organ transplantation

Isotherm, Thermodynamics, and Kinetics of Methyl Orange Adsorption onto Magnetic Resin of Chitosan Microspheres

Severe environmental pollution problems arising from toxic dyestuffs (e.g., methyl orange) are receiving increasing attention. Therefore, dyes’ safe removal has become a research hotspot. Among the many physical–chemical removal techniques, adsorption using renewable biological resources has proved to be more advantageous over others due to its effectiveness and economy. Chitosan is a natural, renewable biopolymer obtained by deactivated chitin. Thus, the magnetic resin of chitosan microspheres (MRCM), prepared by reversed-phase suspension cross-linking polymerization, was used to remove methyl orange from a solution in a batch adsorption system. The main results are as follows: (1) The results of physical and swelling properties of MRCM indicated that MRCM was a type of black spherical, porous, water-absorbing, and weak alkali exchange resin, and it had the ability to adsorb methyl orange when it was applied in solutions above pH 2.0. (2) In batch adsorption studies, the maximum adsorption capacity was obtained at pH 5; the adsorption equilibrium time was 140 min; and the maximum adsorption was reached at 450 mg/L initial concentration. (3) Among the three isotherm adsorption models, Langmuir achieved the best fit for the adsorption of methyl orange onto MRCM. (4) The adsorption thermodynamics indicated that the adsorption was spontaneous, with increasing enthalpy, and was driven by the entropy. (5) The pseudo-second-order kinetics equation was most suitable to describe the adsorption kinetics, and the adsorption kinetics was also controlled by the liquid–film diffusion dynamics. Consequently, MRCM with relatively higher methyl orange adsorption exhibited the great efficiency for methyl orange removal as an environment-friendly sorbent. Thus, the findings are useful for methyl orange pollution control in real-life wastewater treatment applications

CD154 blockade alters innate immune cell recruitment and programs alloreactive CD8+ T cells into KLRG-1(high) short-lived effector T cells.

CD154/CD40 blockade combined with donor specific transfusion remains one of the most effective therapies in prolonging allograft survival. Despite this, the mechanisms by which these pathways synergize to prevent rejection are not completely understood. Utilizing a BALB/c (H2-K(d)) to B6 (H2-K(b)) fully allogeneic skin transplant model system, we performed a detailed longitudinal analysis of the kinetics and magnitude of CD8(+) T cell expansion and differentiation in the presence of CD154/CD40 pathway blockade. Results demonstrated that treatment with anti-CD154 vs. DST had distinct and opposing effects on activated CD44(high) CD62L(low) CD8(+) T cells in skin graft recipients. Specifically, CD154 blockade delayed alloreactive CD8(+) T cell responses, while DST accelerated them. DST inhibited the differentiation of alloreactive CD8(+) T cells into multi-cytokine producing effectors, while CD40/CD154 blockade led to the diminution of the KLRG-1(low) long-lived memory precursor population compared with either untreated or DST treated animals. Moreover, only CD154 blockade effectively inhibited CXCL1 expression and neutrophil recruitment into the graft. When combined, anti-CD154 and DST acted synergistically to profoundly diminish the absolute number of IFN-γ producing alloreactive CD8(+) T cells, and intra-graft expression of inflammatory chemokines. These findings demonstrate that the previously described ability of anti-CD154 and DST to result in alloreactive T cell deletion involves both delayed kinetics of T cell expansion and differentiation and inhibited development of KLRG-1(low) memory precursor cells

A kernel principal component analysis–based degradation model and remaining useful life estimation for the turbofan engine

Remaining useful life estimation of the prognostics and health management technique is a complicated and difficult research question for maintenance. In this article, we consider the problem of prognostics modeling and estimation of the turbofan engine under complicated circumstances and propose a kernel principal component analysis–based degradation model and remaining useful life estimation method for such aircraft engine. We first analyze the output data created by the turbofan engine thermodynamic simulation that is based on the kernel principal component analysis method and then distinguish the qualitative and quantitative relationships between the key factors. Next, we build a degradation model for the engine fault based on the following assumptions: the engine has only had constant failure (i.e. no sudden failure is included), and the engine has a Wiener process, which is a covariate stand for the engine system drift. To predict the remaining useful life of the turbofan engine, we built a health index based on the degradation model and used the method of maximum likelihood and the data from the thermodynamic simulation model to estimate the parameters of this degradation model. Through the data analysis, we obtained a trend model of the regression curve line that fits with the actual statistical data. Based on the predicted health index model and the data trend model, we estimate the remaining useful life of the aircraft engine as the index reaches zero. At last, a case study involving engine simulation data demonstrates the precision and performance advantages of this prediction method that we propose. At last, a case study involving engine simulation data demonstrates the precision and performance advantages of this proposed method, the precision of the method can reach to 98.9% and the average precision is 95.8%

Influence of montmorillonite hydration and delamination on coal flotation

In this study, the influence of montmorillonite (MT) hydration and delamination on coal flotation was investigated through flotation tests using coal-MT mixtures. MT particles were subjected to hydration at different time intervals. The Fuerstenau upgrading curve was plotted to evaluate the change in overall flotation selectivity. The zeta potential and particle size distribution were used to characterize the delamination behavior of MT in deionized water at natural pH level. Atomic force microscopy (AFM) (colloidal probe) was used to analyze the interaction force between coal and MT particles. It was found that smaller particles (individual silicate layers or thin packets of layers) with higher zeta potentials appeared gradually, and their volume proportion increased with increasing hydration time. AFM results showed that a monotonous repulsive force was detected consistently throughout the separation distance between coal and these emerging smaller MT particles. The decrease of these MT coating on coal surface was responsible for the higher flotation recovery and better selectivity. A jump-into-contact phenomenon was observed in coal and MT interaction when MT hydrated incompletely. It showed that heterocoagulation between coal and MT occurred and MT coating on the coal surface was responsible for the depression of flotation

Molecular analysis of green-tide-forming macroalgae in the Yellow Sea

In the summer of 2008, free-floating green algae bloomed in the Yellow Sea. Samples were collected in a wide area (119 degrees 32'-122 degrees 00'E, 32 degrees 25'-36 degrees 49'N). We calculated the sequence divergences of nuclear ITS, chloroplast rbcL, and psbA data of free-floating samples collected from the Yellow Sea and Ulvaceae from Europe and Japan. In the ITS sequence, 19 out of the 21 Yellow Sea samples of 2008 were identical to those of a sample taken at Qingdao in 2007. A low divergence (0.2%) was found in remaining two samples. Similar evidence was shown by pairwise distances of rbcL and psbA gene sequence data, implying the uniformity of the Yellow Sea blooms in 2007 and 2008. The ITS sequence of the Yellow Sea samples differed 8.1-10.8% from free-floating Enteromorpha or Ulva reported worldwide. ITS-based molecular phylogenetic results and rbcL sequence data grouped the free-floating alga in the Yellow Sea into one clade with Enteromorpha procera, Enteromorpha linza and Enteromorpha prolifera. Furthermore, both morphological characteristics and ribotype network of the ITS sequences imply that the blooming algae in 2007 and 2008 were E. prolifera. The haplotypes of the Yellow Sea free-floating E. prolifera are closely related to those from the Japanese coast but less to European and American algae. (C) 2010 Elsevier B.V. All rights reserved.In the summer of 2008, free-floating green algae bloomed in the Yellow Sea. Samples were collected in a wide area (119 degrees 32'-122 degrees 00'E, 32 degrees 25'-36 degrees 49'N). We calculated the sequence divergences of nuclear ITS, chloroplast rbcL, and psbA data of free-floating samples collected from the Yellow Sea and Ulvaceae from Europe and Japan. In the ITS sequence, 19 out of the 21 Yellow Sea samples of 2008 were identical to those of a sample taken at Qingdao in 2007. A low divergence (0.2%) was found in remaining two samples. Similar evidence was shown by pairwise distances of rbcL and psbA gene sequence data, implying the uniformity of the Yellow Sea blooms in 2007 and 2008. The ITS sequence of the Yellow Sea samples differed 8.1-10.8% from free-floating Enteromorpha or Ulva reported worldwide. ITS-based molecular phylogenetic results and rbcL sequence data grouped the free-floating alga in the Yellow Sea into one clade with Enteromorpha procera, Enteromorpha linza and Enteromorpha prolifera. Furthermore, both morphological characteristics and ribotype network of the ITS sequences imply that the blooming algae in 2007 and 2008 were E. prolifera. The haplotypes of the Yellow Sea free-floating E. prolifera are closely related to those from the Japanese coast but less to European and American algae. (C) 2010 Elsevier B.V. All rights reserved