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Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Article Highlights When the tether is only subjected to in-plane or out of plane harmonic loads, if the first-order in-plane and out of plane frequencies of tether are close to each other, the tether is prone to occur modal coupling internal resonance. Since the frequencies of in-plane and out-of-plane of the tether are not exactly the same. Thus, when modal coupling internal resonance occurs, the external excitation frequency is closer to the first-order modal frequency of the non-load acting plane. When excitation amplitude is a fixed value, increasing the damping ratio may inhibit the occurrence of mode coupling internal resonance and effectively reduce the mid-span amplitude of tether.

Cynodon dactylon (L.) Pers. (commonly known as bermudagrass) is a member of the family Poaceae. It is a C4 grass that can grow annually and perennially with clone reproduction and seed-setting. It is not only used as forage but also as a weed in many crops. It grows along roadsides, in barren lands, irrigated lands, and seacoasts, where soil salinity is a major problem. Although bermudagrass is distributed worldwide, it shows limited growth under saline conditions. Under salt stress, the whole-plant growth is disturbed and the forage quality is compromised morphologically. At the physiological level, shoot development is affected owing to the resultant oxidative stress, although the total rate of photosynthesis is not greatly affected. Biochemical changes include a change in the K+/Na+ ratio; antioxidant enzymes such as superoxide dismutase and peroxide dismutase increase, while catalase activity slows down. The anatomical changes are visible as salt crystals on the leaf surface and salt glands on the mesophyll surface. In this paper, the morphological, physiological, biochemical, and proteomic mechanisms of bermudagrass under salt stress are discussed, drawing a study of several genes such as ECA4, RAN1, MHX1, psbA1, psbB1, psbP, and psbY at the molecular level. Therefore, the current review aims to understand how bermudagrass grows and adapts well under salt conditions.

Dendritic cell (DC)-based vaccination is a promising immunotherapeutic strategy for cancer. However, clinical trials have shown only limited efficacy, suggesting the need to optimize protocols for human DC vaccine preparation. In this study, we systemically compared five different human DC vaccine maturation protocols used in clinical trials: (1) a four-cytokine cocktail (TNF-α, IL-6, IL-1β, and PGE2); (2) an α-DC-cytokine cocktail (TNF-α, IL-1β, IFN-α, IFN-γ, and poly I:C); (3) lipopolysaccharide (LPS)/IFN-γ; (4) TNF-α and PGE2; and (5) TriMix (mRNAs encoding CD40L, CD70, and constitutively active Toll-like receptor 4 electroporated into immature DCs). We found that the four-cytokine cocktail induced high levels of costimulatory and HLA molecules, as well as CCR7, in DCs. Mature DCs (mDCs) matured with the four-cytokine cocktail had higher viability than those obtained with the other protocols. Based on these features, we chose the four-cytokine cocktail protocol to further improve the immunizing capability of DCs by introducing exogenous genes. We showed that introducing exogenous Bcl-2 increased DC survival. Furthermore, introducing IL-12p70 rescued the inhibition of IL-12 secretion by PGE2 without impairing the DC phenotype. Introducing both Bcl-2 and IL-12p70 mRNAs into DCs induced enhanced cytomegalovirus pp65-specific CD8+ T cells secreting IFN-γ and TNF-α. Taken together, our data suggest that DC matured by the four-cytokine cocktail combined with exogenous Bcl-2 and IL-12p70 gene expression represents a promising approach for clinical applications in cancer immunotherapy.

To study the nonlinear vibration characteristics of submerged floating tunnel tether, the nonlinear vibration partial differential equation of tether is set up, in which the inclination, sag, initial tension force, and length of tether are taken into account. According to the linear vibration mode of tether, the partial differential equation is converted into ordinary differential equations by Galerkin method and the nonlinear vibration equation of tether for the in-plane first four modes and the out-of-plane first four modes are obtained. The results show that the change of inclination results is in the change of sag. The initial configuration of sag is symmetric. Thus, the sag only affects the damping ratio of the in-plane symmetric mode, namely, that of the first and the third mode. The sag has no effect on the second and forth order modes which are antisymmetric modes. Therefore, the sag is only existed in plane and has no effect on the out-of-plane mode. The first and the third in-plane modal damping ratios of tether are in direct proportion to their inclination, whereas in inverse proportion to their sag. The first modal damping ratio of tether (both in-plane and out-of-plane) is in direct proportion to its length, whereas in inverse proportion to its initial tension.

Background: The incidence of cancer, diabetes, and autoimmune diseases has been increasing. Furthermore, there are more and more patients with solid organ transplants. The survival rate of these immunocompromised individuals is extremely low when they are severely hit-on. In this study, we established cardiac arrest cardiopulmonary resuscitation (CPR) model in severe combined immunodeficient (SCID) mice, analyzed the expression and activation of mitochondrial autophagy and NLRP3 inflammasome/caspase-1, and explored mitochondrial repair and inflammatory injury in immunodeficiency individual during systemic ischemia-reperfusion injury. Methods: A potassium chloride-induced cardiac arrest model was established in C57BL/6 and nonobese diabetic/SCID (NOD/SCID) mice. One hundred male C57BL/6 mice and 100 male NOD/SCID mice were randomly divided into five groups (control, 2 h post-CPR, 12 h post-CPR, 24 h post-CPR, and 48 h post-CPR). A temporal dynamic view of alveolar epithelial cells, macrophages, and neutrophils from bronchoalveolar lavage fluid (BALF) was obtained using Giemsa staining. Spatial characterization of phenotypic analysis of macrophages in the lung interstitial tissue was analyzed by flow cytometry. The morphological changes of mitochondria 48 h after CPR were studied by transmission electron microscopy and quantified according to the Flameng grading system. Western blotting analysis was used to detect the expression and activation of the markers of mitochondrial autophagy, NLRP3 inflammasome, and caspase-1. Results: (1) In NOD/SCID mice, macrophages were disintegrated in BALF, and many alveolar epithelial cells were shed at 48 h after resuscitation. Compared with C57BL/6 mice, the ratio of macrophages/total cells peaked at 12 h and was significantly higher in NOD/SCID mice (31.17 ± 4.13 vs. 49.69 ± 2.43, t = 14.46, P = 0.001). After 24 h, the results showed a downward trend. Furthermore, a large number of macrophages were disintegrated in the BALF. (2) Mitochondrial autophagy was present in both C57BL/6 and NOD/SCID mice after CPR, but it began late in the NOD/SCID mice. Compared with C57BL/6 mice, phos-ULK1 (Ser327) expression was significantly lower at 2 h and 12 h after CPR (2 h after CPR: 1.88 ± 0.36 vs. 1.12 ± 0.11, t = −1.36, P < 0.01 and 12 h after CPR: 1.52 ± 0.16 vs. 1.05 ± 0.12, t = −0.33, P < 0.01), whereas phos-ULK1 (Ser757) expression was significantly higher at 2 h and 12 h after CPR in NOD/SCID mice (2 h after CPR: 1.28 ± 0.12 vs. 1.69 ± 0.14, t = 1.7, P < 0.01 and 12 h after CPR: 1.33 ± 0.10 vs. 1.94 ± 0.13, t = 2.75, P < 0.01). (3) Furthermore, NLRP3 inflammasome/caspase-1 activation in the pulmonary tissues occurred early and for only a short time in C57BL/6 mice, but this phenomenon was sustained in NOD/SCID mice. The expression of the NLRP3 inflammasome increased modestly in the C57 mice, but the increase was higher in the NOD/SCID mice than in the C57BL/6 mice, especially at 12, 24, 48 h after CPR (48 h after CPR: 1.46 ± 0.13 vs. 2.97 ± 0.19, t = 5.34, P = 0.001). The expression of caspase-1-20 generally followed the same pattern as the NLRP3 inflammasome. Conclusions: There is a regulatory relationship between the NLRP3 inflammasome and mitochondrial autophagy after CPR in the healthy mice. This regulatory relationship was disturbed in the NOD/SCID mice because the signals for mitochondrial autophagy occurred late, and NLRP3 inflammasome- and caspase-1-dependent cell injury was sustained.

Genes of selenoproteome have been increasingly implicated in various aspects of neurobiology and neurological disorders, but remain largely elusive in Parkinson's disease (PD). In this study, we investigated the selenotranscriptome (24 selenoproteins in total) in five brain regions (cerebellum, substantia nigra, cortex, pons and hippocampus) by real time qPCR in a two-phase manner using a mouse model of chronic PD. A wide range of changes in selenotranscriptome was observed in a manner depending on selenoproteins and brain regions. While Selv mRNA was not detectable and Dio1& 3 mRNA levels were not affected, 1, 11 and 9 selenoproteins displayed patterns of increase only, decrease only, and mixed response, respectively, in these brain regions of PD mice. In particular, the mRNA expression of Gpx1-4 showed only a decreased trend in the PD mouse brains. In substantia nigra, levels of 17 selenoprotein mRNAs were significantly decreased whereas no selenoprotein was up-regulated in the PD mice. In contrast, the majority of selenotranscriptome did not change and a few selenoprotein mRNAs that respond displayed a mixed pattern of up- and down-regulation in cerebellum, cortex, hippocampus, and/or pons of the PD mice. Gpx4, Sep15, Selm, Sepw1, and Sepp1 mRNAs were most abundant across all these five brain regions. Our results showed differential responses of selenoproteins in various brain regions of the PD mouse model, providing critical selenotranscriptomic profiling for future functional investigation of individual selenoprotein in PD etiology.

Certain ciliary transmembrane and membrane-tethered signaling proteins migrate from the ciliary tip to base via retrograde intraflagellar transport (IFT), essential for maintaining their ciliary dynamics to enable cells to sense and transduce extracellular stimuli inside the cell. During this process, the BBSome functions as an adaptor between retrograde IFT trains and these signaling protein cargoes. The Arf-like 13 (ARL13) small GTPase resembles ARL6/BBS3 in facilitating these signaling cargoes to couple with the BBSome at the ciliary tip prior to loading onto retrograde IFT trains for transporting towards the ciliary base, while the molecular basis for how this intricate coupling event happens remains elusive. Here, we report that Chlamydomonas ARL13 only in a GTP-bound form (ARL13GTP) anchors to the membrane for diffusing into cilia. Upon entering cilia, ARL13 undergoes GTPase cycle for shuttling between the ciliary membrane (ARL13GTP) and matrix (ARL13GDP). To achieve this goal, the ciliary membrane-anchored BBS3GTP binds the ciliary matrix-residing ARL13GDP to activate the latter as an ARL13 guanine nucleotide exchange factor. At the ciliary tip, ARL13GTP recruits the ciliary matrix-residing and post-remodeled BBSome as an ARL13 effector to anchor to the ciliary membrane. This makes the BBSome spatiotemporally become available for the ciliary membrane-tethered phospholipase D (PLD) to couple with. Afterward, ARL13GTP hydrolyzes GTP for releasing the PLD-laden BBSome to load onto retrograde IFT trains. According to this model, hedgehog signaling defects associated with ARL13b and BBS3 mutations in humans could be satisfactorily explained, providing us a mechanistic understanding behind BBSome-cargo coupling required for proper ciliary signaling. [ABSTRACT FROM AUTHOR]

Iron oxide nanoparticles are the most popular magnetic nanoparticles used in biomedical applications due to their low cost, low toxicity, and unique magnetic property. Magnetic iron oxide nanoparticles, including magnetite (Fe3O4) and maghemite (γ-Fe2O3), usually exhibit a superparamagnetic property as their size goes smaller than 20 nm, which are often denoted as superparamagnetic iron oxide nanoparticles (SPIONs) and utilized for drug delivery, diagnosis, therapy, and etc. This review article gives a brief introduction on magnetic iron oxide nanoparticles in terms of their fundamentals of magnetism, magnetic resonance imaging (MRI), and drug delivery, as well as the synthesis approaches, surface coating, and application examples from recent key literatures. Because the quality and surface chemistry play important roles in biomedical applications, our review focuses on the synthesis approaches and surface modifications of iron oxide nanoparticles. We aim to provide a detailed introduction to readers who are new to this field, helping them to choose suitable synthesis methods and to optimize the surface chemistry of iron oxide nanoparticles for their interests. [ABSTRACT FROM AUTHOR]

Microtubule affinity-regulating kinase 2 (MARK2)/PAR-1b and protein kinase A (PKA) are both involved in the regulation of microtubule stability and neurite outgrowth, but whether a direct cross-talk exists between them remains unclear. Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409. PKA could not reverse the microtubule disruption effect induced by a serine 409 to alanine (Ala) mutant of MARK2 (MARK2 S409A). In contrast, mutation of MARK2serine 409 to glutamic acid (Glu) (MARK2 S409E) did not affect microtubule stability and neurite outgrowth. We propose that PKA functions as an upstream inhibitor of MARK2 in regulating microtubule stability and neurite outgrowth by directly interacting and phosphorylating MARK2. [ABSTRACT FROM AUTHOR]