Cancer immunotherapy has made recent breakthrough, including immune checkpoint blockade (ICB) that inhibits immunosuppressive checkpoints such as programmed cell death protein 1 (PD-1) and programmed ...death-ligand 1 (PD-L1). However, most cancer patients do not durably respond to ICB. To predict ICB responses for patient stratification, conventional immunostaining has been used to analyze the PD-L1 expression level on biopsied tumor tissues but has limitations of invasiveness and tumor heterogeneity. Recently, PD-L1 levels on tumor cell exosomes showed the potential to predict ICB response. Here, we developed a non-invasive, sensitive, and fast assay, termed as exosome-hybridization chain reaction (ExoHCR), to analyze tumor cell exosomal PD-L1 levels. First, using αCD63-conjugated magnetic beads, we isolated exosomes from B16F10 melanoma and CT26 colorectal cancer cells that were immunostimulated to generate PD-L1-positive exosomes. Exosomes were then incubated with a conjugate of PD-L1 antibody with an HCR trigger DNA (T), in which one αPD-L1-T conjugate carried multiple copies of T. Next, a pair of metastable fluorophore-labeled hairpin DNA (H1 and H2) were added, allowing T on αPD-L1-T to initiate HCR
in situ
on bead-conjugated exosome surfaces. By flow cytometric analysis of the resulting beads, relative to αPD-L1-fluorophore conjugates, ExoHCR amplified the fluorescence signal intensities for exosome detection by 3–7 times in B16F10 cells and CT26 cells. Moreover, we validated the biostability of ExoHCR in culture medium supplemented with 50% FBS. These results suggest the potential of ExoHCR for non-invasive, sensitive, and fast PD-L1 exosomal profiling in patient stratification of cancer immunotherapy.
Alloxan (AL)-generated Reactive Oxygen Species (ROS) selectively destroy insulin-producing pancreatic β-cells. A previous genome-wide scan (GWS) using a cohort of 296 F2 hybrids between NOD ...(AL-sensitive) and ALR (AL-resistant) mice identified linkages contributing to β-cell susceptibility or resistance to AL-induced diabetes on Chromosomes (Chr) 2, 3, 8, and a single nucleotide polymorphism in
mt-Nd2
of the mitochondrial genome (mtDNA). AL treatment of congenic and consomic NOD mouse stocks confirmed resistance linked to both the mtDNA and the Chr 8 locus from ALR NOD.mt
ALR
.ALR-(
D8Mit293-D8Mit137
). To identify possible epistatic interactions, the GWS analysis was expanded to 678 F2 mice. ALR-derived diabetes-resistance linkages on Chr 8 as well as the
mt-Nd2
a
allele were confirmed and novel additional linkages on Chr 4, 5, 6, 7, and 13 were identified. Epistasis was observed between the linkages on Chr 8 and 2 and Chr 8 and 6. Furthermore, the
mt-Nd2
genotype affected the epistatic interactions between Chr 8 and 2. These results demonstrate that a combination of nuclear-cytoplasmic genome interactions regulates β-cell sensitivity to ROS-mediated ALD.
Western medicine often aims to specifically treat diseased tissues or organs. However, the majority of current therapeutics failed to do so owing to their limited selectivity and the consequent ...“off-target” side effects. Targeted therapy aims to enhance the selectivity of therapeutic effects and reduce adverse side effects. One approach toward this goal is to utilize disease-specific ligands to guide the delivery of less-specific therapeutics, such that the therapeutic effects can be guided specifically to diseased tissues or organs. Among these ligands, aptamers, also known as chemical antibodies, have emerged over the past decades as a novel class of targeting ligands that are capable of specific binding to disease biomarkers. Compared with other types of targeting ligands, aptamers have an array of unique advantageous features, which make them promising for developing aptamer–drug conjugates (ApDCs) for targeted therapy. In this Review, we will discuss ApDCs for targeted drug delivery in chemotherapy, gene therapy, immunotherapy, photodynamic therapy, and photothermal therapy, primarily of cancer.
Protein tyrosine kinase-7 (PTK7) is a catalytically inactive receptor tyrosine kinase (RTK). PTK7 is upregulated in many common human cancers, including colon cancer, lung cancer, gastric cancer and ...acute myeloid leukemia. The reason for this up-regulation is not yet known. To explore the functional role of PTK7, the expression of PTK7 in HCT 116 cells was examined using small interference (siRNA)-mediated gene silencing. Following transfection, the siRNA successfully suppressed PTK7 mRNA and protein expression. Knocking down of PTK7 in HCT 116 cells inhibited cell proliferation compared to control groups and induced apoptosis. Furthermore, this apoptosis was characterized by decreased mitochondrial membrane potential and activation of caspase-9 and -10. Addition of a caspase-10 inhibitor totally blocked this apoptosis, suggesting that caspase-10 may play a critical role in PTK7-knockdown-induced apoptosis, downstream of mitochondria. These observations may indicate a role for PTK7 in cell proliferation and cell apoptosis and may provide a potential therapeutic pathway for the treatment of a variety of cancers.
Vaccines hold tremendous potential for cancer immunotherapy by treating the immune system. Subunit vaccines, including molecular adjuvants and cancer-associated antigens or cancer-specific ...neoantigens, can elicit potent antitumor immunity. However, subunit vaccines have shown limited clinical benefit in cancer patients, which is in part attributed to inefficient vaccine delivery. In this Perspective, we discuss vaccine delivery by synthetic nanoparticles or naturally derived nanoparticles for cancer immunotherapy. Nanovaccines can efficiently codeliver adjuvants and multiepitope antigens into lymphoid organs and into antigen-presenting cells, and the intracellular release of vaccine and cross-presentation of antigens can be fine-tuned via nanovaccine engineering. Aside from peptide antigens, antigen-encoding mRNA for cancer immunotherapy delivered by nanovaccine will also be discussed.
The inexhaustible heat deposit in great depths (5–10 km) is a scientific fact. Such deposit occurs around the globe. Thereby, everybody is enabled to generate autonomously clean and renewable energy, ...ample electricity and heat. The economical exploration and exploitation of this superdeep geothermal heat deposit requires a novel drilling technique, because the currently only deep drilling method (Rotary) is limited to about 5 km, due to the rising costs, depending exponentially on depth. Electro-pulse-boring (EPB) is a valuable option to Rotary drilling. EPB, originally investigated in Russia, is ready to be developed for industrialization. The feasibility of EPB is proven by many boreholes drilled up to 200 m in granite (crystalline). Estimates show outstanding low costs for drilling by EPB: 100 zs/m for a borehole with a large diameter (
Ø
) such as 20″ (50 cm), independent on depth and applicable likewise for sediments and crystalline rocks, such as granite. The current rate of penetration (ROP) of 3 m per hour is planned to be augmented up to 35 m per hour, and again, irrespective whether in sedimentary or crystalline formations. Consequently, a 10 km deep borehole with
Ø
50 cm will ultimately be drilled within 12 days. EPB will create new markets, such as: (i) EPB shallow drilling for geotechnics, energy piles, measures in order to mitigate natural hazards, etc., (ii) EPB deep drilling (3–5 km) for hydro-geothermics, exploration campaigns etc. and (iii) EPB super-deep drilling (5–10 km) for petro-geothermics, enabling the economic generation of electricity. The autonomous and unlimited supply with cost efficient electricity, besides ample heat, ensures reliably clean and renewable energy, thus, high supply security. Such development will provide a substantial relief to cope with the global challenge to limit the climate change below 2 °C. The diminution of fossil fuels, due to the energy transition in order to mitigate the climate change, implies likewise the decrease of air pollution.
Crustal growth and topography development in subduction‐related arcs are intimately related to magmatic processes and melt production above subducting slabs. Lateral and temporal variations in ...crustal thickness and composition have been observed in nature, but until now no integrated approach has been developed to comprehensively understand magmatic activity in subduction‐related arcs. Here we investigate the 4‐D spatial, temporal, and compositional character of continental crustal growth at active margins using a new 4‐D (space‐time) petrological‐thermomechanical numerical model of a subduction‐related magmatic arc. Based on a series of numerical experiments, we demonstrate that crustal growth inside the arc is inherently clustered in both space and time. The characteristic wavelength of variations in crustal thickness and topography along the arc is on the order of 30–80 km and is comparable to volcano clustering in natural arcs. The clusters of new crust are formed mainly by basaltic melt episodically extracted from partially molten peridotite due to lateral variation of water release and transport in the mantle wedge. Melts derived from subducted oceanic crust and sediments could contribute up to 15–50 vol% to the arc crust growth and their relative proportion is maximal at the onset of subduction. The total amount of newly formed crust correlates mainly with the amount of convergence since the beginning of subduction and is not strongly influenced by the plate convergence velocity. Indeed, slower subduction and lower melt extraction efficiency helps partially molten sediments and oceanic crust to be transported into the mantle wedge by hydrated, partially molten diapiric structures. For the modeled regime of stable subduction, the maximum crustal additional rate (25–40 km3/km/Myr) occurs when the amount of convergence reaches around 700 km. Mantle wedge structures developed in our models correlate well with available geophysical (seismological) observations for the Alaskan subduction zone. In particular, partially molten mantle plumes found in our models could explain low seismic anomalies in the mantle wedge, whereas mobile water and water release patterns could reflect paths and sources for magmatic activity evidenced by seismic b‐value and Vp/Vs ratio analysis.
Key Points
Crustal growth inside the arc is inherently clustered in both space and time
Characteristic wavelength of new crust is on the order of 30‐80 km
Basaltic crust is the main component of new crust
Cancer immunotherapy has shown great potential as witnessed by an increasing number of immuno-oncology drug approvals in the past few years. Meanwhile, the field of nucleic acid therapeutics has made ...significant advancement. Nucleic acid therapeutics, such as plasmids, antisense oligonucleotides (ASO), small interfering RNA (siRNA) and microRNA, messenger RNA (mRNA), immunomodulatory DNA/RNA, and gene-editing guide RNA (gRNA) are attractive due to their versatile abilities to alter the expression of target endogenous genes or even synthetic genes, and modulate the immune responses. These abilities can play vital roles in the development of novel immunotherapy strategies. However, limited by the intrinsic physicochemical properties such as negative charges, hydrophilicity, as well as susceptibility to enzymatic degradation, the delivery of nucleic acid therapeutics faces multiple challenges. It is therefore pivotal to develop drug delivery systems that can carry, protect, and specifically deliver and release nucleic acid therapeutics to target tissues and cells. In this review, we attempted to summarize recent advances in nucleic acid therapeutics and the delivery systems for these therapeutics in cancer immunotherapy.
•Cancer immunotherapy has shown great potential as witnessed by an increasing number of immuno-oncology drug approvals in the past few years.•Meanwhile, the field of nucleic acid therapeutics has made significant advancement.•Nucleic acid therapeutics, such as plasmids, antisense oligonucleotides (ASO), small interfering RNA (siRNA) and microRNA, messenger RNA (mRNA), immunomodulatory DNA/RNA, and gene-editing guide RNA (gRNA) are attractive due to their versatile abilities to alter the expression of target endogenous genes or even synthetic genes, and modulate the immune responses.•These abilities can play vital roles in the development of novel immunotherapy strategies.•Due to the intrinsic physicochemical properties such as negative charges, hydrophilicity, as well as susceptibility to enzymatic degradation, the effective delivery of nucleic acid therapeutics can face multiple physiological barriers.•It is therefore pivotal to develop drug delivery systems that can carry, protect, and specifically deliver and release nucleic acid therapeutics to target tissues and cells.•This review attempts to summarize the recent advances in nucleic acid delivery for cancer immunotherapy and offers perspectives on the development of nucleic acid delivery systems for cancer immunotherapy.
This paper reports the fabrication and nanofiltration properties of a sol–gel derived microporous zirconia membrane. Effects of synthesis parameters, including hydrolysis time, hydrolysis ...temperature, hydrolysis ratio and chelating agent dopant, on the state and size of polymeric zirconia sol, were investigated. Highly reproducible and stable zirconia sol after refluxing at 40 °C for 180 min, with an average particle size of approximately 8.6 nm, was synthesized with a recipe of Zirconium n-propoxide: Diethanolamine: 1-propanol: H
2
O being 1: 2.2: 28.7: 9.4 (in molar ratio). The sol was subsequently used for the fabrication of microporous ZrO
2
membranes onto alumina supported mesoporous γ-Al
2
O
3
layers. ZrO
2
membranes with molecular weight cut-off (MWCO) of 354, 1,195, corresponding to the pore size of 0.94 and 1.75 nm, were successfully fabricated. Ionic retention properties of such ZrO
2
membranes with respect to electrolyte solutions, like MgCl
2
, CaCl
2
, NaCl and Na
2
SO
4
, were also determined. Effects of parameters such as concentration of salt solutions and trans-membrane pressure on retention rates of microporous ZrO
2
membranes were studied in detail. Results showed that zirconium n-propoxide derived microporous ZrO
2
membranes exhibited comparatively high retention rates towards divalent ions like Mg
2+
and Ca
2+
, while much lower retention rates were observed for mono-valent ion (Na
+
) in the present study, which are the characteristics of nanofiltration membranes.
In order to understand the possible existence of small-scale convection in the mantle wedge, we have constructed a simple three-dimensional model of convection driven by both thermal and chemical ...buoyancies above the subducting slab. In this model, a chemical agent, which affects both the density and the viscosity of mantle, is introduced from the top of the subducting slab and the associated density and viscosity decreases are treated as parameters. The model does not include the along-arc variation of the source of the chemical agent. We found that the major effects of low density chemical anomaly are to suppress the three-dimensional instability and make the flow two-dimensional, i.e., the flow velocity is normal to the plate boundary. The chemically polluted region tends to stay in the corner of the mantle wedge because of its low density and this results in the low temperature zone there. This suggests the importance of chemical buoyancy on the origin of cold mantle part or “nose” in the corner of the mantle wedge. We also studied the hybrid case: The region closer to the trench is in the low density and viscosity state and the region in the back arc is in the low viscosity state only. This case shows the existence of the low temperature nose and the small-scale thermally driven convection in the back arc. We also investigated the nature of the flip-flop phenomenon of the thermally driven convection and found that the thickness of the thermal boundary layer under the back arc controls it. This flow pattern in the back arc may have a close connection with the temporal and spatial variation of volcano distribution.
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