Integrin α6 targeted cancer imaging and therapy

Integrins represent ideal targets for molecular imaging and targeted therapy of cancer and their role in cancer has been reviewed extensively elsewhere. Except for αVβ3 and αVβ5, the remaining integrins were not systematically considered and tested as potential therapeutic targets. In recent years, the studies on integrin α6 as a cancer imaging and therapeutic target are increasing, due to their highly expressed in several cancers, and their expression has been associated with poor survival. Integrin α6 appears to be a particularly attractive target for cancer imaging and therapy, and therefore we have developed a wide array of integrin α6-target molecular probes for molecular imaging and targeted therapy of different cancers. Despite the studies on integrin α6 as a cancer imaging and therapeutic target increasing in recent years, most of them were derived from preclinical mouse models, revealing that much more can be done in the future. The development of integrin α6 drugs may now be at an important point, with opportunities to learn from previous research, to explore new approaches. In this review, we will briefly introduce integrin α6 and highlighted the recent advances in integrin α6 targeted imaging and therapeutics in cancer

Endocytic sorting and recycling require membrane phosphatidylserine asymmetry maintained by TAT-1/CHAT-1. PLoS Genet

Endocytic sorting is achieved through the formation of morphologically and functionally distinct sub-domains within early endosomes. Cargoes destined for recycling are sorted to and transported through newly-formed tubular membranes, but the processes that regulate membrane tubulation are poorly understood. Here, we identified a novel Caenorhabditis elegans Cdc50 family protein, CHAT-1, which acts as the chaperone of the TAT-1 P4-ATPase to regulate membrane phosphatidylserine (PS) asymmetry and endocytic transport. In chat-1 and tat-1 mutants, the endocytic sorting process is disrupted, leading to defects in both cargo recycling and degradation. TAT-1 and CHAT-1 colocalize to the tubular domain of the early endosome, the tubular endocytic recycling compartment (ERC), and the recycling endosome where PS is enriched on the cytosolic surface. Loss of tat-1 and chat-1 function disrupts membrane PS asymmetry and abrogates the tubular membrane structure. Our data suggest that CHAT-1 and TAT-1 maintain membrane phosphatidylserine asymmetry, thus promoting membrane tubulation and regulating endocytic sorting and recycling

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Background: Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods: A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results: PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion: This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI

A study of multinucleated giant cells in esophageal cancer

Objectives: To evaluate the occurrence, abundance, distribution, nature and clinical significance of multi-nucleated giant cell (MGC) in esophageal cancer. Materials and methods: MGCs were examined with conventional pathology, immunohistochemistry and immunofluorescence in 107 esophageal cancer tissues. The findings were correlated to pathological diagnosis and clinical behavior of the cancers. Results: MGCs were identified in 31.7% (34/107) of the cases. MGCs were positive for CD11c, CD11b, CD32, CD16, HLA-DR and MMP9, and negative for CD163, CD206 and CD64 giving a molecular profile of proinflammatory M1 but not immunosuppressive M2. MGCs were significantly related to decreased lymph node metastasis (p = 0.011), low pTNM stage (p = 0.044), favorable survival (p = 0.04), squamous cell cancer type rather than other histopathological subtypes (p = 0.020) and associated to better differentiation (p = 0.063). Conclusions: MGCs belong to M1 macrophage and perform phagocytosis and scavenging of cancer cells that would benefit patients' survival and could serve as a prognostic marker

Thermosensitive Nanocables Prepared by Surface-Initiated Atom Transfer Radical Polymerization

Thermosensitive nanocables consisting of Au nanowire cores and poly(N-isopropylacrylamide) sheaths (denoted as Au/PNIPAAm) were synthesized by surface-initiated atom transfer radical polymerization (SI-ATRP). The formation of PNIPAAm sheath was verified by Fourier transform infrared (FTIR) and hydrogen nuclear magnetic resonance (1H NMR) spectroscopy. Transmission electron microscope (TEM) results confirmed the core/shell structure of nanohybrids. The thickness and density of PNIPAAm sheaths can be adjusted by controlling the amount of cross-linker during the polymerization. Signature temperature response was observed from Au/cross-linked-PNIPAAm nanocables. Such smart nanocables show immense potentials as building blocks for novel thermosensitive nanodevices in future

Insight-HXMT dedicated 33-day observation of SGR J1935+2154 I. Burst Catalog

Magnetars are neutron stars with extreme magnetic field and sometimes manifest as soft gamma-ray repeaters (SGRs). SGR J1935+2154 is one of the most prolific bursters and the first confirmed source of fast radio burst (i.e. FRB 200428). Encouraged by the discovery of the first X-ray counterpart of FRB, Insight-Hard X-ray Modulation Telescope (Insight-HXMT) implemented a dedicated 33-day long ToO observation of SGR J1935+2154 since April 28, 2020. With the HE, ME, and LE telescopes, Insight-HXMT provides a thorough monitoring of burst activity evolution of SGR J1935+2154, in a very broad energy range (1-250 keV) with high temporal resolution and high sensitivity, resulting in a unique valuable data set for detailed studies of SGR J1935+2154. In this work, we conduct a comprehensive analysis of this observation including detailed burst search, identification and temporal analyses. After carefully removing false triggers, we find a total of 75 bursts from SGR J1935+2154, out of which 70 are single-pulsed. The maximum burst rate is about 56 bursts/day. Both the burst duration and the waiting time between two successive bursts follow log-normal distributions, consistent with previous studies. We also find that bursts with longer duration (some are multi-pulsed) tend to occur during the period with relatively high burst rate. There is no correlation between the waiting time and the fluence or duration of either the former or latter burst. It also seems that there is no correlation between burst duration and hardness ratio, in contrast to some previous reports. In addition, we do not find any X-ray burst associated with any reported radio bursts except for FRB 200428.Comment: 31 pages, 10 figures, accepted for publication in ApJ

Intrinsic plasma flows in straight magnetic fields: generation, frictionless saturation, and interaction

We develop a simple model for the generation and amplification of intrinsic axial flow in a linear device, Controlled Shear Decorrelation Experiment (CSDX). This model develops a novel dynamical symmetry breaking mechanism in drift wave turbulence, which does not require complex magnetic field structure, such as shear. Thus, the model is applicable to both tokamaks and linear devices. This mechanism is, essentially, a form of negative viscosity phenomenon. Negative compressibility ITG turbulence can also induce a negative viscosity increment. However, we show that no intrinsic axial flow can be generated by pure ITG turbulence in a straight magnetic field. When the flow gradient is steepened by any drive mechanism, the flow profile saturates at a level close to the value above which parallel shear flow instability (PSFI) becomes dominant over the ITG instability. This saturated flow gradient exceeds the PSFI linear threshold, and grows with $\nabla T_{i0}$ as $|\nabla V_\parallel| / |k_\parallel c_s| \sim|\nabla T_{i0}|^{2/3} / (k_\parallel T_{i0})^{2/3}$.The coupling of azimuthal and axial flows in CSDX--in absence of magnetic shear--is investigated.In particular, we focus on the apportionment of turbulence energy between azimuthal and axial flows, and how the azimuthal flow shear affects axial flow generation and saturation by drift wave turbulence.Detailed measurements of intrinsic axial flow parallel to the magnetic field are performed on CSDX, with no axial momentum input.The results present a direct demonstration that the broken spectral symmetry of drift wave turbulence causes the development of axial mean flows in cylindrical magnetized plasmas.Measurements suggest the axial flow is parasitic to the drift wave--zonal flow system.Besides, we show that consideration of wave--flow resonance resolves the long-standing problem of how zonal flows (ZFs) saturate in the limit of weak or zero frictional drag and also determines the ZF scale directly from analysis. We show that resonant vorticity mixing, which conserves potential enstrophy, enables ZF saturation in the absence of drag, and so is effective at regulating the Dimits up-shift regime. Vorticity mixing is incorporated as a nonlinear, self-regulation effect in an extended 0D predator--prey model of drift--ZF turbulence