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Exogenous FeIII can be used for cancer magnetic resonance (MR) imaging and potentially for cancer treatment by a ferroptosis pathway or photothermal ablation. To achieve this, effective and accurate delivery of FeIII to cancerous sites is critical, requiring a balance of release kinetics of Fe3+ in tumorous and normal tissues. A nanoprobe is described consisting of upconversion luminescence (UCL) nanoparticles as a core and a coordinatively unsaturated FeIII‐containing Fe3+/gallic acid complex as a shell. Owing to the introduction of an unsaturated coordination structure, FeIII in the nanoprobe can be released only in the tumor microenvironment in response to the lightly acidic pH. The multiple UCLs are used for quantitatively visualizing the release of Fe3+ in vivo, whilst the release resultant serves as a photothermal agent. This nanoprobe exhibited ligand‐free tumor targeting ability, activatable MR imaging performance, and efficacious therapeutic effects against tumors in vivo. [ABSTRACT FROM AUTHOR]

The syndecan family of four transmembrane heparan sulfate proteoglycans binds a variety of soluble and insoluble extracellular effectors. Syndecan extracellular domains (ectodomains) can be shed intact by proteolytic cleavage of their core proteins, yielding soluble proteoglycans that retain the binding properties of their cell surface precursors. Shedding is accelerated by PMA activation of protein kinase C, and by ligand activation of the thrombin (G-protein-coupled) and EGF (protein tyrosine kinase) receptors (Subramanian, S.V., M.L. Fitzgerald, and M. Bernfield. 1997. J. Biol. Chem. 272:14713-14720). Syndecan- 1 and -4 ectodomains are found in acute dermal wound fluids, where they regulate growth factor activity (Kato, M., H. Wang, V. Kainulainen, M.L. Fitzgerald, S. Ledbetter, D.M. Ornitz, and M. Bernfield. 1998. Nat. Med. 4:691-697) and proteolytic balance (Kainulainen, V., H. Wang, C. Schick, and M. Bernfield. 1998. J. Biol. Chem. 273: 11563-11569). However, little is known about how syndecan ectodomain shedding is regulated. To elucidate the mechanisms that regulate syndecan shedding, we analyzed several features of the process that sheds the syndecan-1 and -4 ectodomains. We find that shedding accelerated by various physiologic agents involves activation of distinct intracellular signaling pathways; and the proteolytic activity responsible for cleavage of syndecan core proteins, which is associated with the cell surface, can act on unstimulated adjacent cells, and is specifically inhibited by TIMP-3, a matrix-associated metalloproteinase inhibitor. In addition, we find that the syndecan-1 core protein is cleaved on the cell surface at a juxtamembrane site; and the proteolytic activity responsible for accelerated shedding differs from that involved in constitutive shedding of the syndecan ectodomains. These results demonstrate the existence of highly regulated mechanisms that can rapidly convert syndecans from cell surface receptors or coreceptors to soluble heparan sulfate proteoglycan effectors. Because the shed ectodomains are found and function in vivo, regulation of syndecan ectodomain shedding by physiological mediators indicates that shedding is a response to specific developmental and pathophysiological cues. Key words: cellular stress * heparan sulfate * mitogen-activated protein kinase * protein tyrosine kinase * proteoglycan

Background: A better understanding of the blood supply of the femoral head is essential to guide therapeutic strategies for patients with femoral neck fractures. However, because of the limitations of conventional techniques, the precise distribution and characteristics of intraosseous arteries of the femoral head are not well displayed.Questions/purposes: To explore the characteristics and interconnections of the intraosseous vessel system between different areas of the femoral head and the possible blood supply compensatory mechanism after femoral neck fracture.Methods: The three-dimensional (3-D) structures of the intraosseous blood supply in 30 uninjured normal human femoral heads were reconstructed using angiography methods and microCT scans. The data were imported in the AMIRA® and MIMICS® software programs to reconstruct and quantify the extra- and intraosseous arteries (diameter, length). In a separate experiment, we evaluated the residual blood supply of femoral heads in 27 patients with femoral neck fractures before surgery by analyzing digital subtraction angiography data; during the study period, this was performed on all patients in whom hip-preserving surgery was planned, rather than arthroplasty. The number of affected and unaffected subjects included in the three groups (superior, inferior, and anterior retinacular arteries) with different types of fractures (Garden Types I-IV) were recorded and analyzed (Fisher's exact test) to reflect the affected degrees of these three groups of retinacular arteries in patients after femoral neck fractures.Results: The main results of our cadaver study were: (1) the main blood supply sources of the femoral head were connected by three main network structures as a whole, and the epiphyseal arterial network is the most widely distributed and the primary network structure in the femoral head; (2) the main stems of the epiphyseal arteries which were located on the periphery of the intraosseous vascular system have fewer anastomoses than the network located in the central region; (3) compared with the round ligament artery and anterior retinacular artery, the inferior retinacular artery has a relatively large caliber. Digital subtraction angiography of the 27 patients with hip fractures indicated that the inferior retinacular arterial system had a high likelihood of being unaffected after femoral neck fracture (100% [14 of 14] in nondisplaced fractures and 60% [six of 10] in Garden Type III fractures).Conclusions: The epiphyseal arterial network and inferior retinacular arterial system appear to be two important structures for maintaining the femoral head blood supply after femoral neck fracture. Increased efforts to protect these key structures during surgery, such as drilling and placing internal implants closer to the central region of the femoral head, might be helpful to reduce the effect of iatrogenic injury of the intraosseous vascular system.Clinical Relevance: 3-D anatomic evidence of intraosseous arterial distribution of the femoral head and the high frequency with which the inferior retinacular arteries remained patent after femoral neck fracture lead us to consider the necessity of drilling and placing internal implants closer to the central region of the femoral head during surgery. Future controlled studies might evaluate this proposition. [ABSTRACT FROM AUTHOR]

The most effective treatment of pancreatic cancer (PC) is known as mFOLFIRINOX scheme. However, this regimen has relatively severe toxic effects and are commonly restricted to patients with sound physique, which is poor in drug-selectivity, non-specific causing serious toxicity, greatly limits clinical application. Safer and more effective strategy seamlessly and synchronously is needed as advanced treatments for pancreatic cancer in future. In this report, we exploit a biomimetic nanoparticle-based platform for optimizing mFOLFIRINOX regimen. By coating pancreatic cancer cell membrane (PCCM) onto the surface of polymeric cores that loaded with mFOLFIRINOX, we prepare PCCM-cloaked nanoparticles, namely CNP@folfirinox, which inherit the antigenic exterior structure and associated functions of PC cells. The resulting CNP@folfirinox displays a core-shell nanostructure, which consisting of polymeric core and cancer cell membrane shell with suitable size and surface charge. Particularly, owing to inheriting the inherent membrane protein expressions profile, CNP@folfirinox exhibits prominent advantages in homologous homing to tumor tissue and deep penetration. It also shows lower side effects compared to extensive mFOLFIRINOX i.v. administration with no appreciable toxicity in other organs outside the tumor in vivo. Meanwhile, CNP@folfirinox is endowed with the "Don't eat me" privilege, hard for the immune system to recognize and less reticuloendothelial system uptake, with prolonged blood circulation, therefore improving delivery efficiency of drug after intravenous administration. Thus, this work reshapes a promising paradigm for more safe and more effective mFOLFIRINOX strategy for further clinical pancreatic cancer treatment. [Display omitted] • Nano-design of FOLFIRINOX regimen (NPs), PCCM coating NPs, named as CNP@folfirinox optimizing clinical PC treatment. • CNP@folfirinox enhances synergistic effect and aggrandizes cell apoptosis. • CNP@folfirinox facilitates effective homologous homing, immune escape and reduced side effect. [ABSTRACT FROM AUTHOR]