Despite rapid advancements in the field of nanotechnology, there is mounting frustration in the scientific community regarding the translational impact of nanomedicine. Modest therapeutic performance ...of FDA-approved nanomedicines combined with multiple disappointing clinical trials (such as phase III HEAT trial) have raised questions about the future of nanomedicine. Encouraging breakthroughs, however, have been made in the last few years towards the development of new classes of nanoparticles that can respond to tumor microenvironmental conditions and successfully deliver therapeutic agents to cancer cells. Concurrently, a great deal of effort has also been devoted to alter various parameters of tumor pathophysiology to pre-treat tumors before nanoparticles are administered. Such ‘priming’ treatments improve access of the systemically administered agents to the tumor and promote drug penetration into the deeper layers of tumor tissue. This review will highlight recent advances in cancer nanomedicine exploiting both nanoparticle design and tumor microenvironment modification; and provide a critical perspective on the future development of nanomedicine delivery in oncology.
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Mesogenic soft materials, having single or multiple mesogen moieties per molecule, commonly exhibit typical self‐organization characteristics, which promotes the formation of elegant helical ...superstructures or supramolecular assemblies in chiral environments. Such helical superstructures play key roles in the propagation of circularly polarized light and display optical properties with prominent handedness, that is, chiro‐optical properties. The leveraging of light to program the chiro‐optical properties of such mesogenic helical soft materials by homogeneously dispersing photosensitive chiral material into an achiral soft system or covalently connecting photochromic moieties to the molecules has attracted considerable attention in terms of materials, properties, and potential applications and has been a thriving topic in both fundamental science and application engineering. State‐of‐the‐art technologies are described in terms of the material design, synthesis, properties, and modulation of photoprogrammable chiro‐optical mesogenic soft helical architectures. Additionally, the scientific issues and technical problems that hinder further development of these materials for use in various fields are outlined and discussed. Such photoprogrammable mesogenic soft helical materials are competitive candidates for use in stimulus‐controllable chiro‐optical devices with high optical efficiency, stable optical properties, and easy miniaturization, facilitating the future integration and systemization of chiro‐optical chips in photonics, photochemistry, biomedical engineering, chemical engineering, and beyond.
Photoprogrammable mesogenic helical soft materials with both photosensitive and mesogenic moieties in molecules possess typical chiro‐optical properties, showing handedness dependency on the transmission, reflection, and absorption of an incident circularly polarized light (photonic bandgap and circular dichroism). This can be modulated readily by light irradiation, thus paving the way toward future chiro‐optical devices and systems.
The vital role optical and phototonic technologies have played in medical advances is addresed, as are modern phototheranostic applications. Topics addressed include phototheranostic techniques ...involving singlet state radiative relaxation, phototheranostic techniques involving singlet state radiative relaxation and phototheranostic techniques involving vibrational relaxation.
The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced ...necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca(2+) influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.
In this paper, a sensorless output feedback controller is designed in order to drive the induction motor (IM) without the use of flux and speed sensors. First, a new sliding-mode observer that uses ...only the measured stator currents is synthesized to estimate the speed, flux, and load torque. Second, a current-based field-oriented sliding-mode control is developed so as to steer the estimated speed and flux magnitude to the desired references. A stability analysis based on the Lyapunov theory is also presented in order to guarantee the closed-loop stability of the proposed observer-control system. Two experimental results for a 1.5-kW IM are presented and analyzed by taking into account the unobservability phenomena of the sensorless IM.
Background and Purpose
Necroptosis is a form of programmed, caspase‐independent, cell death, mediated by receptor‐interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase ...domain‐like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan‐Raf inhibitor TAK‐632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK‐632 by targeting RIPK1 and RIPK3.
Experimental Approach
Cell viability was measured by MTT, propidium staining, or CellTiter‐Glo luminescent assays. Effects of TAK‐632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK‐632 were identified by a drug affinity responsive target stability assay and a pull‐down assay with biotinylated TAK‐632. A mouse model of TNF‐α‐induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK‐632 in protecting against necroptosis‐associated inflammation in vivo.
Key Results
TAK‐632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK‐632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK‐632 alleviated TNF‐induced SIRS. Furthermore, we performed a structure–activity relationship analysis of TAK‐632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3.
Conclusions and Implications
TAK‐632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3.
Differentiation to different types of macrophages determines their distinct functions. Tumor-associated mac- rophages （TAMs） promote tumorigenesis owing to their proangiogenic and immune-suppressive ...functions similar to those of alternatively activated （M2） macrophages. We report that reactive oxygen species （ROS） production is criti- cal for macrophage differentiation and that inhibition of superoxide （02-） production specifically blocks the differ- entiation of M2 macrophages. We found that when monocytes are triggered to differentiate, 02- is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole （BHA） and other ROS inhibitors blocks macrophage differentiation. How- ever, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated （M1）, but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment.
Mesenchymal stem cell (MSC)-derived exosomes have shown comprehensive application prospects over the years. Despite performing similar functions, exosomes from different origins present heterogeneous ...characteristics and components; however, the relative study remains scarce. Lacking of a valuable reference, researchers select source cells for exosome studies mainly based on accessibility and personal preference.
In this study, exosomes secreted by MSCs derived from different tissues were isolated, by ultracentrifugation, and proteomics analysis was performed. A total of 1014 proteins were detected using a label-free method.
Bioinformatics analysis revealed their shared function in the extracellular matrix receptor. Bone marrow MSC-derived exosomes showed superior regeneration ability, and adipose tissue MSC-derived exosomes played a significant role in immune regulation, whereas umbilical cord MSC-derived exosomes were more prominent in tissue damage repair.
This study systematically and comprehensively analyzes the human MSC-derived exosomes via proteomics, which reveals their potential applications in different fields, so as to provide a reference for researchers to select optimal source cells in future exosome-related studies.
To investigate the implications of prophylactic intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with D2 radical gastrectomy for locally advanced Gastric Cancer (AGC) in a randomized ...case control study.
Eighty consecutive patients with locally AGC were randomly separated into 2 groups: HIPEC group (Curative Resection + intraoperative HIPEC with cisplatin 50 mg/m
at 42.0 ± 1.0 °C for 60 min) and Control group (Curative Resection only). Intraoperative and post-operative events, clinical recovery, morbidity and the disease-free survival (DFS) rates were closely monitored.
Among the 40 HIPEC group patients, the highest intracranial temperature recorded during the procedure was 38.2 °C but the patient made an eventless recovery. Mild renal dysfunction, hyperbilirubinemia and mild liver dysfunction were recorded in the HIPEC group but their incidences were found to be statistically insignificant when compared with the control group (P > 0.05). The initial post-operative analysis revealed shorter post-operative stay for in the HIPEC group but further analysis revealed that it was related to the incidence of postoperative complication. During a median follow-up time of 41 months, there were 9/39 and 15/38 cases of disease progression in HIPEC and Control groups respectively, with a more favorable 3-year DFS (76.9% vs 60.5%) and a lower peritoneal recurrence rate (5% vs 30%) in the HIPEC group.
Prophylactic HIPEC with radical D2 Gastrectomy is safe and shows favorable survival and peritoneal recurrence rates for AGC with acceptable morbidity. Nevertheless, more structured multi-centered RCT should be carried out for more substantial evidence.
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