Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials.

Introduction: FLT3 mutations are closely associated with the occurrence of hematological and solid malignancies, especially with acute myeloid leukemia. Currently, several FLT3 inhibitors are in clinical trials, and some have been applied in clinic. However, the safety, efficacy and pharmacodynamics of these FLT3 inhibitors have not been systemically analyzed before. Methods: We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023. Results: Our results showed the most common adverse events (AEs) were gastrointestinal adverse reactions, including diarrhea, hand-foot syndrome and nausea, while the most common hematological AEs were febrile neutropenia, anemia, and thrombocytopenia. Based on the published data, the mean overall survival (OS) and the mean progression-free survival (PFS) were 9.639 and 5.905 months, respectively. The incidence of overall response rate (ORR), complete remission (CR), partial response (PR), and stable disease (SD) for all these FLT3 inhibitors was 29.0%, 8.7%, 16.0%, and 42.3%, respectively. The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. Discussion: FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.

Study on the Low Plastic Behavior of Expansion Deformation of Austenitic Stainless Steel.

The plastic deformation of TWIP steel is greatly inhibited during the expansion process. The stress-strain curves obtained through expansion experiments and observations of fracture morphology confirmed the low plastic behavior of TWIP steel during expansion deformation. Through an analysis of the mechanical expansion model, it was found that the expansion process has a lower stress coefficient and a faster strain rate than stretching, which inhibits the plasticity of TWIP steel during expansion deformation. Using metallographic microscopy, transmission electron microscopy, and EBSD to observe the twin morphology during expansion deformation and tensile deformation, it was found that expansion deformation has a higher twin density, which is manifested in a denser twin arrangement and a large number of twin deliveries in the microscopic morphology. During the expansion deformation process, dislocation slips are hindered by twins, the free path of the slips is reduced, and dislocations accumulate significantly. The accumulation area is the initial point of crack expansion. The results show that the significant dislocation accumulation caused by the delivery of a large number of twins under expansion deformation is the main reason for the decrease in the plasticity of TWIP steel.

Exosomal Tenascin-C primes macrophage pyroptosis amplifying aberrant inflammation during sepsis-induced acute lung injury.

Sepsis-induced acute lung injury (ALI) is a serious complication of sepsis and the predominant cause of death. Exosomes released by lung tissue cells critically influence the progression of ALI during sepsis by modulating the inflammatory microenvironment. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbates ALI in septic infection remain undefined. Our study found increased levels of exosomal Tenascin-C (TNC) in the plasma of both patients and mice with ALI, showing a strong association with disease progression. By integrating exosomal proteomics with transcriptome sequencing and experimental validation, we elucidated that LPS induce unresolved endoplasmic reticulum stress (ERs) in alveolar epithelial cells (AECs), ultimately leading to the release of exosomal TNC through the activation of PERK-eIF2α and the transcription factor CHOP. In the sepsis mouse model with TNC knockout, we noted a marked reduction in macrophage pyroptosis. Our detailed investigations found that exosomal TNC binds to TLR4 on macrophages, resulting in an augmented production of ROS, subsequent mitochondrial damage, activation of the NF-κB signaling pathway, and induction of DNA damage response. These interconnected events culminate in macrophage pyroptosis, thereby amplifying the release of inflammatory cytokines. Our findings demonstrate that exosomal Tenascin-C, released from AECs under unresolved ER stress, exacerbates acute lung injury by intensifying sepsis-associated inflammatory responses. This research provides new insights into the complex cellular interactions underlying sepsis-induced ALI.

EGFR-TNFR1 pathway in endothelial cell facilitates acute lung injury by NF-κB/MAPK-mediated inflammation and RIP3-dependent necroptosis.

Tumor necrosis factor-α (TNFα) has emerged as a pivotal effector critically correlated with disease severity in acute lung injury (ALI). Because both the excessive activation of epidermal growth factor receptor (EGFR) and tumor necrosis factor receptor 1 (TNFR1) in sepsis-induced vasculitis are markedly diminished through EGFR tyrosine kinase inhibitor, a specific mechanism must exist to modulate TNFR1 cellular fates regulated by EGFR. Here, we demonstrated that EGFR, a specific binding partner of TNFR1, exhibited an increased NF-κB/MAPK-mediated inflammation that was governed by enhanced recruitment of TNFR-associated factor 2 (TRAF2) to TNFR1 complex I in endothelial cell (EC). Moreover, EGFR activation triggered a remarkable increase in the phosphorylation of receptor-interacting protein 1 (RIP1) and its binding with receptor-interacting protein 3 (RIP3) which led to enhanced frequency of necroptosis in complex IIb. Inhibiting the kinase of EGFR disrupted the formation of complex I and complex IIb and prevents EC from NF-κB/MAPK-mediated inflammation and RIP3-dependent necroptosis. Consistently, pharmacological inhibition of EGFR can limit the destructive effects of neutrophils activation and the hyperpermeability of lung vascular in hyperinflammation period. Collectively, we have identified EC-EGFR as a modulator of TNFR1-mediated inflammation and RIP3-dependent necroptosis, providing a possible explanation for the immunological basis of anti-EGFR therapy in sepsis-induced ALI.

EGFR promotes the apoptosis of CD4+ T lymphocytes through TBK1/Glut1 induced Warburg effect in sepsis.

INTRODUCTION: Sepsis-induced apoptosis leads to lymphopenia including the decrease of CD4+ T cells thus favoring immunosuppression. OBJECTIVES: Although epidermal growth factor receptor (EGFR) inhibitors significantly improve the survival rate of septic mice, the effect of EGFR on the function and metabolism of CD4+ T cells in sepsis remained unknown. METHODS: CD4+ T cells from septic mice and patients were assessed for apoptosis, activation, Warburg metabolism and glucose transporter 1 (Glut1) expression with or without the interference of EGFR activation. RESULTS: EGFR facilitates CD4+ T cell activation and apoptosis through Glut1, which is a key enzyme that controls glycolysis in T cells. EGFR, TANK binding kinase 1 (TBK1) and Glut1 form a complex to facilitate Glut1 transportation from cytoplasm to cell surface. Both the levels of membrane expression of EGFR and Glut1 and the activation levels of CD4+ T cells were significantly higher in patients with sepsis as compared with healthy subjects. CONCLUSION: Our data demonstrated that through its downstream TBK1/Exo84/RalA protein system, EGFR regulates Glut1 transporting to the cell surface, which is a key step for inducing the Warburg effect and the subsequent cellular activation and apoptosis of CD4+ T lymphocytes and may eventually affect the immune functional status, causing immune cell exhaustion in sepsis.

EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis.

EGFR phosphorylation is required for TLR4-mediated macrophage activation during sepsis. However, whether and how intracellular EGFR is transported during endotoxemia have largely been unknown. Here, we show that LPS promotes high levels cell surface expression of EGFR in macrophages through two different transport mechanisms. On one hand, Rab10 is required for EEA1-mediated the membrane translocation of EGFR from the Golgi. On the other hand, EGFR phosphorylation prevents its endocytosis in a kinase activity-dependent manner. Erlotinib, an EGFR tyrosine kinase inhibitor, significantly reduced membrane EGFR expression in LPS-activated macrophage. Mechanistically, upon LPS induced TLR4/EGFR phosphorylation, MAPK14 phosphorylated Rab7a at S72 impaired membrane receptor late endocytosis, which maintains EGFR membrane localization though blocking its lysosomal degradation. Meanwhile, Rab5a is also involved in the early endocytosis of EGFR. Subsequently, inhibition of EGFR phosphorylation switches M1 phenotype to M2 phenotype and alleviates sepsis-induced acute lung injury. Mechanistic study demonstrated that Erlotinib suppressed glycolysis-dependent M1 polarization via PKM2/HIF-1ɑ pathway and promoted M2 polarization through up-regulating PPARγ induced glutamine metabolism. Collectively, our data elucidated a more in-depth mechanism of macrophages activation, and provided stronger evidence supporting EGFR as a potential therapeutic target for the treatment of sepsis.

Honokiol Induces Ferroptosis by Upregulating HMOX1 in Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is one of the malignant hematological cancers with high mortality. Finding a more effective and readily available treatment is of the utmost importance. Here, we aimed to identify the anti-leukemia effect of a natural small molecule compound honokiol on a panel of AML cell lines, including THP-1, U-937, and SKM-1, and explored honokiol's potential biological pathways and mechanisms. The results showed that honokiol decreased the viability of the targeted AML cells, induced their cell cycle arrest at G0/G1 phase, and inhibited their colony-formation capacity. Honokiol also triggers a noncanonical ferroptosis pathway in THP-1 and U-937 cells by upregulating the level of intracellular lipid peroxide and HMOX1 significantly. Subsequent studies verified that HMOX1 was a critical target in honokiol-induced ferroptosis. These results reveal that honokiol is an effective anti-leukemia agent in AML cell lines and may be a potential ferroptosis activator in AML.

Macrophage-derived exosomal aminopeptidase N aggravates sepsis-induced acute lung injury by regulating necroptosis of lung epithelial cell.

Sepsis-induced acute lung injury (ALI) is a serious sepsis complication and the prevailing cause of death. Circulating plasma exosomes might exert a key role in regulating intercellular communication between immunological and structural cells, as well as contributing to sepsis-related organ damage. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbate ALI in septic infection remains undefined. Therefore, we investigated the effect of macrophage-derived exosomal APN/CD13 on the induction of epithelial cell necrosis. Exosomal APN/CD13 levels in the plasma of septic mice and patients with septic ALI were found to be higher. Furthermore, increased plasma exosomal APN/CD13 levels were associated with the severity of ALI and fatality in sepsis patients. We found remarkably high expression of APN/CD13 in exosomes secreted by LPS-stimulated macrophages. Moreover, c-Myc directly induced APN/CD13 expression and was packed into exosomes. Finally, exosomal APN/CD13 from macrophages regulated necroptosis of lung epithelial cells by binding to the cell surface receptor TLR4 to induce ROS generation, mitochondrial dysfunction and NF-κB activation. These results demonstrate that macrophage-secreted exosomal APN/CD13 can trigger epithelial cell necroptosis in an APN/CD13-dependent manner, which provides insight into the mechanism of epithelial cell functional disorder in sepsis-induced ALI.

A smart cauliflower-like carrier for astaxanthin delivery to relieve colon inflammation.

As a fat-soluble carotenoid, astaxanthin has excellent antioxidant and anti-inflammation biological activities, but its poor biocompatibility and low stability limit application of astaxanthin in the food industry. In this study, cauliflower-like carriers (CCs) were constructed based on caseinate, chitosan-triphenylphosphonium (TPP) and sodium alginate through an electrostatic self-assembly method to improve the biocompatibility, stability and targeting transport properties of astaxanthin. The smart CCs showed pH-response release and mitochondrial targeted characteristics. In vitro studies demonstrated that the CCs could improve the internalization of astaxanthin, and significantly inhibited the excessive production of reactive oxygen species and the depolarization of mitochondrial membrane potential caused by oxidative stress. In vivo studies revealed that the astaxanthin-loaded CCs could effectively relieve the colitis induced by dextran sodium sulfate and protect the integrity of the colon tissue structure. The astaxanthin-loaded CCs could significantly inhibit the expression of inflammation factors such as interleukin-1ß, interleukin-6, tumor necrosis factor alpha, cyclooxygenase-2, myeloperoxidase, inducible nitric oxide synthase, and nitric oxide. Moreover, the astaxanthin-loaded CCs could maintain the expression of zonula occludens-1, increase the abundance of Firmicutes and Lactobacillaceae in the intestine. In a word, the constructed astaxanthin delivery system provided a potential application for the oral uptake hydrophobic bio-activator in intervention of ulcerative colitis.

Preparation and characterization of glycosylated protein nanoparticles for astaxanthin mitochondria targeting delivery.

Novel mitochondria targeting nanocarriers were prepared using triphenylphosphonium bromide (TPP)-modified whey protein isolate (WPI)-dextran (DX) conjugates by self-assembly method for astaxanthin mitochondria targeting delivery. The nanocarriers of astaxanthin-loaded WPI-DX and astaxanthin-loaded TPP-WPI-DX were 135.26 and 193.64 nm, respectively, which exhibited a spherical structure and good dispersibility. The mitochondria targeting nanocarriers had good stability in the stimulated blood fluid. In vitro experiments indicated that the TPP-modified nanocarriers could effectively realize lysosomes escape, and specifically accumulate in the cell mitochondria. Simultaneously, the astaxanthin-loaded nanocarriers could significantly reduce reactive oxygen species generation produced from hydrogen peroxide, protect the normal levels of the mitochondrial membrane potential, and dramatically promote the vitality of leukemia cells in mouse macrophage (RAW 264.7) cells. The present study highlights the promising application of mitochondria targeting nanocarriers for enhanced delivery of astaxanthin.

Stem Cells from Human Exfoliated Deciduous Teeth Attenuate Trigeminal Neuralgia in Rats.

Trigeminal neuralgia is an incurable progressive nervous system disease that can last for several months or years. Stem cells from human exfoliated deciduous teeth (SHED) are a candidate source for cell-based therapy. Owing to their neuroprotective and immunomodulatory effects, these neural crest cells have potential roles in mediating chronic pain. In this study, we established a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION) to evaluate the analgesic effect of SHED in neuropathic pain. The effects of local SHED transplantation on inflammatory cell infiltration in the trigeminal nerve were investigated based on hematoxylin and eosin staining. The levels of proinflammatory factors in the injured nerve and transient receptor potential vanilloid type 1 (TRPV1) expression in the trigeminal nerve and ganglion were quantified. The data showed that systemic or local injection of SHED attenuated the sensitivity of rats to mechanical stimuli after nerve injury, and this effect lasted throughout the observation period of 8 weeks. PKH26-labeled SHED were distributed to the ipsilateral trigeminal ganglions 24 and 72 hours after local injection. SHED transplantation at the lesion site led to reduced inflammatory cell infiltration and proinflammatory cytokine levels in the injured nerve and inhibited CCI-ION-induced upregulation of TRPV1 expression in the trigeminal nerve and ganglion in the early phase. Therefore, these results provide preclinical evidence that supports the use of SHED in the treatment of trigeminal neuralgia and potentially other chronic pain conditions.

Digital navigation and 3D model technology in mandibular reconstruction with fibular free flap: A comparative study.

OBJECTIVE: The low accuracy limits the use of fibular free flap (FFF). We apply digital navigation and 3D printing model technology in mandibular reconstruction to improve FFF's accuracy. METHODS: 34 patients who underwent with FFF to repair mandibular defects were divided into Navigation Group (13 cases, using digital navigation and 3D printing model) and Control Group (21 cases, only 3D printing model). We retrospectively reviewed patients' hospitalization information and evaluated patients by subjective and objective items, such as UW-Qol scale, CT data. RESULTS: The operation time of Navigation Group was higher significantly than Control Group (10.36 ± 1.87vs9.00 ± 1.34 h).There were no significant differences in early postoperative complications. The Qol score of appearance, motion, anxiety were higher significantly in Navigation Group. The CT results showed that mandibular angle deviation and chin deflection of Navigation Group were better significantly than Control Group (1.72 ± 1.29° vs 3.69 ± 1.67°, 2.45 ± 1.39 vs 5.19 ± 2.13 mm). CONCLUSIONS: The digital navigation can improve FFF's accuracy in mandibular reconstruction. It doesn't significantly increase complications. The digital navigation's installation and operation methods should be simplified to shorter operation time and expand its application.

Procyanidins-Loaded Complex Coacervates for Improved Stability by Self-Crosslinking and Calcium Ions Chelation.

The purpose of this work was to develop a facile strategy based on self-crosslinking between the core and wall materials in the coacervation system for effective procyanidins (PCs) encapsulation. The coacervates were constructed through the interaction of bioactive PCs, gelatin, and sodium alginate, followed by forming cationic bridge of sodium alginate-calcium ions to improve the stability of PCs. When the concentration of PCs and calcium ions were 6.25 and 0.24 mg/mL, respectively, the PC-loaded coacervates showed spherical shape with a size about 150 nm, and the microcapsulation efficiency and yield was 81.19 ± 1.47 and 87.86 ± 2.67%, respectively. The photothermal stability of PCs was effectively improved by embedding them in coacervates. The decrease of mitochondrial membrane potential in PC-12 cells induced by H2O2 was significantly inhibited by PC coacervates, demonstrating an improved protection effect of PCs after being encapsulated in coacervates.

Assessment of fibula flap with flexor hallucis longus's effect on head & neck tumor patients' quality of life and function of donor site.

OBJECTIVE: Free fibular flaps (FFFs) have been widely used in mandibular reconstruction. It is still unclear whether retaining flexor hallucis longus (FHL) is needed for flaps. This study introduces a comparison in quality of life and donor-site function between those who have and haven't harvested FHL with FFF. METHODS: Patients with FFFs were single-blind-randomly assigned into the FHL group or nFHL group. Patients were followed up preoperatively and 1, 3 and 6 months postoperatively via subjective evaluations (SF-36/AOFAS) and objective evaluation s(muscle strength and range of motion). Patients' hospitalization and intraoperative information, donor site morbidity were recorded. RESULTS: Each group had 15 patients. The flap harvesting time in FHL group was shorter significantly than nFHL group (125.9 ± 24.8 min vs 146.7 ± 29.9 min, P = 0.048). There were no significant differences in hospitalization information such as operation time, hospitalization days and cost. Donor site morbidities at 1, 3 and 6 months postoperatively showed no significant differences except for the presence of claw toes (nFHL group > FHL group, 40% vs 0, P = 0.017; 53.3% vs 6.7%, P = 0.014; 60.0% vs 13.3%, P = 0.021). There were no significant differences in SF-36 and AOFAS scores. There were no significant differences in muscle strength and range of motion. CONCLUSION: Excision of the FHL lowered the flap harvesting time. It did not increase donor site morbidity. The impacts on patients' quality of life and foot function were the same. The surgeons can use the FHL without considering the influence on patients if not retaining the FHL.

FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity.

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells. We propose that FAM210B functions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.

Enhanced transfection efficiency and targeted delivery of self-assembling h-R3-dendriplexes in EGFR-overexpressing tumor cells.

The efficient gene transfection, cellular uptake and targeted delivery in vivo are key issues for non-viral gene delivery vectors in cancer therapy. To solve these issues, we designed a new targeted gene delivery system based on epidermal growth factor receptor (EGFR) targeting strategy. An anti-EGFR monoclonal antibody h-R3 was introduced to dendriplexes of PAMAM and DNA via electrostatic interactions to form self-assembled h-R3-PAMAM-DNA complexes (h-R3-dendriplexes). Dendriplexes h-R3-dendriplexes represented excellent DNA encapsulation ability and formed unique nanostructures. Compared to dendriplexes, h-R3-dendriplexes presented lower cytotoxicity, higher gene transfection efficiency, excellent endosome escape ability and high nuclear accumulation in the EGFR-overexpressing HepG2 cells. Both ex vivo fluorescence imaging and confocal results of frozen section revealed that h-R3-dendriplexes showed higher targeted delivery and much better gene expression in the tumors than dendriplexes at the same N/P ratio, and h-R3-dendriplexes had accumulation primarily in the tumor and kidney. Moreover, h-R3-dendriplexes for p53 delivery indicated efficient cell growth inhibition and potentiated paclitaxel-induced cell death. These results indicate that the h-R3-dendriplexes represent a great potential to be used as efficient targeted gene delivery carriers in EGFR-overexpressing tumor cells.