Background Colorectal cancer (CRC) is a prevalent form of cancer globally, characterized by a high mortality rate. Therefore, discovering effective therapeutic approaches for CRC treatment is critical. Methods The levels of KIF20A in CRC clinical samples were determined using Western Blot and immunofluorescence assay. SW480 cells were transfected with siRNA targeting KIF20A, while HT-29 cells were transfected with a KIF20A overexpression vector. Cell viability and apoptosis of CRC cells were assessed using CCK-8 and TUNEL analysis. Migration ability was investigated using Transwell. The levels of pyruvate, lactate and ATP were determined through corresponding assay kits. Western Blot was applied to confirm the level of proteins associated with glycolysis, cMyc, HIF-1α, PKM2 and LDHA. Subsequently, functional rescue experiments were conducted to investigate further the regulatory relationship between KIF20A, c-Myc, and HIF-1α in colorectal cancer (CRC), employing the c-Myc inhibitor 10058-F4 and c-Myc overexpression plasmids. Results KIF20A was up-regulated in vivo and in vitro in CRC. KIF20A knockdown inhibited cell viability and migration while promoting cell apoptosis in SW480 cells. Conversely, overexpression of KIF20A yielded contrasting effects in HT-29 cells. Moreover, inhibition of KIF20A restrained the pyruvate, lactate production and ATP level, whereas overexpression of KIF20A enhanced the Warburg effect. Western Blot indicated that knockdown KIF20A attenuated the levels of c-Myc, HIF-1α, PKM2 and LDHA. In addition, rescue experiments further verified that KIF20A enhanced the Warburg effect by the KIF20A/c-Myc/HIF-1α axis in CRC. Conclusion KIF20A, being a crucial regulator in the progression of CRC, has the potential to be a promising therapeutic target for the treatment of CRC
Background Reduced supplies of oxygen and nutrients caused by vascular injury lead to difficult-to-heal pressure ulcers (PU) in clinical practice. Rapid vascular repair in the skin wound is the key to the resolution of this challenge, but clinical measures are still limited. We described the beneficial effects of extracellular vesicle-derived silk fibroin nanoparticles (NPs) loaded with milk fat globule EGF factor 8 (MFGE8) on accelerating skin blood vessel and PU healing by targeting CD13 in the vascular endothelial cells (VECs). Methods CD13, the specific targeting protein of NGR, and MFGE8, an inhibitor of ferroptosis, were detected in VECs and PU tissues. Then, NPs were synthesized via silk fibroin, and MFGE8-coated NPs (NPs@MFGE8) were assembled via loading purified protein MFGE8 produced by Chinese hamster ovary cells. Lentivirus was used to over-express MFGE8 in VECs and obtained MFGE8-engineered extracellular vesicles (EVs-MFGE8) secreted by these VECs. The inhibitory effect of EVs-MFGE8 or NPs@MFGE8 on ferroptosis was detected in vitro. The NGR peptide cross-linked with NPs@MFGE8 was assembled into NGR-NPs@MFGE8. Collagen and silk fibroin were used to synthesize the silk fibroin/collagen hydrogel. After being loaded with NGR-NPs@MFGE8, silk fibroin/collagen hydrogel sustained-release carrier was synthesized to investigate the repair effect on PU in vivo. Results MFGE8 was decreased, and CD13 was increased in PU tissues. Similar to the effect of EVs-MFGE8 on inhibiting ferroptosis, NPs@MFGE8 could inhibit the mitochondrial autophagy-induced ferroptosis of VECs. Compared with the hydrogels loaded with NPs or NPs@MFGE8, the hydrogels loaded with NGR-NPs@MFGE8 consistently released NGR-NPs@MFGE8 targeting CD13 in VECs, thereby inhibiting mitochondrial autophagy and ferroptosis caused by hypoxia and accelerating wound healing effectively in rats. Conclusions The silk fibroin/collagen hydrogel sustained-release carrier loaded with NGR-NPs@MFGE8 was of great significance to use as a wound dressing to inhibit the ferroptosis of VECs by targeting CD13 in PU tissues, preventing PU formation and promoting wound healing. Graphical Abstract
Background Laparoscopic access to liver segment 7 (S7) is difficult for deep surgical situations and bleeding control. Herein, our proposed laparoscopic technique for S7 lesions using a self-designed tube method is introduced. Methods Clinical data of patients who underwent laparoscopic anatomical liver resection of S7 (LALR-S7) with the help of our self-designed tube to improve the exposure of S7 and bleeding control in the Second Affiliated Hospital, Third Military Medical University (Army Medical University) from April 2019 to December 2021 were retrospectively analyzed to evaluate feasibility and safety. Results Nineteen patients were retrospectively reviewed. The mean age was 51.3 ± 10.3 years; mean operation time, 194.5 ± 22.7 min; median blood loss, 160.0 ml (150.0–205.0 ml); and median length of hospital stay, 8.0 days (7.0–9.0 days). There was no case conversion to open surgery. Postoperative pathology revealed all cases of hepatocellular carcinoma (HCC). Free surgical margins were achieved in all patients. No major postoperative complications were observed. Patients with postoperative complications recovered after conservative treatment. During outpatient follow-up examination, no other abnormality was presented. All patients survived without tumor recurrence. Conclusions The preliminary clinical effect of our method was safe, reproducible and effective for LALR-S7. Further research is needed due to some limitations of this study.
Bloodstream infection (BSI) caused by bacteria is highly pathogenic and lethal, and easily develops whole-body inflammatory state. Immediate identification of disease-causing bacteria can improve patient prognosis. Traditional testing methods are not only time-consuming, but such tests are limited to laboratories. Recombinase polymerase amplification combined with lateral flow dipstick (RPA-LFD) holds great promise for rapid nucleic acid detection, but the uncapping operation after amplification easily contaminates laboratories. Therefore, the establishment of a more effective integrated isothermal amplification system has become an urgent problem to be solved. In this study, we designed and fabricated a hermetically sealed integrated isothermal amplification system. Combining with this system, a set of RPA-LFD assays for detecting S. aureus, K. peneumoniae, P. aeruginosa, and H. influenza in BSI were established and evaluated. The whole process could be completed in less than 15 min and the results can be visualized by the naked eye. The developed RPA-LFD assays displayed a good sensitivity, and no cross-reactivity was observed in seven similar bacterial genera. The results obtained with 60 clinical samples indicated that the developed RPA-LFD assays had high specifcity and sensitivity for identifying S. aureus, K. peneumoniae, P. aeruginosa, and H. influenza in BSI. In conclusion, our results showed that the developed RPA-LFD assay is an alternative to existing PCR-based methods for detection of S. aureus, K. peneumoniae, P. aeruginosa, and H. influenza in BSI in primary hospitals.
Objective Real-world diagnostic and treatment data for pancreatic cancer in China are lacking. As such, the present study investigated the clinical characteristics, diagnosis, and treatment of advanced pancreatic cancer (including locally advanced and metastatic disease) in the Hospital-based Advanced Pancreatic Cancer Cohort in China of the China Pancreas Data Center database. Methods A total of 5349 Chinese patients with advanced pancreatic cancer were identified from a database. The entire course of real-world pancreatic cancer management was analyzed. Results The proportion of patients with advanced pancreatic cancer was higher among males than females (62.4% versus [vs.] 37.6%, respectively). Patients typically had a history of hypertension (30.8%), diabetes (21.6%), and cholangitis (20.2%). Abdominal pain (51.6%), abdominal distension (27.1%), jaundice (20.1%), and weight loss (16.3%) were the main symptoms observed in patients with advanced pancreatic cancer in this cohort. Serum carbohydrate antigen (CA)19-9 is one of the most common tumor markers. In the present study, 2562 patients underwent first-line therapy. The median progression-free survival (PFS) for patients undergoing first-line therapy was 4.1 months. The major options for first-line therapy included gemcitabine (GEM) plus S-1 (GS/X) (23.4%), nab-paclitaxel plus GEM (AG) (18.1%), oxaliplatin, irinotecan, and leucovorin-modulated fluorouracil (FOLFIRINOX; 11.9%), nab-paclitaxel plus S-1 (AS) (8.9%), and GEM combined with oxaliplatin/cisplatin (GEMOX/GP) (7.6%). The AS and GS/X regimens were associated with the highest PFS rates. Conclusion This is the first study to report multicenter, real-world data regarding advanced pancreatic cancer in China. Results revealed that real-world treatment options differed from guideline recommendations, and PFS was shorter than that in previously reported data. Improving intelligent follow-up systems and standardizing diagnosis and treatment of pancreatic cancer is recommended.
Bone tissue constitutes 15–20% of human body weight and plays a crucial role in supporting the body, coordinating movement, regulating mineral homeostasis, and hematopoiesis. The maintenance of bone homeostasis relies on a delicate balance between osteoblasts and osteoclasts. Osteoclasts, as the exclusive “bone resorbers” in the human skeletal system, are of paramount significance yet often receive inadequate attention. When osteoclast activity becomes excessive, it frequently leads to various bone metabolic disorders, subsequently resulting in secondary bone injuries, such as fractures. This not only reduces life quality of patients, but also imposes a significant economic burden on society. In response to the pressing need for biomaterials in the treatment of osteoclast dysregulation, there has been a surge of research and investigations aimed at osteoclast regulation. Promising progress has been achieved in this domain. This review seeks to provide a comprehensive understanding of how to modulate osteoclast activities. It summarizes bioactive substances that influence osteoclasts and elucidates strategies for constructing related biomaterial systems. It offers practical insights and ideas for the development and application of biomaterials and tissue engineering, with the hope of guiding the clinical treatment of osteoclast‐related bone diseases using biomaterials in the future. This article is protected by copyright. All rights reserved
Postovulatory aging leads to the decline in oocyte quality and subsequent impairment of embryonic development, thereby reducing the success rate of assisted reproductive technology (ART). Potential preventative strategies preventing oocytes from aging and the associated underlying mechanisms warrant investigation. In this study, we identified that cordycepin, a natural nucleoside analogue, promoted the quality of oocytes aging in vitro, as indicated by reduced oocyte fragmentation, improved spindle/chromosomes morphology and mitochondrial function, as well as increased embryonic developmental competence. Proteomic and RNA sequencing analyses revealed that cordycepin inhibited the degradation of several crucial maternal proteins and mRNAs caused by aging. Strikingly, cordycepin was found to suppress the elevation of DCP1A protein by inhibiting polyadenylation during postovulatory aging, consequently impeding the decapping of maternal mRNAs. In humans, the increased degradation of DCP1A and total mRNA during postovulatory aging was also inhibited by cordycepin. Collectively, our findings demonstrate that cordycepin prevents postovulatory aging of mammalian oocytes by inhibition of maternal mRNAs degradation via suppressing polyadenylation of DCP1A mRNA, thereby promoting oocyte developmental competence. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-023-05030-0.
Sacituzumab govitecan(SG)is wide used for the treatment of breast cancer and urothelial carcinoma, but available information regarding AEs is limited. We aim to explore the AE induced by SG by mining the FAERS database.The association between SG and adverse events (AEs) were evaluated using the information component (IC). A multivariate logistic regression analysis was conducted for all identified signals to explore the risk factors associated with AEs leading to hospitalization.In total1884 reports related to SG were retrieved, and 114 AE signals involving 20 systems were identified. The median time for onset of AEs was around 6‐7 days after initiating treatment with SG, with over 80% of AEs occurring within 30 days. Subgroup analysis revealed that 14 signals were reported in the males and 110 in the females. There were 58 signals reported in patients under 65 following the use of SG, 59 signals in patients over 65, and 31 signals were present in both groups. Multivariable analysis showed that the males and the occurrence of Colitis, Pneumonitis, Febrile Neutropenia, Pyrexia, Sepsis, Dehydration, and Diarrhea were risk factors leading to hospitalization with an AUC of 0.89. Additionally, sensitivity analysis revealed that this study had good robustness.This is the first retrospective analysis based on FAERS to review the safety of SG. The results highlight the need to closely monitor adverse reactions such as neutropenia, diarrhea, colitis, and sepsis when using SG.
Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage‐mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3‐associated phagocytosis (LAP), a non‐canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G‐protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL‐induced efferocytosis, anti‐colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3‐associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.
Background Medical university students are confronted with unprecedented uncertainty and stress compared with their peers. Research has explored the effect of intolerance of uncertainty on perceived stress, but little attention was paid to investigate the mediating mechanisms behind this relationship, especially among medical university students. The aim of this study was to examine whether psychological resilience and neuroticism played a mediating role between medical university students’ intolerance of uncertainty and perceived stress. Methods A total of 717 medical university students from Chongqing in Southwest China were recruited to participate in our study and completed demographic information, Intolerance of Uncertainty Scale Short Version (IUS-12), Chinese Version of Perceived Stress Scale (CPSS), Connor-Davidson Resilience Scale-10 (CD-RISC-10) and Eysenck Personality Questionnaire (EPQ). Results (1) Significant correlations between intolerance of uncertainty, perceived stress, psychological resilience and neuroticism were found. (2) Intolerance of uncertainty affected medical university students’ perceived stress via three paths: the mediating effect of psychological resilience, the mediating effect of neuroticism, and the chain mediating effect of both psychological resilience and neuroticism. Conclusions Intolerance of uncertainty could directly affect the perceived stress of medical university students, and also affected perceived stress through the mediating roles of psychological resilience and neuroticism, as well as through the chain mediating role of these two variables.
Corneal injury‐induced stromal scarring causes the most common subtype of corneal blindness, and there is an unmet need to promote scarless corneal wound healing. Herein, a biomimetic corneal stroma with immunomodulatory properties is bioengineered for scarless corneal defect repair. First, a fully defined serum‐free system is established to derive stromal keratocytes (hAESC‐SKs) from a current Good Manufacturing Practice (cGMP)‐grade human amniotic epithelial stem cells (hAESCs), and RNA‐seq is used to validate the phenotypic transition. Moreover, hAESC‐SKs are shown to possess robust immunomodulatory properties in addition to the keratocyte phenotype. Inspired by the corneal stromal extracellular matrix (ECM), a photocurable gelatin‐based hydrogel is fabricated to serve as a scaffold for hAESC‐SKs for bioengineering of a biomimetic corneal stroma. The rabbit corneal defect model is used to confirm that this biomimetic corneal stroma rapidly restores the corneal structure, and effectively reshapes the tissue microenvironment via proteoglycan secretion to promote transparency and inhibition of the inflammatory cascade to alleviate fibrosis, which synergistically reduces scar formation by ≈75% in addition to promoting wound healing. Overall, the strategy proposed here provides a promising solution for scarless corneal defect repair.
Despite remarkable advances in understanding the mechanisms underlying inflammation, the currently available anti‐inflammatory therapies have many limitations, such as poor efficacies, low selectivity, and severe adverse effects. Bioactive materials with intrinsically anti‐inflammatory activities have emerged as promising drug candidates for the treatment of inflammatory disorders. Among them, nanotherapies based on bioactive cyclodextrin (CD) materials have attracted much attention, owing to their multiple advantages, including broad availability, well‐controlled structures, easy functionalization, good processibility, high cost‐effectiveness, and excellent biocompatibility. This review provides a comprehensive overview of the recent advancements in the development and applications of anti‐inflammatory nanoparticles (NPs) based on bioactive CD materials, with special focus on reactive oxygen species‐scavenging NPs and NPs capable of regulating inflammatory cell recruitment and activation. In addition, the applications of these anti‐inflammatory nanotherapies in the treatment of different acute/chronic inflammatory diseases are highlighted. Furthermore, major challenges in the clinical translation of these new generation anti‐inflammatory therapies derived from bioactive CD materials are discussed.
AIM: To compare the clinical outcomes between two approaches for sutureless scleral-fixated intraocular lens (SFIOL) in children with Marfan syndrome (MFS). METHODS: The study included 15 children (26 eyes) with lens subluxation due to MFS. These children underwent lensectomy, anterior vitrectomy, and sutureless SFIOL. According to the position of placement of intraocular lens (IOL) haptics, two study groups were reviewed for best corrected visual acuity (BCVA) and postoperative complications: group A, 14 eyes with haptics fixated at 2.0 mm from the limbus; group B, 12 eyes with the haptics fixated at 2.5 mm from the limbus. RESULTS: The mean axial length for all patients was 25.66±2.35 mm. Postoperative BCVA in logMAR were significant improved in both groups (0.77±0.32 to 0.17±0.12 in group A, 0.66±0.25 to 0.24±0.12 in group B, both P<0.001) while no significant difference between two groups (P>0.05). Pupillary capture was main postoperative complication, occurring between 3d and 18mo. It occurred in 7 eyes in group A and one eye in group B (P=0.02). CONCLUSION: Sutureless SFIOL is an effective treatment approach for lens subluxation in children with MFS. Pupillary capture is the main postoperative complication. Fixated IOL haptics at 2.5 mm from the limbus can reduce the occurrence of pupillary capture.
Atopic dermatitis (AD) is a chronic inflammatory disease associated with immune dysfunction. High levels of reactive oxygen species (ROS) can lead to oxidative stress, release of pro-inflammatory cytokines, and T-cell differentiation, thereby promoting the onset and worsening of AD. In this study, we innovatively used quaternary ammonium chitosan (QCS) and tannic acid (TA) as raw materials to design and prepare a therapeutic hydrogel(H-MnO2-Gel) loaded with hollow manganese dioxide nanoparticles (H-MnO2 NPs). In this system, the hydrogel is mainly cross-linked by dynamic ion and hydrogen bonding between QCS and TA, resulting in excellent moisture retention properties. Moreover, due to the inherent antioxidant properties of QCS/TA, as well as the outstanding H2O2 scavenging ability of H-MnO2 NPs, the hydrogel exhibits significant ROS scavenging capability. In vitro experiments have shown that H-MnO2-Gel exhibits good cellular biocompatibility. Importantly, in an AD-induced mouse model, H-MnO2-Gel significantly enhanced therapeutic effects by reducing epidermal thickness, mast cell number, and IgE antibodies. These findings suggest that H-MnO2-Gel, by effectively clearing ROS and regulating the inflammatory microenvironment, provides a promising approach for the treatment of AD.
Vascular disease is one of the major causes of death worldwide. Endothelial cells are important components of the vascular structure. A better understanding of the endothelial cell changes in the development of vascular disease may provide new targets for clinical treatment strategies. Single-cell RNA sequencing can serve as a powerful tool to explore transcription patterns, as well as cell type identity. Our current study is based on comprehensive scRNA-seq data of several types of human vascular disease datasets with deep-learning-based algorithm. A gene set scoring system, created based on cell clustering, may help to identify the relative stage of the development of vascular disease. Metabolic preference patterns were estimated using a graphic neural network model. Overall, our study may provide potential treatment targets for retaining normal endothelial function under pathological situations.
Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection.
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