Liver X receptors (LXRs) play a key role in cholesterol transport, glucose metabolism and the tumorigenesis. LXR ligands can inhibit tumor growth through several mechanisms, such as suppressing tumor cell proliferation and migration, and inducing tumor cell death. Among them, induction of tumor cell death is one of the main mechanisms by which LXR ligands inhibit tumor growth; but how exactly LXR ligands cause cell death is still unclear. In this study, we found that LXR agonists can induce nonclassical pyroptosis in various cancer cells. Further study we found that Caspase-3-mediated GSDME cleavage is involved in LXR agonist-induced pyroptosis. Mechanically, LXR agonists firstly induce ER stress in tumor cells, then the ER stress induced by LXR agonists alters the integrity of the mitochondrial outer membrane (MOM) through the NOXA and BAX/BAK. Subsequently, mitochondrial permeability transition activates Caspase-4/APAF-1 pyroptosome to activate GSDME-dependent pyroptosis. Finally, we also found that LXR agonists induced GSDME-dependent pyroptosis in mouse cells. Our results demonstrated that LXR agonists can induce nonclassical GSDME-dependent pyroptosis in cancer cells by inducing ER stress, which alters the integrity of MOM to activate Caspase-4/APAF-1 pyroptosome.

Colorectal cancer (CRC), characterized by high incidence and mortality rates, is an aggressive malignancy that significantly burdens public health. Metastasis represents the principal factor contributing to treatment failure in CRC patients, largely due to limited comprehension of the underlying mechanisms governing this phenomenon. CRC metastasis involves multiple factors, including dynamics within the tumor microenvironment (TME), epithelial–mesenchymal transition (EMT), and the dissemination of cancer cells through the circulatory and lymphatic systems. These mechanisms are regulated by complex molecular interactions. A deeper understanding of the metastatic processes and the identification of viable therapeutic targets could substantially advance innovative clinical interventions. This review highlights key contributors to CRC metastasis, integrates relevant molecular mechanisms with distinct patterns of organ-specific spread, and emphasizes the latest advancements in this field. Additionally, it explores experimental models of CRC and metastasis, provides mechanistic insights, and addresses challenges in the clinical management of metastatic CRC. This article aims to facilitate future research and highlight promising therapeutic opportunities for clinical translation.

Exosomal miRNAs (exo-miRNAs) have arisen as novel diagnostic biomarkers for various cancers. However, few reports on exo-miRNAs related to bone metastasis (BM) in lung cancer exist. This study aims to screen out key exo-miRNAs and estimate their prognostic values for predicting BM in lung cancer. The differentially expressed exo-miRNAs between the highly-metastatic (95D) and lowly-metastatic (A549) human lung cancer cell lines were comprehensively analyzed using high-throughput sequencing followed by bioinformatic analyses. 29 candidate exo-miRNAs were identified, and 101 BM-related target genes were predicted. Enrichment analysis revealed that these target genes were mainly involved in regulating transcription and pathways in cancer. An exosomal miRNA-mRNA regulatory network consisting of 7 key miRNAs and 10 hub genes was constructed. Further function analysis indicated that these 10 hub genes were mainly enriched in regulating cancer's apoptosis and central carbon metabolism. The survival analysis indicated that 7 of 10 hub genes were closely related to prognosis. Mutation analysis showed that lung cancer patients presented certain genetic alterations in the 7 real hub genes. GSEA for a single hub gene suggested that 6 of 7 real hub genes had close associations with lung cancer development. Finally, ROC analysis revealed that hsa-miR-151a-3p and hsa-miR-877-5p provided high diagnostic accuracy in discriminating patients with bone metastasis (BM+) from patients without bone metastasis (BM-). These findings provided a comprehensive analysis of exo-miRNAs and target genes in the regulatory network of BM in lung cancer. In particular, hsa-miR-151a-3p and hsa-miR-877-5p may be novel biomarkers for predicting BM in lung cancer.

Aim: The objective was to elucidate the correlation between CMVP and immunosuppressive therapy in IBD patients, we hope this review could expand on the significance of CMV as an opportunistic pathogen and the potential impact on morbidity and mortality in IBD patients. Methods: Records and clinical trajectories linked to CMVP in IBD patients were extracted from the PubMed database, irrespective of language barriers. The reference lists incorporated in these studies were manually inspected. Conclusions were generated using straightforward descriptive analysis.Results: In total, 18 IBD patients, including Crohn's disease (CD, 67%) and Ulcerative Colitis (UC, 33%), affected by CMVP were identified from 17 published articles. A minority of these patients (17%) exhibited active disease, whereas the majority (83%) presented with quiescent disease. Fever (100%) and dyspnea (44%) emerged as the most prevalent clinical symptoms. All the patients had undergone immunosuppressive therapy. A significant proportion, up to 89%, had received thiopurine treatment prior to the CMVP diagnosis. Interestingly, none of the patients were subjected to biological therapy. Half of the patients manifested with Hemophagocytic Lymphohistiocytosis (HLH). Almost all patients (94%) were administered antiviral treatment and a substantial 83% experienced full recovery. Immunosuppressive agents were either tapered or discontinued altogether. A subset of patients, 17%, suffered fatal outcomes.Conclusion: Our findings underscore the need for heightened suspicion of CMVP in IBD patients who exhibit symptoms such as fever and dyspnea. During the COVID-19 pandemic, CMVP should be considered a potential differential diagnosis. It was observed that CMVP primarily transpires during CD remission. Azathioprine emerged as the predominant immunosuppressant linked to CMV reactivation. The prompt application of effective antiviral therapy can substantially enhance patient outcomes. CMV vaccine might serve as a viable prevention strategy.

BackgroundTranssphenoidal secondary operations are a minority but not a rare occurrence. How to viably prevent cerebral fluid (CSF)-related complications and confine surgery-caused injury in secondary surgery as minimally as possible is a huge challenge. This article shares our solution of recycling a prior Hadad-Bassagasteguy flap (HBF) along with a using small piece of free autologous mucosa to reconstruct the skull base.MethodsOf 69 patients, fitted criteria were assigned into 2 different groups: a recycled HBF incorporated with an autologous free mucosa and a recycled HBF incorporated with an artificial dura to rebuild the skull base in secondary transsphenoidal surgery. The postoperative morbidities of pseudomeningocele, CSF leakage and meningitis were recorded and analyzed.ResultsA recycled HBF incorporated with an autologous mucosa is capable of reducing CSF complications compared to that of the matched group, particularly decreasing the morbidity of meningitis in secondary transsphenoidal surgery. Diabetes mellitus, craniopharyngioma, chordoma and the utilization of artificial dura were independent risk factors for CSF complications in secondary transsphenoidal surgery through univariate and multivariate logistic regression. In addition, diabetes mellitus and artificial dura are more likely to induce CSF leakage and meningitis. Patients suffering from craniopharyngioma are more susceptible to meningitis. Chordoma indiscriminately increased the risk of each CSF complication.ConclusionA recycled HBF incorporated with an autologous mucosa is reliable for reconstructing the skull base in secondary transsphenoidal surgery, especially for patients simultaneously suffering from diabetes mellitus and central skull base tumors.

TRAIP, as a 53 kDa E3 ubiquitin protein ligase, is involved in various cellular processes and closely related to the occurrence and development of tumors. At present, few studies on the relationship between TRAIP and triple negative breast cancer (TNBC) were reported. Bioinformatic analysis and Western blot, immunohistochemistry (IHC), CCK-8, colony formation, flow cytometry, wound healing, Transwell, and dual-luciferase reporter assays were performed, and xenograft mouse models were established to explore the role of TRAIP in TNBC. This study showed that the expression of TRAIP protein was upregulated in TNBC tissues and cell lines. Silencing of TRAIP significantly inhibited the proliferation, migration, and invasion of TNBC cells, whereas opposite results were observed in the TRAIP overexpression. In addition, TRAIP regulated cell proliferation, migration, and invasion through RB-E2F signaling and epithelial mesenchymal transformation (EMT). MiR-590-3p directly targeted the TRAIP 3′-UTR, and its expression were lower in TNBC tissues. Its mimic significantly downregulated the expression of TRAIP and subsequently suppressed cell proliferation, migration, and invasion. Rescue experiments indicated that TRAIP silencing reversed the promotion of miR-590-3p inhibitor on cell proliferation, migration, and invasion. TRAIP overexpression could also reverse the inhibition of miR-590-3p mimic on tumorigenesis. Finally, TRAIP knockdown significantly inhibited tumor growth and metastasis in animal experiments. In conclusion, TRAIP is an oncogene that influences the proliferation, migration, and invasion of TNBC cells through RB-E2F signaling and EMT. Therefore, TRAIP may be a potential therapeutic target for TNBC.

Breast cancer is the most common malignant tumors in women. Kinesin family member 3B (KIF3B) is a critical regulator in mitotic progression. The objective of this study was to explore the expression, regulation, and mechanism of KIF3B in 103 cases of breast cancer tissues, 35 metastatic lymph nodes and breast cancer cell lines, including MDA-MB-231, MDA-MB-453, T47D, and MCF-7. The results showed that KIF3B expression was up-regulated in breast cancer tissues and cell lines, and the expression level was correlated with tumor recurrence and lymph node metastasis, while knockdown of KIF3B suppressed cell proliferation, migration, and invasion both in vivo and in vitro . In addition, UALCAN analysis showed that KIF3B expression in breast cancer is increased, and the high expression of KIF3B in breast cancer is associated with poor prognosis. Furthermore, we found that silencing of KIF3B decreased the expression of Dvl2, phospho-GSK-3 β , total and nucleus β -catenin, then subsequent down-regulation of Wnt/ β -catenin signaling target genes such as CyclinD1, C-myc, MMP-2, MMP-7 and MMP-9 in breast cancer cells. In addition, KIF3B depletion inhibited epithelial mesenchymal transition (EMT) in breast cancer cells. Taken together, our results revealed that KIF3B is up-regulated in breast cancer which is potentially involved in breast cancer progression and metastasis. Silencing KIF3B might suppress the Wnt/ β -catenin signaling pathway and EMT in breast cancer cells.

Three-dimensional scaffolds have played an important role in tissue engineering, especially in broad applications to areas such as regenerative medicine. We have rapidly prototyped the 3D printing poly(lactic-co-glycolicacid)-hydroxyapatite (PLGA/HA) bioactive scaffolds to evaluate the effect and biocompatibility of repairing rat full-thickness bone defects in vivo and in vitro. Thirty-six SD (Sprague Dawley) rats were selected to grind out a 4-mm-longfull-thickness bone defect of the bilateral femurs. The sterilized scaffolds were implanted on the left limbs (experimental groups), and the right limbs (control groups) were conducted with blank treatments. Gross, histological inspection of femoral cadavers and the levels of the osteoblast-related genes of IGF-1, COL-1, OC and OPN during bone healing were collected postoperatively to further evaluate the bone repairing distinctions between the two groups. Seeding the mouse osteoblasts (MC3T3-E1) on our pretreated scaffolds in vitro presented good adhesion and adequate extension under a scanning electron microscope (SEM). Finally, HE-staining images demonstrated that the cortex of the new bone in the experimental femur reproduced the structure of the surrounding normal bone tissue combined with complete scaffold degradation. The control groups, on the other hand, suffered a long duration of healing with a poor osteogenic effect. The expression level of osteoblast-related genes in the test limbs was upregulated more highly than that of the control group. Under SEM, our bioactive scaffold featured well-distributed and interconnected porous latticework, a place into which the mouse osteoblasts penetrated, and their processes were closely attached to the material, which presented good growth conditions. Taken together, our innovation in this work demonstrated that the 3D printing PLGA/HA bioactive scaffolds had excellent biocompatibility and osteogenesis and could be potential candidates for bone grafting for future orthopedic applications.

Abstract Cisplatin-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC), but drug resistance occurs in most patients, leading to treatment failure. Recent studies have shown that epithelial–mesenchymal transition (EMT) is associated with drug resistance. However, the underlying mechanism is not entirely clear. In this study, first we showed significant positive correlation between the expression of ERCCl and vimentin, and significant negative correlation between the ERCCl and E-cadherin in the neoadjuvant chemotherapy group and the simple surgery group. Second, we showed that cisplatin-resistant A549 cells (A549/DDP) acquire EMT phenotype with high expression of drug-resistant proteins, P-gp and ERCC1. Knockdown of TGF-β1 may reverse EMT and significantly reduce the expression of P-gp and ERCC1. Moreover, A549/DDP cells become more sensitive to cisplatin. In summary, our results globally confirm a molecular and phenotypic association between chemoresistance and EMT of resistant tumour cells under a histological and cellular level. More importantly, silence of TGF-β1 may enhance sensitivity to cisplatin of A549/DDP through inducing the reversal of EMT and inhibiting the expression of resistance-associated proteins. Hence, inhibition of TGF-β1 could be considered as an effective strategy for eliminating resistant lung cancer.

Failure of cancer treatment caused by drug resistance and metastasis is mainly due to existence of cancer stem cells (CSCs). Therefore, targeting CSCs to overcome cancers is a challenging issue in clinic. In this report, in view of the important role of survivin in tumor growth and CSCs maintaining, we aimed to confirm that FL118, as a novel survivin inhibitor, may effectively inhibit lung cancer stem cells. We showed that lung cancer stem cells have the obviously higher expression of survivin than their parental cells. After treated with FL118, the survivin level in CSCs was suppressed. Consistently, lung cancer stem cells displayed significantly growth inhibition over time. Here, we compared the antitumor efficacy between FL118 and cisplatin. The data revealed that CSCs are more sensitive to FL118 than cisplatin. To further demonstrate the inhibitory effect of FL118 on CSCs, we found that FL118 down-regulated the expression of CSCs markers (ABCG2, ALDH1A1, Oct4) and drug resistant proteins (P-gp, ERCC1), suggesting that FL118 may change CSCs phenotype and improve drug-sensitivity of tumor cells. Moreover, FL118 effectively decreased the invasive ability of CSCs. These findings expand the uniqueness of FL118 as an attractive therapeutic option for cancers with drug-resistant or metastatic potential.

Unlike genetics, epigenetics involves the modification of genome without changes in DNA sequences, including DNA methylation, histone modification, chromatin remodeling and noncoding RNA regulation. MicroRNA (miRNA), a member of noncoding RNAs superfamily, participates in RNA interference through a unique mechanism. Currently, microRNAs have been found to be regulated by some natural compounds. Through altering the expression of miRNAs and influencing the downstream signaling pathways or target genes, several natural compounds exhibit its bioactivity in the prevention, diagnosis, therapy, prognosis and drug resistance of human diseases, such as cancer. In this review, several natural compounds and their studies about miRNA-related action mechanism were summarized. These studies provide a new insight into action mechanism by which natural compound exerts its bioactivity and a novel treatment strategy, demonstrating natural compound a promising remedy for clinical treatments.

Background: FL118 is a newly discovered camptothecin analogue that exerts anti-tumor activity on a wide range of cancers; however, the molecular mechanism underlying FL118's antitumor activity is still far from being completely understood. MicroRNAs (miRNAs) are believed to play an important role in the progression of human malignancies, and increasing evidence shows that these small RNAs also mediates the tumor-suppressing activity of many natural and/or synthetic compounds. Our previous studies indicated that miR-155, which has been confirmed as an oncogenic miRNA in colorectal carcinoma was significantly downregulated after the treatment of FL118.Methods: MTT assay, scratch wound assay, BrdU cell proliferation assay and flow cytometry were employed to detect HCT-116 cell viability, mobility, proliferation, apoptosis and cell cycle under the treatment of FL118, respectively. Xenograft models were established to observe the effect of FL118 on tumor growth in vivo. Also, qRT-PCR was performed to detect the level of miR-155 in colon cancer cells and tumor samples after FL118 administration.Results: Our results showed that FL118 induced cell apoptosis, inhibited cell viability and mobility, suppressed cell proliferation and limited the growth of colon cancer. The levels of miR-155 were downregulated significantly (P<0.05) by FL118 both in vivo and in vitro.Conclusions: FL118 effectively inhibits colon cancer development and downregulates the expression of miR-155 both in vivo and in vitro. With the understanding that miR-155 is closely associated with the pathogenesis and development of colon cancer, its downregulation resulting from FL118 may indicate that miR-155 is likely to participate in, and even mediate the anticancer activity of FL118 on colon carcinoma, which should be noted, and urges further study.

As the first-line drug therapy for non-small cell lung cancer (NSCLC), cisplatin has a wide range of applications. However, inherent and acquired resistance reduces its effectiveness in the treatment of NSCLC. Our study was to investigate the antitumor activity of a new camptothecin analogue FL118 on cisplatin-resistant NSCLC cells. Western blot assay showed that the expression of survivin protein down-regulated by FL118, Flow cytometry analysis displayed that A549 cells and its cisplatin-resistant counterparts (A549/DDP) cells were both arrested in S phase. MTT assay showed that the viability of A549/DDP cells were decreased, indicating that FL118 may effectively inhibit the growth of NSCLC cells regardless of the chemoresistance of tumor cells. Meanwhile, wound healing scratch assay and transwell-matrigel invasion assay were used to demonstrate that FL118 may inhibit the migratory and invasive capabilities of A549 and A549/DDP cells. To further explore the mechanism of antitumor activity of FL118, the expression of ERCC1, P-gp, E-cadherin and Vimentin proteins were examined by immunohistochemistry and western blot. The resistance-associated proteins, P-gp and ERCC1, were both inhibited by the treatment of FL118, suggesting that FL118 may promote the chemosensitivity of tumor cells through inhibiting their expression. Consistent with the change in chemosensitivity, epithelial-mesenchymal transition (EMT) of A549/DDP cells was reversed by FL118, implying that the antitumor efficacy of FL118 is at least partly, dependent on regulating the process of EMT. These findings contribute to the the understanding of the molecular mechanism by which FL118 reverses cisplatin-resistance of NSCLC cells and demonstrates that FL118 is a promising candidate for further clinical lung cancer treatment.

The present report intended to introduce the hemilaminoplasty technique and evaluate the efficacy of our surgical procedure for LISCs.

Background: Because recurrent peroneal subluxation can produce functional impairment in athletes, most authors suggest operative intervention for patients who fail nonoperative treatment. The present report introduces the modified sliding fibular graft repair for this pathology. Methods: This retrospective study was conducted to analyze the clinical results for 26 patients with recurrent peroneal subluxation who underwent this procedure with a follow-up of a minimum of 3 years. Results: Intraoperative observations revealed 15 convex grooves and 11 shallow sulci with a low-lying peroneus brevis muscle belly in 6 patients and a peroneus quartus muscle in 4 patients. All underwent the procedure plus excision of redundant muscle and tendon repair, with an improvement rate of 88.5% according to American Orthopaedic Foot & Ankle Society (AOFAS) score at the final visit. All but 3 patients returned to normal function in 4.4 months with no infection, nonunion, or intra-articular screw placement. A total of 8 patients had minor complications including neurapraxia, synovitis, stress fracture, and delayed union. Conclusion: We found that an anomalous fibular groove plus tendon variants could lead to a further decrease in the volume of the osteofibrous tunnel and might be the reason for recurrent peroneal dislocation; thus, our modified procedure may be a reasonable treatment for this pathological malposition. We found less functional recovery in aged patients due to a higher incidence of tendon tear and postoperative complications. Level of Evidence: Level III, retrospective comparative study.

Objective To observe the effect of pelercan on proliferation of fibroblasts and its relationship with basic fibroblast growth factor (bFGF).Methods The rat model was established,and the scar connective tissue was collected and subjected to the primary culture of rat fibroblasts.Lentivirus was used to downregulate the expression of pelercan.Fluorescent quantitative polymerase chain reaction (FQ-PCR),Western blotting and methyl thiazol tetrazolium (MTT) assay were performed to detect the expression of perlecan and cell proliferation rate.Results After the lentivirus transfection,the perlecan mRNA expre ssion level in fibroblasts was reduced by (75.1 ± 1.1) ％ in perlecan-interfering group.In low-serum condition,the cell proliferation rate was decreased by (40.6 ± 3.1)％ in perlecan-interfering group.Treatment with 1 μg/L bFGF had no significant effect on the cell proliferation (P ＞ 0.05).Conclusion Infection of rat fibroblasts with lentivirus down-regulated the expression of perlecan and bFGF.Cell proliferation rate and sensitivity of rat fibroblasts to bFGF were both reduced when perlecan was downregulated.