Objective:To investigate the impact of circASH1L on subcutaneous tumor growth in nude mice with triple-negative breast cancer via the PI3K/AKT pathway. Methods:The study was conducted using bioinformatics and animal experimental verification methods. circASH1L levels in triple-negative breast cancer (TNBC) were analyzed using a dataset from the gene expression omnibus database. In the animal experiment part, nude mice were divided into shNC group, shcircASH1L-1 group, Oe-NC group, and Oe-circASH1L group. Each group was treated with corresponding circASH1L overexpression or knockdown and transplanted tumor modeling. Immunohistochemistry and western blot experiments were used to verify the effect of circASH1L on the growth of nude mouse transplanted tumors and the PI3K/AKT pathway. Results:A total of 43 circRNAs were significantly associated with TNBC, among which circASH1L was significantly highly expressed in TNBC. circASH1L-1 negatively regulates tumor volume, mass, expression rate of Ki67 cells, and PI3K/AKT pathway marker proteins. Conclusions:CircASH1L is a tumor promoter in TNBC. The expression level of circASH1L influences both the proliferation of TNBC cells and the growth of TNBC nude mice tumors by modulating the PI3K/AKT pathway.

Colorectal cancer is a highly prevalent and deadly malignancy worldwide. Current treatment strategies, including surgery, chemotherapy, and targeted therapy, still face limitations due to recurrence and metastasis. By conducting a weighted gene coexpression network analysis on gene expression data from The Cancer Genome Atlas, we pinpointed critical genes linked to M2 macrophages and tumor metastasis. Among these, FOXC1 emerged as a significant prognostic indicator within our predictive model. Clinical sample analysis further confirmed that FOXC1 is upregulated in colorectal cancer tissues and associated with an unfavorable patient outcome. Both in vivo and in vitro experimental results revealed that FOXC1 promotes CRC cell migration, invasion and proliferation by regulating the expression of Snail and TGF-β/Smad2/3 pathways, thereby facilitating the epithelial-mesenchymal transition process. Additionally, FOXC1 recruits M2 macrophages to the tumor microenvironment by regulating CXCL2 expression through Snail. The TGF-β factor secreted by M2 macrophages further activates the TGF-β/Smad2/3 pathway, forming a positive feedback loop. In these processes, FOXC1 plays a critical regulatory role. In summary, this study highlights the critical significance of FOXC1 in CRC progression and indicates its viability as a therapeutic target, offering a novel theoretical foundation for the development of future CRC treatment strategies.

Colorectal cancer (CRC) patients have had limited benefits from conventional chemotherapy, highlighting the need for improved therapeutic strategies. Natural compounds have emerged as promising alternatives due to their potent anti-cancer properties and reduced side effects. Tamarixetin is an O-methylated flavonol derived from Azadirachta indica , but its potential and clinical utility to suppress CRC progression remain unknown. To figure out the underlying mechanism, the inhibitory effects of Tamarixetin on CRC were evaluated by in vitro assays; the validation of Tamarixetin-mediated tumour suppression was performed with CRC xenografts and patient-derived organoids. Our results demonstrated that Tamarixetin significantly reduced the proliferation of CRC cells (HT-29 and HCT-116) in a dose-dependent manner, with minimal effects on normal colonic epithelial cells (NCM460). Furthermore, Tamarixetin inhibited proliferation, migration, and invasion of CRC cells, leading to reduced xenograft tumour growth and sensitising CRC to Oxaliplatin. Mechanistically, The expression and protein levels of DPP7 in CRC cells were suppressed by Tamarixetin, which lead to the downregulation of WNT3A/β-catenin signalling pathway. This study highlights Tamarixetin as a promising natural compound for CRC treatment by interfering with DPP7-mediated WNT3A/β-catenin signalling pathway. These findings provide a novel therapeutic strategy to improve outcomes of CRC.

Abstract Background The regulatory role of N6-methyladenosine (m6A) modification in the onset and progression of cancer has garnered increasing attention in recent years. However, the specific role of m6A modification in pulmonary metastasis of colorectal cancer remains unclear. Methods This study identified differential m6A gene expression between primary colorectal cancer and its pulmonary metastases using transcriptome sequencing and immunohistochemistry. We investigated the biological function of METTL3 gene both in vitro and in vivo using assays such as CCK-8, colony formation, wound healing, EDU, transwell, and apoptosis, along with a BALB/c nude mouse model. The regulatory mechanisms of METTL3 in colorectal cancer pulmonary metastasis were studied using methods like methylated RNA immunoprecipitation quantitative reverse transcription PCR, RNA stability analysis, luciferase reporter gene assay, Enzyme-Linked Immunosorbent Assay, and quantitative reverse transcription PCR. Results The study revealed high expression of METTL3 and YTHDF1 in the tumors of patients with pulmonary metastasis of colorectal cancer. METTL3 promotes epithelial-mesenchymal transition in colorectal cancer by m6A modification of SNAIL mRNA, where SNAIL enhances the secretion of CXCL2 through the NF-κB pathway. Additionally, colorectal cancer cells expressing METTL3 recruit M2-type macrophages by secreting CXCL2. Conclusion METTL3 facilitates pulmonary metastasis of colorectal cancer by targeting the m6A-Snail-CXCL2 axis to recruit M2-type immunosuppressive macrophages. This finding offers new research directions and potential therapeutic targets for colorectal cancer treatment.

Colorectal cancer (CRC) is the third deadliest cancer in the world, with a high incidence, aggressiveness, poor prognosis, and resistant to drugs. 5-fluorouracil (5-FU) is the most commonly used drug for the chemotherapeutic of CRC, however, CRC is resistant to 5-FU after a period of treatment. Therefore, there is an urgent need to explore the underlying molecular mechanisms of CRC resistance to 5-FU. In the present study, we found that the expression of PANX2 was increased in CRC tissues and metastatic tissues from the TCGA database. The K-M survival curve showed that the high expression of PANX2 was associated with poor cancer prognosis. GDSC database showed that the IC50 of 5-Fu in the PANX2 high expression group was significantly higher, and the results were verified in CRC cells. In vitro cell function and in vivo tumorigenesis experiments showed that PANX2 promoted CRC cell proliferation, clone formation, migration and tumorigenesis in vivo. WB result revealed that PANX2 may lead to resistance to 5-Fu in CRC by affecting the PI3K-AKT signaling pathway. Overall, PANX2 regulates CRC proliferation, clone formation, migration, and 5-Fu resistance by PI3K-AKT signaling pathway.

Purpose Gemcitabine is a basic chemotherapy drug for pancreatic cancer (PC), but resistance is common and causes tumor recurrence and metastasis. Therefore, it is significant to explore gemcitabine resistance-related molecules for individualized treatment and prognosis assessment of PC. Methods In this study, transcriptome sequencing and TCGA database analysis were performed, and a differentiated gene AHNAK2 was screened. MEXPRESS database, tissue microarray analysis, and CIBERSORT and TIMER databases were used to correlate AHNAK2 expression with clinicopathological features and prognosis and immune infiltration of PC. Enrichment analysis was used to investigate the significant biological processes associated with AHNAK2. Results AHNAK2 was highly expressed in gemcitabine-resistant cells. High expression of AHNAK2 increased the risk of poor overall survival (OS) and progression-free survival (PFS) in PC. Clinicopathologic analysis revealed that AHNAK2 correlated with KRAS, TP53 mutations, histologic type, short OS, N stage, and elevated CA199 levels in PC. Knockdown of AHNAK2 inhibited the ability of cell proliferation and colony formation and enhanced the toxic effect of gemcitabine in PC. Meanwhile, the knockdown of AHNAK2 expression enhanced cell-ECM adhesion, inhibited cell-cell adhesion, and downregulated the KRAS/p53 signaling pathway in PC. Furthermore, AHNAK2 was correlated with immune infiltration, especially B cells and macrophages. Conclusions Our study unveils for the first time the pivotal role of AHNAK2 in PC, particularly its association with gemcitabine resistance, clinical prognosis, and immune infiltration. AHNAK2 not only drives the proliferation and drug resistance of PC cells by potentially activating the KRAS/p53 pathway but also significantly impacts cell-cell and cell- ECM adhesion. Additionally, AHNAK2 plays a crucial role in modulating the tumor immune microenvironment. These insights underscore AHNAK2's unique potential as a novel therapeutic target for overcoming gemcitabine resistance, offering new perspectives for PC treatment strategies.

Immune Checkpoint Inhibitors (ICIs) therapy has advanced significantly in treating malignant tumors, though most ‘cold’ tumors show no response. This resistance mainly arises from the varied immune evasion mechanisms. Hence, understanding the transformation from ‘cold’ to ‘hot’ tumors is essential in developing effective cancer treatments. Furthermore, tumor immune profiling is critical, requiring a range of diagnostic techniques and biomarkers for evaluation. The success of immunotherapy relies on T cells’ ability to recognize and eliminate tumor cells. In ‘cold’ tumors, the absence of T cell infiltration leads to the ineffectiveness of ICI therapy. Addressing these challenges, especially the impairment in T cell activation and homing, is crucial to enhance ICI therapy’s efficacy. Concurrently, strategies to convert ‘cold’ tumors into ‘hot’ ones, including boosting T cell infiltration and adoptive therapies such as T cell-recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, are under extensive exploration. Thus, identifying key factors that impact tumor T cell infiltration is vital for creating effective treatments targeting ‘cold’ tumors.

Sialyltransferases are enzymes that play a crucial role in regulating cancer progression by modifying glycoproteins through sialylation. In particular, the ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4) enzyme is known to be upregulated in breast cancer, but its specific biological functions have not been fully understood. This study aimed to investigate the impact and mechanisms of ST3GAL4 on aerobic glycolysis in breast cancer. We examined ST3GAL4 expression in tumor tissue samples and breast cancer cell lines and also manipulated ST3GAL4 expression in breast cancer cells using lentivirus transduction. The study evaluated cellular processes such as cell viability, cell cycle progression, and aerobic glycolysis by measuring parameters like extracellular acidification rate, glucose uptake, lactate production, and lactate dehydrogenase A (LDHA) expression. We found that ST3GAL4 expression was consistently increased in tumor tissues and breast cancer cell lines. High ST3GAL4 expression was associated with a poor prognosis for patients with breast cancer. Inhibiting ST3GAL4 expression decreased cell viability, disrupted cell cycle progression, and reduced aerobic glycolysis and LDHA expression. Furthermore, suppressing ST3GAL4 expression in animal models reduced tumor growth and cell proliferation. Conversely, overexpressing ST3GAL4 promoted cell viability and cell cycle progression, but these effects were reversed when an inhibitor of aerobic glycolysis was used. The study provided evidence in cells and animal models that ST3GAL4 promotes tumorigenesis in breast cancer by enhancing aerobic glycolysis. These findings suggest that targeting ST3GAL4 may be a potential strategy for the treatment of breast cancer.

Diabetic wound healing remains a challenge due to high levels of oxidative stress, excessive inflammation, and bacterial infection. Smart dressings loaded with natural active monomers are proving to be effective strategies for enhancing diabetic wound healing. Herein, the bio-composites (PTIGA-Cur and PTIGA-Cur-Ag) with curcumin (Cur) responsive release were reported for promoting angiogenesis and diabetic wound repair, showing excellent anti-inflammatory, antioxidant, and antibacterial properties. The integration of three-dimensional networks and chemical bonds endowed the bio-composites with superior thermodynamic, mechanical, and self-healing properties. Notably, pH-responsive Schiff base as well as ester groups in the matrix enable the Cur to be released in a controlled manner. A biosensor assembled from PTIGA-Cur-Ag demonstrated electronic conductivity based on in-situ synthesis of AgNPs, which enabled sensitive monitoring of blood glucose levels. In addition, the release of AgNPs enhanced the antibacterial and anti-inflammatory properties. Expectedly, the bio-composites exhibited remarkable biocompatibility, effectively promoting the polarization of macrophages to M2 phenotype, and reducing the expression of proinflammatory cytokines. The full-thickness diabetic wound model revealed that PTIGA-Cur and PTIGA-Cur-Ag were able to effectively promote collagen deposition, neovascularization, and granulation tissue regeneration through their anti-inflammatory, antioxidant, and antibacterial properties. This study provides evidence supporting the potential utility of bio-composites with both pro-healing properties and monitoring functions in the management of diabetic wounds.

E3 ubiquitin ligases have the potential to modulate key oncogenic pathways. RING finger protein 123 (RNF123), as an E3 ubiquitin ligase, has been functioned as a tumor suppressor. This study was designed to explore the role of RNF123 in breast cancer. Immunohistochemistry was applied to examine protein expression in breast cancer tissues. Western blot and Quantitative Real-time PCR were performed to gauge protein and mRNA levels. Lentivirus transduction was used to overexpress or silence genes of interest. Cell Counting Kit-8, flow cytometry, and colony formation assays were used to assess cell viability, cell cycle, and colony formation. Extracellular acidification rate, lactic acid and adenosine triphosphate were used for glycolysis assay. Co-immunoprecipitation (Co-IP) and ubiquitination analysis were used to explore the interaction between RNF123 and 6-Phosphofructo-2-kinase (PFKP). In vivo experiments were performed with xenograft tumor models. RNF123 was downregulated in tumor tissues and cells, overexpression of which significantly decreased the viability and colony-forming ability of tumor cells, suppressed the progression of the cell cycle and glycolytic activity, and suppressed tumor growth in vivo. Co-IP and ubiquitination analysis revealed that there was an interaction between RNF123 and PFKP, and RNF123 could induce ubiquitination of PFKP. PFKP could reverse the effects of RNF123 on tumor cells. RNF123 inhibited cell viability, cell cycle and colony formation of breast cancer cells by inhibiting glycolysis via ubiquitination of PFKP.

Sialyltransferases responsible for glycoprotein sialylation are key regulators in cancer progression. Although ST3 β‑galactoside α‑2,3‑sialyltransferase 4 (ST3GAL4), an important sialyltransferase, is upregulated in breast cancer, its biological functions remain unclear. The present study aimed to investigate the impact and mechanisms of ST3GAL4 on glycolysis in breast cancer. ST3GAL4 expression was examined in tumor tissue specimens and microarrays and breast cancer cell lines BT‑474, SKBR3, MCF‑7, and T47D. ST3GAL4 was silenced or overexpressed by lentivirus transfection in breast cancer cells. Cell viability and cell cycle were evaluated by Cell Counting Kit‑8 and flow cytometry, respectively. Extracellular acidification rate, glucose uptake and lactate production were used for glycolysis assessment. ST3GAL4 was consistently upregulated in tumor tissues and cell lines of breast cancer. High ST3GAL4 expression was associated with poor prognosis of patients with breast cancer. Cell viability was decreased, cell cycle progression was inhibited and glycolysis was inhibited in ST3GAL4‑silenced cells compared with control cells. ST3GAL4 silencing led to suppression of tumor growth and cell proliferation in xenograft mouse models. ST3GAL4 overexpression promoted cell viability and accelerated cell cycle, which were reversed by glycolysis inhibitor. The study provided in vivo and in vitro evidence that ST3GAL4 promoted cell viability and tumor growth by regulating the glycolysis pathway in breast cancer. ST3GAL4 inhibition may serve as a strategy for treatment of breast cancer.

To investigate the effect of breviscapine against hepatic ischemia/reperfusion (I/R) injury and its underlying mechanisms in rats, 40 Sprague-Dawley male rats were randomly assorted into five groups (n=8 per group) as follows: Sham, I/R1 + normal saline (NS), I/R1 + breviscapine (Bre), I/R2 + NS and I/R2 + Bre, where label 1 and 2 denote ischemia time for 20 and 60 min, respectively. Bre or NS (10 mg/kg) was administered to the tail vein 1 h prior to surgery and immediately postoperatively. Reperfusion for 6 h, the blood and hepatic samples were collected immediately to evaluate hepatic function and histopathological changes, in addition with the expression levels of mitofusin 2 (Mfn2) and endoplasmic reticulum stress (ERS)-associated proteins. The results demonstrated that breviscapine decreased the elevated serum level of ALT and AST and ameliorated histopathological changes compared with the NS groups (P<0.05). The expression of Mfn2 and Glucose-regulated protein 78 (GRP78) and Bcl2 protein were significantly increased in the Bre groups (P<0.05), accompanied by decreasing the expression of C/EBP homologous protein (CHOP) and cleaved caspase-3 (P<0.05) compared with the NS groups. These data revealed that breviscapine could ameliorate the hepatic I/R injury, possibly contribute to the up-regulation of Mfn2 expression to inhibit the ERS pathway, thus reducing the apoptosis of hepatocyte.

Hepatic ischemia-reperfusion injury (HIRI) is an additional injury to ischemic tissue after hepatic revascularization, and its pathological mechanism is complex. HIRI is not only involved in the molecular targets that mediate cell death, such as ion channel activation, abnormal protease activation and mitochondrial dysfunction, but also related to the down-regulation of endogenous protective signals. As a by-product of normal aerobic metabolism, reactive oxygen species (ROS) act as a multi effect physiological signal factor at low concentration. However, liver ischemia-reperfusion will lead to excessive ROS accumulation, destroy redox homeostasis, lead to oxidative stress, cause cell death through a variety of mechanisms, and drive the further damage of ischemic liver. Recent studies have found that the antioxidant treatment of nano selenium can reduce the excessive production of ROS and play a potential protective role in reducing HIRI. This paper reviews the molecular mechanism of the antioxidant effect of nano selenium for the prevention and treatment of HIRI, in order to provide further experimental basis for the clinical prevention and treatment of HIRI.

Background: There is increasing evidence that tumour-associated macrophages (TAMs) are critical in the formation of lung metastases. However, the molecular mechanisms of tumour interactions with TAMs via EMT are largely unknown. Methods: The mechanism of lung metastasis was studied in patient tissues. The mechanism of SNAIL regulation of the interaction between mesenchymal cells and M2 macrophages was elucidated using coculture of M2 macrophages and Transwell assays in vitro and in vivo in nude mice and NOD-SCID mice. Results: We demonstrated for the first time that SNAIL and CXCL2 were abnormally overexpressed in colorectal cancer, especially lung metastasis, and were associated with poor prognosis in colorectal cancer patients. We demonstrated that SNAIL promoted the secretion of CXCL2 by mesenchymal cells and induced the activation of M2 macrophages. We found that CXCL2 attracted M2-type macrophages to infiltrate and promote tumour metastasis. Conclusion: These findings suggest that SNAIL promotes epithelial tumour transformation, and that transformed mesenchymal cells secrete CXCL2, which promotes M2 macrophage infiltration and tumour cell metastasis. These findings elucidate the tumour-TAM interaction in the metastatic microenvironment, which is mediated by tumour-derived CXCL2 and affects lung metastasis. This study also provides a theoretical basis for the occurrence of secondary lung cancer.

Abstract Purpose: The purpose of this research was to investigate the prevalence, risk, and prognostic factors associated with liver metastasis (LM) in colorectal adenocarcinoma and to develop a nomogram for predicting LM incidence and prognosis.Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to collect data from patients diagnosed with colorectal adenocarcinoma with liver metastases between 2010 and 2015. We used univariate and LASSO-multivariate logistic regression analyses to identify independent risk factors for LM in colorectal adenocarcinoma patients, and we used univariate and LASSO-multivariate Cox proportional hazards regression analyses to identify independent prognostic factors for colorectal adenocarcinoma with LM. We then made two new nomograms, and the results were checked out by receiver operating characteristic (ROC) curves, calibration curves, and decision curves (DCA).Result: There were 38,941 patients with colorectal adenocarcinoma included in the study, and 4,866 individuals were diagnosed with LM. The age, T, N, tumor size, chemotherapy, radiation, perineural invasion, surgery, and CEA level are all independent risk factors for LM in patients with colorectal adenocarcinoma. The age, grade, tumor size, chemotherapy, T stage, CEA level, marital status, and surgery are all independent prognostic variables for colorectal adenocarcinoma patients with LM. ROC curves, calibration, DCA, and Kaplan–Meier (K-M) survival curves in the training, validation, and expanded testing sets indicated that two nomograms may accurately predict the incidence and prognosis of LM in patients with colorectal adenocarcinoma.Conclusion: LM is quite common in people with colorectal adenocarcinoma. A nomogram based on risk and prognostic indicators for LM was shown to be effective at estimating the probability of LM incidence and prognosis.

OBJECTIVE: The pathogenesis of coronavirus disease 2019 (COVID-19) remains clear, and no effective treatment exists. SARS-CoV-2 is the virus that causes COVID-19 and uses ACE2 as a cell receptor to invade human cells. Therefore, ACE2 is a key factor to analyze the SARS-CoV-2 infection mechanism. MATERIALS AND METHODS: We included 9,783 sequencing results of different organs, analyzed the effects of different ACE2 expression patterns in organs and immune regulation. RESULTS: We found that ACE2 expression was significantly increased in the lungs and digestive tract. The cellular immunity of individuals with elevated ACE2 expression is activated, whereas humoral immunity is dampened, leading to the release of many inflammatory factors dominated by IL6. Furthermore, by studying the sequencing results of SARS-CoV-2-infected and uninfected cells, IL6 was found to be an indicator of a significant increase in the number of infected cells. However, although patients with high expression of ACE2 will release many inflammatory factors dominated by IL6, cellular immunity in the colorectum is significantly activated. This effect may explain why individuals with SARS-CoV-2 infection have severe lung symptoms and digestion issues, which are important causes of milder symptoms. CONCLUSIONS: This finding indicates that ACE2 and IL6 inhibitors have important value in COVID-19.

The treatment strategy for pancreatic metastasis from renal cell carcinoma (PM-ccRCC) is unclear due to its rarity. Pancreatic Metastasis from clear cell renal carcinoma are very rare, yet with a favorable prognosis compared to other pancreatic malignancies. We herein present a case of a women with metastatic disease in the pancreas following complete resection of RCC ten years ago. This case underlines the necessity of long-term follow-up of patients treated for kidney cancer.

病人,男,82岁.因腹痛1 天于2020年1 月21 日入院.病人1 天前突发持续性腹痛,呈全腹隐痛阵发性加剧,伴恶心呕吐,头晕.实验室检查:WBC 16.27 × 109/L,HGB 76 g/L,Glu 16.82 mmol/L,腹部CT检查提示:(1 )考虑门静脉系统广泛积气与肝内胆管多发积气鉴别,门静脉主干及肠系膜上静脉积气;(2)肝S4肝内胆管小结石;(3 )考虑胆囊腺肌症;(4)左肾复杂性囊肿,右肾小结石;(5)双肺下叶多发炎.予以抗感染、抑酸护胃等对症保守治疗未见明显好转.

目的 探讨EPLBD联合乳头括约肌切开术(EST)治疗胆总管结石的临床效果.方法 选取2019年1月～2020年8月我院普通外科收治的胆总管结石患者60例,采用随机数字表法分为对照组和观察组各30例.对照组给予内镜下乳头大球囊扩张术(EPLBD)治疗,观察组给予EPLBD联合乳头括约肌切开术(EST)治疗,比较两组手术相关指标,比较两组一次性结石取尽情况,并比较两组手术相关并发症的发生情况.结果 术前,两组血清淀粉酶水平比较,差异无统计学意义(P>0.05);术后1天,观察组血清淀粉酶水平低于对照组,差异有统计学意义(P<0.05).观察组平均取石时间短于对照组,差异有统计学意义(P<0.05).观察组一次性结石取尽率高于对照组,差异有统计学意义(P<0.05).两组并发症发生率比较,差异无统计学意义(P>0.05).结论 相较于EPLBD治疗,EPLBD联合EST治疗可控制胆总管结石患者血清淀粉酶水平,缩短取石时间,提高一次性结石取尽率,且不会增加并发症的发生风险.