WTAP/IGF2BP3-mediated GBE1 expression accelerates the proliferation and enhances stemness in pancreatic cancer cells via upregulating c-Myc.

BACKGROUND: Pancreatic cancer (PC) is one of the most malignant cancers with highly aggressiveness and poor prognosis. N6-methyladenosine (m6A) have been indicated to be involved in PC development. Glucan Branching Enzyme 1 (GBE1) is mainly involved in cell glycogen metabolism. However, the function of GBE1 and Whether GBE1 occurs m6A modification in PC progression remains to be illustrated. METHODS: The clinical prognosis of GBE1 was analyzed through online platform. The expression of GBE1 was obtained from online platform and then verified in normal and PC cell lines. Lentivirus was used to generated GBE1 stable-overexpression or knockdown PC cells. Cell Counting Kit (CCK-8), colony formation assay, sphere formation assay and flow cytometry assay were conducted to analyze cell proliferation and stemness ability in vitro. Subcutaneous and orthotopic mouse models were used to verify the function of GBE1 in vivo. RNA immunoprecipitation (RIP) assay, RNA stability experiment and western blots were conducted to explore the molecular regulation of GBE1 in PC. RESULTS: GBE1 was significantly upregulated in PC and associated with poor prognosis of PC patients. Functionally, GBE1 overexpression facilitated PC cell proliferation and stemness-like properties, while knockdown of GBE1 attenuated the malignancy of PC cells. Importantly, we found the m6A modification of GBE1 RNA, and WTAP and IGF2BP3 was revealed as the m6A regulators to increase GBE1 mRNA stability and expression. Furthermore, c-Myc was discovered as a downstream gene of GBE1 and functional rescue experiments showed that overexpression of c-Myc could rescue GBE1 knockdown-induced PC cell growth inhibition. CONCLUSIONS: Our study uncovered the oncogenic role of GBE1/c-Myc axis in PC progression and revealed WTAP/IGF2BP3-mediated m6A modification of GBE1, which highlight the potential application of GBE1 in the targeted therapy of PC.

Construction and in vitro evaluation of pH-sensitive nanoparticles to reverse drug resistance of breast cancer stem cells.

Breast cancer is a major threat to safety and health of women. The breast cancer stem cells (BCSCs) have multi-drug resistance to chemotherapy drugs, which leads to chemotherapy failure. We proposed a strategy of delivery of tumor-killing drugs and a resistance reversal agent, to enhance inhibition of BCSCs. Here, schisandrin B (SchB)/AP NPs are constructed using acid-grafted-poly (ß-amino ester) (ATRA-g-PBAE, AP) grafted polymer nanoparticle encapsulated SchB, with pH-sensitive release function. This drug delivery system has good pharmacological properties and can increase the SchB release with the decrease of pH. The NPs showed cytotoxic effects in reversing ATRA resistance to BCSCs. Lysosomal escape was achieved when the nanoparticles were taken up by BCSCs. In addition, we found that NPs may reverse MDR by inhibiting the expression of P-glycoprotein (P-gp) and affecting the energy supply of drug efflux. This study provides a nanodelivery therapy strategy that reverses BCSCs multidrug resistance (MDR) and demonstrates that it did so by interfering with cancer cell energy metabolism. Therefore, the co-delivery strategy of ATRA and SchB provides a new option for the treatment of breast cancer.

Glucose oxidase and metal catalysts combined tumor synergistic therapy: mechanism, advance and nanodelivery system.

Cancer has always posed a significant threat to human health, prompting extensive research into new treatment strategies due to the limitations of traditional therapies. Starvation therapy (ST) has garnered considerable attention by targeting the primary energy source, glucose, utilized by cancer cells for proliferation. Glucose oxidase (GOx), a catalyst facilitating glucose consumption, has emerged as a critical therapeutic agent for ST. However, mono ST alone struggles to completely suppress tumor growth, necessitating the development of synergistic therapy approaches. Metal catalysts possess enzyme-like functions and can serve as carriers, capable of combining with GOx to achieve diverse tumor treatments. However, ensuring enzyme activity preservation in normal tissue and activation specifically within tumors presents a crucial challenge. Nanodelivery systems offer the potential to enhance therapy effectiveness by improving the stability of therapeutic agents and enabling controlled release. This review primarily focuses on recent advances in the mechanism of GOx combined with metal catalysts for synergistic tumor therapy. Furthermore, it discusses various nanoparticles (NPs) constructs designed for synergistic therapy in different carrier categories. Finally, this review provides a summary of GOx-metal catalyst-based NPs (G-M) and offers insights into the challenges associated with G-M therapy, delivery design, and oxygen (O2) supply.

Methylseleninic acid overcomes gefitinib resistance through asparagine-MET-TOPK signaling axis in non-small cell lung cancer cells.

Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC.

Association between obstructive sleep apnea and gastroesophageal reflux disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: We aim to conduct a systematic review and determine the association between obstructive sleep apnea (OSA) and gastroesophageal reflux disease (GERD). METHODS: Literature search for eligible studies was performed across major databases. The main endpoint was to assess the association between GERD and OSA. Subgroup analyses were performed to determine this strength of the association stratified by the diagnostic tools used for OSA (nocturnal polysomnogram or Berlin questionnaire) and GERD (validated reflux questionnaire or esophagogastroduodenoscopy). We also compared sleep efficiency, apnea hypopnea index, oxygen desaturation index, and Epworth Sleepiness Scale in OSA patients with or without GERD. Results were pooled together using Reviewer Manager 5.4. RESULTS: Six studies involving 2950 patients with either GERD or OSA were included in the pooled analysis. Our findings suggest that there was a statistically significant unidirectional association between GERD and OSA (odds ratio [OR] = 1.53, P = 0.0001). Subgroup analyses redemonstrated an OSA-GERD association irrespective of the tools used for diagnosing either GERD or OSA (P = 0.24 and P = 0.82, respectively). Sensitivity analyses demonstrated the same association after controlling for gender (OR = 1.63), BMI (OR = 1.81), smoking (OR = 1.45), and alcohol consumption (OR = 1.79). In patients with OSA, there were no statistically significant differences between patients with or without GERD in terms of apnea hypopnea index (P = 0.30), sleep efficiency (P = 0.67), oxygen desaturation index (P = 0.39), and Epworth Sleepiness Scale (P = 0.07). CONCLUSION: There exists an association between OSA and GERD that is independent of the modalities used for screening or diagnosing both disorders. However, the presence of GERD did not affect the severity of OSA.

Diagnostic Implications of Irritable Bowel Syndrome Is an Independent Risk Factor for Undergoing Surgical Interventions in Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) can present with overlapping symptoms, making diagnosis and management challenging. Patients with IBD in remission may continue to experience IBS symptoms. Patients with IBS were found to have a disproportionately higher prevalence of abdominal and pelvic surgeries than the general population. AIMS: The aim of this study was to determine whether IBS is a risk factor for undergoing surgical interventions in patients with IBD and explore the diagnostic implications of these findings. METHODS: A population-based cohort analysis was performed using TriNetX. Patients with Crohn's disease + IBS (CD + IBS) and ulcerative colitis + IBS (UC + IBS) were identified. The control groups consisted of patients with CD or UC alone without IBS. The main outcome was to compare the risks of undergoing surgical interventions between the cohorts. The secondary outcomes were to compare the risks of developing gastrointestinal symptoms and IBD-related complications between the cohorts. RESULTS: Patients with IBD who subsequently developed IBS were more likely to experience gastrointestinal symptoms than those without IBS (p < 0.0001). Patients with concomitant IBD and IBS were more likely to develop IBD-related complications, including perforation of the intestine, gastrointestinal bleeding, colon cancer, and abdominal abscess (p < 0.05). Patients with concomitant IBD and IBS were more likely to undergo surgical interventions than patients without IBS, including colectomy, appendectomy, cholecystectomy, exploratory laparotomy, and hysterectomy (p < 0.05). CONCLUSIONS: IBS appears to be an independent risk factor for patients with IBD to develop IBD-related complications and undergo surgical interventions. Patients with concomitant IBD and IBS could represent a unique subgroup of IBD patients with more severe symptoms, highlighting the importance of accurate diagnosis and management in this population.

Comprehensive bioinformatics and experimental analysis of SH3PXD2B reveals its carcinogenic effect in gastric carcinoma.

AIMS: We aim to explore the possibility and mechanism of SH3PXD2B as a reliable biomarker for gastric cancer (GC). MAIN METHODS: We used public databases to analyze the molecular characteristics and disease associations of SH3PXD2B, and KM database for prognostic analysis. The TCGA gastric cancer dataset was used for single gene correlation, differential expression, functional enrichment and immunoinfiltration analysis. SH3PXD2B protein interaction network was constructed by the STRING database. And the GSCALite database was used to explore sensitive drugs and perform SH3PXD2B molecular docking. The impact of SH3PXD2B silencing and over-expression by lentivirus transduction on the proliferation and invasion of human GC HGC-27 and NUGC-3 cells was determined. KEY FINDINGS: The high expression of SH3PXD2B in gastric cancer was related to the poor prognosis of patients. It may affect the progression of gastric cancer by forming a regulatory network with FBN1, ADAM15 and other molecules, and the mechanism may involve regulating the infiltration of Treg, TAM and other immunosuppressive cells. The cytofunctional experiments verified that it significantly promoted the proliferation and migration of gastric cancer cells. In addition, we found that some drugs were sensitive to the expression of SH3PXD2B such as sotrastaurin, BHG712 and sirolimus, and they had strong molecular combination of SH3PXD2B, which may provide guidance for the treatment of gastric cancer. SIGNIFICANCE: Our study strongly suggests that SH3PXD2B is a carcinogenic molecule that can be used as a biomarker for GC detection, prognosis, treatment design, and follow-up.

The Activity of Novel BCR-ABL Small-Molecule Degraders Containing Pyrimidine Rings and Their Role in Overcoming Drug Resistance.

Inducing protein degradation by proteolysis-targeting chimeras (PROTACs) has gained tremendous momentum in the field for its promise in the discovery and development of new therapies. Based on our previously reported PROTAC BCR-ABL degraders, we designed and synthesized additional 4 PROTAC compounds with a novel linker that contains pyrimidine rings. Molecular and cellular studies have shown that different linkers affect the degradation activity of small-molecule degraders on the target protein of BCR-ABL. We screened out a lead compound, DMP11, with stable physicochemical properties and high activity. Preliminary evaluation of its pharmacodynamics in vitro model showed that it has a good inhibitory effect on imatinib-resistant chronic myeloid leukemia cell lines, as has been shown in animal models. Our preliminary research into the mechanism of DMP11 found that DMP11 can overcome drug resistance by simultaneously inhibiting the targets of BCR-ABL and SRC-family kinase (SFK).

The role of the endoscopic grading of gastric intestinal metaplasia in assessing gastric cancer risk: A systematic review and meta-analysis.

Background and aim: Patients with gastric intestinal metaplasia (IM) are at increased risk of gastric cancer (GC). The endoscopic grading of gastric intestinal metaplasia (EGGIM) with high-definition endoscopes has shown the potential to facilitate GC risk stratification. However, a comprehensive review and meta-analysis of published articles are lacking. We conducted a meta-analysis to access the value of EGGIM in the assessment of histological IM. Materials: Studies were selected from PubMed, Medline, Embase, and Cochrane (last selection, Jun 2022). We extracted relevant data to calculate the accuracy of EGGIM compared with the operative link of gastric intestinal metaplasia (OLGIM) and to calculate pooled odds ratio (OR) with a 95% confidence interval (CI) assessing GC risk with different grading. Results: Four diagnostic studies and three case-control clinical trials were included in the analysis, which included 665 patients and 738 patients, respectively. Compared with OLGIM III/IV, EGGIM(5-10) had a pooled sensitivity and specificity of 0.92(95%CI 0.86-0.96) and 0.90(95%CI 0.88-0.93), and the area under the curve(AUC) was 0.9702. In assessing early GC, the pooled OR of patients with EGGIM(5-10) was 7.46(95%CI 3.41-16.31) compared with that of EGGIM(0-4). Conclusions: EGGIM is highly consistent with OLGIM, and patients with EGGIM(5-10) are at a higher risk for early GC. Some heterogeneity in the current research suggests that we need to carry out more strict control of confounding factors. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=248691], (Prospero registration number: 248691).

Hyaluronic acid and cholecalciferol conjugate based nanomicelles: Synthesis, characterization, and cytotoxicity against MCF-7 breast cancer cells.

Recently, growing and conclusive evidences showed the particularly close ties between the vitamin D (VD) and breast cancer (BC). However, few researches were focused on the delivery system against breast cancer which based on cholecalciferol (VD3). Herein, we designed a series of self-assembled micelles. The conjugate (HA-VD) of VD3 with hyaluronic acid (HA) actively targeting breast cancer can efficiently delivery doxorubicin (DOX). The HA-VD conjugate was successfully synthesized, which was confirmed using 1H nuclear magnetic resonance (NMR) and Fourier transform infrared (FITR). Preliminary studies of its physical and chemical properties indicated that VD3 was successfully grafted with the HA (HAVD). When the molar ratio was 1:2 and the degree of substitution (DS) was 18.6%, the minimum critical micelle concentration (CMC) value was 0.0137 mg/mL. For DOX-loaded HAVD micelles (DOX/HAVD), the drug loading (DL) was 6.2% and drug encapsulation efficiency (EE) was 79.5%. The DOX/HAVD micelles remain stable in serum for 48 h. The in vitro release rate of DOX decreased after encapsulating compared with that without HAVD encapsulation. The decrease with IC50 of DOX/HAVD micelle was significantly stronger than that of free DOX (p < 0.05) and blank micelles (p < 0.01). At 50% cell inhibition rate, VD3 and DOX acted synergistically on BC cells. Hence, the HAVD micelles can significantly improve the therapeutic effect of DOX against BC cells. In a word, the DOX/HAVD micelles have great potential in treating breast cancer.

Long-term effects of hematopoietic growth factors in aplastic anemia patients treated with immunosuppression: Meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: Immunosuppressive therapy is the frontline treatment for aplastic anemia patients ineligible for transplantation. The long-term effects of hematopoietic growth factors (HGF) added to standard immunosuppressive therapy are still unclear. We performed a systematic review and meta-analysis to clarify this issue. METHODS: A comprehensive search of databases was conducted including 5 international electronic databases (Cochrane, PubMed, Embase, Web of Science, and LILACS) and 4 Chinese electronic databases (Chinese Bio-medicine Database, Chinese National Knowledge Infrastructure, WanFang Data, and China Science and Technology Journal Database databases) from database inception until February, 2022. We included randomized controlled trials that assigned patients with acquired aplastic anemia treated with immunosuppressive therapy (IST), which compared between the addition of HGF and placebo or no treatment. The co-primary outcome were the overall survival (OS) and late clonal malignant evolution at the end of follow-up. RESULTS: Nine randomized controlled trials including 719 participants were identified. The addition of growth factors to immunosuppression yielded no difference in OS (relative risks [RR], 1.08, 95% confidence interval [CI] 0.99-1.18). HGF was not associated with higher occurrence of secondary myelodysplastic syndromes/acute myeloid leukemia (RR, 1.09, 95% CI 0.43-2.78) or paroxysmal nocturnal hemoglobulinemia (RR, 1.38, 95% CI 0.68-2.81) at the end of follow-up. No difference were found in overall response (RR, 1.16, 95% CI 0.98-1.37), infections occurrence (RR, 0.82; 95% CI, 0.51-1.31) or relapse (RR, 0.65; 95% CI, 0.37-1.13). CONCLUSIONS: HGF as an adjunct to IST has no impact on long-term OS, late clonal malignant evolution, response rate, relapse or infections occurrence. HGF could be added to standard IST for high-risk patients with delayed neutrophil recovery without concern for long-term consequences but could not be recommended as routine clinical practice. TRIAL REGISTRATION NUMBER: PROSPERO CRD42021275188.

Novel pH-sensitive nanoparticles based on prodrug strategy to delivery All-Trans Retinoic Acid for breast cancer.

Developing chemotherapy with nanoparticle-based prodrugs provides promising strategies for improving the safety and delivery of anti-cancer drugs therapeutics and effective cancer treatment. Herein, we developed a pH-sensitive prodrug delivery system (All-Trans-Retinoic Acid (ATRA) grafted poly (ß-amino esters) (PBAE) copolymers, ATRA-g-PBAE) for delivery of ATRA with some physicochemical and biological properties. The in vitro release of ATRA-g-PBAE prodrug nanoparticles (PNPs) was sustained-release and pH-sensitive. The cytotoxicity and uptake of different preparations in vitro were evaluated on MCF-7 cells at pH 7.4 and 5.5. The carrier PBAE had no cytotoxicity, and ATRA-g-PBAE PNPs could significantly inhibit cell growth at pH 5.5. MCF-7 cells treated with Cy5.5 grafted PBAE (Cy5.5-PBAE) showed stronger fluorescence signals at pH 5.5. Meanwhile, ATRA-g-PBAE PNPs entered the cell via a clathrin-mediated endocytic pathway. Subsequently, PBAE protonation facilitated the escape of PNPs from the lysosome and released the drug. ATRA-g-PBAE seems promising as a novel pH-sensitive prodrug to overcome the limitations of ATRA for breast cancer therapy.

Prediction of carotid plaque by blood biochemical indices and related factors based on Fisher discriminant analysis.

OBJECTIVE: This study aims to establish the predictive model of carotid plaque formation and carotid plaque location by retrospectively analyzing the clinical data of subjects with carotid plaque formation and normal people, and to provide technical support for screening patients with carotid plaque. METHODS: There were 4300 subjects in the ultrasound department of Maanshan People's Hospital collected from December 2013 to December 2018. We used demographic and biochemical data from 3700 subjects to establish predictive models for carotid plaque and its location. The leave-one-out cross-validated classification, 600 external data validation, and area under the receiver operating characteristic curve (AUC) were used to verify the accuracy, sensitivity, specificity, and application value of the model. RESULTS: There were significant difference of age (F = - 34.049, p < 0.01), hypertension (χ2 = 191.067, p < 0.01), smoking (χ2 = 4.762, p < 0.05) and alcohol (χ2 = 8.306, p < 0.01), Body mass index (F = 15.322, p < 0.01), High-density lipoprotein (HDL) (F = 13.840, p < 0.01), Lipoprotein a (Lp a) (F = 52.074, p < 0.01), Blood Urea Nitrogen (F = 2.679, p < 0.01) among five groups. Prediction models were built: carotid plaque prediction model (Model CP); Prediction model of left carotid plaque only (Model CP Left); Prediction model of right carotid plaque only (Model CP Right). Prediction model of bilateral carotid plaque (Model CP Both). Model CP (Wilks' lambda = 0.597, p < 0.001, accuracy = 78.50%, sensitivity = 78.07%, specificity = 79.07%, AUC = 0.917). Model CP Left (Wilks' lambda = 0.605, p < 0.001, accuracy = 79.00%, sensitivity = 86.17%, specificity = 72.70%, AUC = 0.880). Model CP Right (Wilks' lambda = 0.555, p < 0.001, accuracy = 83.00%, sensitivity = 81.82%, specificity = 84.44%, AUC = 0.880). Model CP Both (Wilks' lambda = 0.651, p < 0.001, accuracy = 82.30%, sensitivity = 89.50%, specificity = 72.70%, AUC = 0.880). CONCLUSION: Demographic characteristics and blood biochemical indexes were used to establish the carotid plaque and its location discriminant models based on Fisher discriminant analysis (FDA), which has high application value in community screening.

Combined toxicity of food-borne mycotoxins and heavy metals or pesticides.

Food can be contaminated by multiple classes of toxic substances, mainly including mycotoxins, heavy metals and pesticides, which leads to a possibility of simultaneous exposure to two or more food contaminants for humans. Thus, it is necessary to examine whether the combined exposure could result in enhanced toxicity. Initially, the studies on the combined toxicity of food contaminants mainly focus on the mixtures of same classes of food contaminants due to their co-occurrence feature in foodstuffs, such as mixtures of mycotoxins or mixtures of heavy metals. Given the possibility that consumers are likely exposed to mixtures of different classes of food contaminants, recently, studies on the combined toxicity of different classes of food contaminants have been receiving increasing attentions. In this review article, we summarize the findings of combined toxicity studies related to co-exposure to food-borne mycotoxins and other classes of food contaminants mainly heavy metals or pesticides, and propose issues that need to be addressed in future studies for more accurately performing risk assessment of co-exposure to mycotoxins and other classes of food contaminants.

Phenotypic and genotypic characterization of two factor VII deficiency patients from southeastern China.

The congenital factor VII deficiency (FVIID) is a rare autosomal recessive haemorrhagic disease caused by mutations in the F7 gene. The aim of this study was to identify the mutations causing FVII deficiency and explain the genotype-phenotype association in two unrelated Chinese patients. Mutation detection was conducted by sequencing the whole F7 gene coding exons, exon-intron boundaries and the untranslated regions of 3' and 5'. Then, the genetic information was analyzed to predict the structures of the mutated proteins. A total of four different mutations were detected, including three missense mutations (c.64G>A, c.286A>G, and c.722C>A, predicting p.Gly22Ser, p.Arg96Gly, p.Thr241Asn, respectively) and one insertion mutation (c.204_205insCGGC, predicting p. Leu68Argfs ∗ 37), among which two were reported for the first time (p.Arg96Gly, p.Leu68Argfs ∗ 37). Multiple sequence alignments of FVII protein revealed that the residues p.Arg96 and p.Thr241 were highly conserved. The novel missense mutation p.Arg96Gly was determined as damaging with online software Polyphen-2 and SIFT. We investigated two asymptomatic patients diagnosed with severe FVII deficiency and identified two novel mutations (the mutation p.Arg96Gly and p.Leu68Argfs ∗ 37). Identification of the F7 mutations was important for genetic counseling and accurate prediction of the inheritance pattern.