The Clinical Significance and Expression Level of miR-411-5p in Colorectal Cancer.

Background: MicroRNAs (miRNAs) have been widely recognized as crucial regulators in the development and progression of various cancers, including colorectal cancer (CRC). Previous studies have highlighted the involvement of several miRNAs in CRC, such as miR-145, miR-29a-3p, and miR-196. However, the specific role and clinical significance of miR-411-5p in CRC have not been thoroughly investigated, representing a significant gap in the current understanding of CRC biology. While miR-411-5p has been implicated in the pathogenesis of other human malignancies, its precise mechanisms and impact on CRC development and prognosis remain largely unexplored. Understanding the functional relevance of miR-411-5p in CRC and elucidating its molecular interactions can provide valuable insights into the underlying mechanisms of CRC progression and potentially identify novel therapeutic targets. Therefore, this study aims to investigate the clinical value and level of miR-411-5p in colorectal cancer, shedding light on its potential as a diagnostic and prognostic biomarker. Additionally, we aim to explore the molecular mechanisms underlying the effects of miR-411-5p on CRC cells, particularly its interaction with the target gene NFE2L3. By filling this knowledge gap, our research contributes to a deeper understanding of the role of miR-411-5p in CRC and opens avenues for developing targeted therapies for this prevalent malignancy. Methods: Colorectal cancer (CRC) tissue samples and corresponding normal paracancerous tissue samples were collected from 60 CRC patients treated at the Affiliated Hospital of Hebei University. Normal paracancerous tissue refers to the healthy tissue adjacent to the cancerous region. These tissue samples were obtained through biopsies, and the patients provided informed consent for their use in the study. To investigate the expression levels of miR-411-5p and NFE2L3, we employed quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. This technique allowed us to measure the levels of miR-411-5p and NFE2L3 mRNA in both CRC and normal tissue samples. Additionally, we validated the protein levels of NFE2L3 using Western blot analysis. Furthermore, we assessed the functional impact of miR-411-5p on CRC cells through various assays. The MTT assay determined cell viability, the transwell migration assay evaluated cell migration and invasion abilities, and flow cytometry measured the rate of apoptosis in CRC cells. To confirm the molecular interaction between miR-411-5p and its target gene NFE2L3, we conducted dual-luciferase reporter assays. These assays enabled us to validate the binding between miR-411-5p and the 3' untranslated region (3'UTR) of the NFE2L3 mRNA. To investigate the potential therapeutic role of NFE2L3 in CRC, we transfected CRC cells with pcDNA3.0-NFE2L3, a plasmid overexpressing NFE2L3. This allowed us to assess the impact of NFE2L3 restoration on the behavior of CRC cells. Results: Overexpression of miR-411-5p in CRC cells significantly reduced cell viability, inhibited migration and invasion, and increased the rate of apoptosis. Conversely, inhibition of miR-411-5p expression exerted the opposite effects on the biological behavior of CRC cells. Furthermore, our study revealed that NFE2L3 is a downstream target of miR-411-5p. Dual-luciferase reporter assays confirmed the binding between miR-411-5p and the 3'UTR of NFE2L3 mRNA, indicating a direct interaction between them. To investigate the therapeutic potential of targeting NFE2L3 in CRC, we transfected CRC cells with pcDNA3.0-NFE2L3, resulting in the restoration of NFE2L3 levels. This restoration effectively reversed the effects induced by miR-411-5p mimics on the behavior of CRC cells. Conclusion: Our study provides compelling evidence for the tumor-suppressive role of miR-411-5p in CRC. The overexpression of miR-411-5p resulted in reduced cell viability, inhibited migration and invasion, and increased apoptosis in CRC cells. Importantly, we identified NFE2L3 as a downstream target of miR-411-5p and demonstrated its involvement in mediating the effects of miR-411-5p on CRC cell behavior. These findings not only confirm the tumor-suppressive role of miR-411-5p in CRC but also highlight NFE2L3 as a promising target for novel therapeutic strategies. Targeting NFE2L3 to modulate the biological function of CRC cells may hold therapeutic potential and serve as a basis for the development of targeted drugs. Further investigations are warranted to fully elucidate the underlying molecular mechanisms of miR-411-5p-NFE2L3 interaction and its impact on CRC progression. Additionally, future studies could explore the clinical implications of miR-411-5p as a diagnostic or prognostic biomarker in CRC patients. By advancing our understanding of the intricate regulatory networks involved in CRC, we can pave the way for personalized therapeutic approaches and improve patient outcomes.

Agreement of ejection fraction measured by coronary computed tomography (CT) and cardiac ultrasound in evaluating patients with chronic heart failure: an observational comparative study.

Background: Cardiac ultrasound is one of the most important examinations in cardiovascular medicine, but the technical requirements for the operator are relatively high, which to some extent affects the scope of its use. This study was dedicated to investigating the agreement of ejection fraction between coronary computed tomography (CT) and cardiac ultrasound and diagnostic performance in evaluating the clinical diagnosis of patients with chronic heart failure. Methods: We conducted a single-center-based retrospective study including 343 consecutive patients enrolled between January 2019 to April 2020, all of whom presented with suspected symptoms of heart failure within one month. All enrolled cases performed cardiac ultrasound and coronary CT scans. The CT images were analyzed using accurate left ventricle (AccuLV) artificial intelligence (AI) software to calculate the ejection fraction-computed tomography (EF-CT) and it was compared with the ejection fraction (EF) obtained based on ultrasound. Cardiac insufficiency was determined if the EF measured by ultrasound was below 50%. Diagnostic performance analysis, correlation analysis and Bland-Altman plot were used to compare agreement between EF-CT and CT. Results: Of the 319 successfully performed patients, 220 (69%) were identified as cardiac insufficiency. Quantitative consistency analysis showed a good correlation between EF-CT and EF values in all cases (R square =0.704, r=0.837). Bland-Altman analysis showed mean bias of 6.6%, mean percentage error of 27.5% and 95% limit of agreement of -17% to 30% between EF and EF-CT. The results of the qualitative diagnostic study showed that the sensitivity and specificity of EF measured by coronary CT reached a high level of 91% [95% confidence interval (CI): 86-94%], and the positive diagnostic value was up to 96% (95% CI: 92-98%). Conclusions: The EF-CT and EF have excellent agreement, and AccuLV-based AI left ventricular function analysis software perhaps can be used as a clinical diagnostic reference.

RUNX1::ETO and CBFß::MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core-binding factor-acute myeloid leukaemia.

Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFß::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFß::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.

Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.

Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.

[Retracted] MicroRNA­30a suppresses the proliferation, migration and invasion of human renal cell carcinoma cells by directly targeting ADAM9.

[This retracts the article DOI: 10.3892/ol.2018.8999.].

Hexaxial external fixator versus intramedullary nail in treating segmental tibial fractures: a retrospective study.

BACKGROUND: It's difficult to treat segmental tibial fractures (STFs), which are intricate injuries associated with significant soft tissue damage. The aim of this study was to compare the clinical effect of hexaxial external fixator (HEF) and intramedullary nail (IMN) in treatment of STFs. METHODS: A total of 42 patients with STFs were finally recruited between January 2018 and June 2022. There were 25 males and 17 females with age range of 20 to 60 years. All fractures were classified as type 42C2 using the Arbeitsgemeinschaftfür Osteosythese/Orthopaedic Trauma Association (AO/OTA) classification. 22 patients were treated with HEF and 20 patients were treated with IMN. The condition of vascular and neural injuries, time of full weight bearing, bone union time and infection rate were documented and analyzed between the two groups. The mechanical medial proximal tibial angle (mMPTA), mechanical posterior proximal tibial angle (mPPTA), mechanical lateral distal tibial angle (mLDTA), mechanical anterior distal tibial angle (mADTA), hospital for special surgery (HSS) knee joint score, American Orthopaedic Foot and Ankle Society (AOFAS) ankle joint score, range of motion (ROM) of flexion of keen joint and ROM of plantar flexion and dorsal flexion of ankle joint were compared between the two groups at the last clinical visit. RESULTS: There were no vascular and neural injuries or other severe complications in both groups. All 22 patients in HEF group underwent closed reduction but 3 patients in IMN group were treated by open reduction. The time of full weight bearing was (11.3 ± 3.2) days in HEF group and (67.8 ± 5.8) days in IMN group(P < 0.05), with bone union time for (6.9 ± 0.8) months and (7.7 ± 1.4) months, respectively(P < 0.05). There was no deep infection in both groups. In the HEF group and IMN group, mMPTA was (86.9 ± 1.5)° and (89.7 ± 1.8)°(P < 0.05), mPPTA was (80.8 ± 1.9)° and (78.6 ± 2.0)°(P < 0.05), mLDTA was (88.5 ± 1.7)° and (90.3 ± 1.7)°(P < 0.05), while mADTA was (80.8 ± 1.5)° and (78.4 ± 1.3)°(P < 0.05). No significant differences were found between the two groups at the last clinical visit concerning HSS knee joint score and AOFAS ankle joint score, ROM of flexion of keen joint and ROM of plantar flexion of ankle joint (P > 0.05). The ROM of dorsal flexion of ankle joint in IMN group was (30.4 ± 3.5)°, better than (21.6 ± 2.8)° in HEF group (P < 0.05). CONCLUSION: In terms of final clinical outcomes, the use of either HEF or IMN for STFs can achieve good therapeutic effects. While HEF is superior to IMN in terms of completely closed reduction, early full weight bearing, early bone union and alignment. Nevertheless, HEF has a greater impact on the ROM of dorsal flexion of the ankle joint, and much more care and adjustment are needed for the patients than IMN.

Perianal rhabdomyosarcoma in an adult: A case report and review of the literature.

Perianal/perineal rhabdomyosarcomas (PRMS) is rare, and the outcome is poor. A 29-year-old female presented with perineal rhabdomyosarcomas revealed metastases to inguinal lymph nodes on the bilateral side. Disease progression was discovered when the patient got adjuvant epirubicin, ifosfamide, and bevacizumab for 2 cycles. After 3 cycles of nivolumab, dacarbazine, cisplatin, and vinblastine therapy, a partial response was identified in the patient. The surgical resection was performed. The patient received neoadjuvant chemotherapy before surgery and was weak after surgery, so he did not receive chemoradiotherapy. The patient succumbed after 11 months postoperatively due to widespread intraabdominal metastasis.

Joint effect of RRP9 and DDX21 on development of colorectal cancer and keloid.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy in the gastrointestinal tract. Keloid refers to abnormal scar tissue that forms on the skin or mucous membrane. The relationship between RRP9 and DDX21 and the two diseases is unclear. METHODS: Download the colorectal cancer dataset GSE134834, GSE206800, GSE209892 and keloid dataset GSE44270 from the GEO database. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis (WGCNA) was performed. The construction and analysis of protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis (GSEA). Gene expression heat map was drawn. The comparative toxicogenomics database (CTD) analysis was performed to find diseases most related to core genes. TargetScan screened miRNAs that regulated central DEGs. We conducted experimental validation using Western blotting and Polymerase Chain Reaction (PCR). RESULTS: In the colorectal cancer dataset and the scar tissue dataset, we identified 1380 DEGs and 1000 DEGs, respectively. The enrichment pattern for scar tissue was similar to that of colorectal cancer. We identified two core genes, RRP9 and DDX21. CTD analysis indicated that RRP9 and DDX21 are associated with proliferation, scar tissue, colorectal tumors, scleroderma, and inflammation. We found that the core genes (RRP9 and DDX21) were highly expressed in colorectal cancer and scar tissue samples, while their expression was lower in normal samples. This was further validated through Western blotting (WB) and Polymerase Chain Reaction (PCR). CONCLUSIONS: The higher the expression of RRP9 and DDX21 in colorectal cancer and keloid, the worse the prognosis.

RRP9 and DDX21 as new biomarkers of colorectal cancer.

Colorectal cancer originates from the epithelium of the large intestine and is a common malignant tumor in the gastrointestinal tract. However, the relationship between RRP9 and DDX21 and colorectal cancer (CRC) remains unclear. GSE134834, GSE206800, and GSE209892 profiles for CRC were downloaded from the gene expression omnibus database generated using GPL20115 and GPL23126. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis was performed. The construction and analysis of protein-protein interaction network. Functional enrichment analysis and gene set enrichment analysis were performed. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to the core gene. TargetScan was used to screen miRNAs regulating central DEGs. One thousand three hundred eighty DEGs were identified. According to gene ontology analysis, they were mainly concentrated in signal receptor activity regulation and metal titanase activity. Kyoto encyclopedia of gene and genome analysis showed that they mainly focused on IL17 signal pathway, PPAR signal pathway, protein digestion, and absorption, and the interaction of viral proteins with cytokines and cytokine receptors. The intersection of enrichment items and GOKEGG enrichment items of differentially expressed genes is mainly concentrated in PPAR signal pathway and the interaction of viral proteins with cytokines and cytokine receptors. The protein-protein interaction network obtained 16 core genes (MAD2L1, MELK, TPX2, UBE2C, RFC4, PLK1, RACGAP1, DKC1, DDX21, L Y AR, WDR3, RRP9, WDR43, NOLC1, BRIX1, and GTPBP4). Heat map of gene expression showed that core genes (TPX2, UBE2C, RFC4, PLK1, DKC1, LYAR, WDR3, NOLC1, and BRIX1) were not significantly differentially expressed between CRC and normal tissue samples. Core genes (MAD2L1, MELK, RACGAP1, RRP9, WDR43, DDX21, and GTPBP4) were highly expressed in CRC tissue samples and lowly expressed in normal tissue samples. Comparative toxicogenomics database analysis showed that 7 genes (MAD2L1, MELK, RACGAP1, RRP9, WDR43, DDX21, and GTPBP4) were related to necrosis, inflammation, tumor, precancerous symptoms, hemorrhage, and weightlessness. RRP9 and DDX21 are highly expressed in CRC. The higher the expression level of RRP9 and DDX21, the worse the prognosis.

Association of stress hyperglycemia with clinical outcomes in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention: a cohort study.

BACKGROUND: In recent years, several studies have demonstrated that stress hyperglycemia is significantly associated with poor prognosis in patients diagnosed with acute coronary syndrome (ACS). In the present study, we aimed to investigate the potential associations between various markers of stress hyperglycemia, such as admission blood glucose (ABG), fasting blood sugar (FBS), and stress hyperglycemia ratio (SHR) with different definitions, and the occurrence of adverse cardiovascular events in patients diagnosed with ST-elevation myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI). METHODS: Our study enrolled a total of 1099 patients diagnosed with STEMI who underwent PCI from 2016 to 2021. The primary outcomes of this study were in-hospital death and all-cause mortality. RESULTS: Stress hyperglycemia was associated with a higher incidence of in-hospital death (ABG OR: 1.27 95% CI 1.19-1.36; FBS OR: 1.25 95% CI 1.16-1.35; SHR1 OR: 1.61 95% CI 1.21-2.14; SHR2 OR: 1.57, 95%CI 1.22-2.01; SHR3 OR: 1.59, 95%CI 1.24-2.05) and all-cause mortality (ABG HR: 1.10, 95% CI 1.07-1.14; FBS HR: 1.12, 95 CI 1.07-1.17; SHR1 HR: 1.19 95% CI 1.03-1.39; SHR2 HR: 1.28, 95%CI 1.14-1.44; SHR3 HR: 1.29, 95%CI 1.14-1.45) after adjusting for ischemic time, age, gender, BMI, hypertension, hyperlipidemia, diabetes mellitus (DM), current smoking history, chronic kidney disease (CKD), previous history of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, cancer, culprit vessel, multi-vessel disease. These associations exhibited a non-linear, J-shaped pattern, wherein the risk significantly increased when the ABG and FBS levels exceeded 5mmol/L. Moreover, the inflection point for SHR was estimated to be 1.2. CONCLUSIONS: Stress hyperglycemia was significantly associated with an increased risk of in-hospital death and all-cause mortality in STEMI patients treated with PCI. Stress hyperglycemia should be considered a high-risk prognostic marker in all STEMI patients, regardless of with or without diabetes.

Exosomal Circ_FMN2 Derived from the Serum of Colorectal Cancer Patients Promotes Cancer Progression by miR-338-3p/MSI1 Axis.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high incidence and mortality. Exosomal circular RNA (circRNA) has been shown to be associated with the malignant progression of cancers, including CRC. Circ_0005100 (named as circ_FMN2) has been shown to promote CRC cell proliferation and migration. However, whether exosomal circ_FMN2 participated in CRC progression remains unclear. METHODS: Exosomes were isolated from the serum of CRC patients and then identified using transmission electron microscope. Western blot assay was used to test the protein levels of exosome markers, proliferation-related marker, metastasis-related markers and musashi-1 (MSI1). The expression levels of circ_FMN2, microRNA (miR)-338-3p and MSI1 were detected by qPCR. Flow cytometry, colony formation assay, MTT assay, and transwell assay were employed to measure cell cycle, apoptosis, colony formation ability, viability, migration and invasion. Dual-luciferase reporter assay was performed to assess the interaction between miR-338-3p and circ_FMN2 or MSI1. BALB/c nude mice was used to conduct animal experiments. RESULTS: Circ_FMN2 was overexpressed in the exosomes of CRC patient's serums and CRC cells. Overexpressed exosomal circ_FMN2 could promote CRC cell proliferation, metastasis, and suppress apoptosis. Circ_FMN2 acted as miR-338-3p sponge. MiR-338-3p overexpression reversed the promotion effect of circ_FMN2 on CRC progression. MSI1 was found to be a target of miR-338-3p, and its overexpression revoked the inhibitory effect of miR-338-3p on CRC progression. Furthermore, exosomal circ_FMN2 overexpression also could facilitate CRC tumor growth in vivo. CONCLUSION: Exosomal circ_FMN2 accelerated CRC progression through miR-338-3p/MSI1 axis, revealing that exosomal circ_FMN2 might be a target for CRC treatment.

LncRNA IGFL2-AS1 as a ceRNA Promotes HCT116 Cell Malignant Proliferation via the miR-433-3p/PAK4 Axis.

BACKGROUND: Colorectal cancer is a common gastrointestinal malignancy worldwide. Many studies have proved that long noncoding RNA alterations participate in colorectal cancer development. This study sought to probe the regulatory mechanism of lncRNA IGF-like family member 2 antisense RNA 1 (IGFL2-AS1) in colorectal cancer cell malignant proliferation. METHODS: LncRNA IGFL2-AS1 expression in colorectal cancer cancer and para-cancerous tissues and colorectal cancer cell lines was detected via quantitative real-time polymerase chain reaction. HCT116 cells were transfected with si-IGFL2-AS1, microRNA (miR)- 433-3p inhibitor or p21 (RAC1)-activated kinase 4, PAK4 and IGFL2-AS1 overexpression vector, followed by assessment of cell proliferation and clone formation using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay and colony formation assay. The subcellular localization of lncRNA IGFL2-AS1 was predicted and testified via the nuclear/cytosol fractionation assay. The downstream miRNA of lncRNA IGFL2-AS1 and downstream target of miRNA were predicted, and their binding relationships were testified using dualluciferase assay and RNA immunoprediction experiment. RESULTS: LncRNA IGFL2-AS1 was abundantly expressed in colorectal cancer tissues and cells. Silencing lncRNA IGFL2-AS1 discouraged HCT116 cell malignant proliferation, while lncRNA IGFL2-AS1 overexpression played an opposite role. LncRNA IGFL2-AS1 was mainly expressed in the cytoplasm of HCT116 cells. LncRNA IGFL2-AS1 bound to miR-433-3p and inhibited its expression. miR-433-3p tar geted PAK4. Silencing lncRNA IGFL2-AS1 facilitated miR-433-3p to suppress PAK4 transcription. miR-433-3p inhibition or PAK4 overexpression partly reversed the inhibition of lncRNA IGFL2-AS1 on HCT116 cell malignant proliferation. CONCLUSION: LncRNA IGFL2-AS1 was abundantly expressed in colorectal cancer tissues and cells, and comparatively bound to miR433-3p to facilitate PAK4 transcription, thus promoting HCT116 cell malignant proliferation.

Recurrent noncoding somatic and germline WT1 variants converge to disrupt MYB binding in acute promyelocytic leukemia.

Genetic alternations can occur at noncoding regions, but how they contribute to cancer pathogenesis is poorly understood. Here, we established a mutational landscape of cis-regulatory regions (CREs) in acute promyelocytic leukemia (APL) based on whole-genome sequencing analysis of paired tumor and germline samples from 24 patients and epigenetic profiling of 16 patients. Mutations occurring in CREs occur preferentially in active enhancers bound by the complex of master transcription factors in APL. Among significantly enriched mutated CREs, we found a recurrently mutated region located within the third intron of WT1, an essential regulator of normal and malignant hematopoiesis. Focusing on noncoding mutations within this WT1 intron, an analysis on 169 APL patients revealed that somatic mutations were clustered into a focal hotspot region, including one site identified as a germline polymorphism contributing to APL risk. Significantly decreased WT1 expression was observed in APL patients bearing somatic and/or germline noncoding WT1 variants. Furthermore, biallelic WT1 inactivation was recurrently found in APL patients with noncoding WT1 variants, which resulted in the complete loss of WT1. The high incidence of biallelic inactivation suggested the tumor suppressor activity of WT1 in APL. Mechanistically, noncoding WT1 variants disrupted MYB binding on chromatin and suppressed the enhancer activity and WT1 expression through destroying the chromatin looping formation. Our study highlights the important role of noncoding variants in the leukemogenesis of APL.

Protein Phosphatase PPM1B Inhibits Gastric Cancer Progression and Serves as a Favorable Prognostic Biomarker.

BACKGROUND: Protein phosphatase PPM1B, also named as PP2Cß, is a member of serine/threonine phosphatase family. Dysregulated expression of PPM1B has been reported in several malignancies; nevertheless, its role in gastric cancer remains unknown. Here, we aimed to initially investigate the expression and function of PPM1B in gastric adenocarcinoma. METHODS: We firstly evaluated the protein expression of PPM1B in our enrolled retrospective cohort (n=161) via immunohistochemistry staining. Univariate and multivariate analyses were conducted to assess its prognostic value. Cellular experiments and xenografts in mice model were also performed to validate the role of PPM1B in gastric adenocarcinoma progression. RESULTS: The advanced tumor stage was characterized with a lower PPM1B level. Lower PPM1B was associated with poor prognosis in both The Cancer Genome Atlas (TCGA) dataset and our cohort (P<0.05). Furthermore, Cox regression analysis demonstrated that PPM1B was a novel independent prognostic factor for gastric adenocarcinoma patients (hazard ratio=0.35, P=0.001). Finally, cellular and xenografts data confirmed that overexpressing PPM1B can remarkably attenuated gastric adenocarcinoma growth. CONCLUSION: Low expression of PPM1B may be a potential molecular marker for poor prognosis in gastric adenocarcinoma.

The TIM-3 Rs10053538 Polymorphism Is Associated with Clinical Prognosis of Colorectal Cancer.

BACKGROUND: Genetic variants in the T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) gene have been reported to be associated with the risk of cancers and patients' outcomes. The aims of this study were to explore the role of TIM-3 polymorphisms in the risk of colorectal cancer (CRC) and the prognosis of CRC patients in a northern Chinese population. METHODS: Two polymorphisms of TIM-3 were genotyped using polymerase chain reaction and ligase detection reaction in 364 CRC patients and 372 healthy control subjects. The levels of TIM-3 mRNA were investigated in 65 CRC tissues by quantitative real-time PCR. RESULTS: The results showed that neither rs10053538 nor rs10515746 was associated with susceptibility to CRC. However, the CA+AA genotypes of rs10053538 were related to an advanced clinical stage and increased risk of lymph nodemetastasis (P = .046 and 0.024, respectively). Multivariate analyses performed after adjusting for clinical variables showed that patients with the CA+AA genotypes of rs10053538 exhibited a significantly shorter disease-free survival (DFS) and overall survival (OS) time compared with those carrying the CC genotype (HR = 1.91, 95% CI = 1.04-3.51; HR = 2.61, 95% CI = 1.35-5.03). In addition, the expression of TIM-3 mRNA was significantly increased in the CRC tissues of patients carrying the rs10053538 CA+AA genotypes compared with patients carrying the CC genotype (P = .019). CONCLUSION: The rs10053538 may serve as an independent molecular marker for predicting the clinical outcome of CRC patients in the study population.

Iron-based magnetic superconductorsAEuFe4As4(A=Rb, Cs): natural superconductor-ferromagnet hybrids.

Superconductivity (SC) and ferromagnetism (FM) are normally antagonistic, and their coexistence in a single crystalline material appears to be very rare. Over a decade ago, the iron-based pnictides of doped EuFe2As2were found to render such a coexistence, primarily because of the Fe-3dmulti-orbitals which simultaneously satisfy the superconducting pairing and the ferromagnetic exchange interaction among Eu local spins. In 2016, the discovery of the iron-based superconductorsAEuFe4As4(A= Rb, Cs) provided an additional and complementary material basis for the study of the coexistence and the interplay between SC and FM. The two sibling compounds, which can be viewed as an intergrowth or a hybrid betweenAFe2As2and EuFe2As2, show SC in the FeAs bilayers atTc= 35-37 K and magnetic ordering atTm∼ 15 K in the sandwiched Eu2+-ion sheets. BelowTm, the Eu2+spins align ferromagnetically within each Eu plane, making the system as a natural atomic-thick superconductor-ferromagnet superlattice. This paper reviews the main research progress in the emerging topic during the past five years. An outlook for the future research opportunities is also presented.

circ-SIRT1 Promotes Colorectal Cancer Proliferation and EMT by Recruiting and Binding to eIF4A3.

Circular RNA (circRNA), a recently identified type of endogenous noncoding RNA, has been implicated in the occurrence and development of a variety of tumors; however, whether circ-SIRT1, derived from pre-mRNA of the parental SIRT1 gene, is involved in colorectal cancer (CRC) remains unknown, as do the potential underlying mechanisms. The expression of circ-SIRT1 in CRC cells and tissue was detected by RT-qPCR. Colony formation and Cell Counting Kit-8 assays were used to evaluate the effect of circ-SIRT1 knockdown on the proliferative ability of CRC cells. Wound healing and Transwell assays were used to assess the effect of circ-SIRT1 knockdown on the migratory and invasive capacity of CRC cells. RNA immunoprecipitation and RNA pull-down assays were employed to validate the binding of circ-SIRT1 to EIF4A3. Western blot was used to identify the changes in the expression of EIF4A3 and EMT-related proteins. The RT-qPCR results showed that circ-SIRT1 was highly expressed in CRC cells and tissue and was positively correlated with the depth of tumor invasion. Knocking down circ-SIRT1 inhibited the proliferation and invasion of CRC cells and EMT. We further found that EIF4A3 could bind to circ-SIRT1, and that overexpressing circ-SIRT1 decreased the abundance of EIF4A3 at the mRNAs of the EMT marker proteins N-cadherin and vimentin. Combined, our findings suggested that circ-SIRT1 regulates the expression of EMT-related proteins by preventing EIF4A3 recruitment to the respective mRNAs. Our results further indicate that circ-SIRT1 functions as an oncogene in CRC by promoting the proliferation, invasion, and EMT of CRC cells through the circ-SIRT1/EIF4A3/N-cadherin/vimentin pathway.

Screening and Identification of Key Biomarkers of Gastric Cancer: Three Genes Jointly Predict Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common cancers all over the world, causing high mortality. Gastric cancer screening is one of the effective strategies used to reduce mortality. We expect that good biomarkers can be discovered to diagnose and treat gastric cancer as early as possible. METHODS: We download four gene expression profiling datasets of gastric cancer (GSE118916, GSE54129, GSE103236, GSE112369), which were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between gastric cancer and adjacent normal tissues were detected to explore biomarkers that may play an important role in gastric cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of overlap genes were conducted by the Metascape online database; the protein-protein interaction (PPI) network was constructed by the STRING online database, and we screened the hub genes of the PPI network using the Cytoscape software. The survival curve analysis was conducted by km-plotter and the stage plots of hub genes were created by the GEPIA online database. PCR, WB, and immunohistochemistry were used to verify the expression of hub genes. A neural network model was established to quantify the predictors of gastric cancer. RESULTS: The relative expression level of cadherin-3 (CDH3), lymphoid enhancer-binding factor 1 (LEF1), and matrix metallopeptidase 7 (MMP7) were significantly higher in gastric samples, compared with the normal groups (p<0.05). Receiver operator characteristic (ROC) curves were constructed to determine the effect of the three genes' expression on gastric cancer, and the AUC was used to determine the degree of confidence: CDH3 (AUC = 0.800, P<0.05, 95% CI =0.857-0.895), LEF1 (AUC=0.620, P<0.05, 95%CI=0.632-0.714), and MMP7 (AUC=0.914, P<0.05, 95%CI=0.714-0.947). The high-risk warning indicator of gastric cancer contained 8