Pan-Cancer Proteomics Analysis Reveals Wiskott-Aldrich Syndrome Protein as a Potential Regulator of Programmed Death-Ligand 1.

The programmed death-ligand 1 (PD-L1) is a key mediator of immunosuppression in the tumor microenvironment. The expression of PD-L1 in cancer cells is useful for the clinical determination of an immune checkpoint blockade (ICB). However, the regulatory mechanism of the PD-L1 abundance remains incompletely understood. Here, we integrated the proteomics of 52 patients with solid tumors and examined immune cell infiltration to reveal PD-L1-related regulatory modules. Wiskott-Aldrich syndrome protein (WASP) was identified as a potential regulator of PD-L1 transcription. In two independent cohorts containing 164 cancer patients, WASP expression was significantly associated with PD-L1. High WASP expression contributed to immunosuppressive cell composition, including cells positive for immune checkpoints (PD1, CTLA4, TIGIT, and TIM3), FoxP3+ Treg cells, and CD163+ tumor-associated macrophages. Overexpression of WASP increased, whereas knockdown of WASP decreased the protein level of PD-L1 in cancer cells without alteration of PD-L1 protein stability. The WASP-mediated cell migration and invasion were markedly attenuated by the silence of PD-L1. Collectively, our data suggest that WASP is a potential regulator of PD-L1 and the WASP/PD-L1 axis is responsible for cell migration and an immunosuppressive microenvironment.

Correlation between S100A7 and immune characteristics, methylation, tumor stemness and tumor heterogeneity in pan-cancer and its role in chemotherapy resistance in breast cancer.

OBJECTIVE: To explore the relationships between S100A7 and the immune characteristics, tumor heterogeneity, and tumor stemness pan-cancer as well as the effect of S100A7 on chemotherapy sensitivity in breast cancer. METHODS: TCGA-BRCA and TCGA-PANCANCER RNA-seq data and clinical follow-up survival data were collected from the University of California Santa Cruz database. Survival analyses were performed to explore the relationship between S100A7 expression and pan-cancer prognosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and Gene Set Enrichment Analysis (GSEA) were used to identify the potential pathways related to the differentially expressed genes in breast cancer. Spearman's and Wilcoxon's tests were used to investigate the relationships between S100A7 expression and immune characteristics, methylation, tumor heterogeneity, and tumor stemness. The potential functions of S100A7 and its influence on chemotherapy sensitivity in breast cancer were elucidated using reverse transcription-quantitative PCR, Cell Counting Kit-8 (CCK-8) assay, Transwell assay, and wound healing assay. RESULTS: S100A7 was highly expressed in most types of tumors and was associated with poor prognosis. S100A7 was closely associated with immunomodulators, immune checkpoint and immune cell infiltration. Further, S100A7 was related to tumor mutational burden, tumor heterogeneity, methylation and tumor stemness in breast cancer. High S100A7 expression was associated with the invasiveness, migration, proliferation and chemotherapy resistance of breast cancer cells in vitro experiments. CONCLUSION: High S100A7 expression was related with poor prognosis and chemotherapy resistance in breast cancer, making it a potential immune and chemotherapy resistance biomarker.

A prognostic model based on Scissor+ cancer associated fibroblasts identified from bulk and single cell RNA sequencing data in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most lethal diseases in the world, which often recur after multimodality treatment approaches, leading to a poor prognosis. Fibroblasts, a heterogeneous component of the tumor microenvironment, can modulate numerous aspects of tumor biology and have been increasingly acknowledged in dictating the clinical outcome of patients with HNSCC. However, the subpopulation of fibroblasts that are related to the prognosis of HNSCC has not yet been fully explored. To do so, we combined a single-cell RNA sequencing (scRNA-seq) dataset and bulk RNA-sequencing dataset with clinical information, identifying the fibroblast population that are related to poor prognosis of HNSCC. We found these specific population of fibroblasts are less differentiated. In addition, to identify the prognostic signatures of HNSCC, bioinformatics analysis included least absolute shrinkage and selection operator (LASSO) analyses and univariate cox and were performed. We selected 12 prognosis-related genes for constructing a risk model using The Cancer Genome Atlas (TCGA). The AUC values and calibration plots of this model indicated good prognostic prediction efficacy. This model also was validated in two Gene Expression Omnibus (GEO) datasets. In conclusion, we constructed an optimal model that was derived from single cell RNA-seq and bulk RNA-seq to predict the survival probability of HNSCC patients. Among this model, AKR1C3 higher expression in cancer associated fibroblasts (CAFs) of HNSCC has been confirmed by preliminary experiments.

Risk factors and predictive model for recurrence in papillary thyroid carcinoma: a single-center retrospective cohort study based on 955 cases.

Background: The 2015 American Thyroid Association guidelines proposed recurrence risk stratification of differentiated thyroid carcinoma, including papillary thyroid carcinoma (PTC), but this stratification excluded non-initial treatment patients with worse outcomes. This study aimed to explore the potential risk factors for recurrence in PTC and develop a predictive model for both initial and non-initial treatment of patients with PTC. Methods: A total of 955 patients were included in this study. Differences between the recurrence (-) and recurrence (+) groups were compared. The 955 patients were randomized into two groups: the training group (671 cases) and the validation group (284 cases). All variables were selected using the LASSO regression analysis. A nomogram was developed based on the results of the univariate and multivariate logistic regression analyses. The nomogram performance was evaluated using discrimination and calibration. Results: Patients aged ≥55 years, extranodal extension (ENE), metastatic LN ratio (LNR) >0.5, and non-initial treatment were identified as potential risk factors for recurrence through LASSO regression and univariate and multivariate analyses. The receiver operating characteristic curve (ROC curve) showed high efficiency, with an area under the ROC curve (AUC) of 0.819 (95% confidence interval [CI], 0.729-0.909) and 0.818 (95% CI, 0.670-0.909) in the training and validation groups, respectively. The calibration curve indicated that the nomogram had a good consistency. Conclusion: In patients with PTC, age ≥55 years, ENE, LNR >0.5, and non-initial treatment are potential risk factors for recurrence. The predictive model of recurrence was confirmed to be a practical and convenient tool for clinicians to accurately predict PTC recurrence.

METTL3-mediated ALDH m6 A methylation regulates the malignant behavior of BMI1+ HNSCC stem cells.

OBJECTIVES: To reveal the effect and mechanism of methyltransferase-like 3 (METTL3) on cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: First, we analyzed 14-HNSCC-patients' scRNA-seq dataset and TCGA dataset of HNSCC. Then, Mettl3 knockout or overexpression mice models were studied via tracing and staining technologies. In addition, we took flow cytometry sorting and sphere formation assays to observe tumorigenicity and used cell transfection and western blotting to verify target protein expression levels. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-quantitative real-time PCR (MeRIP-qPCR) were taken to identify the mechanism of Mettl3 regulating Bmi1+ CSCs in HNSCC. RESULTS: Due to SOX4 transcriptional regulation, METTL3 regulated the malignant behavior of BMI1+ HNSCC stem cells through cell division pathway. The progression and malignancy of HNSCC were decreased after Mettl3 knocked-out, while increased after Mettl3 knocked-in in Bmi1+ CSCs in vivo. Knockdown of Mettl3 inhibited stemness properties of CSCs in vitro. Mechanically, Mettl3 mediated the m6 A modification of ALDH1A3 and ALDH7A1 mRNA in Bmi1+ HNSCC CSCs. CONCLUSION: Regulated by SOX4, METTL3-mediated ALDH m6 A methylation regulates the malignant behavior of BMI1+ HNSCC CSCs through cell division pathway.

Pediatric acute heart failure caused by endocardial fibroelastosis mimicking dilated cardiomyopathy: A case report.

BACKGROUND: Endocardial fibroelastosis (EFE) is a diffuse endocardial collagen and elastin hyperplasia disease of unknown etiology, which may be accompanied by myocardial degenerative changes leading to acute or chronic heart failure. However, acute heart failure (AHF) without obvious associated triggers is rare. Prior to the report of endomyocardial biopsy, the diagnosis and treatment of EFE are highly susceptible to being confounded with other primary cardiomyopathies. Here, we report a case of pediatric AHF caused by EFE mimicking dilated cardiomyopathy (DCM), with the aim of providing a valuable reference for clinicians to early identify and diagnose EFE-induced AHF. CASE SUMMARY: A 13-mo-old female child was admitted to hospital with retching. Chest X-ray demonstrated enhanced texture in both lungs and an enlarged heart shadow. Color doppler echocardiography showed an enlarged left heart with ventricular wall hypokinesis and decreased left heart function. Abdominal color ultrasonography revealed a markedly enlarged liver. Pending the result of the endomyocardial biopsy report, the child was treated with a variety of resuscitative measures including nasal cannula for oxygen, intramuscular sedation with chlorpromazine and promethazine, cedilanid for cardiac contractility enhancement, and diuretic treatment with furosemide. Subsequently, the child's endomyocardial biopsy report result was confirmed as EFE. After the above early interventions, the child's condition gradually stabilized and improved. One week later, the child was discharged. During a 9-mo follow-up period, the child took intermittent low-dose oral digoxin with no signs of recurrence or exacerbation of the heart failure. CONCLUSION: Our report suggests that EFE-induced pediatric AHF may present in children over 1 year of age without any apparent precipitants, and that the associated clinical presentations are grossly similar to that of pediatric DCM. Nonetheless, it is still possible to be diagnosed effectively on the basis of the comprehensive analysis of auxiliary inspection findings before the result of the endomyocardial biopsy is reported.

Analysis of T1-T2 stage oropharyngeal squamous cell carcinoma treated with transoral robotic surgery.

Objective: Transoral robotic surgery (TORS) has become an effective treatment for early-stage oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to analyze the clinical safety and efficacy of TORS for human papilloma virus (HPV)-positive and HPV-negative OPSCC in China. Methods: Patients with OPSCC of pT1-T2 stage who underwent TORS from March 2017 to December 2021 were analyzed. Results: A total of 83 patients (HPV-positive, n = 25; HPV-negative, n = 58) were included. The median age of the patients was 57.0 years and 71 were men. The majority of primary tumor sites were palatine tonsils (52, 62.7%) and base of tongues (20, 24.1%). Three patients have a positive margin. A total of 12 (14.5%) patients received tracheotomies, the average duration of tracheostomy tube use was 9.4 days, and nasogastric tube was 14.5 days. No patient had a long-term tracheotomy. The 3-year overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) for all 83 patients were 89.5%, 80.1%, and 83.3%, respectively. The OS at 3 years between the HPV-positive group and HPV-negative group were 100% versus 84.3% (P = .07), while the DFS and RFS between two groups also showed no significant difference. Among multivariate cox regression analysis of all potential risk factors, smoking was the significant risk factors for disease recurrence (P < .05). Conclusion: Transoral robotic surgery achieved encouraging oncologic outcomes and safety in T1-T2 stage OPSCC treatment, regardless of HPV status. Level of Evidence: 4.

Immunogenic cell death-related gene landscape predicts the overall survival and immune infiltration status of ovarian cancer.

Background: Ovarian cancer (OC) is the most troubling malignant tumor of the female reproductive system. It has a low early diagnosis rate and a high tumor recurrence rate after treatment. Immunogenic cell death (ICD) is a unique form of regulated cell death that can activate the adaptive immune system through the release of DAMPs and cytokines in immunocompromised hosts and establish long-term immunologic memory. Therefore, this study aims to explore the prognostic value and underlying mechanisms of ICD-related genes in OC on the basis of characteristics. Methods: The gene expression profiles and related clinical information of OC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. ICD-related genes were collected from the Genecards database. ICD-related prognostic genes were obtained by intersecting ICD-related genes with the OC prognostic-related genes that were analyzed in the TCGA database. Functional enrichment, genetic mutation, and immune infiltration correlation analyses were further performed to identify underlying mechanisms. Subsequently, we developed a TCGA cohort-based prognostic risk model that included a nine-gene signature through univariate and multivariate Cox regression and LASSO regression analyses. Meanwhile, external validation was performed on two sets of GEO cohorts and the TCGA training cohort for three other common tumors in women. In addition, a nomogram was established by integrating clinicopathological features and ICD-related gene signature to predict survival probability. Finally, functional enrichment and immune infiltration analyses were performed on the two risk subgroups. Results: By utilizing nine genes (ERBB2, RB1, CCR7, CD38, IFNB1, ANXA2, CXCL9, SLC9A1, and SLAMF7), we constructed an ICD-related prognostic signature. Subsequently, patients were subdivided into high- and low-risk subgroups in accordance with the median value of the risk score. In multivariate Cox regression analyses, risk score was an independent prognostic factor (hazard ratio = 2.783; p < 0.01). In the TCGA training cohort and the two GEO validation cohorts, patients with high-risk scores had worse prognosis than those with low-risk scores (p < 0.05). The time-dependent receiver operating characteristic curve further validated the prognostic power of the gene signature. Finally, gene set enrichment analysis indicated that multiple oncological pathways were significantly enriched in the high-risk subgroup. By contrast, the low-risk subgroup was strongly related to the immune-related signaling pathways. Immune infiltration analysis further illustrated that most immune cells showed higher levels of infiltration in the low-risk subgroup than in the high-risk subgroup. Conclusion: We constructed a novel ICD-related gene model for forecasting the prognosis and immune infiltration status of patients with OC. In the future, new ICD-related genes may provide novel potential targets for the therapeutic intervention of OC.

Allogeneic hematopoietic stem cell transplantation overcome the poor prognosis of patients with IKZF1plus CD20-a very high-risk subtype in B-cell acute lymphoblastic leukemia.

Genetic deletions of IKZF1 (IKZF1del) and IKZF1del plus other mutations (IKZF1plus) have been identified in B-cell acute lymphoblastic leukemia (B-ALL) with a poor prognosis. Herein, we investigated the combination of IKZF1del and CD20 immunotypes in adult patients with B-ALL in the PDT-ALL-2016 cohort. This study cohort consisted of 161 patients with B-ALL with detailed information on IKZF1del and CD20 expression. The independent cohort included 196 patients from the TARGET dataset. IKZF1del was detected in 36.0% of patients with 3-year event-free survival (EFS) of 37.1 ± 6.7% and overall survival (OS) of 51.5 ± 7.3%, compared to IKZF1 wild-type (IKZF1wt) with an EFS 55.3 ± 5.1% (P = 0.011) and OS 74.4 ± 4.5% (P = 0.013), respectively. CD20-positive (CD20+) was associated with inferior EFS compared to the CD20-negative (CD20-) group (P = 0.020). Furthermore, IKZF1del coupled with CD20+, IKZF1del/CD20+, comprised 12.4% of patients with a 3-year EFS of 25.0 ± 9.7%, compared with IKZF1wt/CD20- (P ≤ 0.001) and IKZF1del/CD20- (P = 0.047) groups. Multivariable analyses demonstrated the independence of IKZF1del/CD20+, with the highest predicted hazard ratio for EFS and OS. Furthermore, the prognostic panel of IKZF1del/CD20+ was confirmed in the TARGET cohort. Notably, neither the IKZF1del, CD20+, or IKZF1del/CD20+ groups were identified to have poor outcomes in the cohort of allogeneic hematopoietic stem cell transplantation (n = 81).Collectively, our data define IKZF1del/CD20+ as a very high-risk subtype in B-ALL, and allo-HSCT could abrogate the poor outcome of both IKZF1del and IKZF1del/CD20+ subsets.

Retraction Notice to: Upregulation of OIP5-AS1 Predicts Poor Prognosis and Contributes to Thyroid Cancer Cell Proliferation and Migration.

[This retracts the article DOI: 10.1016/j.omtn.2019.11.036.].

Remediation of soils co-contaminated with cadmium and dichlorodiphenyltrichloroethanes by king grass associated with Piriformospora indica: Insights into the regulation of root excretion and reshaping of rhizosphere microbial community structure.

Cadmium (Cd) and dichlorodiphenyltrichloroethane (DDT) are frequently detected in agricultural soils, which poses a threat to public health. This study investigated the effects of inoculation of king grass with Piriformospora indica on the remediation of soils co-contaminated with Cd and DDTs. After treatment for 90 days, the dry shoot and root biomass of king grass inoculated with P. indica markedly increased by 13.0-15.8% and 24.1-46.4%, respectively, compared with those of uninoculated plants. Inoculation with P. indica also increased the uptake of Cd and DDTs by shoots and roots of king grass. The removal efficiency of Cd and DDTs from soils reached 4.88-17.4% and 48.4-51.0%, respectively, in the presence of king grass inoculated with P. indica. Under three Cd-DDTs contamination conditions, root secretion of organic acids, alcohol, and polyamines was distinctively stimulated by P. indica inoculation of king grass compared with planting king grass alone. After phytoremediation, changes in soil bacterial and fungal community composition occurred at different contamination levels. Overall, the results showed that king grass associated with P. indica can be adopted for phytoextraction of Cd and DDTs from moderately contaminated soils by regulating root excretion and reshaping rhizosphere microbial community structure.

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma.

Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1's role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer's genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.

FMNL1 Exhibits Pro-Metastatic Activity via CXCR2 in Clear Cell Renal Cell Carcinoma.

Formin-like (FMNL) proteins are responsible for cytoskeletal remodeling and have been implicated in the progression and spread of human cancers. Yet the clinical significance and biological function of FMNL1 in clear cell renal cell carcinoma (ccRCC) remain unclear. In this study, the expression of FMNL1 in ccRCC and its clinical value were determined by tissue microarray-based IHC and statistical analyses. The role of FMNL1 in ccRCC metastasis and the underlying mechanism were investigated via in vitro and in vivo models using gene regulation detection, ChIP, Luciferase reporter assays, and rescue experiments. We show that FMNL1 is upregulated in ccRCC and exhibits pro-metastatic activity via induction of CXCR2. High expression of FMNL1 is significantly correlated with advanced tumor stage, higher pathological tumor grade, tumor metastasis, and unfavorable prognosis in two independent cohorts containing over 800 patients with ccRCC. The upregulation of FMNL1 in ccRCC is mediated by the loss of GATA3. Ectopic expression of FMNL1 promotes, whereas FMNL1 depletion inhibits cell migration in vitro and tumor metastasis in vivo. The FMNL1-enhanced cell mobility is markedly attenuated by the knockdown of CXCR2. Further studies demonstrate that FMNL1 increases the expression of CXCR2 via HDAC1. In clinical samples, FMNL1 expression is positively associated with CXCR2, and is negatively connected to GATA3 expression. Collectively, our data suggest FMNL1 serve as a potential prognostic factor and function as an oncogene. The axis of GATA3/FMNL1/CXCR2 may present a promising therapeutic target for tumor metastasis in ccRCC.

METTL3 Promotes Tumorigenesis and Metastasis through BMI1 m6A Methylation in Oral Squamous Cell Carcinoma.

RNA modification plays an essential function in regulating gene expression and diverse biological processes. RNA modification enzyme methyltransferase-like 3 (METTL3) affects tumor progression by regulating the N6-methyladenosine (m6A) modification in the mRNAs of critical oncogenes or tumor suppressors, but its effect in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we revealed that METTL3 was consistently upregulated in two OSCC cohorts, and high METTL3 expression was associated with poor prognosis. Functionally, cell proliferation, self-renewal, migration, and invasion ability in vitro and tumor growth and metastasis in vivo were decreased after METTL3 knockdown in OSCC cells. In contrast, the opposite results were obtained after METTL3 overexpression. In addition, the results obtained with the Mettl3 genetically modified mouse model validated the essential role of Mettl3 in chemical-induced oral carcinogenesis. In mechanism, methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-quantitative real-time PCR, and luciferase reporter and mutagenesis assays identified that METTL3 mediates the m6A modification in the 3' UTR of BMI1 mRNA. METTL3 promotes BMI1 translation in OSCC under the cooperation with m6A reader IGF2BP1. Our findings revealed that METTL3 promotes OSCC proliferation and metastasis through BMI1 m6A methylation, suggesting that the METTL3-m6A-BMI1 axis may serve as a prognostic biomarker or therapeutic target in patients with OSCC.

Amycolatopsis anabasis sp. nov., a novel endophytic actinobacterium isolated from roots of Anabasis elatior.

A novel endophytic actinobacterium, designated strain EGI 650086T, was isolated from the roots of Anabasis elatior (C.A.Mey.) Schischk. collected in Xinjiang, north-west China. The taxonomic position of the strain was investigated using a polyphasic taxonomic approach. Growth occurred at 15-40 °C, pH 6.0-8.0 and in the presence of 0-6 % NaCl (w/v). Phylogenetic analysis based on 16S rRNA gene sequence and concatenation of 22 protein marker genes revealed that strain EGI 650086T formed a monophyletic clade within the genus Amycolatopsis and shared the highest sequence similarities with Amycolatopsis nigrescens JCM 14717T (97.1 %) and Amycolatopsis sacchari DSM 44468T (97.0 %). Sequence similarities with type strains of other species of the genus Amycolatopsis were less than 97.0 %. The average nucleotide identity and DNA-DNA hybridization values between strain EGI 650086T and the reference strains were 78.1-79.8 % and 22.1-23.0 %, respectively. The genome of strain EGI 650086T was 10.9 Mb, with a DNA G+C content of 70.1 mol%. The diagnostic diamino acid in the peptidoglycan was meso-diaminopimelic acid. The major whole-cell sugars contained arabinose, galactose, glucose and ribose. The predominant menaquinones were MK-9 (H4) and MK-9 (H2). Major fatty acids were iso-C16 : 0 and summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B). The polar lipid profile of strain EGI 650086T included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, hydroxy-phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannosides, two unknown phospholipids, an unknown glycolipid and an unknown lipid. Polyphasic taxonomic characteristics indicated that strain EGI 650086T represents a novel species of the genus Amycolatopsis, for which the name Amycolatopsis anabasis sp. nov. is proposed. The type strain is EGI 650086T (=KCTC 49044T=CGMCC 4.7188T).

Upregulation of OIP5-AS1 Predicts Poor Prognosis and Contributes to Thyroid Cancer Cell Proliferation and Migration.

As a common malignancy, thyroid cancer mainly occurs in the endocrine system. There have been accumulating studies on therapeutic methods of thyroid cancer, but its internal molecular mechanism is still not fully understood. Long noncoding RNA (lncRNA) OIP5-AS1 was confirmed as an oncogene and related to poor prognosis in various cancers. Nevertheless, its role and underlying mechanism remain unclear in thyroid cancer. Here, we observed a significant upregulation of OIP5-AS1 in thyroid cancer tissues and cells, and upregulated OIP5-AS1 was correlated with poor prognosis in thyroid cancer. Moreover, OIP5-AS1 knockdown resulted in the inhibited cell proliferation and migration, while overexpressed OIP5-AS1 exhibited the reverse function in thyroid cancer. Besides, OIP5-AS1 was found to positively regulate Wnt/ß-catenin signaling pathway. Through mechanism exploration, OIP5-AS1 was discovered to activate Wnt/ß-catenin signaling pathway via FXR1/YY1/CTNNB1 axis. Finally, rescue assays indicated that the inhibitive role of silenced OIP5-AS1 in thyroid cancer cell growth and Wnt/ß-catenin signaling pathway could be rescued by overexpression of CTNNB1 or addition of lithium chloride (LiCl). In conclusion, upregulation of OIP5-AS1 predicted unfavorable prognosis and enhanced thyroid cancer cell growth by activating Wnt/ß-catenin signaling pathway.

Early T-Cell Precursor Leukemia Has a Higher Risk of Induction-Related Infection among T-Cell Acute Lymphoblastic Leukemia in Adult.

BACKGROUND: Infections are an important cause of morbidity and mortality for acute lymphoblastic leukemia (ALL). However, the reports regarding risk factors of induction-related infection are roughly unknown/limited in adult T-ALL during induction chemotherapy. METHODS: We performed a retrospective cohort study for the prevalence and risk predictors of induction-related infection among consecutive T-ALL patients (N = 97) enrolled in a PDT-ALL-LBL clinical trial. Of 97 patients with T-ALL enrolled in the trial, 46 were early T-cell precursor (ETP) ALL and 51 were non-ETP ALL. RESULTS: When compared with non-ETP, ETP ALL subtype was characterized with lower neutrophil count (1.35 × 109/L vs. 8.7 × 109/L, P < 0.001) and lower myeloid percentage in the bone marrow (13.35% vs. 35.31%, P = 0.007). Additionally, ETP ALL had longer neutropenia before diagnosis (P < 0.001), as well as during induction chemotherapy (P < 0.001). Notably, the ETP cohort experienced higher cumulative incidence of clinically documented infections (CDI; 33.33%, P = 0.001), microbiologically documented infections (MDI; 45.24%, P = 0.006), resistant infection (11.9%, P = 0.013), and mixed infection (21.43%, P = 0.003), respectively, than those of the non-ETP cohort. Furthermore, multivariable analysis revealed that T-ALL mixed infection was more likely related to chemotherapy response (OR, 0.025; 95% CI 0.127-0.64; P = 0.012) and identified myeloid percentage as a predictor associated with ETP-ALL mixed infection (OR, 0.915; 95% CI 0.843-0.993; P = 0.033), with ROC-defined cut-off value of 2.24% in ETP cohorts. CONCLUSIONS: Our data for the first time demonstrated that ETP-ALL characterized with impaired myelopoiesis were more susceptible to induction-related infection among T-ALL populations.

Knockdown of DDX46 inhibits trophoblast cell proliferation and migration through the PI3K/Akt/mTOR signaling pathway in preeclampsia.

Preeclampsia (PE) is a serious disease during pregnancy associated with the dysfunction of trophoblast cell invasion. DDX46 is a kind of RNA helicase that has been found to regulate cancer cell metastasis. However, the role of DDX46 in PE remains unclear. Our results showed that the mRNA levels of DDX46 in placental tissues of pregnant women with PE were markedly lower than those in normal pregnancies. Loss-of-function assays showed that knockdown of DDX46 significantly suppressed cell proliferation of trophoblast cells. Besides, DDX46 knockdown decreased trophoblast cell migration and invasion capacity. In contrast, the overexpression of DDX46 promoted the migration and invasion of trophoblast cells. Furthermore, knockdown of DDX46 caused significant decrease in the levels of p-PI3K, p-Akt, and p-mTOR in HTR-8/SVneo cells. In addition, treatment with IGF-1 reversed the inhibitory effects of DDX46 knockdown on proliferation, migration, and invasion of HTR-8/SVneo cells. In conclusion, these data suggest that DDX46 might be involved in the progression of PE, which might be attributed to the regulation of PI3K/Akt/mTOR signaling pathway. Thus, DDX46 might serve as a therapeutic target for the treatment of PE.

An E2F1/DDX11/EZH2 Positive Feedback Loop Promotes Cell Proliferation in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for one of the leading causes of cancer-related death, and is attributed to the dysregulation of genes involved in genome stability. DDX11, a DNA helicase, has been implicated in rare genetic disease and human cancers. Yet, its clinical value, biological function, and the underlying mechanism in HCC progression are not fully understood. Here, we show that DDX11 is upregulated in HCC and exhibits oncogenic activity via EZH2/p21 signaling. High expression of DDX11 is significantly correlated with poor outcomes of HCC patients in two independent cohorts. DDX11 overexpression increases HCC cell viabilities and colony formation, whereas DDX11 knockdown arrests cells at G1 phase without alteration of p53 expression. Ectopic expression of DDX11 reduces, while depletion of DDX11 induces the expression of p21. Treatment of p21 siRNA markedly attenuates the cell growth suppression caused by DDX11 silence. Further studies reveal that DDX11 interacts with EZH2 in HCC cells to protect it from ubiquitination-mediated protein degradation, consequently resulting in the downregulation of p21. In addition, E2F1 is identified as one of the upstream regulators of DDX11, and forms a positive feedback loop with EZH2 to upregulate DDX11 and facilitate cell proliferation. Collectively, our data suggest DDX11 as a promising prognostic factor and an oncogene in HCC via a E2F1/DDX11/EZH2 positive feedback loop.

PRMT6 promotes endometrial cancer via AKT/mTOR signaling and indicates poor prognosis.

Arginine methylation plays essential roles in post-transcriptional modification and signal transduction. Dysregulation of protein arginine methyltransferases (PRMTs) has been reported in human cancers, yet the expression and biological function of PRMT6 in endometrial cancer (EMC) remains unclear. Here, we show that PRMT6 is upregulated in EMC and exhibits oncogenic activities via activation of AKT/mTOR pathway. The expression of PRMT6 in EMC is much higher than that in the adjacent nontumorous tissues. Elevated PRMT6 expression is significantly associated with higher histological tumor grade and unfavorable prognosis in two independent cohorts consisting of a total of 564 patients with EMC. In vitro data demonstrate that PRMT6 expression was identified as a downstream target of miR-372-3p. Ectopic expression of miR-372-3p downregulates PRMT6. Overexpression of PRMT6 promotes EMC cell proliferation and migration, whereas knockdown of PRMT6 leads to opposite phenotypes. Mechanistically, PRMT6 induces the phosphorylation of AKT and mTOR in EMC cells. Inhibition of AKT/mTOR signaling by MK2206 or rapamycin attenuates the PRMT6-mediated EMC progression. In clinical samples, high expression of PRMT6 was correlated to low expression of miR-372-3p and high expression of phosphorylated AKT. Collectively, our findings suggest PRMT6 may function as an oncogene to promote tumor progression, and be of prognostic value to predict disease-free survival of patients with EMC. The newly identified miR-372-3p/PRMT6/AKT/mTOR axis represents a new promising target for EMC management.