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Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2–NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.

NPRL2 (nitrogen permease regulator like 2) is a component of the GATOR1(GAP activity towards rags complex 1) proteins, which is an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. GATOR1 complex variations were reported to correlate with familial focal epilepsy with variable foci (FFEVF). However, FFEVF caused by NPRL2 variants has not been widely explored. Here, we describe a variant, 339+2T>C, in NPRL2 identified by trio whole-exome sequencing (WES) in a family. This splicing variant that occurred at the 5′ end of exon 3 was confirmed by minigene assays, which affected alternative splicing and led to exon 3 skipping in NPRL2. Our cases presented multiple seizure types (febrile seizures, infantile spasms, focal seizures, or focal to generalized tonic-clonic seizures). Electroencephalogram (EEG) showed frequent discharges in the left frontal and central regions. A favorable prognosis was achieved in response to vitamin B6 and topiramate when the patient was seven months old. Our study expands the phenotype and genotype spectrum of FFEVF and provides solid diagnostic evidence for FFEVF.

Cytidine base editors are powerful genetic tools that catalyse cytidine to thymidine conversion at specific genomic loci, and further improvement of the editing range and efficiency is critical for their broader applications. Through insertion of a non-sequence-specific single-stranded DNA-binding domain from Rad51 protein between Cas9 nickase and the deaminases, serial hyper cytidine base editors were generated with substantially increased activity and an expanded editing window towards the protospacer adjacent motif in both cell lines and mouse embryos. Additionally, hyeA3A-BE4max selectively catalysed cytidine conversion in TC motifs with a broader editing range and much higher activity (up to 257-fold) compared with eA3A-BE4max. Moreover, hyeA3A-BE4max specifically generated a C-to-T conversion without inducing bystander mutations in the haemoglobin gamma gene promoter to mimic a naturally occurring genetic variant for amelioration of β-haemoglobinopathy, suggesting the therapeutic potential of the improved base editors.

TP53 mutations was reported to be correlated to the efficacy of program death-1 (PD-1) and program death ligand-1 (PD-L1). The role of co-mutations of TP53 with other recurrently mutated genes in outcome of anti-PD-(L)1 treatment for non-small cell lung cancer (NSCLC) is unknown. Here we mined a previously generated dataset to address the effect of co-mutations on the progression free survival (PFS) of NSCLC patients. Non-synonymous mutations and clinical data of 240 NSCLC patients with anti-PD-(L)1 based therapy was downloaded from cBioPortal. Totally 206 patients received monotherapy and 34 patients received combination therapy. In 240 NSCLC patients, TP53 mutation rate was 59.2%. For the monotherapy cohort, TP53 mutated NSCLC patients have a significantly longer PFS (4.3 VS 2.5 months, P = 0.0019) compared with TP53 wild type NSCLC patients. The same tendency was also observed in the combination therapy cohort, but the difference in PFS (6.3 VS 5.4 months, P = 0.12) was not significant. Ever-smoker had a longer PFS compared to never-smokers (4.0 vs 2.7 months). For further co-mutation analysis with TP53 including KEAP1 mutation (53/240, 22.1%), KMT3C mutation (26/240, 10.8%), STK11 mutation (56/240, 23.3%), EGFR mutation (28/240, 11.7%) and KRAS mutation (86/240, 35.8%). Patients with both TP53 plus KEAP1 mutations in all 240 patients had a longer PFS compared with co-wild population (PFS 9.2 vs 4.2 months, P = 0.012) when treated with PD-1/PD-L1 inhibitors. TP53 might be the dominating mutation correlating with longer PFS in PD-1/PD-L1 monotherapy. Different genes displayed distinct effect when co-mutated with TP53 in NSCLC patients.

Thoracic aortic aneurysm and dissection (TAAD) is a high-risk aortic disease. Mouse models are usually used to explore the pathological progression of TAAD. In our studies, we performed bioinformatics analysis on a microarray dataset (GSE36778) and verified experiments to define the integrated hub genes of TAAD in three different mouse models. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein–protein interaction (PPI) network analyses, and histological and quantitative reverse transcription-PCR (qRT–PCR) experiments were used in our study. First, differentially expressed genes (DEGs) were identified, and twelve common differentially expressed genes were found. Second, genes related to the cell cycle and inflammation were enriched by using GO and PPI. We focused on filtering and validating eighteen hub genes that were upregulated. Then, expression data from human ascending aortic tissues in the GSE153434 dataset were also used to verify our findings. These results indicated that cell cycle-related genes participate in the pathological mechanism of TAAD and provide new insight into the molecular mechanisms of TAAD.

Background The classification and treatment strategy of atypical central neurocytomas (CNs) are still controversial largely, this study aimed to explore the optical treatment strategy and characteristics in transcriptomic profile. Methods This study retrospectively analyzed data from Sixty-one patients with CNs who underwent surgery in single institution. Whole-transcriptome analysis was used to investigate the differences between typical and atypical CNs. Results The five-year OS (P= 0.015) and PFS rates (P= 0.000002) were significantly higher in the complete resection group than in the incomplete resection group. Postoperative radiotherapy did not affect OS (P=0.255) or PFS (P=0.398) in the complete resection group. The five-year PFS rate (P=0.000038) among patients in the complete resection group who did not receive radiotherapy was significantly longer than that among patients in the incomplete resection group who received radiotherapy. The extent of surgical resection and operative approaches were irrelevant to perioperative complications and dsyfunctions at the last follow-up. Compared with caudate control, some of differentially expressed genes may involve cancer. Finally, the overexpression of ten genes (AMOTL1, PIK3R3, TGFBR1, SMO, COL4A6, MGP, SOX4, IGF2, Slit1 and CKS2) in atypical CNs may be associated with malignancy in atypical CNs. Conclusion Complete resection is relatively the best therapeutic modality for atypical CNs, radiotherapy is not necessary for patients after complete resection of the tumor. Although the previous definition of atypical CNs may not have significant prognostic value, the overexpression of ten genes may be involved in malignant behaviors and potential candidate hallmarks for differentiating the atypical CNs. Although the number of cases was relatively small, the findings could be helpful and instructive in the clinical treatment of this disease.

Cholesterol contributes to the structural basis of biological membranes and functions as a signaling molecule, whose dysregulation has been associated with various human diseases. Here, we report that the long non-coding RNA (lncRNA) SNHG6 increases progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) by modulating cholesterol-induced mTORC1 activation. Mechanistically, cholesterol binds ER-anchored FAF2 protein to promote the formation of a SNHG6-FAF2-mTOR complex. As a putative cholesterol effector, SNHG6 enhances cholesterol-dependent mTORC1 lysosomal recruitment and activation via enhancing FAF2-mTOR interaction at ER-lysosome contacts, thereby coordinating mTORC1 kinase cascade activation with cellular cholesterol biosynthesis in a self-amplified cycle to accelerate cholesterol-driven NAFLD-HCC development. Notably, loss of SNHG6 inhibits mTORC1 signaling and impairs growth of patient-derived xenograft liver cancer tumors, identifyifng SNHG6 as a potential target for liver cancer treatment. Together, our findings illustrate the crucial role of organelle-associated lncRNA in organelle communication, nutrient sensing, and kinase cascades.

Background: Multiple myeloma (MM) is one of the most common incurable malignancies in malignant plasma cell disease. EPB41L4A is a target gene for the Wnt/β-catenin pathway, which is closely related to the survival of multiple myeloma cells. However, there is currently no research report on the prognostic significance of the EPB41L4A gene in MM. Methods: We studied the biological significance and prognostic significance of EPB41L4A expression in MM by integrating 1956 MM samples from 7 datasets, and explored the relationship between EPB41L4A expression and MM ISS stage, molecular type, therapeutic response and survival. Results: We found that the expression level of EPB41L4A is inversely proportional to the copy number of 1q21 (P = 3.4e-13). EPB41L4A was low expressed in MAF, MMSET and proliferating molecular typing patients (P

Aims:Chest pain is a common complaint at pediatric cardiology clinics and often leads to an extensive cardiac evaluation. In this study, we analyzed the causes of chest pain in Chinese children and developed diagnostic procedures and criteria for targeted myocardial enzyme testing.Methods and Results:We retrospectively analyzed the clinical data of patients aged below 18 years visiting our hospital for chest pain between 2005 and 2019. Based on auxiliary exams and clinical diagnosis, we developed diagnostic procedures and criteria for targeted myocardial enzyme testing in children with chest pain. A total of 7,251 children were included in this study. The chest pain was of cardiac origin in 581 patients (8.0%). The incidence of non-cardiac chest pain was significantly higher in the preschool group and the school-age group than in the adolescent group (93.5 vs. 93.8 vs. 90.3%,P< 0.05). Among children with cardiac chest pain, the most common concomitant symptom was chest tightness (67.0%). Myocardial enzyme testing was performed in 5,408 patients and was abnormal in 453 patients. We developed a diagnostic procedure and criteria for targeted myocardial enzyme testing using pertinent history, physical examination, and ECG findings or UCG finding. Applying the diagnostic procedure and criteria could lead to the reduction in myocardial enzyme testing while still capturing all cardiac diagnoses.Conclusion:In children, chest pain is mostly benign and rarely cardiac. During diagnosis, targeted myocardial enzyme testing based on medical history and physical examination can effectively reduce resource use.

Background Chest pain is a common complaint at pediatric cardiology clinics and often leads to an extensive cardiac evaluation. In this study, we analyzed the causes of chest pain in Chinese children and developed criteria for targeted myocardial enzyme testing.Methods We retrospectively analyzed the clinical data of patients aged below 18 years visiting our hospital for chest pain between 2005 and 2019. Based on auxiliary exams and clinical diagnosis, we analyzed the positive rate of myocardial enzyme testing in identifying the causes of chest pain in children.Results A total of 7251 children were included in this study. The chest pain was of cardiac origin in 581 patients (8.0%). The incidence of noncardiac chest pain was significantly higher in the preschool group and the school-age group than in the adolescent group (93.5% vs 93.8% vs 90.3%, P < 0.05). Among children with cardiac chest pain, the most common concomitant symptom was chest tightness (67.0%). Myocardial enzyme testing was performed in 5408 patients and was abnormal in 453 (8.4%) patients.Conclusions In children, chest pain is mostly benign and rarely cardiac. During diagnosis, targeted myocardial enzyme testing based on medical history and physical examination can effectively reduce resource use.

Low-grade gliomas (LGGs) are the most common CNS tumors, and the main therapy for LGGs is complete surgical resection, due to its curative effect. However, LGG recurrence occurs frequently. Biomarkers play a crucial role in evaluating the recurrence and prognosis of LGGs. Numerous studies have focused on LGG prognosis. However, the multiomics research investigating the roles played by gene methylation and expression in LGG recurrence remains limited. In this study, we integrated the TCGA and GEO datasets, analyzing RNA and methylation data for recurrence (R) and nonrecurrence (NR) groups. We found a low expression of TLX1NB and high methylation in recurrence patients. Low expression of TLX1NB is associated with poor survival (OS: p = 0.04 ). The expression of TLX1NB is likely to play a role in the prognosis of LGG. Therefore, TLX1NB may represent an alternative early biomarker for the recurrence of low-grade gliomas.

Multiple myeloma (MM) is one of hematological malignancies, characterized by malignant proliferation of plasma cells. Biomarkers play an important role in evaluating the development and prognosis of MM. Ubiquitin-conjugating enzyme E2T (UBE2T) is served to connect with particular E3 ubiquitin ligase to degraded-related substrates, contributing to DNA repair in the Fanconi anemia pathway. Also, numerous evidences reported that UBE2T is closely related to cell proliferation and carcinogenesis. However, the relationship between MM and UBE2T has not been studied. Here, we integrated eight datasets and analyzed the relationship of expression of UBE2T and ISS, 1q21, relapse and survival in MM 2684 patients (totally 2893 samples). We found that the expression of UBE2T increased with the deterioration of MM (P = 1.4e-07), especially in the early stage. UBE2T is closely related to IgG serotype MM (P = 6.9e-05). High expression of UBE2T is associated with poor survival and prognosis (EFS: P = 1.43e-03, OS: P = 5.47e-05). UBE2T is likely to play a part in the cell division pathway, affecting the survival and prognosis of MM. Therefore, UBE2T could be considered as an early alternative biomarker for the prognosis of MM.

Rationale Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare congenital malformation in neonates that results in severe respiratory distress and pulmonary hypertension. ACD/MPV is caused by mutations in the FOXF1 gene. Herein, a new case of a girl with ACD/MPV carrying a novel pathogenic variant of FOXF1 was reported. Patient concerns A 3-month-old Chinese girl was admitted to the hospital presenting a complaint of cyanosis for 10 days and respiratory distress for 2 days. The history of foreign body inhalation was denied. Diagnoses Blood routine, liver and kidney function, electrolytes, type B natriuretic peptide, electrocardiogram, cardiac computed tomography (CT), and echocardiography were done after admission. Dysplasia of the alveolar and the left upper pulmonary vein was displayed through cardiac CT. Echocardiography showed atrial septal defect, tricuspid valve malformation, and pulmonary hypertension. Sequence analysis of FOXF1 from genomic deoxyribonucleic acid (DNA) revealed that the patient was heterozygous for a novel missense variant (c.418 C>T, p.Pro140Gly). Furthermore, genetic analysis of both parents confirmed the de novo occurrence of the variant. Conservation analysis showed that the locus was highly conserved across species. Then, ACD/MPV was a clinical diagnosis. Interventions After admission, nasal catheter oxygen inhalation, cefazoxime sodium, furosemide diuretic, milrinone lactate, and Bosentan were given to the patient. Outcomes After 6 days of hospitalization, the patient's condition did not improved, the parents gave up treatment and discharged. The patient died half a month after discharge. Lessons ACD/MPV is a rare congenital malformation with a poor prognosis. A new de novo mutation of FOXF1 was found in our case. Non-invasive methods such as DNA sequencing and FOXF1 analysis are helpful in the clinical diagnosis of ACD/MPV especially in early infants with respiratory distress and pulmonary hypertension.

Multiple myeloma is a hematological tumor with a malignant proliferation of myeloma cells. Although the survival time after treatment has improved, the recurrence rate of MM is still high. Choroideremia-like (CHML) protein is essential for the prenylation modification of various Rab proteins and it exerts biological effects on vesicle trafficking and signal transduction. However, little is identified about the relationship between CHML gene and MM. We integrated gene expression profiles of 1907 MM patients (1959 MM samples) from the 7 datasets. The relationship between CHML gene expression level and event-free survival (EFS), overall survival (OS), ISS stage, molecular subtype, relapse, therapy was analyzed. The differential gene exression profile of CHML-high MM group and CHML-low MM group and possible pathway related to CHML were conducted. Our data showed that EFS (P < 0.0001) and OS (P < 0.0001) in MM patients with high expression of CHML were lower than those with low CHML expression. The gene expression level of CHML was increased in subtypes of MM with poor prognosis, especially in proliferation subtype (P < 0.001). Cell division pathway (P < 0.01) was high enriched of the differential expressed genes of CHML-high group vs CHML-low group. CHML gene can be considered as an independent factor to evaluate the prognosis of MM. High expression of CHML is associated with poor survival, which is related to cell proliferation and cell division of myeloma cells.

Background Multiple myeloma (MM) is the plasma cell tumor, which is characterized by clonal proliferation of tumor cells, with high risk of progression to renal impairment, bone damage and amyloidosis. Although the survival rate of patients with MM has improved in the past decade, most people inevitably relapse. The treatment and prognosis of MM are still urgent problems. Breast Cancer Antiestrogen Resistance 3 (BCAR3) is a protein-coding gene that is associated with many tumors. However, there have been few studies on the relationship of BCAR3 and MM. Methods We analyzed 1878 MM patients (1930 samples) from 7 independent datasets. First, we compared the BCAR3 expression level of MM patients in different stages and MM patients with different amplification of 1q21. Second, we analyzed BCAR3 expression levels in MM patients with different molecular subtypes. Finally, we explored the event-free survival rate (EFS) and overall survival rate (OS) of MM patients with high or low BCAR3 expression, including patients before and after relapse, and their therapeutic responses to bortezomib and dexamethasone. Results The expression of BCAR3 showed a decreasing trend in stages I, II and III (P = 0.00068). With the increase of 1q21 amplification level, the expression of BCAR3 decreased (P = 0.022). Patients with high BCAR3 expression had higher EFS and OS (EFS: P

Plasma cell myeloma (PCM) secretes monoclonal immunoglobulin (Ig) by clonal plasma cells of abnormal proliferation in the bone marrow. As PCM is incurable, it is necessary to find new biomarkers to predict the prognosis and recurrence of PCM. The relationship between cancer and RBBP8 has not been fully studied. The role of RBBP8 in tumorigenesis remains inconsistent. We described the expression of RBBP8 in the gene expression profile of 1930 PCM samples (1878 PCM patients) from seven independent data sets. We analyzed the relationship between RBBP8 and survival prognosis, recurrence, and treatment response in patients with PCM, and the biological significance of RBBP8 in PCM. The gene expression level of RBBP8 was significantly related to the International staging system (ISS) grade of PCM (P = 0.0012). RBBP8 expression in different molecular subtypes was different (P

Additional file 1: Figure S1. The expression level of BCAR3 in different molecular subtypes. The X-axis represents the 9 molecular subtypes; the Y-axis represents the gene expression. The dotted line represents the average of BCAR3 gene expression levels of all molecular subtypes, including CD1, CD2, CTA, HY, MF, MS, myeloid, NFKB, PR. P = 7.8E−10, Anova test. Figure S2. The expression level of BCAR3 in different ISS stages and 3 serotypes in MM patients. A, The expression of BCAR3 was compared between different ISS stages in MM patients. The X-axis represents the ISS stages; the Y-axis represents BCAR3 expression level (log2). P = 0.00068, Kruskal–Wallis test. B, The expression of BCAR3 in different ISS stages were compared under different serotype stratification (FLC: Serum free light chain, IgA: Serum immunoglobulin A, IgG: serum immunoglobulin G). Kruskal–Wallis test. Figure S3. Heat map of different expression genes between BCAR3-low and BCAR3-high groups and related enrichment pathways. A, Heat map shows top 12 up-regulated genes and top 12 down-regulated genes. The red represents high expression, the white represents intermediate expression, and the green represents low expression. The foldchange (log2) of different expressed genes is ranked, and the corresponding P-value (− log10) is on the right in the heat map. B, The enrichment pathways for different expression genes. The X-axis represents p-value (− log10) and the Y-axis represents different enriched pathways. Figure S4. The expression levels of 11 different genes in the immune response pathway in the BCAR3-high group and the BCAR3-low group were compared. Unpaired t test, two sided. Figure S5. BCAR3 expression in different therapeutic response to bortezomib and dexamethasone. The left side shows the therapeutic response to bortezomib. The therapeutic response to dexamethasone was shown on the right. The expressions of BCAR3 were compared between complete remission (CR), partial remission (PR), minimal response (MR), no change (NC), and disease progression (DP) group. The dotted line represents the average of BCAR3 gene expression levels in all treatment responses. Bortezomib: P = 0.21, dexamethasone: P = 0.65, Anova test, two sided. Statistical significance: ns: P > 0.05; *: P 0.05 *: P

MicroRNAs are a group of endogenously expressed, single-stranded, 18-24 nt RNAs that regulate diverse cellular pathways. Although documented evidence indicates that some microRNAs can function as oncogenes or tumor-suppressors, the role of miR-214 in regulating human cervical cancer cells remains unexplored. We determined the expression level of miR-214 and found it is downregulated in cervical cancer compared with normal tissue. Overexpression of miR-214 in HeLa cells, a human cervical cancer cell line, significantly inhibited cell proliferation according to the MTT and colony forming assays. HeLa cells that stably overexpress miR-214 downregulate the expression of MEK3 and JNK1 at both mRNA and protein levels. Further investigation revealed that miR-214 regulates the expression of MEK3 and JNK1 by targeting the 3'UTRs of these genes. Collectively, these results suggest that miR-214 negatively regulates HeLa cell proliferation by targeting the noncoding regions of MEK3 and JNK1 mRNAs.