Intervertebral disc (IVD) degeneration (IDD) is a common disorder that affects the spine and is a major cause of lower back pain (LBP). The extracellular matrix (ECM) is the structural foundation of the biomechanical properties of IVD, and its degradation is the main pathological characteristic of IDD. Matrix metalloproteinases (MMPs) are a group of endopeptidases that play an important role in the degradation and remodeling of the ECM. Several recent studies have shown that the expression and activity of many MMP subgroups are significantly upregulated in degenerated IVD tissue. This upregulation of MMPs results in an imbalance of ECM anabolism and catabolism, leading to the degradation of the ECM and the development of IDD. Therefore, the regulation of MMP expression is a potential therapeutic target for the treatment of IDD. Recent research has focused on identifying the mechanisms by which MMPs cause ECM degradation and promote IDD, as well as on developing therapies that target MMPs. In summary, MMP dysregulation is a crucial factor in the development of IDD, and a deeper understanding of the mechanisms involved is needed to develop effective biological therapies that target MMPs to treat IDD.

Driver genomic alterations in pediatric immature T-cell acute lymphoblastic leukemia are not fully known. We report two cases of novel EVX fusions involved in the transcriptional activation of HOX family genes, ETV6::EVX2 and MSI2::EVX1/HOXA13, which activate HOXD and HOXA cluster genes transcription through enhancer hijacking. HOXA and HOXD were the only key transcription factors activated in these cases, which indicates their important roles in leukemogenesis. Our findings elucidate potential drivers for development of T-cell lymphoblastic leukemia, and are valuable for diagnosis and risk stratification of pediatric T-ALL in the era of precision medicine.

The ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motif, defined by the consensus sequence patterns LxLxL or DLNx(x)P, is found in a diverse range of plant species. It is the most predominant form of active transcriptional repression motif identified so far in plants. Despite its small size (5 to 6 amino acids), the EAR motif is primarily involved in the negative regulation of developmental, physiological and metabolic functions in response to abiotic and biotic stresses. Through an extensive literature review, we identified 119 genes belonging to 23 different plant species that contain an EAR motif and function as negative regulators of gene expression in various biological processes, including plant growth and morphology, metabolism and homeostasis, abiotic stress response, biotic stress response, hormonal pathways and signalling, fertility, and ripening. Positive gene regulation and transcriptional activation are studied extensively, but there remains much more to be discovered about negative gene regulation and the role it plays in plant development, health, and reproduction. This review aims to fill the knowledge gap and provide insights into the role that the EAR motif plays in negative gene regulation, and provoke further research on other protein motifs specific to repressors.

BACKGROUND: The mortality rate and prognosis of patients with hepatocellular carcinoma (HCC) are well known. A variety of highly malignant human cancers express mitotic arrest deficient 2 like 1 (MAD2L1), a transcription factor that plays a critical role in their development and progression. However, MAD2L1\'s particular mechanisms and effects on HCC remain uncertain.
METHODS: We performed a pan-cancer analysis for MAD2L1 prognosis and expression using The Cancer Genome Atlas and Genotype-Tissue Expression data in the present study. MAD2L1 may act as an oncogene in HCC, and a combination of in silico analyses, including expression, survival, and correlation analyses, were performed to identify non-coding ribonucleic acids (ncRNAs) that contribute to MAD2L1 overexpression.
RESULTS: In conclusion, MAD2L1 is most likely regulated by HCP5/miRNA-139-5p/MAD2L1 in HCC based on its upstream ncRNA-related pathway. A significant positive association was also found between MAD2L1 levels and tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint expression.
CONCLUSIONS: Our findings demonstrate that ncRNA-mediated upregulation of MAD2L1 in HCC is closely related to poor prognosis and tumor infiltration.

Dual specificity phosphatases (DUSPs) play a crucial role in the regulation of intracellular signalling pathways, which in turn influence a broad range of physiological processes. DUSP malfunction is increasingly observed in a broad range of human diseases due to deregulation of key pathways, most notably the MAP kinase (MAPK) cascades. Dual specificity phosphatase 26 (DUSP26) is an atypical DUSP with a range of physiological substrates including the MAPKs. The residues that govern DUSP26 substrate specificity are yet to be determined; however, recent evidence suggests that interactions with a binding partner may be required for DUSP26 catalytic activity. DUSP26 is heavily implicated in cancer where, akin to other DUSPs, it displays both tumour-suppressive and -promoting properties, depending on the context. Here we review DUSP26 by evaluating its transcriptional patterns, protein crystallographic structure and substrate binding, as well as its physiological role(s) and binding partners, its role in human disease and the development of DUSP26 inhibitors.

Even though the accrual of transcripts is implicated in distinct disease states, our knowledge regarding their functional role remains obscure. The CRISPR system has surged at the forefront of genome engineering tools in the field of RNA modulation. In the present review, we discuss some exciting applications of the CRISPR system, including the manipulation of RNA sequences, the visualization of chromosomal loci in living cells and the modulation of transcription. The CRISPR system has been documented to be very reliable and specific in altering gene expression, via leveraging inactive catalytically dead CRISPR-associated protein 9 (Cas9). In the present review, the CRISPR system is presented as an eminent tool for the meticulous analysis of gene regulation, loci mapping and complex pathways.

The aberrant dysregulation of taurine upregulated 1, a novel discovered long non-coding RNA, was ubiquitous in different human solid tumors. Accumulating researches have indicated that taurine upregulated 1 is an independent prognostic indicator in cancer patients. This investigation aimed to further explore the prognostic and clinical significance of taurine upregulated 1 in various types of cancers. Eligible studies were systematically searched in PubMed, Embase, Medline, and Web of Science databases. A total of 12/14 studies with 1303/1228 individuals were included to evaluate the association of taurine upregulated 1 with overall survival and clinicopathological features by pooled hazard ratio and odds ratio in malignancies. The meta-analysis suggested overexpression of taurine upregulated 1 was significantly correlated with unfavorable overall survival in patients with cancer (pooled hazard ratio = 1.63, 95% confidence interval: 1.29-2.06). There was also a significantly positive correlation between high level of taurine upregulated 1 and high pathological grade carcinoma (pooled odds ratio = 4.41, 95% confidence interval: 3.07-6.43) and positive lymphatic metastasis (pooled odds ratio = 2.00, 95% confidence interval: 1.31-3.06). In summary, upregulated taurine upregulated 1 is correlated with more advanced clinicopathological characteristics and poor prognosis, suggesting that taurine upregulated 1 may serve as a novel predictive biomarker of patients with numerous tumors.

The last few years have seen the identification of pharmacologic approaches to target bromodomain and extraterminal (BET) proteins for cancer treatment. These proteins have an essential role in gene transcription regulation by binding acetylated lysine residues on histone tails, activating gene transcription. BET inhibitors have been tested in preclinical models including pediatric malignancies and several adult clinical trials are ongoing. Since the development of new drugs in pediatric cancer has long lagged behind programs for adults, the aim of this review is to show the importance of these therapies in pediatric malignancies to support their development in pediatric oncology/hematology.

Hypoxia-inducible factor (HIF)-1 is a central regulator in the adaptation process of cell response to hypoxia (low oxygen). Emerging evidence has demonstrated that HIF-1 plays an important role in the development and progression of many types of human diseases, including pathogen-associated cancers. In the present review, we summarize the recent understandings of how human pathogenic agents including viruses, bacteria and parasites deregulate cellular HIF-1 signaling pathway in their associated cancer cells, and highlight the common molecular mechanisms of HIF-1 signaling activated by these pathogenic infection, which could act as potential diagnostic markers and new therapeutic strategies against human infectious cancers.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs).
METHODS: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed.
RESULTS: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only.
CONCLUSIONS: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.