Single-cell landscape of peripheral immune response in patients with anti-melanoma differentiation-associated gene 5 dermatomyositis.

OBJECTIVE: Anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (DM) is a rare but life-threatening autoimmune disorder with a high risk to develop rapidly progressive interstitial lung disease. Current empirical therapies have limited improvement on patients' survival, as little is known about the aetiology of MDA5 DM. To best understand its immune landscape, we applied single-cell RNA sequencing (scRNA-seq) to peripheral blood samples from DM patients and healthy controls. METHODS: Peripheral blood mononuclear cells (PBMCs) from eight DM patients, comprising three distinct subtypes, as well as two healthy donors, were sequenced by 10X Genomics platform. Additional scRNA-seq data of four healthy donors were incorporated for further bioinformatic analysis. RESULTS: Aberrant increased proportions of CD14+ monocyte and plasma cells were observed in MDA5 DM samples. Moreover, we found overactivated type I interferon response and antiviral immunity in both innate and adaptive immune cells derived from MDA5 DM patients, which was positively correlated with disease severity. Importantly, a unique subset of CD14+ monocyte that highly expressed interferon alpha-inducible protein 27 (IFI27, a biomarker for viral infection) and interferon induced with helicase C domain 1 (IFIH1, encodes MDA5) was specifically identified in MDA5 DM samples for the first time. CONCLUSION: Our study demonstrates the peripheral immune cell atlas of different DM subtypes, provides compelling evidence for viral infection-derived origin of MDA5 DM, and offers potential targets for innovative therapeutic interventions.

Lifelong deformities in an adult caused by vitamin D­dependent rickets type 1A: A case report.

Vitamin D-dependent rickets (VDDR) type 1A is a rare autosomal recessive disorder caused by cytochrome P450 family 27 subfamily B member 1 (CYP27B1) mutations and can lead to deficiencies in 1α-hydroxylase activity. The present study describes the case of a 39-year-old male patient who presented with rickets and deformities of limbs. Blood biochemical analysis revealed hypocalcemia and high serum parathyroid hormone (PTH) levels. Whole-exome Sanger sequencing using peripheral venous blood of this patient and his parents revealed exon1 c.182T>C, a novel mutation. Through physical examination, laboratory tests, imaging including lower limbs and lumbar spine X-ray and pelvis CT scan, and genetic testing, the patient was diagnosed with VDDR-1A. Following 1 month of treatment with 0.5 µg 1,25-dihydroxy-vitamin D3 twice daily and 0.6 g calcium carbonate once daily, follow-up examinations revealed that the patient's PTH and serum calcium levels had returned to normal. As the patient was diagnosed in his adulthood and missed the optimal treatment period, he developed irreversible deformities. If VDDR-1A can be diagnosed during infancy and childhood, skeletal deformities may be prevented. Therefore, the present report supports the proposal of early genetic sequencing in children with calcium deficiencies for the early diagnosis of rare diseases such as VDDR-1A, -1B and -2A and hereditary hypophosphatemic rickets. Since VDDR-1A diagnosed in adults is rare, the present case may provide clinicians with further insights into the characteristics of this rare disease.

Long-term Remission of Acute Intermittent Porphyria Treated with Gonadotropin-Releasing Hormone Analogues and Estrogen: a Case Report.

BACKGROUND: Acute intermittent porphyria (AIP) is an autosomal dominant hepatic porphyria characterized by a partial deficiency of hydroxymethylbilane synthase involved in heme biosynthesis. It is difficult for all patients to achieve complete control of AIP episodes. METHOD: We report on a 20-year-old female woman who suffered from recurrent abdominal pain and was diagnosed as "acute intermittent porphyria". She failed to respond to conventional symptomatic treatment and subsequently was treated with gonadotropin-releasing hormone analogues (GnRH) combined with estrogen for one year. RESULT: The case did not experience acute attacks and obtained long-term clinical remission to date. CONCLUSIONS: GnRH combined with estrogen, one of the treatment options for menstrual-associated AIP, might induce long-term remission.

Musashi1 Contribution to Glioblastoma Development via Regulation of a Network of DNA Replication, Cell Cycle and Division Genes.

RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in their levels are often observed in tumors with numerous oncogenic RBPs identified in recent years. Musashi1 (Msi1) is an RBP and stem cell gene that controls the balance between self-renewal and differentiation. High Msi1 levels have been observed in multiple tumors including glioblastoma and are often associated with poor patient outcomes and tumor growth. A comprehensive genomic analysis identified a network of cell cycle/division and DNA replication genes and established these processes as Msi1's core regulatory functions in glioblastoma. Msi1 controls this gene network via two mechanisms: direct interaction and indirect regulation mediated by the transcription factors E2F2 and E2F8. Moreover, glioblastoma lines with Msi1 knockout (KO) displayed increased sensitivity to cell cycle and DNA replication inhibitors. Our results suggest that a drug combination strategy (Msi1 + cell cycle/DNA replication inhibitors) could be a viable route to treat glioblastoma.

Homocystinuria in a Family with Novel Cystathionine Beta Synthase Gene Mutations.

BACKGROUND: Classic homocystinuria is caused by cystathionine beta synthase deficiency owing to genetic mutations. The most common symptoms are ectopia lentis, osteoporosis, thrombosis, and mental retardation. This disease is prone to misdiagnosis and delayed diagnosis. METHODS: Here, we report a 19-year-old woman with Marfan's morphotype, high blood homocysteine, and a history of ectopia lentis. Total homocysteine levels became normal following treatment with vitamin therapy. RESULTS: Genetic analysis revealed two heterozygous nucleotide mutations in the parents. The mutation from the patient's father had not been described previously. CONCLUSIONS: Screening for blood homocysteine should be performed early. Early diagnosis and treatment can prevent related symptoms.

The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation.

BACKGROUND: RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy. RESULTS: We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites. CONCLUSIONS: SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.

Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells.

RNA binding proteins have emerged as critical oncogenic factors and potential targets in cancer therapy. In this study, we evaluated Musashi1 (Msi1) targeting as a strategy to treat glioblastoma (GBM); the most aggressive brain tumor type. Msi1 expression levels are often high in GBMs and other tumor types and correlate with poor clinical outcome. Moreover, Msi1 has been implicated in chemo- and radio-resistance. Msi1 modulates a range of cancer relevant processes and pathways and regulates the expression of stem cell markers and oncogenic factors via mRNA translation/stability. To identify Msi1 inhibitors capable of blocking its RNA binding function, we performed a ~ 25,000 compound fluorescence polarization screen. NMR and LSPR were used to confirm direct interaction between Msi1 and luteolin, the leading compound. Luteolin displayed strong interaction with Msi1 RNA binding domain 1 (RBD1). As a likely consequence of this interaction, we observed via western and luciferase assays that luteolin treatment diminished Msi1 positive impact on the expression of pro-oncogenic target genes. We tested the effect of luteolin treatment on GBM cells and showed that it reduced proliferation, cell viability, colony formation, migration and invasion of U251 and U343 GBM cells. Luteolin also decreased the proliferation of patient-derived glioma initiating cells (GICs) and tumor-organoids but did not affect normal astrocytes. Finally, we demonstrated the value of combined treatments with luteolin and olaparib (PARP inhibitor) or ionizing radiation (IR). Our results show that luteolin functions as an inhibitor of Msi1 and demonstrates its potential use in GBM therapy.