CD138 as a Specific CSF Biomarker of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The aim of this study was to identify novel biomarkers for multiple sclerosis (MS) diagnosis and prognosis, addressing the critical need for specific and prognostically valuable markers in the field. METHODS: We conducted an extensive proteomic investigation, combining analysis of (1) CSF proteome from symptomatic controls, fast and slow converters after clinically isolated syndromes, and patients with relapsing-remitting MS (n = 10 per group) using label-free quantitative proteomics and (2) oligodendrocyte secretome changes under proinflammatory or proapoptotic conditions using stable isotope labeling by amino acids in cell culture. Proteins exhibiting differential abundance in both proteomic analyses were combined with other putative MS biomarkers, yielding a comprehensive list of 87 proteins that underwent quantification through parallel reaction monitoring (PRM) in a novel cohort, comprising symptomatic controls, inflammatory neurologic disease controls, and patients with MS at various disease stages (n = 10 per group). The 11 proteins that passed this qualification step were subjected to a new PRM assay within an expanded cohort comprising 158 patients with either MS at different disease stages or other inflammatory or noninflammatory neurologic disease controls. RESULTS: This study unveiled a promising biomarker signature for MS, including previously established candidates, such as chitinase 3-like protein 1, chitinase 3-like protein 2, chitotriosidase, immunoglobulin kappa chain region C, neutrophil gelatinase-associated lipocalin, and CD27. In addition, we identified novel markers, namely cat eye syndrome critical region protein 1 (adenosine deaminase 2, a therapeutic target in multiple sclerosis) and syndecan-1, a proteoglycan, also known as plasma cell surface marker CD138 and acting as chitinase 3-like protein 1 receptor implicated in inflammation and cancer signaling. CD138 exhibited good diagnostic accuracy in distinguishing MS from inflammatory neurologic disorders (area under the curve [AUC] = 0.85, CI 0.75-0.95). CD138 immunostaining was also observed in the brains of patients with MS and cultured oligodendrocyte precursor cells but was absent in astrocytes. DISCUSSION: These findings identify CD138 as a specific CSF biomarker for MS and suggest the selective activation of the chitinase 3-like protein 1/CD138 pathway within the oligodendrocyte lineage in MS. They offer promising prospects for improving MS diagnosis and prognosis by providing much-needed specificity and clinical utility. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CD138 distinguishes multiple sclerosis from other inflammatory neurologic disorders with an AUC of 0.85 (95% CI 0.75-0.95).

18F-FDOPA-PET in pseudotumoral brain lesions.

INTRODUCTION: 3,4-Dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) is sensitive for identifying primary brain tumors. However, increased FDOPA uptake has been reported in pseudotumoral brain lesions. Our aim was to analyse FDOPA-PET in patients with pseudotumoral brain lesions and to compare them with patients with brain tumors. METHODS: We retrospectively analysed consecutively recruited patients with suspected primary brain tumor (based on clinical and magnetic resonance imaging findings) referred for FDOPA-PET in our centre between November 2013 and June 2019 (n = 74). FDOPA-PET parameters (maximum and mean lesion standardised uptake values [SUV] and ratios comparing lesion with different background uptake SUV) and thresholds were evaluated to determine which offered optimal discrimination between pseudotumoral and tumoral lesions. RESULTS: Overlapping PET values were observed between pseudotumoral (n = 26) and tumoral (n = 48) lesion, particularly for low-grade tumors. Based on receiver operating characteristic (ROC) analyses, the optimal PET parameters to discriminate pseudotumoral from tumoral lesions were SUVmax lesion/basal ganglia, SUVmax lesion/grey matter, SUVmean lesion/grey matter, and SUVmax lesion/mirror area in contralateral hemisphere (all ratios showing area under the curve [AUC] 0.85, 95% CI). The narrowest 95% sensitivity-95% specificity window was observed for SUVmax lesion/basal ganglia ratio, with ratio values of 0.79 and 1.35 corresponding to 95% sensitivity and 95% specificity, respectively. CONCLUSION: FDOPA-PET uptake should be interpreted with caution in patients with suspected primary brain tumor, especially in patients showing low or intermediate SUV values and ratios. CLINICAL TRIAL REGISTRATION-URL: https://www.clinicaltrials.gov . Unique identifier: NCT04306484.

NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.

Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 functions as a corepressor when associated with CSL-repressor complex and as a NOTCH1 coactivator upon Notch activation. Our work provides new insights into the molecular mechanisms that govern Notch transcriptional activity and represents glimpse into NOTCH1 interaction landscape, which will help in deciphering mechanisms of NOTCH1 functions and regulation.

Intestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation.

The idea that stem cells of adult tissues with high turnover are protected from DNA replication-induced mutations by maintaining the same 'immortal' template DNA strands together through successive divisions has been tested in several tissues. In the epithelium of the small intestine, the provided evidence was based on the assumption that stem cells are located above Paneth cells. The results of genetic lineage-tracing experiments point instead to crypt base columnar cells intercalated between Paneth cells as bona fide stem cells. Here we show that these cells segregate most, if not all, of their chromosomes randomly, both in the intact and in the regenerating epithelium. Therefore, the 'immortal' template DNA strand hypothesis does not apply to intestinal epithelial stem cells, which must rely on other strategies to avoid accumulating mutations.