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Multiple myeloma (MM) is linked to chronic NF-κB activity in myeloma cells, but this activity is generally considered a cell-autonomous property of the cancer cells. The precise extent of NF-κB activation and the contributions of the physical microenvironment and of cell-to-cell communications remain largely unknown. By quantitative immunofluorescence, we found that NF-κB is mildly and heterogeneously activated in a fraction of MM cells in human BMs, while only a minority of MM cells shows a strong activation. To gain quantitative insights on NF-κB activation in living MM cells, we combined advanced live imaging of endogenous p65 Venus-knocked-in in MM.1S and HS-5 cell lines to model MM and mesenchymal stromal cells (MSCs), cell co-cultures, microfluidics and custom microbioreactors to mimic the 3D-interactions within the bone marrow (BM) microenvironment. We found that i) reciprocal MM-MSC paracrine crosstalk and cell-to-scaffold interactions shape the inflammatory response in the BM; ii) the pro-inflammatory cytokine IL-1β, abundant in MM patients' plasma, activates MSCs, whose paracrine signals are responsible for strong NF-κB activation in a minority of MM cells; iii) IL-1β, but not TNF-α, activates NF-κB in vivo in BM-engrafted MM cells, while its receptor inhibitor Anakinra reduces the global NF-κB activation. We propose that NF-κB activation in the BM of MM patients is mild, restricted to a minority of cells and modulated by the interplay of restraining physical microenvironmental cues and activating IL-1β-dependent stroma-to-MM crosstalk., (© 2024. The Author(s).)

Background and Aims: Ultrasound nerve cross-sectional area (CSA) of patients affected with axonal neuropathy usually shows normal value. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) seems to represent an exception, showing smaller CSA, but previous reports did not test for biallelic RFC1 gene repeat expansions., Methods: We compared nerve CSA from CANVAS patients (tested positive for biallelic RFC1 gene repeat expansions) with the CSA from a group of patients with chronic idiopathic axonal polyneuropathy (CIAP) who tested negative for RFC1 gene repeat expansions, hereditary axonal neuropathy (Charcot-Marie-Tooth type 2, CMT2), and Friedreich ataxia (FRDA)., Results: We enrolled 15 CANVAS patients (eight men, mean age 66.3 ± 11.5 years, mean disease duration 9.3 ± 4.1 years), affected with sensory axonal neuronopathy. Controls consisted of 13 CIAP (mean age 68.5 ± 12.8 years, seven men), seven CMT2 (mean age 47.9 ± 18.1 years, four men), 12 FRDA (mean age 33.7 ± 8.8, five men). Nerve ultrasound was performed at median, ulnar, sciatic, sural, and tibial nerves and brachial plexus, bilaterally. The nerve CSA from CANVAS patients was significantly smaller than the one from the other cohorts at several sites with significant and high accuracy at Receiver-operating characteristic (ROC) curve analyses. RFC1 AAGGG pentanucleotide expansion, disease duration, and disability did not correlate with CSA at any site, after Bonferroni correction., Interpretation: Decreased sonographic nerve sizes, in arms and legs, in patients with sensory neuropathy and normal motor conduction studies could point to CANVAS-spectrum disease and help guide appropriate genetic testing., (© 2024 Peripheral Nerve Society.)

A "watch and wait" strategy, delaying treatment until active disease manifests, is adopted for most CLL cases; however, prognostic models incorporating biomarkers have shown to be useful to predict treatment requirement. In our prospective O-CLL1 study including 224 patients, we investigated the predictive role of 513 microRNAs (miRNAs) on time to first treatment (TTFT). In the context of this study, six well-established variables (i.e., Rai stage, beta-2-microglobulin levels, IGVH mutational status, del11q, del17p, and NOTCH1 mutations) maintained significant associations with TTFT in a basic multivariable model, collectively yielding a Harrell's C-index of 75% and explaining 45.4% of the variance in the prediction of TTFT. Concerning miRNAs, 73 out of 513 were significantly associated with TTFT in a univariable model; of these, 16 retained an independent relationship with the outcome in a multivariable analysis. For 8 of these (i.e., miR-582-3p, miR-33a-3p, miR-516a-5p, miR-99a-5p, and miR-296-3p, miR-502-5p, miR-625-5p, and miR-29c-3p), a lower expression correlated with a shorter TTFT, whereas in the remaining eight (i.e., miR-150-5p, miR-148a-3p, miR-28-5p, miR-144-5p, miR-671-5p, miR-1-3p, miR-193a-3p, and miR-124-3p), the higher expression was associated with shorter TTFT. Integrating these miRNAs into the basic model significantly enhanced predictive accuracy, raising the Harrell's C-index to 81.1% and the explained variation in TTFT to 63.3%. Moreover, the inclusion of the miRNA scores enhanced the integrated discrimination improvement (IDI) and the net reclassification index (NRI), underscoring the potential of miRNAs to refine CLL prognostic models and providing insights for clinical decision-making. In silico analyses on the differently expressed miRNAs revealed their potential regulatory functions of several pathways, including those involved in the therapeutic responses. To add a biological context to the clinical evidence, an miRNA-mRNA correlation analysis revealed at least one significant negative correlation between 15 of the identified miRNAs and a set of 50 artificial intelligence (AI)-selected genes, previously identified by us as relevant for TTFT prediction in the same cohort of CLL patients. In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility.

Background : The necessity of using central venous catheters (CVCs) in hemodialysis, coupled with their associated complications, remains a critical concern in nephrology. This study aims to compare the short-term prognosis of tunneled (T-CVC) and non-tunneled (NT-CVC) CVCs in acute hemodialysis patients, specifically focusing on infection rates, malpositioning, and lumen thrombosis within the first three weeks post-insertion. Methods : A retrospective analysis was conducted on 176 CVCs placed between January and December 2023 at the Policlinico di Modena and the Ospedale Civile di Baggiovara. Patient demographics, CHA2DS2-VASc scores, and comorbid conditions were recorded at the time of catheter placement. Outcomes assessed included catheter-related infections, malpositioning, and lumen thrombosis. Statistical analyses, including Chi-square tests, Fisher's exact tests, and Kaplan-Meier survival analysis, were performed to evaluate differences between T-CVCs and NT-CVCs. Results : The sample comprised 43% females with a mean age of 69.3 years (SD 13.9) and a mean CHADS-VASC score of 3.72 (SD 1.4). Hypertension (90%) was the most prevalent comorbidity. Of the 176 CVCs, 127 were T-CVCs and 49 were NT-CVCs. Infection rates were 3.15% for T-CVCs and 8.16% for NT-CVCs ( p = 0.07). Malpositioning occurred in 0.79% of T-CVCs and 4.08% of NT-CVCs ( p = 0.47). There was one case of lumen thrombosis in the NT-CVC group. Kaplan-Meier analysis indicated a significant divergence in infection-related catheter survival favoring T-CVCs after ten days ( p = 0.034). Conclusions : While non-tunneled CVCs do not significantly alter short-term prognosis compared to tunneled CVCs, the latter show a better infection-related survival rate beyond ten days. Therefore, primary insertion of T-CVCs may be preferable when resources and clinical conditions permit, although NT-CVCs remain a viable option when immediate T-CVC insertion is challenging.

Background: We aimed to investigate the clinical features of a large cohort of patients with myelin protein zero ( MPZ )-related neuropathy, focusing on the five main mutation clusters across Italy., Methods: We retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids., Results: We collected data from 186 patients: 60 had the p.Ser78Leu variant ('classical' CMT1B; from Eastern Sicily), 42 the p.Pro70Ser (CMT2I; mainly from Lombardy), 38 the p.Thr124Met (CMT2J; from Veneto), 25 the p.Ser44Phe (CMT2I; from Sardinia) and 21 the p.Asp104ThrfsX13 (mild CMT1B; from Apulia) mutation. Disease severity (CMTES) was higher (p<0.001) in late-onset axonal forms (p.Thr124Met=9.2±6.6; p.Ser44Phe=7.8±5.7; p.Pro70Ser=7.6±4.8) compared with p.Ser78Leu (6.1±3.5) patients. Disease progression (ΔCMTES/year) was faster in the p.Pro70Ser cohort (0.8±1.0), followed by p.Ser44Phe (0.7±0.4), p.Thr124Met (0.4±0.5) and p.Ser78Leu (0.2±0.4) patients. Disease severity (CMTES=1.2±1.5), progression (ΔCMTES/year=0.1±0.4) and motor involvement were almost negligible in p.Asp104ThrfsX13 patients, who, however, frequently (78%, p<0.001) complained of neuropathic pain. In the other four clusters, walking difficulties were reported by 69-85% of patients, while orthotic and walking aids use ranged between 40-62% and 16-28%, respectively., Conclusions: This is the largest MPZ (and late-onset CMT2) cohort ever collected, reporting clinical features and disease progression of 186 patients from five different clusters across Italy. Our findings corroborate the importance of differentiating between 'classical' childhood-onset demyelinating, late-onset axonal and mild MPZ -related neuropathy, characterised by different pathomechanisms, in view of different therapeutic targets., Competing Interests: Competing interests: GMF acknowledges donations from Pfizer to support research activities of his Research Unit, financial support from Akcea, Kedrion, Pfizer for participation in national and international meetings and from Akcea, Alnylam and Pharnext for participation in Advisory Boards; MG acknowledges donations from Sanofi Genzyme to support research activities of her Research Unit, financial support from Alnylam and Sanofi Genzyme for participation in national and international Meetings, participation in Advisory Board of Pfizer, speaker honorarium from Sanofi Genzyme; AM acknowledges financial support from Pfizer, Alnylam and Akcea for participation in national and international meetings, participation in Advisory Board of Pfizer, Alnylam and Akcea; DP acknowledges participation in Advisory Board of Inflectis, Alnylam, Akcea, Arvinas, Augustine Tx, DTx; ST is supported by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) - A multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). AB, LG, TC, PS, MR, SM, YMF, EM, FT, AG, GO, MF, EC, LC, PM, FB, SM, FT, SCP, AS, FM, CP report no disclosure., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Cell-free nucleic acids (cf-NAs) represent a promising biomarker of various pathological and physiological conditions. Since its discovery in 1948, cf-NAs gained prognostic value in oncology, immunology, and other relevant fields. In peritoneal dialysis (PD), blood purification is performed by exposing the peritoneal membrane. Relevant sections: Complications of PD such as acute peritonitis and peritoneal membrane aging are often critical in PD patient management. In this review, we focused on bacterial DNA, cell-free DNA, mitochondrial DNA (mtDNA), microRNA (miRNA), and their potential uses as biomarkers for monitoring PD and its complications. For instance, the isolation of bacterial DNA in early acute peritonitis allows bacterial identification and subsequent therapy implementation. Cell-free DNA in peritoneal dialysis effluent (PDE) represents a marker of stress of the peritoneal membrane in both acute and chronic PD complications. Moreover, miRNA are promising hallmarks of peritoneal membrane remodeling and aging, even before its manifestation. In this scenario, with multiple cytokines involved, mtDNA could be considered equally meaningful to determine tissue inflammation., Conclusions: This review explores the relevance of cf-NAs in PD, demonstrating its promising role for both diagnosis and treatment. Further studies are necessary to implement the use of cf-NAs in PD clinical practice.