IntroductionMultiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS with an autoimmune pathogenesis. Over the years, numerous disease-modifying therapies (DMTs) have proven effective in disease control; to date, there is a need to identify a personalized treatment effective in ensuring disease-free status or no evidence of disease activity (NEDA). Objectiveidentify clinical, demographic and treatment approach characteristics that affect the maintenance of NEDA-3 and the occurrence of clinical relapses during a 6-years follow-up. Materials and methoda retrospective study was conducted on a cohort of MS patients followed up with six-year period. All participants were treated with first- or second-line MS drugs.Clinical relapse, NEDA-3 at 6 years and sustained EDSS were assessed as disease activity outcomes. Patients with follow-up of less than 6 years and insufficient clinical and radiological data were excluded from the study. ResultsTwo-hundred-eighty naive patients (mean age was 49.8 years, SD & PLUSMN; 11.35 years, 23-76, F/M 182/98), with MS were followed up for 6 years.The mean age at diagnosis was 34.3 years (SD & PLUSMN;11.5, 14-62 years), the mean EDSS score at the onset was 1.9 (& PLUSMN;1.3), 76.8% of patients had an EDSS below or equal to 2.5 at diagnosis.In the cohort 37 (13.2%) directly received second-line treatment, 243 (86.8%) received first-line drugs.The analysis showed that second-line treatment from beginning had a protective effect for the achievement of NEDA-3 (p = 0.029), on the prevention of clinical relapse (p = 0.018) and on number of relapses (p = 0.010); this finding was confirmed by logistic regression analysis (p = 0.04) and Kaplan-Meier analysis (p = 0.034). ConclusionThe results of this study demonstrate the efficacy of targeted and early intervention so as to act in the right time window, ensuring a favorable outcome in both clinical and radiological terms; this could be decisive in reducing clinical relapse, disease progression and related disability. Therefore, prescribing highly effective drug in the early stages of the disease represents a leading strategy with the most favorable cost-benefit ratio.

Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.

Factor quinolinone inhibitors are promising anti-cancer compounds, initially characterized as specific inhibitors of the oncogenic transcription factor LSF (TFCP2). These compounds exert anti-proliferative activity at least in part by disrupting mitotic spindles. Herein, we report additional interphase consequences of the initial lead compound, FQI1, in two telomerase immortalized cell lines. Within minutes of FQI1 addition, the microtubule network is disrupted, resulting in a substantial, although not complete, depletion of microtubules as evidenced both by microtubule sedimentation assays and microscopy. Surprisingly, this microtubule breakdown is quickly followed by an increase in tubulin acetylation in the remaining microtubules. The sudden breakdown and partial depolymerization of the microtubule network precedes FQI1-induced morphological changes. These involve rapid reduction of cell spreading of interphase fetal hepatocytes and increase in circularity of retinal pigment epithelial cells. Microtubule depolymerization gives rise to FH-B cell compaction, as pretreatment with taxol prevents this morphological change. Finally, FQI1 decreases the rate and range of locomotion of interphase cells, supporting an impact of FQI1-induced microtubule breakdown on cell motility. Taken together, our results show that FQI1 interferes with microtubule-associated functions in interphase, specifically cell morphology and motility.