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Among bacteria used as anticancer vaccines, attenuated Listeria monocytogenes (Lm at ) stands out, because it spreads from one infected cancer cell to the next, induces a strong adaptive immune response, and is suitable for repeated injection cycles. Here, we use click chemistry to functionalize the Lm at cell wall and turn the bacterium into an "intelligent carrier" of the chemotherapeutic drug doxorubicin. Doxorubicin-loaded Lm at retains most of its biological properties and, compared to the control fluorophore-functionalized bacteria, shows enhanced cytotoxicity against melanoma cells both in vitro and in a xenograft model in zebrafish. Our results show that drugs can be covalently loaded on the Lm at cell wall and pave the way to the development of new two-in-one therapeutic approaches combining immunotherapy with chemotherapy.

Introduction: People with Parkinson's Disease (PD) experience reduced voice intensity and dysphagia. Organs related to voice production and swallowing are structurally and neurologically intertwined. Thus, instrumental voice assessment may be useful in identifying voice impairments that can show swallowing disorders. Timely assessment of swallowing disorders may prevent the occurrence of malnutrition, dehydration, pneumonia, and death., Objective: The aim of this study was to investigate the relationship between voice intensity and swallowing function in PD., Methods: 30 participants with PD were recruited. Motor disability was evaluated by the Unified Parkinson's Disease Rating Scale part III; voice intensity was assessed by PRAAT software during sustained /a/ and 1 min of monologue. The Penetration Aspiration Scale, the Dysphagia Outcome Severity Scale, and the Videofluoroscopic Dysphagia Scale were used to assess swallowing during videofluoroscopy. Spearman correlation coefficients, logistic, and linear models were used to analyze data., Results: Voice intensity correlated with swallowing: as voice intensity decreased, swallowing function deteriorated (Spearman coefficients from -0.42 to -0.72 across scales), and this holds even when adjusted for MDS-UPDRS motor scores. Swallowing impairment is 56 times more likely (p<0.01) when the voice intensity is below the normal cut-off score (60 dB) with a positive predictive value of 93%., Conclusions: Reduction in voice intensity is indicative of a higher risk of swallowing dysfunction. Thus, an instrumental voice analysis seems to be a non-invasive, lowcost, easy-to-use tool to identify people with PD in need of an assessment to allow for timely swallowing management and reduction of complications caused by dysphagia., (© 2024. Fondazione Società Italiana di Neurologia.)

Objective: Alterations in voice intensity and quality may constitute a social life limitation in people with multiple sclerosis (MS), but only 2% of cases receive speech therapy. Especially the Lee Silverman Voice Treatment (LSVT)-Loud is a highly effective intensive method for voice intensity, requiring subjects' repeated attendance at the clinic. Telerehabilitation may represent a feasible solution to bypass potential barriers related to speech therapy attendance, scaling up the beneficial effects of the treatment to a broader population. The proposed protocol aims to test the feasibility and the pilot efficacy of the LSVT-Loud delivered in telerehabilitation (Tele-LSVT-Loud), compared to the same treatment delivered in the clinic (LSVT-Loud)., Methods: A single-blinded, parallel, two-arm, pilot randomized (1:1 ratio) controlled trial will be performed involving 20 people with MS. Patients will be allocated to 4 weeks of Tele-LSVT-Loud by accessing a telerehabilitation platform at home or LSVT-Loud conventionally delivered in the clinic. Feasibility and pilot effectiveness will be evaluated three times: before (T0), after the treatment (T1), and 3-month follow-up (T2). Feasibility measures will include adherence, adverse events, user experience, motivation, engagement, and acceptability. Vocal intensity during a 1-minute monologue will be the primary outcome measure. Secondary outcome measures will be the vocal quality during a 1-minute monologue, sustained /a/ voice intensity, quality and stability, voice use in daily life, voice subjective perception in daily life, and quality of life., Results: Expected results will be (1) high feasibility of Tele-LSVT-Loud and (2) a non-inferiority effect of Tele-LSVT-Loud compared with face-to-face treatment delivery on voice intensity and quality outcomes., Conclusions: Tele-LSVT-Loud may be a feasible intervention for MS alteration in voice intensity and quality with a non-inferior effect compared to LSVT-Loud., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

BRAF represents one of the most frequently mutated protein kinase genes and BRAF V600E mutation may be found in many types of cancer, including hairy cell leukemia (HCL), anaplastic thyroid cancer (ATC), colorectal cancer and melanoma. Herein, a fluorescent probe, based on the structure of the highly specific BRAF V600E inhibitor Vemurafenib (Vem, 1) and featuring the NIR fluorophore cyanine-5 (Cy5), was straightforwardly synthesized and characterized (Vem-L-Cy5, 3), showing promising spectroscopic properties. Biological validation in BRAF V600E -mutated cancer cells evidenced the ability of 3 to penetrate inside the cells, specifically binding to its elective target BRAF V600E with high affinity, and inhibiting MEK phosphorylation and cell growth with a potency comparable to that of native Vem 1. Taken together, these data highlight Vem-L-Cy5 3 as a useful tool to probe BRAF V600E mutation in cancer cells, and suitable to acquire precious insights for future developments of more informed BRAF inhibitors-centered therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: The ability to increase their degree of pigmentation is an adaptive response that confers pigmentable melanoma cells higher resistance to BRAF inhibitors (BRAFi) compared to non-pigmentable melanoma cells., Methods: Here, we compared the miRNome and the transcriptome profile of pigmentable 501Mel and SK-Mel-5 melanoma cells vs. non-pigmentable A375 melanoma cells, following treatment with the BRAFi vemurafenib (vem). In depth bioinformatic analyses (clusterProfiler, WGCNA and SWIMmeR) allowed us to identify the miRNAs, mRNAs and biological processes (BPs) that specifically characterize the response of pigmentable melanoma cells to the drug. Such BPs were studied using appropriate assays in vitro and in vivo (xenograft in zebrafish embryos)., Results: Upon vem treatment, miR-192-5p, miR-211-5p, miR-374a-5p, miR-486-5p, miR-582-5p, miR-1260a and miR-7977, as well as GPR143 , OCA2 , RAB27A , RAB32 and TYRP1 mRNAs, are differentially expressed only in pigmentable cells. These miRNAs and mRNAs belong to BPs related to pigmentation, specifically melanosome maturation and trafficking. In fact, an increase in the number of intracellular melanosomes-due to increased maturation and/or trafficking-confers resistance to vem., Conclusion: We demonstrated that the ability of pigmentable cells to increase the number of intracellular melanosomes fully accounts for their higher resistance to vem compared to non-pigmentable cells. In addition, we identified a network of miRNAs and mRNAs that are involved in melanosome maturation and/or trafficking. Finally, we provide the rationale for testing BRAFi in combination with inhibitors of these biological processes, so that pigmentable melanoma cells can be turned into more sensitive non-pigmentable cells.

Background: Vocal disorders are frequent in people with multiple sclerosis (MS). Cognitive impairment, fatigue, depression, and other clinical characteristics can be associated with treatment effectiveness in rehabilitation. Finding baseline characteristics that identify those who are responding to treatment can help the clinical decision-making process, which can then help improve the effectiveness of voice treatment. We developed a model to identify factors associated with treatment-related improvement on voice intensity in people with MS., Methods: Data are from a randomized controlled trial of the effects of voice therapy. Forty-four people with MS were enrolled and randomized to receive Lee Silverman Voice Treatment LOUD, specifically addressing voice intensity, or conventional speech-therapy group. Voice intensity (dB) was measured during monologue before and after treatment and was used to differentiate those who responded (posttreatment voice intensity > 60 dB) from those who did not. Possible associated factors were cognitive impairment, fatigue, depression, disability, and disease duration. Associations were assessed by univariate logistic regression and univariate and multivariate linear regressions., Results: Mean ± SD monologue voice intensity is improved in the whole sample (before rehabilitation: 51.8 ± 4.2 dB; and after rehabilitation 57.0 ± 6.5 dB; P < .001), and 11 people with MS (27.5%) responded to treatment. Specificity of treatment was associated with the return to normal voice intensity (OR, 14.28; 95% CI, 12.17-309.56) and we found a linear association between voice improvement and the specificity of treatment (6.65 [SE = 1.54] dB; P < .05). Moreover, the analysis revealed a nonlinear association between improvement and fatigue, suggesting increased benefits for people with MS with moderate fatigue. Other factors were not significantly associated with treatment effectiveness., Conclusions: Moderate fatigue and the specificity of the intervention seem to be key factors associated with clinically relevant improvement in voice intensity even in people with MS with a high level of disability and long disease duration., Competing Interests: FINANCIAL DISCLOSURES: The authors declare no conflicts of interest., (© 2023 Consortium of Multiple Sclerosis Centers.)

Aim: The rehabilitation of voice disorders is an unmet need in multiple sclerosis (MS). The Lee Silverman Voice Treatment (LSVT LOUD) is a well-documented and effective speech treatment, developed to treat voice disorders in Parkinson Disease. The purpose of the present study was to examine the viability of applying the LSVT LOUD to individuals with MS and verify short- and long-term improvements in acoustic and perceptual voice parameters., Methods: A single subject design was performed in a consecutive sample of 8 subjects with MS. The subjects' voice was recorded with PRAAT software for 5 days at baseline during the 16  treatment sessions, and at follow-up (FU) 6/12 months later. PRAAT provided data on sustained /a/ (SPL/a/) voice intensity and maximum phonation time (MPT/a/) of sustained /a/, and on functional sentences voice intensity. In addition, self-assessment questionnaire Voice Handicap Index, the perceptual GIRBAS scale and intensity of monologue were collected at first day of baseline, post-treatment and at FU. In the treatment phase each subject received treatment according to LSVT LOUD protocol. Visual analysis calculated for daily acoustic variables was used to determine baseline stability and analyse changes following treatment. The Wilcoxon test was used to assess statistically significant differences between baseline and post treatment., Results: All participants completed the LSVT LOUD programme; one participant dropped out at FU. Improvements in acoustic analysis were found: SPL/a/ improved on average (± standard deviation) 11.64 ± 4.19 dB with 7 subjects showing statistically significant improvement (P < 0.05); MPT/a/ improved on average 1.2 ± 1.53seconds, while intensity of functional sentences improved on average 8.11 ± 3.46  dB with 4 and 5 subjects showed statistically significant improvement, respectively. Intensity of monologue improved 14.90 ± 3.33 dB. Acoustic values are maintained or increased at FU respect to baseline. All subjects improved perceptual ratings at Voice Handicap Index and results were maintained at FU. These changes were associated with improvements on five parameters on the GIRBAS scale at post-treatment, however no further improvement were observed at FU., Conclusion: Intensive LSVT LOUD treatment is a viable approach to treat hypophonia in MS. LSVT LOUD improved both quantitative-instrumental and perceptive-subjective assessments. Randomised controlled trials are needed to provide a firm support on the effectiveness of LSVT LOUD in MS., (Copyright © 2020 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hypophonia is a prevailing problem in people with multiple sclerosis (PwMS). However, evidence supporting the effectiveness of voice rehabilitation is lacking., Objective: The aim of this study was to identify the most effective method to reduce hypophonia., Methods: In this randomized controlled trial, 44 PwMS were randomized to intensive and high-effort voice treatment groups, the LSVT-LOUD ® , and conventional treatment group. Subjects received 16 treatments (4 sessions/week) lasting 45 minutes. The primary outcome was voice intensity (dB) in monologue, vocalization, and sentences while voice handicap index (VHI) measured voice self-perception. Outcomes were assessed by a blinded observer at baseline, post-treatment, and 15-month follow-up (FU)., Results: Linear models revealed a significant post-intervention between-group mean difference in favor of LSVT-LOUD for monologue: +6.3 dB (95% CI: 2.5 to 10.1); vocalization: +7.4 dB (95% CI: 2.3 to 12.5); and sentences: +9.5 dB (95% CI: 4.7 to 14.3). However, 43.7% PwMS in the LSVT-LOUD and 10% in the conventional treatment group obtained a full recovery of voice intensity (>60 dB) post-treatment, Fisher's test = 13.3, p  < 0.01. However, these improvements were not maintained at FU. Between-group differences at VHI were -10.8 (95% CI: -21.2 to -0.4) and -11.3 (95% CI: -24.3 to -1.7) in favor of LSVT-LOUD at post and FU., Conclusion: LSVT-LOUD can be a valid treatment to increase voice intensity in PwMS. However, results suggest the need for FU interventions targeting maintenance.

Purpose: The aim of this study was to develop an exercise protocol to improve maximal mouth opening (MMO), tongue protrusion (Tprot), tongue strength (Tstren), and lip strength (Lstren), and to assess its effects on subjects with scleroderma., Methods: We performed four replicated single-system studies in a consecutive sample of subjects with scleroderma. An instrumented assessment measured MMO, Tprot, Tstren, and Lstren. Each day, subjects were assessed and performed orofacial exercises conducted by speech therapists. Treatments were first aimed at improving mouth physical characteristics by impairment-oriented exercises and then to improve skills with function-oriented exercises., Results: The mean phase differences between assessment and treatment phases across subjects were from 0.88 to 9.56 mm in MMO, from 2.03 to 12.3 mm in Tprot, from -0.12 to 5.35 N in Tstren, and from -0.84 to 5.19 N in Lstren. After treatment, 3 subjects crossed the 5th percentile discriminating normal from abnormal performances for both Tstren and Tprot, while this occurred in 2 subjects for MMO and Lstren., Conclusions: The results of this study suggest that rehabilitation appears to be useful in reducing tongue and lip impairments and in improving oral functions in subjects with scleroderma., (© 2019 S. Karger AG, Basel.)

The aim of the present study was to provide quantitative data of oral function in healthy subjects (HSs), validity of measurements and estimation of measurement bias, as well as quantify oral impairment in persons with scleroderma (SSc). 151 HSs and 12 subjects with SSc were recruited and assessed using instrumented tools, measuring maximal mouth opening; lip strength; and tongue strength, protrusion, retraction, and endurance. Twenty HSs were also retested 3-5 weeks later in order to assess the test-retest reliability of the measurements. Intraclass correlation coefficients proved to be satisfactory (>0.8) for both inter-rater and test-retest reliabilities of all measurements except for tongue retraction. In the HS group, maximal mouth opening and tongue and lips strength values were larger (P < 0.05) for males than females, while no significant differences were found for other variables. Older subjects had statistically significantly lower tongue retraction values and tongue endurance values than younger subjects. The SSc group showed a statistically significant decrease (P < 0.05) in almost all the measurements. Assessment procedures proved to be valid and reliable. Gender and height were predictors of mouth opening, lip and tongue strength, while age correlates with tongue retraction and endurance. Measurements highlighted the strong impact of SSc on oral functions and in particular on tongue protrusion, tongue strength, and endurance.