The Use of Botulinum Toxin A as an Adjunctive Therapy in the Management of Chronic Musculoskeletal Pain: A Systematic Review with Meta-Analysis

Several studies have investigated the effect of botulinum toxin A (BoNT-A) for managing chronic musculoskeletal pain, bringing contrasting results to the forefront. Thus far, however, there has been no synthesis of evidence on the effect of BoNT-A as an adjunctive treatment within a multimodal approach. Hence, Medline via PubMed, EMBASE, and the Cochrane Library-CENTRAL were searched until November 2020 for randomised controlled trials (RCTs) that investigated the use of BoNT-A as an adjunctive therapy for chronic musculoskeletal pain. The risk of bias (RoB) and the overall quality of the studies were assessed through RoB 2.0 and the GRADE approach, respectively. Meta-analysis was conducted to analyse the pooled results of the six included RCTs. Four were at a low RoB, while two were at a high RoB. The meta-analysis showed that BoNT-A as an adjunctive therapy did not significantly decrease pain compared to the sole use of traditional treatment (SDM −0.89; 95% CI −1.91; 0.12; p = 0.08). Caution should be used when interpreting such results, since the studies displayed very high heterogeneity (I = 94%, p < 0.001). The overall certainty of the evidence was very low. The data retrieved from this systematic review do not support the use of BoNT-A as an adjunctive therapy in treating chronic musculoskeletal pain

RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome

: Heterozygous mutations in the gene encoding RagD GTPase were shown to cause a novel autosomal dominant condition characterized by kidney tubulopathy and cardiomyopathy. We previously demonstrated that RagD, and its paralogue RagC, mediate a non-canonical mTORC1 signaling pathway that inhibits the activity of TFEB and TFE3, transcription factors of the MiT/TFE family and master regulators of lysosomal biogenesis and autophagy. Here we show that RagD mutations causing kidney tubulopathy and cardiomyopathy are "auto- activating", even in the absence of Folliculin, the GAP responsible for RagC/D activation, and cause constitutive phosphorylation of TFEB and TFE3 by mTORC1, without affecting the phosphorylation of "canonical" mTORC1 substrates, such as S6K. By using HeLa and HK-2 cell lines, human induced pluripotent stem cell-derived cardiomyocytes and patient-derived primary fibroblasts, we show that RRAGD auto-activating mutations lead to inhibition of TFEB and TFE3 nuclear translocation and transcriptional activity, which impairs the response to lysosomal and mitochondrial injury. These data suggest that inhibition of MiT/TFE factors plays a key role in kidney tubulopathy and cardiomyopathy syndrome

Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma

Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation. The compounds showed anti-tumor activity in in&nbsp;vitro and in&nbsp;vivo models, linked to suppression of MITF function. Both drugs profoundly sensitize melanoma cells to MAPK inhibitors, regulating key signaling networks in melanoma, including the MITF/APAF-1 axis. Significant activity of the two compounds in inhibiting specific epigenetic modulators of MITF/APAF-1 expression, such as histone deacetylases, was observed. In summary, we demonstrate that targeting the MITF/APAF-1 axis may overcome resistance and could be exploited as a potential therapeutic approach to treat resistant melanoma

Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma

Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation. The compounds showed anti-tumor activity in in vitro and in vivo models, linked to suppression of MITF function. Both drugs profoundly sensitize melanoma cells to MAPK inhibitors, regulating key signaling networks in melanoma, including the MITF/APAF-1 axis. Significant activity of the two compounds in inhibiting specific epigenetic modulators of MITF/APAF-1 expression, such as histone deacetylases, was observed. In summary, we demonstrate that targeting the MITF/APAF-1 axis may overcome resistance and could be exploited as a potential therapeutic approach to treat resistant melanoma