Remission of severe restless legs syndrome and periodic limb movements in sleep after bilateral excision of multiple foot neuromas: a case report

<p>Abstract</p> <p>Introduction</p> <p>Restless legs syndrome is a sensorimotor neurological disorder characterized by an urge to move the legs in response to uncomfortable leg sensations. While asleep, 70 to 90 percent of patients with restless legs syndrome have periodic limb movements in sleep. Frequent periodic limb movements in sleep and related brain arousals as documented by polysomnography are associated with poorer quality of sleep and daytime fatigue. Restless legs syndrome in middle age is sometimes associated with neuropathic foot dysesthesias. The causes of restless legs syndrome and periodic limb movements in sleep are unknown, but the sensorimotor symptoms are hypothesized to originate in the central nervous system. We have previously determined that bilateral forefoot digital nerve impingement masses (neuromas) may be a cause of both neuropathic foot dysesthesias and the leg restlessness of restless legs syndrome. To the best of our knowledge, this case is the first report of bilateral foot neuromas as a cause of periodic limb movements in sleep.</p> <p>Case presentation</p> <p>A 42-year-old Caucasian woman with severe restless legs syndrome and periodic limb movements in sleep and bilateral neuropathic foot dysesthesias was diagnosed as having neuromas in the second, third, and fourth metatarsal head interspaces of both feet. The third interspace neuromas represented regrowth (or 'stump') neuromas that had developed since bilateral third interspace neuroma excision five years earlier. Because intensive conservative treatments including repeated neuroma injections and various restless legs syndrome medications had failed, radical surgery was recommended. All six neuromas were excised. Leg restlessness, foot dysesthesias and subjective sleep quality improved immediately. Assessment after 18 days showed an 84 to 100 percent reduction of visual analog scale scores for specific dysesthesias and marked reductions of pre-operative scores of the Pittsburgh sleep quality index, fatigue severity scale, and the international restless legs syndrome rating scale (36 to 4). Polysomnography six weeks post-operatively showed improved sleep efficiency, a marked increase in rapid eye movement sleep, and marked reductions in hourly rates of both periodic limb movements in sleep with arousal (135.3 to 3.3) and spontaneous arousals (17.3 to 0).</p> <p>Conclusion</p> <p>The immediate and near complete remission of symptoms, the histopathology of the excised tissues, and the marked improvement in polysomnographic parameters documented six weeks after surgery together indicate that this patient's severe restless legs syndrome and periodic limb movements in sleep was of peripheral nerve (foot neuroma) origin. Further study of foot neuromas as a source of periodic limb movements in sleep and as a cause of sleep dysfunction in patients with or without concomitant restless legs syndrome, is warranted.</p

MIR137 is an androgen regulated repressor of an extended network of transcriptional coregulators

Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of mIR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression

Resveratrol increases BRCA1 and BRCA2 mRNA expression in breast tumour cell lines

International audienceThe phytochemical resveratrol, found in grapes, berries and peanuts, has been found to possess cancer chemopreventive effects by inhibiting diverse cellular events associated with tumour initiation, promotion and progression. Resveratrol is also a phyto-oestrogen, binds to and activates oestrogen receptors that regulate the transcription of oestrogen-responsive target genes such as the breast cancer susceptibility genes BRCA1 and BRCA2. We investigated the effects of resveratrol on BRCA1 and BRCA2 expression in human breast cancer cell lines (MCF7, HBL 100 and MDA-MB 231) using quantitative real-time RT-PCR, and by perfusion chromatography of the proteins. All cell lines were treated with 30 microM resveratrol. The expressions of BRCA1 and BRCA2 mRNAs were increased although no change in the expression of the proteins were found. These data indicate that resveratrol at 30 micro M can increase expression of genes involved in the aggressiveness of human breast tumour cell lines

All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all-trans-retinoic acid (ATRA) can restore retinoid-induced transcription and promote degradation of the PML-RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re-modeling. Recent studies have identified autophagy as an integral component of ATRA-induced myeloid differentiation. Methods: As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy-related transcripts. Results: ATRA altered the expression of >80 known autophagy-related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5-fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA-resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA. Conclusions: We show for the first time that TFEB plays an important role in ATRA-induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note: this study includes data obtained from NCT00195156, https://clinicaltrials.gov/show/NCT00195156)

All-Trans-Retinoic Acid Combined With Valproic Acid Can Promote Differentiation in Myeloid Leukemia Cells by an Autophagy Dependent Mechanism

Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Application of differentiation therapy to other AML subtypes would be a major treatment advance. Recent studies have indicated that autophagy plays a key role in the differentiation of ATRA-responsive APL cells. In this study, we have investigated whether differentiation could be enhanced in ATRA resistant cells by promoting autophagy induction with valproic acid (VPA). ATRA sensitive (NB4) and resistant leukemia cells (NB4R and THP-1) were co-treated with ATRA and valproic acid, followed by assessment of autophagy and differentiation. The combination of VPA and ATRA induced autophagic flux and promoted differentiation in ATRA-sensitive and -resistant cell lines. shRNA knockdown of ATG7 and TFEB autophagy regulators impaired both autophagy and differentiation, demonstrating the importance of autophagy in the combination treatment. These data suggest that ATRA combined with valproic acid can promote differentiation in myeloid leukemia cells by mechanism involving autophagy

Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau.

BACKGROUND: In Guinea-Bissau we conducted three trials of neonatal vitamin A supplementation (NVAS) from 2002 to 2008. None of the trials found a beneficial effect on mortality. From 2003 to 2007, an early measles vaccine (MV) trial was ongoing, randomizing children 1:2 to early MV at 4.5 months or no early MV, in addition to the usual MV at 9 months. We have previously found interactions between vitamin A and vaccines. OBJECTIVE: We investigated whether there were interactions between NVAS and early MV. DESIGN: We compared the mortality of NVAS and placebo recipients: first, from 4.5 to 8 months for children randomized to early MV or no early MV; and second, from 9 to 17 months in children who had received two MV or one MV. Mortality rates (MR) were compared in Cox models producing mortality rate ratios (MRR). RESULTS: A total of 5141 children were randomized to NVAS (N=3015) or placebo (N=2126) and were later randomized to early MV (N=1700) or no early MV (N=3441). Between 4.5 and 8 months, NVAS compared with placebo was associated with higher mortality in early MV recipients (MR=30 versus MR=0, p=0.01), but not in children who did not receive early MV (p for interaction between NVAS and early MV=0.03). From 9 to 17 months NVAS was not associated with mortality. Overall, from 4.5 to 17 months NVAS was associated with increased mortality in early MV recipients (Mortality rate ratio=5.39 (95% confidence interval: 1.62, 17.99)). CONCLUSIONS: These observations indicate that NVAS may interact with vaccines given several months later. This may have implications for the planning of future child intervention programs

An RBP4 promoter polymorphism increases risk of type 2 diabetes

Aims/hypothesis: Retinol-binding protein 4 (RBP4), originally known for retinol transport, was recently identified as an adipokine affecting insulin resistance. The RBP4 -803GA promoter polymorphism influences binding of hepatic nuclear factor 1α and is associated with type 2 diabetes in case-control studies. We hypothesised that the RBP4 -803GA polymorphism increases type 2 diabetes risk at a population-based level. In addition, information on retinol intake and plasma vitamin A levels enabled us to explore the possible underlying mechanism. Methods: In the Rotterdam Study, a prospective, population-based, follow-up study, the -803GA polymorphism was genotyped. In Cox proportional hazards models, associations of the -803GA polymorphism and retinol intake with type 2 diabetes risk were examined. Moreover, the interaction of the polymorphism with retinol intake on type 2 diabetes risk was assessed. In a subgroup of participants the association of the polymorphism and vitamin A plasma levels was investigated. Results: Homozygous carriers of the -803A allele had increased risk of type 2 diabetes (HR 1.83; 95% CI 1.26-2.66). Retinol intake was not associated with type 2 diabetes risk and showed no interaction with the RBP4 -803GA polymorphism. Furthermore, there was no significant association of the polymorphism with plasma vitamin A levels. Conclusions/interpretation: Our results provide evidence that homozygosity for the RBP4 -803A allele is associated with increased risk of type 2 diabetes in the Rotterdam population. This relationship was not clearly explained by retinol intake and vitamin A plasma levels. Therefore, we cannot differentiate between a retinol-dependent or -independent mechanism of this RBP4 variant

Trastuzumab Produces Therapeutic Actions by Upregulating miR-26a and miR-30b in Breast Cancer Cells

OBJECTIVE: Trastuzumab has been used for the treatment of HER2-positive breast cancer (BC). However, a subset of BC patients exhibited resistance to trastuzumab therapy. Thus, clarifying the molecular mechanism of trastuzumab treatment will be beneficial to improve the treatment of HER2-positive BC patients. In this study, we identified trastuzumab-responsive microRNAs that are involved in the therapeutic effects of trastuzumab. METHODS AND RESULTS: RNA samples were obtained from HER2-positive (SKBR3 and BT474) and HER2-negetive (MCF7 and MDA-MB-231) cells with and without trastuzumab treatment for 6 days. Next, we conducted a microRNA profiling analysis using these samples to screen those microRNAs that were up- or down-regulated only in HER2-positive cells. This analysis identified miR-26a and miR-30b as trastuzumab-inducible microRNAs. Transfecting miR-26a and miR-30b induced cell growth suppression in the BC cells by 40% and 32%, respectively. A cell cycle analysis showed that these microRNAs induced G1 arrest in HER2-positive BC cells as trastuzumab did. An Annexin-V assay revealed that miR-26a but not miR-30b induced apoptosis in HER2-positive BC cells. Using the prediction algorithms for microRNA targets, we identified cyclin E2 (CCNE2) as a target gene of miR-30b. A luciferase-based reporter assay demonstrated that miR-30b post-transcriptionally reduced 27% (p = 0.005) of the gene expression by interacting with two binding sites in the 3'-UTR of CCNE2. CONCLUSION: In BC cells, trastuzumab modulated the expression of a subset of microRNAs, including miR-26a and miR-30b. The upregulation of miR-30b by trastuzumab may play a biological role in trastuzumab-induced cell growth inhibition by targeting CCNE2