Mining Facebook Data of People with Rare Diseases: A Content-Based and Temporal Analysis

Subirats L, Reguera N, Bañón AM, Gómez-Zúñiga B, Minguillón J, Armayones M.; Int J Environ Res Public Health. 2018;15(9):1877. Published 2018 Aug 30. doi:10.3390/ijerph15091877

This research characterized how Facebook deals with rare diseases. This characterization included a content-based and temporal analysis, and its purpose was to help users interested in rare diseases to maximize the engagement of their posts and to help rare diseases organizations to align their priorities with the interests expressed in social networks. This research used Netvizz to download Facebook data, word clouds in R for text mining, a log-likelihood measure in R to compare texts and TextBlob Python library for sentiment analysis. The Facebook analysis shows that posts with photos and positive comments have the highest engagement. We also observed that words related to diseases, attention, disability and services have a lot of presence in the decalogue of priorities (which serves for all associations to work on the same objectives and provides the lines of action to be followed by political decision makers) and little on Facebook, and words of gratitude are more present on Facebook than in the decalogue. Finally, the temporal analysis shows that there is a high variation between the polarity average and the hour of the day.

Real‐time use of audio‐biofeedback can improve postural sway in patients with degenerative ataxia

Zofia Fleszar, Sabato Mellone, Martin Giese, Carlo Tacconi, Clemens Becker, Ludger Schöls, Matthis Synofzik, Winfried Ilg; Annals of Clinical and Translational Neurology, Early View, First published: 28 November 2018 doi:10.1002/acn3.699

Our findings provide proof‐of‐principle evidence that subjects with cerebellar degeneration are still able to integrate additional sensory modalities to compensate for deficient postural control: They can use auditory cues functionally similar to vision in the absence of vision, and additive to vision in the presence of vision (in case of pronounced postural sway). These findings might inform future assistive strategies for cerebellar ataxia

Mitochondria, Nrf2 and mTOR

Gino Cortopassi. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S7, doi:10.1016/j.freeradbiomed.2018.10.382.

Abstract: Friedreich's ataxia (FA) is the most common recessive ataxia, and it's phenotype is clinically indistinguishable from AVED, a deficiency of Vitamin E transport. We were the first to show that Friedreich's patient cells are very sensitive to oxidative stress. Ultimately this defect appears to reside in a deficiency of the antioxidant pathway Nrf2, which is less active in Friedreich's patient cells, and in FA animal models. Perhaps as a result of this Nrf2 defect, there is increased inflammation in Friedreich's patient cells and mice. But as Nrf2 is not only important in antioxidant homeostasis, but also mitochondrial homeostasis, this was investigated in Friedreich's models and patients. We found that Friedreich's cells, mice, and even people have an approximately 40% mitochondrial biogenesis defect. A high-throughput screening campaign for drugs that rescued Friedreich's cells from death identified three Nrf2 inducers, which could be of benefit in human Friedreich's therapy. One of these drugs, dimethyl fumarate, was shown to dose-dependently increase mitochondrial biogenesis and function when dosed in cells, and to increase mitochondrial biogenesis in mouse and human tissues, with a mechanism that appears to require Nrf2. Thus there is an interplay between Nrf2, mitochondrial biogenesis, and antioxidant status. We observed in a particular cancer there are alterations of mitochondrial biogenesis, which appear to result from differential Nrf2 activity. These differences in mitochondrial number allow the selective killing of such cells by mitochondrial inhibitors and a novel category of mTOR inhibitors.

Heme oxygenase-1 is required for iron homeostasis and mitochondrial respiration

Jennifer Carr, Ping La, Phyllis Dennery. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S81, doi.org/10.1016/j.freeradbiomed.2018.10.182.

Heme is an essential cofactor in several enzymes of the electron transport chain (ETC) where its primary function is the coordination of iron to facilitate redox reactions. Unbound, free heme is strongly oxidative such that the cell has evolved mechanisms to prevent it from causing oxidative damage. This includes the catalytic breakdown of heme by heme oxygenase (HO-1), generating antioxidants CO and biliverdin. However the catabolism of heme also releases highly toxic free iron which seems counter productive to the antioxidant effort. We sought to explore the role of HO-1 in iron homeostasis using HO-1 knockout mouse embryonic fibroblasts and HO-1 deficient human liver cells. By Western blot these cells showed dysregulated iron handling including increased expression of transferrin receptor and decreased expression of ferritin and ferroportin compared to wild type controls. Additionally cytosolic aconitase activity was decreased in HO-1 deficient cells while the mutually exclusive mRNA binding activity of aconitase was increased. This switch is indicative of reduced FeS cluster availability. Consistent with FeS cluster deficiency we observed decreased frataxin mRNA levels, the product of which is involved in FeS cluster assembly in the mitochondria. Because FeS clusters are important in the ETC we examined mitochondrial respiration with a Seahorse Bioanalyzer (Agilent) and found it to be markedly reduced in HO-1 knockout cells. Interestingly, this was partially rescued by exogenous iron (1nM transferrin). Our findings suggest that an additional and important role of HO-1 is the maintenance of cellular iron homeostasis via the release of iron upon breakdown of heme.

Corporate Social Responsibility (CSR) of Innovative Pharmaceutical Corporations. The Case of BIOGEN

Janina Witkowska. Comparative Economic Research, Volume 21: Issue 3 45–62, First Online: 19 Sep 2018 DOI:10.2478/cer-2018-0018

The aim of a paper published in Comparative Economic Research was to discuss the common features and specificity of Corporate Social Responsibility (CSR) practices of innovative transnational corporations acting in the pharmaceutical industry, understood as their ability to make a breakthrough in the treatment of rare, incurable diseases. Traditional CSR practices include corporate philanthropy, community and neighbourhood programmes, volunteerism, etc. The author of the paper argues that the issue of CSR in the innovative pharmaceutical industry is the pricing of orphan and ultra-orphan drugs, while the case study of BIOGEN seems to show that the company is aware of the need to remove barriers to access the medicines. The author also suggests that a stronger international cooperation is needed to ensure equity of medicine access in a more efficient way.

Depression disorder in patients with cerebellar damage: Awareness of the mood state

ilvia Clausi, Michela Lupo, Giusy Olivito, Libera Siciliano, Maria Pia Contento, Fabio Aloise, Luigi Pizzamiglio, Marco Molinari, Maria Leggio. Journal of Affective Disorders, Volume 245, 2019, Pages 386-393, doi:10.1016/j.jad.2018.11.029.

Cerebellar dysfunction might slow the data integration necessary for mood state awareness, resulting in difficulty of depressed CB patients in explicitly recognizing their mood “in the here and now”.
In conclusion, cerebellar involvement in the conscious component of emotional behaviour, related to awareness of one's affective state and interpretation of one's mood, may contribute to a loss of the‘online’ self-perception of negative mood that characterizes depressive disorders in the presence of cerebellar pathology. These data may help explain why depression in cerebellar patients is often underdiagnosed.

Paradoxical disruption of Nrf2 signaling despite mitochondrial iron driven oxidative stress in Friedreich’s ataxia cardiomyopathy

Michael Huang, Amy Anzovino, Shannon Chiang, Bronwyn Brown, Clare Hawkins, Des Richardson. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S131, doi.org/10.1016/j.freeradbiomed.2018.10.346

Cardiomyopathy is the leading cause of mortality for the most prevalent inherited ataxia, Friedreich’s ataxia (FA). Deficient expression of the mitochondrial protein frataxin that is crucial for mitochondrial iron metabolism is the cause of FA, which exhibits marked mitochondrial Fe accumulation. Our studies using a conditional cardiac frataxin knockout (KO) mouse that mirrors FA cardiomyopathy have shown frataxin deletion leads to pronounced trafficking of cardiac iron from the cytosol to the mitochondrion, leading to a cytosolic iron-deficiency and mitochondrial iron accumulation in the form of non-protein-bound, biomineral iron aggregates. The ensuing oxidative stress is likely a key contributor to FA pathology. The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is the master regulator of cellular antioxidant response. In the frataxin KO mouse, our studies demonstrated increased protein and GSH oxidation in the KO relative to wild-type (WT) littermates. Despite this, we found paradoxical decreases in total and nuclear Nrf2 protein and an increase in its inhibitor, Keap1, which mediates Nrf2 degradation in the cytosol. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via Gsk3β-signaling was found in the KO heart. This is evident by: (i) increased Gsk3β activation; (ii) increased Fyn-mediated nuclear Nrf2 export; and (iii) increased expression of β-TrCP that is involved in Nrf2 degradation. Furthermore, a corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA was observed in KO heart. Collectively, despite marked mitochondrial iron accumulation in FA cardiomyopathy, Nrf2 activity was disrupt via two mechanisms: increased Keap1 that decreases cytosolic Nrf2, and the activation of Gsk3β-signaling that decreases nuclear Nrf2.

Del deseo a la realidad: la edición genética (aún) no está preparada para tratar a pacientes

SINC, la ciencia es noticia (17 noviembre 2018). Lluís Montoliu, es investigador científico del Centro Nacional de Biotecnología (CNB-CSIC) y Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER-ISCIII), además de miembro del Comité de Ética del CSIC.

Las terapias génicas basadas en CRISPR para curar enfermedades todavía tardarán en llegar. Quizás no sea este el titular que quisiéramos leer, pero es el mensaje que hay que repetir para no generar falsas expectativas sobre esta potente herramienta de corta-pega genético.

Hoy en día se están desarrollando múltiples variantes de la técnica CRISPR, a cual más innovadora e imaginativa. Algunas de ellas son extremadamente prometedoras, como los editores de bases, una evolución de las herramientas CRISPR capaz de cambiar nucleótidos concretos del genoma sin necesidad de cortarlo. Pero todas ellas conllevan todavía riesgos inaceptables, tanto en seguridad como en eficacia, para saltar al hospital.

Son métodos sofisticados que nos permiten abordar experimentos en el laboratorio como nunca antes habíamos podido hacerlo, pero que todavía no pueden trasladarse a la clínica. Necesitan de mucho más trabajo, mucha más investigación en el laboratorio.

Mitochondrial calcium signalling and neurodegenerative diseases

Elena Britti, Fabien Delaspre, Jordi Tamarit, Joaquim Ros; Neuronal Signaling Dec 2018, 2 (4) NS20180061; DOI: 10.1042/NS20180061

Mitochondrial calcium homoeostasis clearly contributes to cellular fitness and survival. Maintenance of accurate calcium levels is highly regulated by mitochondrial proteins that are connected, either directly or via other proteins, to ER calcium stores. As described in this review, prior to cell death, mitochondrial calcium deregulation could be the consequence of increased influx (MCU complex), or decreased efflux (Na+/Ca2+ exchanger) or altered capacity for calcium buffering caused by mitochondrial damage, such as MPTP opening. Calcium deregulation would then lead to several neurodegenerative processes that resulted in cell death. Thus, identifying specific targets to maintain calcium balance and mitochondrial function appears to be of paramount importance in preventing, alleviating or even curing neurodegenerative diseases.
Although the initial steps of the process through which decreased levels of frataxin leads to neurodegeneration are still unknown, the above-reported findings clearly point to an important role of calcium deregulation in the pathophysiology of FA. Therapeutic strategies that impact on the proteins responsible for calcium overload and its consequences could be of great value for developing a cure for the disease.

FAST-1 antisense RNA epigenetically alters FXN expression

Hajar Mikaeili, Madhavi Sandi, Aurélien Bayot, Sahar Al-Mahdawi & Mark A. Pook; Scientific Reports, volume 8, Article number: 17217 (2018). doi:10.1038/s41598-018-35639-2

Our results show that knocking down FAST-1 in FRDA fibroblast cells increases FXN gene expression (Fig. 10). Therefore, it can be concluded that, since FAST-1 is associated with epigenetic repression of the FXN gene, inhibition of FAST-1 may be an approach to increase the FXN transcripts and stimulate subsequent protein expression. Indeed, our results demonstrate that knocking down FAST-1 in FRDA results in a significant increase in aconitase enzyme activity, a good indicator of frataxin function within cells. Our data suggest that since FAST-1 is associated with FXN gene silencing, inhibition of FAST-1 may be an approach for FRDA therapy. Considering the nature of NATs and the fact that many currently available drugs would not affect the activity of non-coding RNA molecules, developing new methods to disrupt the function of NATs seems necessary.

NMR as a Tool to Investigate the Processes of Mitochondrial and Cytosolic Iron-Sulfur Cluster Biosynthesis

Cai, K.; Markley, J.L.; Molecules 2018, 23, 2213. doi:10.3390/molecules23092213

Defects in protein components of the mitochondrial ISC machinery are associated with numerous diseases, including Friedreich ataxia (defects in frataxin), myopathy (defects in ISCU or FDX2), and multiple mitochondrial dysfunction syndromes (defects in NFU1, BOLA3, ISCA2, and IBA57). Extensive investigations over the past two decades have identified many new components and established key steps in the ISC machinery. A growing number of diseases associated with ISC defects are being discovered through clinical, genetic, and biochemical studies.

Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes

Lili Guo, Qingqing Wang, Liwei Weng, Lauren A. Hauser, Cassandra J. Strawser, Clementina Mesaros, David R. Lynch & Ian A. Blair; Scientific Reports volume 8, Article number:17043 (2018) DOI:10.1038/s41598-018-35346-y

The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich’s ataxia and monitor the efficacy of therapeutic interventions.

Emerging and Dynamic Biomedical Uses of Ferritin

Brian Chiou and James R. Connor; Pharmaceuticals 2018, 11(4), 124; doi:10.3390/ph11040124

Review

One interesting new development has been proposed in Friedreich’s Ataxia where the authors discuss the hypothesis that the mitochondrial protein frataxin may oligomerize like ferritin and perform functions redundant with mitochondrial ferritin, acting as another iron storage molecule. Loss of frataxin and this iron storage property may result in Friedreich’s Ataxia and subsequent neurodegeneration.

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties

Caridad Pontes, Juan Manuel Fontanet, Roser Vives, Aranzazu Sancho, Mònica Gómez-Valent, José Ríos, Rosa Morros, Jorge Martinalbo, Martin Posch, Armin Koch, Kit Roes, Katrien Oude Rengerink, Josep Torrent-Farnell and Ferran Torres; Orphanet Journal of Rare Diseases 2018 13:206 doi:10.1186/s13023-018-0926-z

The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.

Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Zeitlberger Anna M., Thomas-Black Gilbert, Garcia-Moreno Hector, Foiani Martha, Heslegrave Amanda J., Zetterberg Henrik, Giunti Paola; Frontiers in Cellular Neuroscience 2018, 12 366, DOI=10.3389/fncel.2018.00366

This study provides the first assessment of plasma markers of neurodegeneration in FRDA, illustrating that NfL, GFAP, and UCHL1 are significantly raised in FRDA compared to aged-matched control. These observations may serve as the basis of further exploration of these brain-derived proteins as promising biomarkers in FRDA. In addition, we show for the first time in vivo an increase of GFAP reflecting astrocyte activation. This is confirmatory of in vitro studies suggesting a role of astrocytes in FRDA pathology. Finally, UCHL1 increase may reflect non-specific neuronal damage or alterations in the UPP. Future studies are needed to confirm our findings and determine whether, when applied to more heterogeneous cohorts, they serve as useful markers of disease severity.

Neuromuscular diseases with hypertrophic cardiomyopathy

Cesar S.; Global Cardiology Science and Practice 2018:27 doi:10.21542/gcsp.2018.27

Patient with FA and HCM have an early onset within the first or second decades with a poor correlation with the neurological level of disability. Histologically, left ventricle cellular hypertrophy, diffuse fibrosis and focal myocardial necrosis have been described. Echocardiographic hallmark is a concentric LV hypertrophy with absence of left ventricular outflow tract obstruction, but eccentric hypertrophy might be present.
There is no specific treatment for HCM in FA patients. Management of heart failure symptoms (salt restriction, diuretic therapy), ACE inhibitors or angiotensin II receptor blockers may be beneficial in long-term treatment. Treatment of atrial arrhythmias is mandatory, because the important atrial role to LV filling and cardiac output14. The drug idebenone acts as a transporter in the electron transport chain and has been advocated for use in FA following studies showing mild diastolic improvement and reduction LVH21,22. However, further trials have shown no benefit. Cardiac transplantation is not commonly performed, due to advanced impairment of both motor skills and muscle strength.

Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA

Phillip Ward, Ian H Harding, Thomas G Close, Louise A Corben, Martin B Delatycki, Elsdon Storey, Nellie Georgiou-Karistianis, Gary F. Egan. bioRxiv 464537; doi: 10.1101/464537 (This article is a preprint and has not been peer-reviewed)

Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.

Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia

Lynch, D. R., Farmer, J. , Hauser, L. , Blair, I. A., Wang, Q. Q., Mesaros, C. , Snyder, N. , Boesch, S. , Chin, M. , Delatycki, M. B., Giunti, P. , Goldsberry, A. , Hoyle, C. , McBride, M. G., Nachbauer, W. , O'Grady, M. , Perlman, S. , Subramony, S. H., Wilmot, G. R., Zesiewicz, T. and Meyer, C. (2018), Ann Clin Transl Neurol. . doi:10.1002/acn3.660

Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.