Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy

$\textbf{Objective}$: Evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting multiple sclerosis (RRMS). $\textbf{Methods}$: Alemtuzumab-treated patients in CARE-MS I (NCT00530348) received treatment courses at Months 0 and 12; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs). $\textbf{Results}$: Most alemtuzumab-treated patients (95.1%) who completed CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in Years 3, 4, and 5 (0.19, 0.14, 0.15). Over Years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, 62.4%) had annual NEDA in Years 3, 4, and 5. Median yearly BVL improved over Years 2–4, and remained low in Year 5 (Year 1–5: –0.59%, –0.25%, –0.19%, –0.15%, –0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at Year 3 and subsequently declined. $\textbf{Conclusions}$: Based on these data, alemtuzumab has the potential to provide durable efficacy through 5 years in the absence of continuous treatment. $\textbf{Classification of Evidence}$: This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in RRMS patients.Supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals

The p53 Tumor Suppressor Is Stabilized by Inhibitor of Growth 1 (ING1) by Blocking Polyubiquitination

The INhibitor of Growth tumor suppressors (ING1-ING5) affect aging, apoptosis, DNA repair and tumorigenesis. Plant homeodomains (PHD) of ING proteins bind histones in a methylation-sensitive manner to regulate chromatin structure. ING1 and ING2 contain a polybasic region (PBR) adjacent to their PHDs that binds stress-inducible phosphatidylinositol monophosphate (PtIn-MP) signaling lipids to activate these INGs. ING1 induces apoptosis independently of p53 but other studies suggest proapoptotic interdependence of ING1 and p53 leaving their functional relationship unclear. Here we identify a novel ubiquitin-binding domain (UBD) that overlaps with the PBR of ING1 and shows similarity to previously described UBDs involved in DNA damage responses. The ING1 UBD binds ubiquitin with high affinity (Kd∼100 nM) and ubiquitin competes with PtIn-MPs for ING1 binding. ING1 expression stabilized wild-type, but not mutant p53 in an MDM2-independent manner and knockdown of endogenous ING1 depressed p53 levels in a transcription-independent manner. ING1 stabilized unmodified and six multimonoubiquitinated forms of wild-type p53 that were also seen upon DNA damage, but not p53 mutants lacking the six known sites of ubiquitination. We also find that ING1 physically interacts with herpesvirus-associated ubiquitin-specific protease (HAUSP), a p53 and MDM2 deubiquitinase (DUB), and knockdown of HAUSP blocks the ability of ING1 to stabilize p53. These data link lipid stress signaling to ubiquitin-mediated proteasomal degradation through the PBR/UBD of ING1 and further indicate that ING1 stabilizes p53 by inhibiting polyubiquitination of multimonoubiquitinated forms via interaction with and colocalization of the HAUSP-deubiquitinase with p53

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127, suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated

Indigenous Knowledge and Long-term Ecological Change: Detection, Interpretation, and Responses to Changing Ecological Conditions in Pacific Island Communities

When local resource users detect, understand, and respond to environmental change they can more effectively manage environmental resources. This article assesses these abilities among artisanal fishers in Roviana Lagoon, Solomon Islands. In a comparison of two villages, it documents local resource users’ abilities to monitor long-term ecological change occurring to seagrass meadows near their communities, their understandings of the drivers of change, and their conceptualizations of seagrass ecology. Local observations of ecological change are compared with historical aerial photography and IKONOS satellite images that show 56 years of actual changes in seagrass meadows from 1947 to 2003. Results suggest that villagers detect long-term changes in the spatial cover of rapidly expanding seagrass meadows. However, for seagrass meadows that showed no long-term expansion or contraction in spatial cover over one-third of respondents incorrectly assumed changes had occurred. Examples from a community-based management initiative designed around indigenous ecological knowledge and customary sea tenure governance show how local observations of ecological change shape marine resource use and practices which, in turn, can increase the management adaptability of indigenous or hybrid governance systems

Immunological mechanism of action and clinical profile of disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials

A Research Agenda for Helminth Diseases of Humans: Diagnostics for Control and Elimination Programmes

Diagnostic tools appropriate for undertaking interventions to control helminth infections are key to their success. Many diagnostic tests for helminth infection have unsatisfactory performance characteristics and are not well suited for use in the parasite control programmes that are being increasingly implemented. Although the application of modern laboratory research techniques to improve diagnostics for helminth infection has resulted in some technical advances, uptake has not been uniform. Frequently, pilot or proof of concept studies of promising diagnostic technologies have not been followed by much needed product development, and in many settings diagnosis continues to rely on insensitive and unsatisfactory parasitological or serodiagnostic techniques. In contrast, PCR-based xenomonitoring of arthropod vectors, and use of parasite recombinant proteins as reagents for serodiagnostic tests, have resulted in critical advances in the control of specific helminth parasites. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR) was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, the diagnostic technologies relevant to control of helminth infections, either available or in development, are reviewed. Critical gaps are identified and opportunities to improve needed technologies are discussed

Berry Flesh and Skin Ripening Features in Vitis vinifera as Assessed by Transcriptional Profiling

Background Ripening of fleshy fruit is a complex developmental process involving the differentiation of tissues with separate functions. During grapevine berry ripening important processes contributing to table and wine grape quality take place, some of them flesh- or skin-specific. In this study, transcriptional profiles throughout flesh and skin ripening were followed during two different seasons in a table grape cultivar ‘Muscat Hamburg’ to determine tissue-specific as well as common developmental programs. Methodology/Principal Findings Using an updated GrapeGen Affymetrix GeneChip® annotation based on grapevine 12×v1 gene predictions, 2188 differentially accumulated transcripts between flesh and skin and 2839 transcripts differentially accumulated throughout ripening in the same manner in both tissues were identified. Transcriptional profiles were dominated by changes at the beginning of veraison which affect both pericarp tissues, although frequently delayed or with lower intensity in the skin than in the flesh. Functional enrichment analysis identified the decay on biosynthetic processes, photosynthesis and transport as a major part of the program delayed in the skin. In addition, a higher number of functional categories, including several related to macromolecule transport and phenylpropanoid and lipid biosynthesis, were over-represented in transcripts accumulated to higher levels in the skin. Functional enrichment also indicated auxin, gibberellins and bHLH transcription factors to take part in the regulation of pre-veraison processes in the pericarp, whereas WRKY and C2H2 family transcription factors seems to more specifically participate in the regulation of skin and flesh ripening, respectively. Conclusions/Significance A transcriptomic analysis indicates that a large part of the ripening program is shared by both pericarp tissues despite some components are delayed in the skin. In addition, important tissue differences are present from early stages prior to the ripening onset including tissue-specific regulators. Altogether, these findings provide key elements to understand berry ripening and its differential regulation in flesh and skin.This study was financially supported by GrapeGen Project funded by Genoma España within a collaborative agreement with Genome Canada. The authors also thank The Ministerio de Ciencia e Innovacion for project BIO2008-03892 and a bilateral collaborative grant with Argentina (AR2009-0021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference