pinecone/core-2020-05-10-deduplication huggingface dataset:
Predictors of functional dependency in Parkinson’s disease

Financial disclosures/conflicts of interest: Dr Macleod was funded by a Clinical Academic Fellowship from the Chief Scientist Office of the Scottish Government and received grant funding from Parkinson’s UK, the Wellcome Trust, University of Aberdeen, and NHS Grampian endowments relating to this research. Dr Counsell received grant funding from Parkinson’s UK, National Institute for Health Research, the Scottish Chief Scientist Office, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, NHS Grampian endowments and SPRING relating to this research. We declare we have no conflicts of interest. Financial support: This study was funded by Parkinson’s UK, the Scottish Chief Scientist Office, NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, and SPRING.  Peer reviewedPublisher PD
A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington&#039;s disease

BACKGROUND: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington\u27s disease.
METHODS: Ninety-six patients with early-stage Huntington\u27s disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo.
RESULTS: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated.
CONCLUSIONS: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington\u27s disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society
The antiparkinsonian actions and pharmacokinetics of transdermal (+)-4-propyl-9-hydroxynaphthoxazine (+PHNO): preliminary results

(+)-4-Propyl-9-hydroxynaphthoxazine (+PHNO) is a potent dopamine agonist that has been administered transdermally to four patients with Parkinson's disease and "on-off" fluctuations. Skin patches of increasing size were used to treat these patients, who also received infrequent doses of oral levodopa if required. The effect of +PHNO was measured as an increased duration of action of individual levodopa doses. The clinical effect measured in this way was directly proportional to the plasma concentrations of +PHNO achieved. The plasma concentrations of +PHNO began to rise 4-6 h after patch application and reached a steady state by 24 h. The final plasma concentration of +PHNO was proportional to the area of skin covered
Case ascertainment uncertainties in prevalence surveys of Parkinson's disease

Using unpublished data from five completed prevalence surveys of Parkinson's disease (PD), we investigated case ascertainment uncertainties that potentially have a direct effect on prevalence. These uncertainties arise from the choice of diagnostic criteria, the choice of screening method, and the amount of information lost because of nonresponse. The surveys were conducted in Argentina, India, China, Italy, and the Netherlands. Our analyses consisted of simple comparisons of prevalence results, positive predictive values (a screening measure), and nonresponse percentages. We found that (a) prevalence comparisons between surveys have diminished value if the surveys used different diagnostic criteria for PD; (b) screening performance may be affected adversely if symptom questions are answered by one family member for the entire family living together rather than by each family member individually; and (c) nonresponse from refusal or unavailability does not necessarily lead to bias, but special caution may be appropriate with prevalence results pertaining to elderly women
Therapeutic applications of glycosidic carbonic anhydrase inhibitors

The zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1) are very efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate and hence play an important physiological role. In humans, 16 different isozymes have been described, some of them being involved in various pathological disorders. Several of these isozymes are considered as drug targets, and the design of selective inhibitors is a long-standing goal that has captured the attention of researchers for 40 years and has lead to clinical applications against different pathologies such as glaucoma, epilepsy, and cancer. Among the different strategies developed for designing selective CA inhibitors (CAIs), the "sugar approach" has recently emerged as a new attractive and versatile tool. Incorporation of glycosyl moieties in different aromatic/heterocyclic sulfonamide/sulfamides/sulfamates scaffolds has led to the development of numerous and very effective inhibitors of potential clinical value. The clinical use of a highly active carbohydrate-based CA inhibitor, i.e., topiramate, constitutes an interesting demonstration of the validity of this approach. Other carbohydrate-based compounds also demonstrate promising potential for the treatment of ophthalmologic diseases. This review will focus on the development of this emerging sugar-based approach for the development of CAIs.Full Tex
ROS Receptor Tyrosine Kinase: A New Potential Target for Anticancer Drugs

ROS kinase is one of the last two remaining orphan receptor tyrosine kinases with an as yet unidentified ligand. The normal functions of human ROS kinase in different body tissues have not been fully identified so far. However, the ectopic expression, as well as the production of variable mutant forms of ROS kinase has been reported in a number of cancers, such as glioblastoma multiforme, and non-small cell lung cancer, suggesting a role for ROS kinase in deriving such tumors. It is thought also that c-ROS gene may have a role in some cardiovascular diseases, and the fact that homozygous male mice targeted against c-ROS gene are healthy but infertile, has inspired researchers to think about ROS inhibition as a method for development of new male contraceptives. The recent discovery of new selective and potent inhibitors for ROS kinase, along with the development of new specific diagnostic methods for the detection of ROS fusion proteins, raises the importance of using these selective inhibitors for targeting ROS mutations as a new method for treatment of cancers harboring such genes. This review focuses on the ectopic expression of ROS and its fusion proteins in different cancer types and highlights the importance of targeting these proteins for treatment of substantial cancers. It describes also the recent advances in the field of ROS kinase inhibition, and the potential clinical applications of ROS kinase inhibitors.Full Tex
Potential of carbohydrate-binding agents as therapeutics against enveloped viruses

Twenty-seven years after the discovery of HIV as the cause of AIDS more than 25 drugs directed against four different viral targets (i.e. reverse transcriptase, protease, integrase, envelope gp41) and one cellular target (i.e. CCR5 co-receptor) are available for treatment. However, the search for an efficient vaccine is still ongoing. One of the main problems is the presence of a continuously evolving dense carbohydrate shield, consisting of N-linked glycans that surrounds the virion and protects it against efficient recognition and persistent neutralization by the immune system. However, several lectins from the innate immune system specifically bind to these glycans in an attempt to process the virus antigens to provoke an immune response. Across a wide variety of different species in nature lectins can be found that can interact with the glycosylated envelope of HIV-1 and can block the infection of susceptible cells by the virus. In this review, we will give an overview of the lectins from non-mammalian origin that are endowed with antiviral properties and discuss the complex interactions between lectins of the innate immune system and HIV-1. Also, attention will be given to different carbohydrate-related modalities that can be exploited for antiviral chemotherapy.  © 2010 Wiley Periodicals, Inc. Med Res Rev.status: publishe
Doxorubicin-Induced Cardiotoxicity: From Bioenergetic Failure and Cell Death to Cardiomyopathy

Doxorubicin (DOX) is an anticancer anthracycline that presents a dose-dependent and cumulative
cardiotoxicity as one of the most serious side effects. Several hypotheses have been advanced to explain DOX cardiac side effects, which culminate in the development of life-threatening cardiomyopathy.
One of the most studied mechanisms involves the activation of DOX molecule into a more reactive
semiquinone by mitochondrial Complex I, resulting in increased oxidative stress. The present review describes and critically discusses what is known about some of the potential mechanisms of DOX-induced cardiotoxicity including mitochondrial oxidative damage and loss of cardiomyocytes. We also discuss alterations
of mitochondrial metabolism and the unique characteristics of DOX delayed toxicity, which can
also interfere on how the cardiac muscle handles a “second-hit stress.” We also present pharmaceutical and nonpharmaceutical approaches that may decrease DOX cardiac alterations in animal models and humans and discuss the limitations of each strategy
Perspectives and Potential Applications of Mitochondria-Targeted Antioxidants in Cardiometabolic Diseases and Type 2 Diabetes

There is abundant evidence to suggest that mitochondrial dysfunction is a main cause of insulin resistance and related cardiometabolic comorbidities. On the other hand, insulin resistance is one of the main characteristics of type 2 diabetes, obesity, and metabolic syndrome. Lipid and glucose metabolism require mitochondria to generate energy, and when O2 consumption is low due to inefficient nutrient oxidation, there is an increase in reactive oxygen species, which can impair different types of molecules, including DNA, lipids, proteins, and carbohydrates, thereby inducing proinflammatory processes. Factors which contribute to mitochondrial dysfunction, such as mitochondrial biogenesis and genetics, can also lead to insulin resistance in different insulin-target tissues, and its association with mitochondrial dysfunction can culminate in the development of cardiovascular diseases. In this context, therapies that improve mitochondrial function may also improve insulin resistance. This review explains mechanisms of mitochondrial function related to the pathological effects of insulin resistance in different tissues. The pathogenesis of cardiometabolic diseases will be explained from a mitochondrial perspective and the potential beneficial effects of mitochondria-targeted antioxidants as a therapy for modulating mitochondrial function in cardiometabolic diseases, especially diabetes, will also be considered.Contract grant sponsor: PI10/1195; Contract grant sponsor: PI 12/1984; Contract grant sponsor: CIBERehd CB06/04/0071; Contract grant sponsor: PROMETEO 2010/060; Contract grant sponsor: ACOMP/2012/042; Contract grant sponsor: ACOMP/2012/045; Contract grant sponsor: ACOMP2013/061; Contract grant sponsor: European Regional Development Fund (ERDF)
Emerging antiviral strategies to interfere with influenza virus entry

Influenza A and B viruses are highly contagious respiratory pathogens with a considerable medical and socioeconomical burden and known pandemic potential. Current influenza vaccines require annual updating and provide only partial protection in some risk groups. Due to the global spread of viruses with resistance to the M2 proton channel inhibitor amantadine or the neuraminidase inhibitor oseltamivir, novel antiviral agents with an original mode of action are urgently needed. We here focus on emerging options to interfere with the influenza virus entry process, which consists of the following steps: attachment of the viral hemagglutinin to the sialylated host cell receptors, endocytosis, M2-mediated uncoating, low pH-induced membrane fusion, and, finally, import of the viral ribonucleoprotein into the nucleus. We review the current functional and structural insights in the viral and cellular components of this entry process, and the diverse antiviral strategies that are being explored. This encompasses small molecule inhibitors as well as macromolecules such as therapeutic antibodies. There is optimism that at least some of these innovative concepts to block influenza virus entry will proceed from the proof of concept to a more advanced stage. Special attention is therefore given to the challenging issues of influenza virus (sub)type-dependent activity or potential drug resistance.status: publishe
Molecular biology and inhibitors of hepatitis A virus

Hepatitis A virus (HAV) is a faeco-orally transmitted picornavirus and is one of the main causes of acute hepatitis worldwide. An overview of the molecular biology of HAV is presented with an emphasis on recent findings. Immune evasion strategies and a possible correlation between HAV and atopy are discussed as well. Despite the availability of efficient vaccines, antiviral drugs targeting HAV are required to treat severe cases of fulminant hepatitis, contain outbreaks, and halt the potential spread of vaccine-escape variants. Additionally, such drugs could be used to shorten the period of illness and decrease associated economical costs. Several known inhibitors of HAV with various mechanisms of action will be discussed. Since none of these molecules is readily useable in the clinic and since the availability of an anti-HAV drug would be of clinical importance, increased efforts should be targeted toward discovery and development of such antivirals.status: publishe
The influenza virus polymerase complex: an update on its structure, functions, and significance for antiviral drug design

Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti-influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure-aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap-binding PB2 subunit. Alternatively, inhibitors may target a protein-protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX-787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.status: publishe
Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.Project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000021), co-funded by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund (ERDF) and also supported by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)info:eu-repo/semantics/publishedVersio
Tumor angiogenesis revisited: Regulators and clinical implications

Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases
Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research-practice gaps, challenges, and insights

To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune-based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life-threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer-related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research-practice gaps, addressing real-world challenges and pinpointing real-time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio-oncology and crosses the interface between oncology and onco-pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research-practice gaps may advance research initiatives on the development of mechanism-based diagnoses and treatments for the effective clinical management of cardiotoxicity
All the World's a Stage: Making Sense of Shakespeare

This paper reports on the findings of a study examining how theatre professionals (actors, directors and others) make sense of the works of a culturally iconic author (William Shakespeare). The findings of the study are based on interviews with 35 theatre professionals in Canada, Finland and the UK. The study aims a more holistic approach to the study of information behaviour, one which acknowledges the complexity of sense-making as more than the problem-solving behaviour of individuals as an embodied, social process, involving emotion as well as rationality. In doing so it draws on theoretical approaches from a range of different disciplines and traditions, including Dervin's Sense-Making, Foucault's discourse analysis and Derrida's deconstructionism
Media awareness in the age of new media: a case study of Primary 4 students in Hong Kong

This study examined media use and media awareness for Primary 4 students from four schools in Hong Kong (equivalent to Grade 4 in America) and how well their teachers understood their habits of and preferences for media use. The media awareness and media use patterns of students with regard to newspapers, television programmes, radio channels and the Internet were investigated. Results showed that, these students, despite being the new generation of the new media still believed that the news from television, radio and newspapers are more reliable. In addition, they were found to be more proactive media users than their teachers thought. They were more content-oriented in choosing a particular newspaper or TV channel instead of being influenced by their teachers and parents. The teachers were also not able to make very accurate predictions of their students' skills in media evaluation. The findings suggested that more contextual and in-depth approaches are needed to assess the students' media use patterns, from which relevant media education models can be derived.postprin