Platelets at the interface of thrombosis, inflammation, and cancer

Abstract Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet’s origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet’s involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.

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The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks

Cancers ◽

10.3390/cancers13092042 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2042 ◽

Cited By ~ 1

Author(s):

Máté A. Demény ◽

László Virág

Keyword(s):

Cancer Biology ◽

Cancer Metabolism ◽

Replicative Senescence ◽

Synthetic Lethality ◽

Family Members ◽

Hallmarks Of Cancer ◽

Novel Therapy ◽

Cancer Hallmarks ◽

Enzyme Family ◽

Wide Range

The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

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Healthcare apps on smartphones available in Brazil: a preliminary classification (Preprint)

10.2196/preprints.20795 ◽

2020 ◽

Author(s):

André De Faria Pereira Neto ◽

Leticia Barbosa ◽

Rodolfo Paolucci

Keyword(s):

Health Promotion ◽

Disease Prevention ◽

Digital Health ◽

Disease Process ◽

World Health ◽

Computing Device ◽

Care Treatment ◽

Wide Range ◽

The World ◽

Health Applications

UNSTRUCTURED Billions of people in the world own a smartphone. It is a low-cost, portable computing device with countless features, among which applications stand out, which are programs or software developed to meet a specific goal. A wide range of applications available ranging from entertainment and personal organization to work and education is available currently. It is a vast and profitable market. Health applications have been a means of intervention for different areas, including chronic diseases, epidemics, and health emergencies. A recently published paper in the journal with the highest impact factor in Digital Health (“Journal of Medical Internet Research”) proposes a classification of health applications. This study performs a critical analysis of this organization and presents other sort criteria. This paper also presents and analyzes the “Meu Info Saúde” (“My Health Info”) app – a pioneering government initiative focused on primary care launched by the Oswaldo Cruz Foundation. The application classification proposal that will be presented builds on the intervention strategies in the health-disease process, namely: “Health Promotion”, “Disease Prevention” and “Care, Treatment and Rehabilitation”, as defined by official documents such as the World Health Organization and the Centers for Disease Control and Prevention. Most applications present in the sample are of private and foreign origin, free to download, but with a display of ads or the sale of products and services. The sampled applications were classified as “Health Promotion”, and some applications have also been categorized as “Disease Prevention” or “Care, Treatment or Rehabilitation” because they have multiple functionalities. The applications identified as “Health Promotion” focused only on individuals’ lifestyle and their increased autonomy and self-care management capacity. From this perspective, the apps analyzed in this paper differ from the “Meu Info-Saúde” application developed at Fiocruz.

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Methods Used and Application of the Mouse Grimace Scale in Biomedical Research 10 Years On: A Scoping Review

Animals ◽

10.3390/ani11030673 ◽

2021 ◽

Vol 11 (3) ◽

pp. 673

Author(s):

Alexandra L. Whittaker ◽

Yifan Liu ◽

Timothy H. Barker

Keyword(s):

Animal Models ◽

Mouse Models ◽

Biomedical Research ◽

Scoping Review ◽

Facial Features ◽

Inclusion Criteria ◽

Academic Literature ◽

Research Fields ◽

Neuroscience Research ◽

Wide Range

The Mouse Grimace Scale (MGS) was developed 10 years ago as a method for assessing pain through the characterisation of changes in five facial features or action units. The strength of the technique is that it is proposed to be a measure of spontaneous or non-evoked pain. The time is opportune to map all of the research into the MGS, with a particular focus on the methods used and the technique’s utility across a range of mouse models. A comprehensive scoping review of the academic literature was performed. A total of 48 articles met our inclusion criteria and were included in this review. The MGS has been employed mainly in the evaluation of acute pain, particularly in the pain and neuroscience research fields. There has, however, been use of the technique in a wide range of fields, and based on limited study it does appear to have utility for pain assessment across a spectrum of animal models. Use of the method allows the detection of pain of a longer duration, up to a month post initial insult. There has been less use of the technique using real-time methods and this is an area in need of further research.

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Animal Experiments and their Alternatives in Psychiatry

Alternatives to Laboratory Animals ◽

10.1177/026119298801500409 ◽

1988 ◽

Vol 15 (4) ◽

pp. 313-318

Author(s):

Anthony Stevens

Keyword(s):

Animal Models ◽

Human Study ◽

Animal Experiments ◽

Experimental Production ◽

Potential Utility ◽

Pharmacological Agents ◽

Wide Range ◽

Influential Paper ◽

Adequate Data ◽

Human Primate

During the last twenty years, the most enthusiastic advocates of the use of animal models in the study of human psychiatric dysfunction have been Harlow and Suomi. In an influential paper, Induced Depression in Monkeys (1974), they argued that more extensive use of non-human primates “would have great potential utility since many manipulations and measurements presently prohibited in human study by ethical and practical considerations could be readily performed on non-human primate subjects in well-controlled experimental environments.” Harlow & Suomi concluded this paper with the following statement: “The results obtained to date on induced depression in monkeys show that proper and profound depressions can be produced relatively easily by a variety of techniques. These induced depressions either bear a close resemblance to human depression or have such similarity as to suggest that closely correlated human and animal depressive patterns may be achieved with refined techniques. The results to date also provide adequate data for the conduct of meaningful researches on the effects of pharmacological agents which either enhance, inhibit or preclude the experimental production of depression. Further, the existence of firm and fast monkey depression syndromes offers vast opportunities for testing a wide range of therapeutic techniques, either behavioural or biochemical.”

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Pathogen Dose in Animal Models of Hemorrhagic Fever Virus Infections and the Potential Impact on Studies of the Immune Response

Pathogens ◽

10.3390/pathogens10030275 ◽

2021 ◽

Vol 10 (3) ◽

pp. 275

Author(s):

Bryce M. Warner

Keyword(s):

Immune Response ◽

Animal Models ◽

Hemorrhagic Fever ◽

Virus Infections ◽

Critical Determinant ◽

Animal Models Of Disease ◽

Hemorrhagic Fever Virus ◽

Immune Correlates ◽

Clinical Drug Development ◽

Wide Range

Viral hemorrhagic fever viruses come from a wide range of virus families and are a significant cause of morbidity and mortality worldwide each year. Animal models of infection with a number of these viruses have contributed to our knowledge of their pathogenesis and have been crucial for the development of therapeutics and vaccines that have been approved for human use. Most of these models use artificially high doses of virus, ensuring lethality in pre-clinical drug development studies. However, this can have a significant effect on the immune response generated. Here I discuss how the dose of antigen or pathogen is a critical determinant of immune responses and suggest that the current study of viruses in animal models should take this into account when developing and studying animal models of disease. This can have implications for determination of immune correlates of protection against disease as well as informing relevant vaccination and therapeutic strategies.

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Progress in Defining the Role of RSV in Allergy and Asthma: From Clinical Observations to Animal Models

Clinical and Developmental Immunology ◽

10.1080/10446670410001722131 ◽

2004 ◽

Vol 11 (2) ◽

pp. 113-119 ◽

Cited By ~ 22

Author(s):

W. V. Kalina ◽

L. J. Gershwin

Keyword(s):

Animal Models ◽

Rna Virus ◽

Allergic Sensitization ◽

Upper Respiratory Tract ◽

Young Infants ◽

Wide Range ◽

Similar Disease ◽

Rsv Infection ◽

Syncytial Virus ◽

The Impact

Respiratory syncytial virus (RSV), an RNA virus in the family Paramyxoviridae, causes respiratory disease in humans. A closely related bovine RSV is responsible for a remarkably similar disease syndrome in young cattle. Severe RSV disease is characterized by bronchiolitis. The impact of RSV on human health is demonstrated annually when infants are admitted to the hospital in large numbers. Nearly every child will have been infected with RSV by the age of 3 years. While the disease is most severe in young infants and elderly people, it can re-infect adults causing mild upper respiratory tract disease throughout life. In addition, there is growing evidence that RSV infection may also predispose some children to the development of asthma. This is based on the observation that children who wheeze with RSV-induced bronchiolitis are more likely to develop into allergic asthmatics. Recent studies describe attempts to create an RSV induced asthma model in mice and other species; these have shown some degree of success. Such reports of case studies and animal models have suggested a wide range of factors possibly contributing to RSV induced asthma, these include timing of RSV infection with respect to allergen exposure, prior allergic sensitization, environmental conditions, exposure to endotoxin, and the genetic background of the person or animal. Herein, we primarily focus on the influence of RSV infection and inhalation of extraneous substances (such as allergens or endotoxin) on development of allergic asthma.

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Non-negative Independent Factor Analysis for single cell RNA-seq

10.1101/2020.01.31.927921 ◽

2020 ◽

Author(s):

Weiguang Mao ◽

Maziyar Baran Pouyan ◽

Dennis Kostka ◽

Maria Chikina

Keyword(s):

Factor Analysis ◽

Single Cell ◽

Matrix Factorization ◽

Component Analysis ◽

Computational Techniques ◽

Cell Type ◽

Analysis Model ◽

Factor Analysis Model ◽

Type Identity ◽

Wide Range

AbstractMotivationSingle cell RNA sequencing (scRNA-seq) enables transcriptional profiling at the level of individual cells. With the emergence of high-throughput platforms datasets comprising tens of thousands or more cells have become routine, and the technology is having an impact across a wide range of biomedical subject areas. However, scRNA-seq data are high-dimensional and affected by noise, so that scalable and robust computational techniques are needed for meaningful analysis, visualization and interpretation. Specifically, a range of matrix factorization techniques have been employed to aid scRNA-seq data analysis. In this context we note that sources contributing to biological variability between cells can be discrete (or multi-modal, for instance cell-types), or continuous (e.g. pathway activity). However, no current matrix factorization approach is set up to jointly infer such mixed sources of variability.ResultsTo address this shortcoming, we present a new probabilistic single-cell factor analysis model, Non-negative Independent Factor Analysis (NIFA), that combines features of complementary approaches like Independent Component Analysis (ICA), Principal Component Analysis (PCA), and Non-negative Matrix Factorization (NMF). NIFA simultaneously models uni- and multi-modal latent factors and can so isolate discrete cell-type identity and continuous pathway-level variations into separate components. Similar to NMF, NIFA constrains factor loadings to be non-negative in order to increase biological interpretability. We apply our approach to a range of data sets where cell-type identity is known, and we show that NIFA-derived factors outperform results from ICA, PCA and NMF in terms of cell-type identification and biological interpretability. Studying an immunotherapy dataset in detail, we show that NIFA identifies biomedically meaningful sources of variation, derive an improved expression signature for regulatory T-cells, and identify a novel myeloid cell subtype associated with treatment response. Overall, NIFA is a general approach advancing scRNA-seq analysis capabilities and it allows researchers to better take advantage of their data. NIFA is available at https://github.com/wgmao/[email protected]

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Inhibitory activities of short linear motifs underlie Hox interactome specificity in vivo

eLife ◽

10.7554/elife.06034 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 26

Author(s):

Manon Baëza ◽

Séverine Viala ◽

Marjorie Heim ◽

Amélie Dard ◽

Bruno Hudry ◽

...

Keyword(s):

Cell Fate ◽

Drosophila Embryo ◽

Traditional Role ◽

Hox Proteins ◽

Short Linear Motifs ◽

Wide Range ◽

Mouse Species ◽

Inhibitory Activities ◽

Linear Motifs

Hox proteins are well-established developmental regulators that coordinate cell fate and morphogenesis throughout embryogenesis. In contrast, our knowledge of their specific molecular modes of action is limited to the interaction with few cofactors. Here, we show that Hox proteins are able to interact with a wide range of transcription factors in the live Drosophila embryo. In this context, specificity relies on a versatile usage of conserved short linear motifs (SLiMs), which, surprisingly, often restrains the interaction potential of Hox proteins. This novel buffering activity of SLiMs was observed in different tissues and found in Hox proteins from cnidarian to mouse species. Although these interactions remain to be analysed in the context of endogenous Hox regulatory activities, our observations challenge the traditional role assigned to SLiMs and provide an alternative concept to explain how Hox interactome specificity could be achieved during the embryonic development.

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HUMANIZED MICE: CREATION, MODELS AND USE IN EXPERIMENTAL ONCOLOGY (REVIEW)

Biomeditsina ◽

10.33647/2074-5982-15-4-67-81 ◽

2019 ◽

pp. 67-81

Author(s):

O. I. Kit ◽

A. Yu. Maksimov ◽

T. P. Protasova ◽

A. S. Goncharova ◽

D. S. Kutilin ◽

...

Keyword(s):

Cancer Biology ◽

Human Cancer ◽

Transgenic Animals ◽

Humanized Mice ◽

Humanized Mouse ◽

Antitumour Agents ◽

Human Genes ◽

Oncology Review ◽

Wide Range ◽

Humanized Mouse Models

Research laboratories in various countries are constantly endeavouring to improve the existing and to create new biological objects to simulate various human diseases. Immunodefi cient mice with transplanted human functional cells and tissues, as well as transgenic animals with the relevant human genes integrated in their genome — i. e. humanized mice — are increasingly used as test systems in biomedical studies. Humanized mouse models are constantly being improved to fi nd application in studies investigating human biological reactions and identifying the pathogenetic mechanisms behind a wide range of diseases, or as preclinical tools for medicine testing. In particular, such animals play an increasingly important role both in studies of human-specifi c infectious agents, cancer biology research and in the development of new antitumour agents. In addition, humanized mice are increasingly used as translational models in many areas of clinical research, including transplantology, immunology and oncology. Ultimately, the use of humanized animals can lead to the introduction of a truly personalized medicine into clinical practice. In this review, we discuss modern advances in the creation and use of humanized mice, emphasizing their usefulness for the pathogenesis study, as well as the development of new methods for human cancer treatment.

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Myomirnas Role in Als Suggest a Crosstalk between Muscle and Motor Neuron

10.20944/preprints201810.0709.v1 ◽

2018 ◽

Author(s):

Valentina Pegoraro ◽

Antonio Merico ◽

Corrado Angelini

Keyword(s):

Skeletal Muscle ◽

Motor Neuron ◽

Aerobic Exercise ◽

Muscle Atrophy ◽

Motor Neurons ◽

Neuromuscular Junctions ◽

Neurodegenerative Disorder ◽

Disease Process ◽

Muscle Fibres ◽

Wide Range

Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads from lower motor neuron involvement to progressive muscle atrophy, weakness, fasciculations for the upper motor neuron involvement to spasticity. Muscle atrophy in ALS is caused by a dysregulation in the molecular network controlling fast and slow muscle fibres. Denervation and reinnervation processes in skeletal muscle occur in the course of ALS and are modulated by rehabilitation. MicroRNAs (miRNAs) are small non-coding RNAs that modulate a wide range of biological functions under various pathophysiological conditions. MiRNAs can be secreted by various cell types and they are markedly stable in body fluids. MiR-1, miR-133 a, miR-133b, and miR-206 are called “myomiRs” and are considered markers of myogenesis during muscle regeneration and neuromuscular junction stabilization or sprouting. We observed a positive effect of a standard aerobic exercise rehabilitative protocol conducted for six weeks in 18 ALS patients during hospitalization in our center. We correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, myomiRNAs were down-regulated, suggesting an active proliferation of satellite cells in muscle and increased neuromuscular junctions. Our data suggest that circulating miRNAs modulate during skeletal muscle recovery in response to physical rehabilitation in ALS.

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