ResearchPad - invited-review https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Towards the clinical translation of optogenetic skeletal muscle stimulation]]> https://www.researchpad.co/article/elastic_article_9968 Paralysis is a frequent phenomenon in many diseases, and to date, only functional electrical stimulation (FES) mediated via the innervating nerve can be employed to restore skeletal muscle function in patients. Despite recent progress, FES has several technical limitations and significant side effects. Optogenetic stimulation has been proposed as an alternative, as it may circumvent some of the disadvantages of FES enabling cell type–specific, spatially and temporally precise stimulation of cells expressing light-gated ion channels, commonly Channelrhodopsin2. Two distinct approaches for the restoration of skeletal muscle function with optogenetics have been demonstrated: indirect optogenetic stimulation through the innervating nerve similar to FES and direct optogenetic stimulation of the skeletal muscle. Although both approaches show great promise, both have their limitations and there are several general hurdles that need to be overcome for their translation into clinics. These include successful gene transfer, sustained optogenetic protein expression, and the creation of optically active implantable devices. Herein, a comprehensive summary of the underlying mechanisms of electrical and optogenetic approaches is provided. With this knowledge in mind, we substantiate a detailed discussion of the advantages and limitations of each method. Furthermore, the obstacles in the way of clinical translation of optogenetic stimulation are discussed, and suggestions on how they could be overcome are provided. Finally, four specific examples of pathologies demanding novel therapeutic measures are discussed with a focus on the likelihood of direct versus indirect optogenetic stimulation.

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<![CDATA[Macrophage subsets in atherosclerosis as defined by single‐cell technologies]]> https://www.researchpad.co/article/elastic_article_8260 Macrophages play a major role in the pathogenesis of atherosclerosis. Many studies have shone light on the different phenotypes and functions that macrophages can acquire upon exposure to local cues. The microenvironment of the atherosclerotic plaque contains a plethora of macrophage‐controlling factors, such as cytokines, oxidised low‐density lipoproteins and cell debris. Previous research has determined macrophage function within the plaque mainly by using immunohistochemistry and bulk analysis. The recent development and rapid progress of single‐cell technologies, such as cytometry by time of flight and single‐cell RNA sequencing, now enable comprehensive mapping of the wide range of cell types and their phenotypes present in atherosclerotic plaques. In this review we discuss recent advances applying these technologies in defining macrophage subsets residing in the atherosclerotic arterial wall of mice and men. Resulting from these studies, we describe three main macrophage subsets: resident‐like, pro‐inflammatory and anti‐inflammatory foamy TREM2hi macrophages, which are found in both mouse and human atherosclerotic plaques. Furthermore, we discuss macrophage subset‐specific markers and functions. More insights into the characteristics and phenotype of immune cells within the atherosclerotic plaque may guide future clinical approaches to treat disease. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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<![CDATA[Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression]]> https://www.researchpad.co/article/elastic_article_7047 Mesenchymal stem or stromal cells (MSCs) are pluripotent cells implicated in a broad range of physiological events, including organogenesis and maintenance of tissue homeostasis as well as tissue regeneration and repair. Because their current definition is somewhat loose – based primarily on their ability to differentiate into a variety of mesenchymal tissues, adhere to plastic, and express, or lack, a handful of cell surface markers – MSCs likely encompass several subpopulations, which may have diverse properties. Their diversity may explain, at least in part, the pleiotropic functions that they display in different physiological and pathological settings. In the context of tissue injury, MSCs can respectively promote and attenuate inflammation during the early and late phases of tissue repair. They may thereby act as sensors of the inflammatory response and secrete mediators that boost or temper the response as required by the stage of the reparatory and regenerative process. MSCs are also implicated in regulating tumor development, in which they are increasingly recognized to play a complex role. Thus, MSCs can both promote and constrain tumor progression by directly affecting tumor cells via secreted mediators and cell–cell interactions and by modulating the innate and adaptive immune response. This review summarizes our current understanding of MSC involvement in tumor development and highlights the mechanistic underpinnings of their implication in tumor growth and progression. © 2020 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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<![CDATA[Radiation‐induced tissue damage and response]]> https://www.researchpad.co/article/elastic_article_6903 Normal tissue responses to ionizing radiation have been a major subject for study since the discovery of X‐rays at the end of the 19th century. Shortly thereafter, time–dose relationships were established for some normal tissue endpoints that led to investigations into how the size of dose per fraction and the quality of radiation affected outcome. The assessment of the radiosensitivity of bone marrow stem cells using colony‐forming assays by Till and McCulloch prompted the establishment of in situ clonogenic assays for other tissues that added to the radiobiology toolbox. These clonogenic and functional endpoints enabled mathematical modeling to be performed that elucidated how tissue structure, and in particular turnover time, impacted clinically relevant fractionated radiation schedules. More recently, lineage tracing technology, advanced imaging and single cell sequencing have shed further light on the behavior of cells within stem, and other, cellular compartments, both in homeostasis and after radiation damage. The discovery of heterogeneity within the stem cell compartment and plasticity in response to injury have added new dimensions to the consideration of radiation‐induced tissue damage. Clinically, radiobiology of the 20th century garnered wisdom relevant to photon treatments delivered to a fairly wide field at around 2 Gy per fraction, 5 days per week, for 5–7 weeks. Recently, the scope of radiobiology has been extended by advances in technology, imaging and computing, as well as by the use of charged particles. These allow radiation to be delivered more precisely to tumors while minimizing the amount of normal tissue receiving high doses. One result has been an increase in the use of schedules with higher doses per fraction given in a shorter time frame (hypofractionation). We are unable to cover these new technologies in detail in this review, just as we must omit low‐dose stochastic effects, and many aspects of dose, dose rate and radiation quality. We argue that structural diversity and plasticity within tissue compartments provides a general context for discussion of most radiation responses, while acknowledging many omissions. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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<![CDATA[Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine]]> https://www.researchpad.co/article/elastic_article_6815 Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease‐modifying treatment. The biggest drawback of today's COPD treatment regimen is the ‘one size fits all’ pharmacological intervention, mainly based on disease severity and symptoms and not the individual's disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age‐related changes, structural changes in the small airways and the role of sex‐related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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<![CDATA[The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis]]> https://www.researchpad.co/article/elastic_article_6764 Tumours evolve to cope with environmental stresses or challenges such as nutrient starvation, depletion of survival factors, and unbalanced mechanical forces. The uncontrolled growth and aberrant deregulation of core cell homeostatic pathways induced by genetic mutations create an environment of stress. Here, we explore how the adaptations of tumours to the changing environment can drive changes in the motility machinery of cells, affecting migration, invasion, and metastasis. Tumour cells can invade individually or collectively, or they can be extruded out of the surrounding epithelium. These mechanisms are thought to be modifications of normal processes occurring during development or tissue repair. Therefore, tumours may activate these pathways in response to environmental stresses, enabling them to survive in hostile environments and spread to distant sites. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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<![CDATA[Limitations of Continuous Neural Monitoring in Thyroid Surgery]]> https://www.researchpad.co/article/N0b51815c-5257-418e-84a1-d51a1218aa90 Continuous intraoperative neuromonitoring is currently the gold standard technique available to prevent recurrent laryngeal nerve injuries. It significantly reduces the complication rate compared with intermittent intraoperative neuromonitoring, and represents significant progress in thyroid surgery, particularly in cases of more difficult dissections.

There are, however, some technological and interpretative limits related to the lack of standardization of continuous intraoperative neuromonitoring and the prolonged length of time employed in the surgical positioning of the probe, despite various proposed approaches to the vagal nerve.

Nonetheless, this method can be considered a safe and modern approach to thyroid surgery that reduces post-surgical complications and provides useful information.

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<![CDATA[肺癌术后胸腔闭式引流术应用的新观念]]> https://www.researchpad.co/article/5c052c0fd5eed0c4848a7707 肺叶切除术后应用传统胸腔闭式引流术,被大多数胸外科医生所采用的主要原因:一是引流效果好;二是经验、习惯和观念。外科技术的发展和医疗观念的更新使传统胸腔闭式引流术在临床应用中的不足越来越明显,但尚未引起足够重视。近几年对肺癌术后引流问题无论是应用方法还是观念都有更新和发展。本文将结合国内外研究进展和我们工作中的体会,从以下三方面进行概述:一是胸腔引流术应用现状和存在问题;二是常规水封引流系统加用负压吸引之优势与不足;三是单胸腔引流管的临床应用进展与争议。

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<![CDATA[核糖核苷酸还原酶和非小细胞肺癌]]> https://www.researchpad.co/article/5c052ac6d5eed0c4848a4c12 <![CDATA[MicroRNA and Cardiovascular Diseases]]> https://www.researchpad.co/article/N7d0ce531-cf53-4670-badb-ed5441927bbc

Cardiovascular diseases are one of the most common causes of death in both developing and developed countries worldwide. Even though there have been improvements in primary prevention, the prevalence of cardiovascular diseases continues to increase in recent years. Hence, it is crucial to both investigate the molecular pathophysiology of cardiovascular diseases in-depth and find novel biomarkers regarding the early and proper prevention and diagnosis of these diseases. MicroRNAs, or miRNAs, are endogenous, conserved, single-stranded non-coding RNAs of 21-25 nucleotides in length. miRNAs have important roles in various cellular events such as embryogenesis, proliferation, vasculogenesis, apoptosis, cell growth, differentiation, and tumorigenesis. They also have potential roles in the cardiovascular system, including angiogenesis, cardiac cell contractility, control of lipid metabolism, plaque formation, the arrangement of cardiac rhythm, and cardiac cell growth. Circulating miRNAs are promising novel biomarkers for purposes of the diagnosis and prognosis of cardiovascular diseases. Cell or tissue specificity, stability in serum or plasma, resistance to degradative factors such as freeze-thaw cycles or enzymes in the blood, and fast-release kinetics, provide the potential for miRNAs to be surrogate markers for the early and accurate diagnosis of disease and for predicting middle- or long-term prognosis. Moreover, it may be a logical approach to combine miRNAs with traditional biomarkers to improve risk stratification and long-term prognosis. In addition to their efficacy in both diagnosis and prognosis, miRNA-based therapeutics may be beneficial for treating cardiovascular diseases using novel platforms and computational tools and in combination with traditional methods of analysis. microRNAs are promising, novel therapeutic agents, which can affect multiple genes using different signaling pathways. miRNAs therapeutic modulation techniques have been used in the settings of atherosclerosis, acute myocardial infarction, restenosis, vascular remodeling, arrhythmias, hypertrophy and fibrosis, angiogenesis and cardiogenesis, aortic aneurysm, pulmonary hypertension, and ischemic injury. This review presents detailed information about miRNAs regarding structure and biogenesis, stages of synthesis and functions, expression profiles in serum/plasma of living organisms, diagnostic and prognostic potential as novel biomarkers, and therapeutic applications in various diseases.

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<![CDATA[The role of phosphatidylserine recognition receptors in multiple biological functions]]> https://www.researchpad.co/article/N258498d5-4dc1-4708-9109-b81b7465520c

Apoptotic cells are rapidly engulfed and degraded by phagocytes through efferocytosis. Efferocytosis is a highly regulated process. It is triggered upon the activation of caspase-dependent apoptosis, which in turn promotes the expression of “eat me” signals on the surface of dying cells and the release of soluble “find me” signals for the recruitment of phagocytes. To date, many “eat me” signals have been recognized, including phosphatidylserine (PS), intercellular adhesion molecule-3, carbohydrates (e.g., amino sugars, mannose) and calreticulin. Among them, PS is the most studied one. PS recognition receptors are different functionally active receptors expressed by phagocytes. Various PS recognition receptors with different structure, cell type expression, and ability to bind to PS have been recognized. Although PS recognition receptors do not fall into a single classification or family of proteins due to their structural differences, they all share the common ability to activate downstream signaling pathways leading to the production of anti-inflammatory mediators. In this review, available evidence regarding molecular mechanisms underlying PS recognition receptor-regulated clearance of apoptotic cells is discussed. In addition, some efferocytosis-independent biological functions of PS recognition receptors are reviewed.

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<![CDATA[MERS, SARS and other coronaviruses as causes of pneumonia]]> https://www.researchpad.co/article/Ncef4cd94-f8ee-48fc-baff-72f1f8f36c70

ABSTRACT

Human coronaviruses (HCoVs) have been considered to be relatively harmless respiratory pathogens in the past. However, after the outbreak of the severe acute respiratory syndrome (SARS) and emergence of the Middle East respiratory syndrome (MERS), HCoVs have received worldwide attention as important pathogens in respiratory tract infection. This review focuses on the epidemiology, pathogenesis and clinical characteristics among SARS‐coronaviruses (CoV), MERS‐CoV and other HCoV infections.

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<![CDATA[Severe acute respiratory syndrome (SARS) in Hong Kong]]> https://www.researchpad.co/article/Nb1d94261-e8a3-417a-b4c5-b4152a9358ca

Abstract:  Severe acute respiratory syndrome (SARS) is a recently recognized and highly contagious pneumonic illness, caused by a novel coronavirus. While developments in diagnostic, clinical and other aspects of SARS research are well underway, there is still great difficulty for frontline clinicians as validated rapid diagnostic tests or effective treatment regimens are lacking. This article attempts to summarize some of the recent developments in this newly recognized condition from the Asia Pacific perspective.

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<![CDATA[Pathogenesis of Middle East respiratory syndrome coronavirus]]> https://www.researchpad.co/article/Nbb9b8530-7cb3-4b44-92a6-3bb40347f310

Abstract

Human coronaviruses (CoVs) mostly cause a common cold that is mild and self‐limiting. Zoonotic transmission of CoVs such as the recently identified Middle East respiratory syndrome (MERS)‐CoV and severe acute respiratory syndrome (SARS)‐CoV, on the other hand, may be associated with severe lower respiratory tract infection. This article reviews the clinical and pathological data available on MERS and compares it to SARS. Most importantly, chest radiographs and imaging results of patients with MERS show features that resemble the findings of organizing pneumonia, different from the lesions in SARS patients, which show fibrocellular intra‐alveolar organization with a bronchiolitis obliterans organizing pneumonia‐like pattern. These findings are in line with differences in the induction of cytopathological changes, induction of host gene responses and sensitivity to the antiviral effect of interferons in vitro when comparing both MERS‐CoV and SARS‐CoV. The challenge will be to translate these findings into an integrated picture of MERS pathogenesis in humans and to develop intervention strategies that will eventually allow the effective control of this newly emerging infectious disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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<![CDATA[Understanding the role of antibody glycosylation through the lens of severe viral and bacterial diseases]]> https://www.researchpad.co/article/N300d2b71-e22d-495e-8a88-402f842b538f

Abstract

Abundant evidence points to a critical role for antibodies in protection and pathology across infectious diseases. While the antibody variable domain facilitates antibody binding and the blockade of infection, the constant domain (Fc) mediates cross talk with the innate immune system. The biological activity of the Fc region is controlled genetically via class switch recombination, resulting in the selection of distinct antibody isotypes and subclasses. However, a second modification is made to all antibodies, via post-translational changes in antibody glycosylation. Studies from autoimmunity and oncology have established the role of immunoglobulin G (IgG) Fc glycosylation as a key regulator of humoral immune activity. However, a growing body of literature, exploring IgG Fc glycosylation through the lens of infectious diseases, points to the role of inflammation in shaping Fc-glycan profiles, the remarkable immune plasticity in antibody glycosylation across pathogen-exposed populations, the canonical and noncanonical functions of glycans and the existence of antigen-specific control over antibody Fc glycosylation. Ultimately, this work provides critical new insights into the functional roles for antibody glycosylation as well as lays the foundation for leveraging antibody glycosylation to drive prevention or control across diseases.

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<![CDATA[SOX2 in cancer stemness: tumor malignancy and therapeutic potentials]]> https://www.researchpad.co/article/N0eeb2a3a-5aab-4019-b87b-3d64f35fcacc

Abstract

Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.

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<![CDATA[Challenges in the Etiology and Diagnosis of Acute Febrile Illness in Children in Low- and Middle-Income Countries]]> https://www.researchpad.co/article/N39ffb3f4-e3ad-47e6-afb7-81e10fd67ef8

Abstract

Acute febrile illness is a common cause of hospital admission, and its associated infectious causes contribute to substantial morbidity and death among children worldwide, especially in low- and middle-income countries. Declining transmission of malaria in many regions, combined with the increasing use of rapid diagnostic tests for malaria, has led to the increasing recognition of leptospirosis, rickettsioses, respiratory viruses, and arboviruses as etiologic agents of fevers. However, clinical discrimination between these etiologies can be difficult. Overtreatment with antimalarial drugs is common, even in the setting of a negative test result, as is overtreatment with empiric antibacterial drugs. Viral etiologies remain underrecognized and poorly investigated. More-sensitive diagnostics have led to additional dilemmas in discriminating whether a positive test result reflects a causative pathogen. Here, we review and summarize the current epidemiology and focus particularly on children and the challenges for future research.

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<![CDATA[Assessment of the economic impacts of porcine epidemic diarrhea virus in the United States]]> https://www.researchpad.co/article/Nda056cf6-629a-4825-852b-c2d1fd93e5cc

ABSTRACT

Porcine epidemic diarrhea virus (PEDV), which first emerged in the United States in 2013, spread throughout the U.S. hog population. Limited preemptive knowledge impeded the understanding of PEDV introduction, spread, and prospective economic impacts in the United States. To assess these impacts, this article reviews the timeline of PEDV in the United States and the corresponding impacts. PEDV is a supply-impacting disease and is not demand inhibiting, as pork demand remained strong since PEDV first appeared. Pig losses reached significant levels during September 2013 through August 2014, with the majority of pork production impacts occurring in 2014. PEDV had differing impacts for subsectors of the pork industry. A budget model demonstrates that producers could have had pig losses and decreases in productivity proportionally smaller than price increases, resulting in net returns above what was expected before the major outbreak of PEDV. Previous literature is reviewed to identify the potential main industry beneficiaries of the PEDV outbreaks in the United States. As a result of reduced volumes of available pig and hog supplies, reductions in annual returns likely occurred for packers, processors, distributors, and retailers. In addition, pork consumers who experienced reduced-supply-induced pork-price increases were likely harmed directly by higher prices paid for pork and indirectly as prices of competing meats were also likely strengthened by PEDV. This article also identifies future considerations motivated by the appearance of PEDV in the United States, such as discussions of industry-wide efficiency and competitive advantage, the future role of PEDV vaccines, enhancement in biosecurity measures, and consumer perceptions of food safety and insecurity.

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<![CDATA[Expanding Existing Antimicrobial Stewardship Programs in Pediatrics: What Comes Next]]> https://www.researchpad.co/article/N65c7e40f-fc4a-4d8c-94a4-2b6d6b64e063

The prevalence of pediatric antimicrobial stewardship programs (ASPs) is increasing. We review strategies for ASPs to adapt and report standardized metrics, expand activities to specialized populations, and implement novel diagnostics for continued progress in improving antibiotic use and patient outcomes.

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<![CDATA[Clinical diagnosis and treatment of immune checkpoint inhibitor‐associated adverse events in the digestive system]]> https://www.researchpad.co/article/N264d6e8a-365a-464b-b649-0b1a0afa41b6

Immunotherapy for malignant tumors is a hot spot in current research and the treatment of cancer. The activation of programmed cell death receptor‐1 (PD‐1) and cytotoxic T lymphocyte‐associated antigen 4 (CTLA)‐4 relevant signaling pathway can inhibit the activation of T lymphocytes. Tumor cells can achieve immune escape by activating this signaling pathway. By inhibiting this signaling pathway, immune‐checkpoint inhibitors (ICIs) activate T lymphocytes to clear the tumor cells. Therefore, the adverse effects of ICIs are mainly immune‐related adverse events (irAEs). The digestive system, including the gastrointestinal tract and liver which are vital organs of digestion and absorption, metabolism and detoxification, as well as important immune‐related organs, is the most commonly affected system of irAEs. This review explains the incidence, clinical features, diagnosis and treatment of liver and gastrointestinal adverse events in ICIs.

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