WIREs Mechanisms of Disease最新文献

Since the declaration of the novel SARS-CoV-2 virus pandemic, health systems/ health-care-workers globally have been overwhelmed by a vast number of COVID-19 related hospitalizations and intensive care unit (ICU) admissions. During the early stages of the pandemic, the lack of formalized evidence-based guidelines in all aspects of patient management was a significant challenge. Coupled with a lack of effective pharmacotherapies resulted in unsatisfactory outcomes in ICU patients. The anticipated increment in ICU surge capacity was staggering, with almost every ICU worldwide being advised to increase their capacity to allow adequate care provision in response to multiple waves of the pandemic. This increase in surge capacity required advanced planning and reassessments at every stage, taking advantage of experienced gained in combination with emerging evidence. In University Hospital Southampton General Intensive Care Unit (GICU), despite the initial lack of national and international guidance, we enhanced our ICU capacity and developed local guidance on all aspects of care to address the rapid demand from the increasing COVID-19 admissions. The main element of this success was a multidisciplinary team approach intertwined with equipment and infrastructural reorganization. This narrative review provides an insight into the approach adopted by our center to manage patients with COVID-19 critical illness, exploring the initial planning process, including contingency preparations to accommodate (360% capacity increment) and adaptation of our management pathways as more evidence emerged throughout the pandemic to provide the most appropriate levels of care to our patients. We hope our experience will benefit other intensive care units worldwide. This article is categorized under: Infectious Diseases > Genetics/Genomics/Epigenetics.

Chimeric antigen receptor T-cell (CAR-T) treatment has revolutionized the landscape of cancer therapy with significant efficacy on hematologic malignancy, especially in relapsed and refractory B cell malignancies. However, unexpected serious toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) still hamper its broad application. Clinical trials using CAR-T cells targeting specific antigens on tumor cell surface have provided valuable information about the characteristics of ICANS. With unclear mechanism of ICANS after CAR-T treatment, unremitting efforts have been devoted to further exploration. Clinical findings from patients with ICANS strongly indicated existence of overactivated peripheral immune response followed by endothelial activation-induced blood-brain barrier (BBB) dysfunction, which triggers subsequent central nervous system (CNS) inflammation and neurotoxicity. Several animal models have been built but failed to fully replicate the whole spectrum of ICANS in human. Hopefully, novel and powerful technologies like single-cell analysis may help decipher the precise cellular response within CNS from a different perspective when ICANS happens. Moreover, multidisciplinary cooperation among the subjects of immunology, hematology, and neurology will facilitate better understanding about the complex immune interaction between the peripheral, protective barriers, and CNS in ICANS. This review elaborates recent findings about ICANS after CAR-T treatment from bed to bench, and discusses the potential cellular and molecular mechanisms that may promote effective management in the future. This article is categorized under: Cancer > Biomedical Engineering Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.

Tuberculosis (TB) poses a serious threat to public health worldwide since it was discovered. Until now, TB has been one of the top 10 causes of death from a single infectious disease globally. The treatment of active TB cases majorly relies on various anti-tuberculosis drugs. However, under the selection pressure by drugs, the continuous evolution of Mycobacterium tuberculosis (Mtb) facilitates the emergence of drug-resistant strains, further resulting in the accumulation of tubercle bacilli with multiple drug resistance, especially deadly multidrug-resistant TB and extensively drug-resistant TB. Researches on the mechanism of drug action and drug resistance of Mtb provide a new scheme for clinical management of TB patients, and prevention of drug resistance. In this review, we summarized the molecular mechanisms of drug resistance of existing anti-TB drugs to better understand the evolution of drug resistance of Mtb, which will provide more effective strategies against drug-resistant TB, and accelerate the achievement of the EndTB Strategy by 2035. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.

Extracellular vesicles (EVs) released by regenerative cells such as mesenchymal stem cells are effective facilitators of healing, therapy, and repair. Conversely, EVs released from infected and/or diseased cells could be useful as markers in the detection and diagnosis of disease conditions such as cancer at their earliest most detectable, and treatable stage. A very important type of EVs, termed exosomes offer a hypothetical new paradigm in disease detection, diagnosis, and treatment. A broad range of exosome-based biomedical and therapeutic applications are now being evaluated in recent clinical trials. Exosomes are found in virtually all bodily fluids and cells and are capable of crossing tight junctions and toughly regulated boundaries such as the blood-brain barrier. Exosomes' expedition ends when they are taken up by bystander cells which corroborates the fact that they are conduits for cells releasing them. Exosomes released by diseased cells have been associated with cell-to-cell progression of diseases like viral disease, neurodegeneration, and certain cancers. Due to high discrimination in most disease conditions, exosome uptake is usually cell-specific. Lots of research evidence have revealed that infusion of exosomes derived from regenerative cells such as stem cells could impede the development of certain infections and age-related diseases by activating self-repair machinery through RNA, DNA, protein, and lipid transfer between cells in patients. They have also been demonstrated in the restoration of the circulating population of exosomes in tissues and the fluid of recipients. The first human clinical trials of exosome therapies are now underway, establishing the future of regenerative exosome in regenerative medicine. This article is categorized under: Cancer > Stem Cells and Development Immune System Diseases > Stem Cells and Development Immune System Diseases > Molecular and Cellular Physiology.

Among various types of cancers, kidney cancer is unique with respect to a low frequency of mutations and a relatively higher level of chemotherapy resistance. Resistance to chemotherapy is a major challenge in kidney cancer treatment in the clinic. Tremendous progress has been made in identifying the molecular changes associated with chemotherapy resistance in RCC. However, the exact contribution of these molecular changes to the acquisition of chemotherapy resistance is not fully understood. In addition to genetic changes, epigenetic alterations have been shown to contribute to various pathways associated with chemotherapy resistance, such as increased cell proliferation and survival, regulation of drug influx and efflux transporters, increased DNA repair, loss of DNA-damage-dependent apoptotic potential, cellular dedifferentiation to cancer stem cell, and epithelial-mesenchymal transitions (EMT). Moreover, recent studies suggest that epigenetic aberrations that can be reversed by epigenetic therapeutics can potentially be targeted to restore chemosensitivity in chemorefractory kidney cancer. This review article highlights current knowledge of the role of genetic and epigenetic aberrations as well as the physiological and metabolic changes associated with chemotherapeutic resistance. Additionally, current approaches and future directions for overcoming chemotherapeutic resistance including the potential of epigenetic therapeutic in chemorefractory kidney cancer have also been discussed. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics.

Ceftazidime/avibactam (CAZ/AVI), a combination of ceftazidime and a novel β-lactamase inhibitor (avibactam) that has been approved by the U.S. Food and Drug Administration, the European Union, and the National Regulatory Administration in China. CAZ/AVI is used mainly to treat complicated urinary tract infections and complicated intra-abdominal infections in adults, as well as to treat patients infected with Carbapenem-resistant Enterobacteriaceae (CRE) susceptible to CAZ/AVI. However, increased clinical application of CAZ/AVI has resulted in the development of resistant strains. Mechanisms of resistance in most of these strains have been attributed to bla_KPC mutations, which lead to amino acid substitutions in β-lactamase and changes in gene expression. Resistance to CAZ/AVI is also associated with reduced expression and loss of outer membrane proteins or overexpression of efflux pumps. In this review, the prevalence of CAZ/AVI-resistance bacteria, resistance mechanisms, and selection of detection methods of CAZ/AVI are demonstrated, aiming to provide scientific evidence for the clinical prevention and treatment of CAZ/AVI resistant strains, and provide guidance for the development of new drugs. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.

The development of novel pain therapeutics hinges on the identification and rigorous validation of potential targets. Model organisms provide a means to test the involvement of specific genes and regulatory elements in pain. Here we provide a list of genes linked to pain-associated behaviors. We capitalize on results spanning over three decades to identify a set of 242 genes. They support a remarkable diversity of functions spanning action potential propagation, immune response, GPCR signaling, enzymatic catalysis, nucleic acid regulation, and intercellular signaling. Making use of existing tissue and single-cell high-throughput RNA sequencing datasets, we examine their patterns of expression. For each gene class, we discuss archetypal members, with an emphasis on opportunities for additional experimentation. Finally, we discuss how powerful and increasingly ubiquitous forward genetic screening approaches could be used to improve our ability to identify pain genes. This article is categorized under: Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Molecular and Cellular Physiology.

Neural tube closure (NTC) is crucial for proper development of the brain and spinal cord and requires precise morphogenesis from a sheet of cells to an intact three-dimensional structure. NTC is dependent on successful regulation of hundreds of genes, a myriad of signaling pathways, concentration gradients, and is influenced by epigenetic and environmental cues. Failure of NTC is termed a neural tube defect (NTD) and is a leading class of congenital defects in the United States and worldwide. Though NTDs are all defined as incomplete closure of the neural tube, the pathogenesis of an NTD determines the type, severity, positioning, and accompanying phenotypes. In this review, we survey pathogenesis of NTDs relating to disruption of cellular processes arising from genetic mutations, altered epigenetic regulation, and environmental influences by micronutrients and maternal condition. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Stem Cells and Development.

We review the current understanding of formation and development of the coronary microvasculature which supplies oxygen and nutrients to the heart myocardium and removes waste. We emphasize the close relationship, mutual development, and communication between microvasculature endothelial cells and surrounding cardiomyocytes. The first part of the review is focused on formation of microvasculature during embryonic development. We summarize knowledge about establishing the heart microvasculature density based on diffusion distance. Then signaling mechanisms which are involved in forming the microvasculature are discussed. This includes details of cardiomyocyte-endothelial cell interactions involving hypoxia, VEGF, NOTCH, angiopoietin, PDGF, and other signaling factors. The microvasculature is understudied due to difficulties in its visualization. Therefore, currently available imaging methods to delineate the coronary microvasculature in development and in adults are discussed. The second part of the review is dedicated to the importance of the coronary vasculature in disease. Coronary microvasculature pathologies are present in many congenital heart diseases (CHD), especially in pulmonary atresia, and worsen outcomes. In CHDs, where the development of the myocardium is impaired, microvasculature is also affected. In adult patients coronary microvascular disease is one of the main causes of sudden cardiac death, especially in women. Coronary microvasculature pathologies affect myocardial ischemia and vice versa; myocardial pathologies such as cardiomyopathies are closely connected with coronary microvasculature dysfunction. Microvasculature inflammation also worsens the outcomes of COVID-19 disease. Our review stresses the importance of coronary microvasculature and provides an overview of its formation and signaling mechanisms and the importance of coronary vasculature pathologies in CHDs and adult diseases. This article is categorized under: Cardiovascular Diseases > Stem Cells and Development Congenital Diseases > Molecular and Cellular Physiology Cardiovascular Diseases > Molecular and Cellular Physiology.

Angiogenesis is a highly regulated multiscale process that involves a plethora of cells, their cellular signal transduction, activation, proliferation, differentiation, as well as their intercellular communication. The coordinated execution and integration of such complex signaling programs is critical for physiological angiogenesis to take place in normal growth, development, exercise, and wound healing, while its dysregulation is critically linked to many major human diseases such as cancer, cardiovascular diseases, and ocular disorders; it is also crucial in regenerative medicine. Although huge efforts have been devoted to drug development for these diseases by investigation of angiogenesis-targeted therapies, only a few therapeutics and targets have proved effective in humans due to the innate multiscale complexity and nonlinearity in the process of angiogenic signaling. As a promising approach that can help better address this challenge, systems biology modeling allows the integration of knowledge across studies and scales and provides a powerful means to mechanistically elucidate and connect the individual molecular and cellular signaling components that function in concert to regulate angiogenesis. In this review, we summarize and discuss how systems biology modeling studies, at the pathway-, cell-, tissue-, and whole body-levels, have advanced our understanding of signaling in angiogenesis and thereby delivered new translational insights for human diseases. This article is categorized under: Cardiovascular Diseases > Computational Models Cancer > Computational Models.