Abstract
Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.
Authors
Charles D. Hwang, Chase A. Pagani, Johanna H. Nunez, Masnsen Cherief, Qizhi Qin, Mario Gomez-Salazar, Balram Kadaikal, Heeseog Kang, Ashish R. Chowdary, Nicole Patel, Aaron W. James, Benjamin Levi
Abstract
MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.
Authors
Débora Malta Cerqueira, Maliha Tayeb, Jacqueline Ho
Abstract
In recent decades, immunotherapeutic strategies have been used to treat a wide range of pathologies, many of which were previously incurable, such as cancer and autoimmune disorders. Despite this unprecedented success, a considerable number of patients fail to respond to currently approved immunotherapies or develop resistance over time. Therefore, there is an urgent need to develop the next generation of immune-targeted therapies. Various members of the Ig superfamily play essential roles in regulating leukocyte functions. One such group, the leukocyte Ig-like receptors (LILRs), have been implicated in both innate and adaptive immune regulation. Human inhibitory LILRs (LILRBs) are primarily expressed on leukocytes and mediate their signaling through multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Engagement of LILRBs by endogenous and pathogenic ligands can markedly suppress immune responses, leading to tolerance or immunoevasion, whereas blocking these inhibitory receptors can potentiate immune responses. In this Review, we discuss the immunoregulatory functions of human LILRBs and the potential of targeting them to manipulate immune responses in various pathologies.
Authors
Calvin D. De Louche, Ali Roghanian
Abstract
KRAS mutations are the drivers of various cancers, including non–small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.
Authors
Hande Asimgil, Utku Ertetik, Nedim Can Çevik, Menar Ekizce, Alper Doğruöz, Muazzez Gökalp, Elif Arık-Sever, Rouzanna Istvanffy, Helmut Friess, Güralp Onur Ceyhan, Ihsan Ekin Demir
Abstract
Circular RNAs (circRNAs) represent a type of endogenous noncoding RNA generated by back-splicing events. Unlike the majority of RNAs, circRNAs are covalently closed, without a 5′ end or a 3′ poly(A) tail. A few circRNAs can be associated with polysomes, suggesting a protein-coding potential. CircRNAs are not degraded by RNA exonucleases or ribonuclease R and are enriched in exosomes. Recent developments in experimental methods coupled with evolving bioinformatic approaches have accelerated functional investigation of circRNAs, which exhibit a stable structure, a long half-life, and tumor specificity and can be extracted from body fluids and used as potential biological markers for tumors. Moreover, circRNAs may regulate the occurrence and development of cancers and contribute to drug resistance through a variety of molecular mechanisms. Despite the identification of a growing number of circRNAs, their effects in hematological cancers remain largely unknown. Recent studies indicate that circRNAs could also originate from fusion genes (fusion circRNAs, f-circRNAs) next to chromosomal translocations, which are considered the primary cause of various cancers, notably hematological malignancies. This Review will focus on circRNAs and f-circRNAs in hematological cancers.
Authors
Loelia Babin, Elissa Andraos, Steffen Fuchs, Stéphane Pyronnet, Erika Brunet, Fabienne Meggetto
Abstract
p38 MAPKs play a central role in orchestrating the cellular response to stress and inflammation and in the regulation of myogenesis. Potent inhibitors of p38 MAPKs have been pursued as potential therapies for several disease indications due to their antiinflammatory properties, although none have been approved to date. Here, we provide a brief overview of p38 MAPKs, including their role in regulating myogenesis and their association with disease progression. Finally, we discuss targeting p38 MAPKs as a therapeutic approach for treating facioscapulohumeral muscular dystrophy and other muscular dystrophies by addressing multiple pathological mechanisms in skeletal muscle.
Authors
Christopher M. Brennan, Charles P. Emerson Jr., Jane Owens, Nicolas Christoforou
Abstract
The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) has resulted in an unprecedented pandemic that has been accompanied by a global health crisis. Although the lungs are the main organs involved in COVID-19, systemic disease with a wide range of clinical manifestations also develops in SARS-CoV-2-infected patients. One of the major systems affected by this virus is the cardiovascular system. The presence of pre-existing cardiovascular disease increases mortality in COVID-19 patients, and cardiovascular injuries, including myocarditis, cardiac rhythm abnormalities, endothelial cell injury, thrombotic events, and myocardial interstitial fibrosis, are observed in some COVID-19 patients. The underlying pathophysiology of COVID-19-associated cardiovascular complications is not fully understood, although direct viral infection of myocardium and cytokine storm have been suggested as possible mechanisms of myocarditis. In this review, we summarize available data on SARS-CoV-2-related cardiac damage and discuss potential mechanisms of cardiovascular implications of this rapidly spreading virus.
Authors
Farnaz Farshidfar, Navid Koleini, Hossein Ardehali
Abstract
Oxygen-sensing mechanisms allow cells to adapt and respond to changes in cellular oxygen tension, including hypoxic conditions. Hypoxia-inducible factor (HIF) is a central mediator in this fundamental adaptive response, and has critical functions in normal and disease physiology. Viruses have been shown to manipulate HIFs during their life cycle to facilitate replication and invasion. Conversely, HIFs are also implicated in the development of the host immune system and response to viral infections. Here, we highlight the recent revelations of host-pathogen interactions that involve the hypoxic response pathway and the role of HIF in emerging viral infectious diseases, as well as discussing potential antiviral therapeutic strategies targeting the HIF signaling axis.
Authors
Richard Huang, Melissa Huestis, Esther Shuyi Gan, Eng Eong Ooi, Michael Ohh
Abstract
Roughly one year after the first case of COVID-19 was identified and less than one year after the sequencing of SARS-CoV-2, multiple SARS-CoV-2 vaccines with demonstrated safety and efficacy in phase III clinical trials are available. The most promising vaccines have targeted the surface glycoprotein (S-protein) of SARS-CoV-2 and achieved an approximate 85-95% reduction in the risk of symptomatic COVID-19, while retaining excellent safety profiles and modest side effects in the phase III clinical trials. The mRNA, replication-incompetent viral vector, and protein subunit vaccine technologies have all been successfully employed. Some novel SARS-CoV-2 variants evade but do not appear to fully overcome the potent immunity induced by these vaccines. Emerging real-world effectiveness data add evidence for protection from severe COVID-19. This is an impressive first demonstration of the effectiveness of the mRNA vaccine and vector vaccine platforms. The success of SARS-CoV-2 vaccine development should be credited to open science, industry partnerships, harmonization of clinical trials, and the altruism of study participants. The manufacturing and distribution of the emergency use-authorized SARS-CoV-2 vaccines are ongoing challenges. What remains now is to ensure broad and equitable global vaccination against COVID-19.
Authors
Jonathan L. Golob, Njira Lugogo, Adam S. Lauring, Anna S. Lok
Abstract
Since their relatively recent discovery, innate lymphoid cells (ILCs) have been shown to be tissue-resident lymphocytes that are critical mediators of tissue homeostasis, regeneration, and pathogen response. However, ILC dysregulation contributes to a diverse spectrum of human diseases, spanning virtually every organ system. ILCs rapidly respond to environmental cues by altering their own phenotype and function as well as influencing the behavior of other local tissue-resident cells. With a growing understanding of ILC biology, investigators continue to elucidate mechanisms that expand our ability to phenotype, isolate, target, and expand ILCs ex vivo. With mounting preclinical data and clinical correlates, the role of ILCs in both disease pathogenesis and resolution is evident, justifying ILC manipulation for clinical benefit. This Review will highlight areas of ongoing translational research and critical questions for future study that will enable us to harness the full therapeutic potential of these captivating cells.
Authors
Laura M. Cobb, Michael R. Verneris
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