Pub Date : 2024-01-24Epub Date: 2023-10-13DOI: 10.1146/annurev-pathmechdis-051122-094743
Sumeet Solanki, Yatrik M Shah
Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, the presence of oxygen gradients or physiologic hypoxia is necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets.
{"title":"Hypoxia-Induced Signaling in Gut and Liver Pathobiology.","authors":"Sumeet Solanki, Yatrik M Shah","doi":"10.1146/annurev-pathmechdis-051122-094743","DOIUrl":"10.1146/annurev-pathmechdis-051122-094743","url":null,"abstract":"<p><p>Oxygen (O<sub>2</sub>) is essential for cellular metabolism and biochemical reactions. When the demand for O<sub>2</sub> exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, the presence of oxygen gradients or physiologic hypoxia is necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"291-317"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-10-13DOI: 10.1146/annurev-pathmechdis-051122-111408
John P Dekker
Bacterial pathogens undergo remarkable adaptive change in response to the selective forces they encounter during host colonization and infection. Studies performed over the past few decades have demonstrated that many general evolutionary processes can be discerned during the course of host adaptation, including genetic diversification of lineages, clonal succession events, convergent evolution, and balanced fitness trade-offs. In some cases, elevated mutation rates resulting from mismatch repair or proofreading deficiencies accelerate evolution, and active mobile genetic elements or phages may facilitate genome plasticity. The host immune response provides another critical component of the fitness landscapes guiding adaptation, and selection operating on pathogens at this level may lead to immune evasion and the establishment of chronic infection. This review summarizes recent advances in this field, with a special focus on different forms of bacterial genome plasticity in the context of infection, and considers clinical consequences of adaptive changes for the host.
{"title":"Within-Host Evolution of Bacterial Pathogens in Acute and Chronic Infection.","authors":"John P Dekker","doi":"10.1146/annurev-pathmechdis-051122-111408","DOIUrl":"10.1146/annurev-pathmechdis-051122-111408","url":null,"abstract":"<p><p>Bacterial pathogens undergo remarkable adaptive change in response to the selective forces they encounter during host colonization and infection. Studies performed over the past few decades have demonstrated that many general evolutionary processes can be discerned during the course of host adaptation, including genetic diversification of lineages, clonal succession events, convergent evolution, and balanced fitness trade-offs. In some cases, elevated mutation rates resulting from mismatch repair or proofreading deficiencies accelerate evolution, and active mobile genetic elements or phages may facilitate genome plasticity. The host immune response provides another critical component of the fitness landscapes guiding adaptation, and selection operating on pathogens at this level may lead to immune evasion and the establishment of chronic infection. This review summarizes recent advances in this field, with a special focus on different forms of bacterial genome plasticity in the context of infection, and considers clinical consequences of adaptive changes for the host.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"203-226"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-10-03DOI: 10.1146/annurev-pathmechdis-051022-014433
Nobuhiko Kayagaki, Joshua D Webster, Kim Newton
Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases.
{"title":"Control of Cell Death in Health and Disease.","authors":"Nobuhiko Kayagaki, Joshua D Webster, Kim Newton","doi":"10.1146/annurev-pathmechdis-051022-014433","DOIUrl":"10.1146/annurev-pathmechdis-051022-014433","url":null,"abstract":"<p><p>Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"157-180"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41156198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-10-13DOI: 10.1146/annurev-pathmechdis-051222-122724
Rashmi Kanagal-Shamanna, David B Beck, Katherine R Calvo
Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.
{"title":"Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.","authors":"Rashmi Kanagal-Shamanna, David B Beck, Katherine R Calvo","doi":"10.1146/annurev-pathmechdis-051222-122724","DOIUrl":"10.1146/annurev-pathmechdis-051222-122724","url":null,"abstract":"<p><p>Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"479-506"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-10-13DOI: 10.1146/annurev-pathmechdis-051122-110348
Maya Anjali Jayaram, Joanna J Phillips
Gliomas are a diverse group of primary central nervous system tumors that affect both children and adults. Recent studies have revealed a dynamic cross talk that occurs between glioma cells and components of their microenvironment, including neurons, astrocytes, immune cells, and the extracellular matrix. This cross talk regulates fundamental aspects of glioma development and growth. In this review, we discuss recent discoveries about the impact of these interactions on gliomas and highlight how tumor cells actively remodel their microenvironment to promote disease. These studies provide a better understanding of the interactions in the microenvironment that are important in gliomas, offer insight into the cross talk that occurs, and identify potential therapeutic vulnerabilities that can be utilized to improve clinical outcomes.
{"title":"Role of the Microenvironment in Glioma Pathogenesis.","authors":"Maya Anjali Jayaram, Joanna J Phillips","doi":"10.1146/annurev-pathmechdis-051122-110348","DOIUrl":"10.1146/annurev-pathmechdis-051122-110348","url":null,"abstract":"<p><p>Gliomas are a diverse group of primary central nervous system tumors that affect both children and adults. Recent studies have revealed a dynamic cross talk that occurs between glioma cells and components of their microenvironment, including neurons, astrocytes, immune cells, and the extracellular matrix. This cross talk regulates fundamental aspects of glioma development and growth. In this review, we discuss recent discoveries about the impact of these interactions on gliomas and highlight how tumor cells actively remodel their microenvironment to promote disease. These studies provide a better understanding of the interactions in the microenvironment that are important in gliomas, offer insight into the cross talk that occurs, and identify potential therapeutic vulnerabilities that can be utilized to improve clinical outcomes.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"181-201"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-10-13DOI: 10.1146/annurev-pathmechdis-051122-100856
Martí Duran-Ferrer, José Ignacio Martín-Subero
Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.
{"title":"Epigenomic Characterization of Lymphoid Neoplasms.","authors":"Martí Duran-Ferrer, José Ignacio Martín-Subero","doi":"10.1146/annurev-pathmechdis-051122-100856","DOIUrl":"10.1146/annurev-pathmechdis-051122-100856","url":null,"abstract":"<p><p>Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"371-396"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-10-23DOI: 10.1146/annurev-pathmechdis-051222-121126
Carlos R Ferreira, Thomas O Carpenter, Demetrios T Braddock
The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PPi) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.
{"title":"ENPP1 in Blood and Bone: Skeletal and Soft Tissue Diseases Induced by ENPP1 Deficiency.","authors":"Carlos R Ferreira, Thomas O Carpenter, Demetrios T Braddock","doi":"10.1146/annurev-pathmechdis-051222-121126","DOIUrl":"10.1146/annurev-pathmechdis-051222-121126","url":null,"abstract":"<p><p>The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (<i>ENPP1</i>) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP<sub>i</sub>) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"507-540"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11062289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49693604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-09-22DOI: 10.1146/annurev-pathmechdis-031521-042754
Katharina Röltgen, Scott D Boyd
As the COVID-19 pandemic has evolved during the past years, interactions between human immune systems, rapidly mutating and selected SARS-CoV-2 viral variants, and effective vaccines have complicated the landscape of individual immunological histories. Here, we review some key findings for antibody and B cell-mediated immunity, including responses to the highly mutated omicron variants; immunological imprinting and other impacts of successive viral antigenic variant exposures on antibody and B cell memory; responses in secondary lymphoid and mucosal tissues and non-neutralizing antibody-mediated immunity; responses in populations vulnerable to severe disease such as those with cancer, immunodeficiencies, and other comorbidities, as well as populations showing apparent resistance to severe disease such as many African populations; and evidence of antibody involvement in postacute sequelae of infection or long COVID. Despite the initial phase of the pandemic ending, human populations will continue to face challenges presented by this unpredictable virus.
{"title":"Antibody and B Cell Responses to SARS-CoV-2 Infection and Vaccination: The End of the Beginning.","authors":"Katharina Röltgen, Scott D Boyd","doi":"10.1146/annurev-pathmechdis-031521-042754","DOIUrl":"10.1146/annurev-pathmechdis-031521-042754","url":null,"abstract":"<p><p>As the COVID-19 pandemic has evolved during the past years, interactions between human immune systems, rapidly mutating and selected SARS-CoV-2 viral variants, and effective vaccines have complicated the landscape of individual immunological histories. Here, we review some key findings for antibody and B cell-mediated immunity, including responses to the highly mutated omicron variants; immunological imprinting and other impacts of successive viral antigenic variant exposures on antibody and B cell memory; responses in secondary lymphoid and mucosal tissues and non-neutralizing antibody-mediated immunity; responses in populations vulnerable to severe disease such as those with cancer, immunodeficiencies, and other comorbidities, as well as populations showing apparent resistance to severe disease such as many African populations; and evidence of antibody involvement in postacute sequelae of infection or long COVID. Despite the initial phase of the pandemic ending, human populations will continue to face challenges presented by this unpredictable virus.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"69-97"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41158606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-09-22DOI: 10.1146/annurev-pathmechdis-051122-110756
Mirja Thomsen, Lara M Lange, Michael Zech, Katja Lohmann
Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., KMT2B, THAP1), calcium homeostasis (e.g., ANO3, HPCA), striatal dopamine signaling (e.g., GNAL), endoplasmic reticulum stress response (e.g., EIF2AK2, PRKRA, TOR1A), autophagy (e.g., VPS16), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.
{"title":"Genetics and Pathogenesis of Dystonia.","authors":"Mirja Thomsen, Lara M Lange, Michael Zech, Katja Lohmann","doi":"10.1146/annurev-pathmechdis-051122-110756","DOIUrl":"10.1146/annurev-pathmechdis-051122-110756","url":null,"abstract":"<p><p>Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., <i>KMT2B</i>, <i>THAP1</i>), calcium homeostasis (e.g., <i>ANO3</i>, <i>HPCA</i>), striatal dopamine signaling (e.g., <i>GNAL</i>), endoplasmic reticulum stress response (e.g., <i>EIF2AK2</i>, <i>PRKRA</i>, <i>TOR1A</i>), autophagy (e.g., <i>VPS16</i>), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"99-131"},"PeriodicalIF":36.2,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41123252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24Epub Date: 2023-10-13DOI: 10.1146/annurev-pathmechdis-031621-025610
Ben Z Stanger, Geoffrey M Wahl
In the 160 years since Rudolf Virchow first postulated that neoplasia arises by the same law that regulates embryonic development, scientists have come to recognize the striking overlap between the molecular and cellular programs used by cancers and embryos. Advances in cancer biology and molecular techniques have further highlighted the similarities between carcinogenesis and embryogenesis, where cellular growth, differentiation, motility, and intercellular cross talk are mediated by common drivers and regulatory networks. This review highlights the many connections linking cancer biology and developmental biology to provide a deeper understanding of how a tissue's developmental history may both enable and constrain cancer cell evolution.
Rudolf Virchow首次假设肿瘤是由调节胚胎发育的同一定律引起的,在这160年里,科学家们已经认识到癌症和胚胎所使用的分子和细胞程序之间的惊人重叠。癌症生物学和分子技术的进展进一步突出了致癌作用和胚胎发生之间的相似性,其中细胞生长、分化、运动和细胞间串扰是由共同的驱动因素和调节网络介导的。这篇综述强调了癌症生物学和发育生物学之间的许多联系,以更深入地了解组织的发育史如何既能促进又能限制癌症细胞的进化。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
{"title":"Cancer as a Disease of Development Gone Awry.","authors":"Ben Z Stanger, Geoffrey M Wahl","doi":"10.1146/annurev-pathmechdis-031621-025610","DOIUrl":"10.1146/annurev-pathmechdis-031621-025610","url":null,"abstract":"<p><p>In the 160 years since Rudolf Virchow first postulated that neoplasia arises by the same law that regulates embryonic development, scientists have come to recognize the striking overlap between the molecular and cellular programs used by cancers and embryos. Advances in cancer biology and molecular techniques have further highlighted the similarities between carcinogenesis and embryogenesis, where cellular growth, differentiation, motility, and intercellular cross talk are mediated by common drivers and regulatory networks. This review highlights the many connections linking cancer biology and developmental biology to provide a deeper understanding of how a tissue's developmental history may both enable and constrain cancer cell evolution.</p>","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":" ","pages":"397-421"},"PeriodicalIF":28.4,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}