-
International Journal of Molecular... Apr 2022Retinitis pigmentosa (RP) is genetically heterogeneous retinopathy caused by photoreceptor cell death and retinal pigment epithelial atrophy that eventually results in... (Review)
Review
Retinitis pigmentosa (RP) is genetically heterogeneous retinopathy caused by photoreceptor cell death and retinal pigment epithelial atrophy that eventually results in blindness in bilateral eyes. Various photoreceptor cell death types and pathological phenotypic changes that have been disclosed in RP demand in-depth research of its pathogenic mechanism that may account for inter-patient heterogeneous responses to mainstream drug treatment. As the primary method for studying the genetic characteristics of RP, molecular biology has been widely used in disease diagnosis and clinical trials. Current technology iterations, such as gene therapy, stem cell therapy, and optogenetics, are advancing towards precise diagnosis and clinical applications. Specifically, technologies, such as effective delivery vectors, CRISPR/Cas9 technology, and iPSC-based cell transplantation, hasten the pace of personalized precision medicine in RP. The combination of conventional therapy and state-of-the-art medication is promising in revolutionizing RP treatment strategies. This article provides an overview of the latest research on the pathogenesis, diagnosis, and treatment of retinitis pigmentosa, aiming for a convenient reference of what has been achieved so far.
Topics: Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Pathology, Molecular; Photoreceptor Cells; Retinitis Pigmentosa
PubMed: 35563274
DOI: 10.3390/ijms23094883 -
Virchows Archiv : An International... Aug 2016Colorectal cancer (CRC) shows variable underlying molecular changes with two major mechanisms of genetic instability: chromosomal instability and microsatellite... (Review)
Review
Colorectal cancer (CRC) shows variable underlying molecular changes with two major mechanisms of genetic instability: chromosomal instability and microsatellite instability. This review aims to delineate the different pathways of colorectal carcinogenesis and provide an overview of the most recent advances in molecular pathological classification systems for colorectal cancer. Two molecular pathological classification systems for CRC have recently been proposed. Integrated molecular analysis by The Cancer Genome Atlas project is based on a wide-ranging genomic and transcriptomic characterisation study of CRC using array-based and sequencing technologies. This approach classified CRC into two major groups consistent with previous classification systems: (1) ∼16 % hypermutated cancers with either microsatellite instability (MSI) due to defective mismatch repair (∼13 %) or ultramutated cancers with DNA polymerase epsilon proofreading mutations (∼3 %); and (2) ∼84 % non-hypermutated, microsatellite stable (MSS) cancers with a high frequency of DNA somatic copy number alterations, which showed common mutations in APC, TP53, KRAS, SMAD4, and PIK3CA. The recent Consensus Molecular Subtypes (CMS) Consortium analysing CRC expression profiling data from multiple studies described four CMS groups: almost all hypermutated MSI cancers fell into the first category CMS1 (MSI-immune, 14 %) with the remaining MSS cancers subcategorised into three groups of CMS2 (canonical, 37 %), CMS3 (metabolic, 13 %) and CMS4 (mesenchymal, 23 %), with a residual unclassified group (mixed features, 13 %). Although further research is required to validate these two systems, they may be useful for clinical trial designs and future post-surgical adjuvant treatment decisions, particularly for tumours with aggressive features or predicted responsiveness to immune checkpoint blockade.
Topics: Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Microsatellite Instability; Mutation; Pathology, Molecular; ras Proteins
PubMed: 27325016
DOI: 10.1007/s00428-016-1956-3 -
Journal of Clinical Oncology : Official... Apr 2020Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including (95%-97%), (30%-40%), (17%), and (8%-15%).... (Review)
Review
Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including (95%-97%), (30%-40%), (17%), and (8%-15%). Deletions involving chromosome 6q are common in patients with mutated and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of and mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by and/or mutation status. The mutation status of both and can be used for a precision-guided treatment approach to WM.
Topics: DNA Copy Number Variations; Genomics; Humans; Mutation; Myeloid Differentiation Factor 88; Pathology, Molecular; Receptors, CXCR4; Waldenstrom Macroglobulinemia
PubMed: 32083995
DOI: 10.1200/JCO.19.02314 -
Journal of Experimental & Clinical... Jun 2020Accumulating evidence indicates that intratumoral heterogeneity contributes to the development of resistance to anticancer therapeutics. Fibroblasts, which are... (Review)
Review
Accumulating evidence indicates that intratumoral heterogeneity contributes to the development of resistance to anticancer therapeutics. Fibroblasts, which are components of the paraneoplastic stroma, play a crucial role in the wound-healing process. Activated fibroblasts accumulate in the wound and are involved in many aspects of the tissue remodeling cascade that initiates the repair process and prevents further tissue damage. The pathophysiological roles of cancer-associated fibroblasts (CAFs) in the heterogeneous tumor microenvironment have attracted increasing interest. CAFs play crucial roles in tumor progression and the response to chemotherapy. Several cytokines and chemokines are involved in the conversion of normal fibroblasts into CAFs, and some of these form a feedback loop between cancer cells and CAFs. In addition, the physical force between tumor cells and CAFs promotes cooperative invasion or co-migration of both types of cells. Pro-inflammatory cytokines, such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), are secreted by both cancer cells and CAFs, and mediate the epigenetic modification of CAFs. This enhances the pro-tumorigenic function of CAFs mediated by promoting actomyosin contractility and extracellular matrix remodeling to form the tracks used for collective cancer cell migration. The concept of intra-tumoral CAF heterogeneity refers to the presence of inflammatory CAFs with low levels of α-smooth muscle actin (α-SMA) and high levels of IL-6 expression, which are in striking contrast to transforming growth factor-β (TGF-β)-dependent myofibroblastic CAFs with high α-SMA expression levels. CAF populations that suppress tumor growth and progression through stroma-specific Hedgehog (Hh) activation have been detected in different murine tumor models including those of the bladder, colon, and pancreas. A new therapeutic strategy targeting CAFs is the "stromal switch," in which tumor-promoting CAFs are changed into tumor-retarding CAFs with attenuated stromal stiffness. Several molecular mechanisms that can be exploited to design personalized anticancer therapies targeting CAFs remain to be elucidated. Strategies aimed at targeting the tumor stroma as well as tumor cells themselves have attracted academic attention for their application in precision medicine. This novel review discusses the role of the activation of EGFR, Wnt/β-catenin, Hippo, TGF-β, and JAK/STAT cascades in CAFs in relation to the chemoresistance and invasive/metastatic behavior of cancer cells. For instance, although activated EGFR signaling contributes to collective cell migration in cooperation with CAFs, an activated Hippo pathway is responsible for stromal stiffness resulting in the collapse of neoplastic blood vessels. Therefore, identifying the signaling pathways that are activated under specific conditions is crucial for precision medicine.
Topics: Animals; Cancer-Associated Fibroblasts; Humans; Neoplasms; Pathology, Molecular; Signal Transduction
PubMed: 32546182
DOI: 10.1186/s13046-020-01611-0 -
Advances in Anatomic Pathology Nov 2017Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies... (Review)
Review
Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and...
Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.
Topics: Biomarkers, Tumor; Biopsy; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Endometrial Neoplasms; Female; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Humans; Immunohistochemistry; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating; Melanoma; Mesothelioma; Ovarian Neoplasms; Pathology; Phenotype; Predictive Value of Tests; Skin Neoplasms; Squamous Cell Carcinoma of Head and Neck; Urogenital Neoplasms
PubMed: 28777143
DOI: 10.1097/PAP.0000000000000161 -
The Lancet. Microbe Jul 2022Tuberculosis remains a leading cause of global mortality, especially for adults and children living with HIV (CLHIV) underdiagnosed by sputum-based assays....
BACKGROUND
Tuberculosis remains a leading cause of global mortality, especially for adults and children living with HIV (CLHIV) underdiagnosed by sputum-based assays. Non-sputum-based assays are needed to improve tuberculosis diagnosis and tuberculosis treatment monitoring. Our aim in this study was to determine whether ultrasensitive detection of Mycobacterium tuberculosis cell-free DNA (Mtb-cfDNA) in blood can diagnose tuberculosis and evaluate tuberculosis treatment responses.
METHODS
In this molecular diagnostics study we analysed archived serum from two patient populations evaluated for tuberculosis in Eswatini and Kenya to detect Mtb-cfDNA, analysing serum from all individuals who had both sufficient serum volumes and clear diagnostic results. An optimised CRISPR-mediated tuberculosis (CRISPR-TB) assay was used to detect Mtb-cfDNA in serum at enrolment from adults and children with presumptive tuberculosis and their asymptomatic household contacts, and at enrolment and during tuberculosis treatment from a cohort of symptomatic CLHIV at high risk for tuberculosis, who provided longitudinal serum at enrolment and during tuberculosis treatment.
FINDINGS
CRISPR-TB identified microbiologically and clinically confirmed tuberculosis cases in the predominantly HIV-negative Eswatini adult cohort with 96% sensitivity (27 [96%] of 28, 95% CI 80-100) and 94% specificity (16 [94%] of 17, 71-100), and with 83% sensitivity (5 [83%] of 6, 36-100) and 95% specificity (21 [95%] of 22, 77-100) in the paediatric cohort, including all six cases of extrapulmonary tuberculosis. In the Kenyan CLHIV cohort, CRISPR-TB detected all (13 [100%] of 13, 75-100) confirmed tuberculosis cases and 85% (39 [85%] of 46, 71-94) of unconfirmed tuberculosis cases diagnosed by non-microbiological clinical findings. CLHIV who were CRISPR-TB positive at enrolment had a 2·4-times higher risk of mortality by 6 months after enrolment. Mtb-cfDNA signal decreased after tuberculosis treatment initiation, with near or complete Mtb-cfDNA clearance by 6 months after tuberculosis treatment initiation.
INTERPRETATION
CRISPR-mediated detection of circulating Mtb-cfDNA shows promise to increase the identification of paediatric tuberculosis and HIV-associated tuberculosis, and potential for early diagnosis and rapid monitoring of tuberculosis treatment responses.
FUNDING
US Department of Defense, National Institute of Child Health and Human Development, National Institute of Allergy and Infectious Diseases, University of Washington Center for AIDS Research, and the Weatherhead Presidential Endowment fund.
Topics: Adult; Cell-Free Nucleic Acids; Child; Clustered Regularly Interspaced Short Palindromic Repeats; HIV Infections; Humans; Kenya; Mycobacterium tuberculosis; Pathology, Molecular; Sensitivity and Specificity; Tuberculosis, Lymph Node; United States
PubMed: 35659882
DOI: 10.1016/S2666-5247(22)00087-8 -
Neuro-oncology Oct 2022Safe sampling of central nervous system tumor tissue for diagnostic purposes may be difficult if not impossible, especially in pediatric patients, and an unmet need...
BACKGROUND
Safe sampling of central nervous system tumor tissue for diagnostic purposes may be difficult if not impossible, especially in pediatric patients, and an unmet need exists to develop less invasive diagnostic tests.
METHODS
We report our clinical experience with minimally invasive molecular diagnostics using a clinically validated assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA). All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families.
RESULTS
We analyzed 64 CSF samples from 45 pediatric, adolescent and young adult (AYA) patients (pediatric = 25; AYA = 20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n = 10), medulloblastoma (n = 10), pineoblastoma (n = 5), low-grade glioma (n = 4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n = 4), retinoblastoma (n = 4), ependymoma (n = 3), and other (n = 5). Somatic alterations were detected in 30/64 samples (46.9%) and in at least one sample per unique patient in 21/45 patients (46.6%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (81.5% of samples from patients with disseminated disease were positive). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient's disease course.
CONCLUSIONS
We identified three general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: (1) diagnosis and/or identification of actionable alterations; (2) monitor response to therapy; and (3) tracking tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population to improve care.
Topics: Adolescent; Brain Neoplasms; Cell-Free Nucleic Acids; Central Nervous System Neoplasms; Child; Glioma; High-Throughput Nucleotide Sequencing; Humans; Mutation; Pathology, Molecular; Young Adult
PubMed: 35148412
DOI: 10.1093/neuonc/noac035 -
Canadian Medical Association Journal Nov 1964Ataxia-telangiectasia is a syndrome of progressive cerebellar ataxia and other neurological manifestations associated with conjunctival and cutaneous telangiectases and...
Ataxia-telangiectasia is a syndrome of progressive cerebellar ataxia and other neurological manifestations associated with conjunctival and cutaneous telangiectases and with recurrent sino-pulmonary infections. Immunological and endocrine abnormalities occur. Two girls with this disease are described. The first had only minor respiratory infections; her serum proteins and immunity responses appeared normal. The second had recurrent pulmonary infections and bronchiectasis; she also exhibited sclerodermatous changes, poor development of secondary sexual characteristics with low urinary excretion of 17-ketosteroids, and lymphopenia. Autopsy at 17 years showed bilateral ovarian dysgerminomata and excessive cutaneous collagen as well as atrophy, and perhaps hypoplasia, of adrenals, thymus, spleen and lymphoid tissue (after steroid therapy). The cerebellum exhibited cortical degeneration. Both lungs were fibrotic with old and recent bronchopneumonia and bronchiectasis. The left lung was studied by injection of a latex preparation; no arteriovenous aneurysms were found, but the smaller pulmonary vessels showed some unusual morphological characteristics.
Topics: 17-Ketosteroids; Adolescent; Ataxia; Ataxia Telangiectasia; Atrophy; Blood Protein Electrophoresis; Bronchiectasis; Cerebellar Diseases; Child; Conjunctiva; Dysgerminoma; Eosinophils; Female; Genetics, Medical; Humans; Hypogonadism; Immunoelectrophoresis; Infant; Infant, Newborn; Leukocyte Count; Lymphocytes; Neoplasms, Germ Cell and Embryonal; Neurologic Manifestations; Ovarian Neoplasms; Pathology; Pulmonary Circulation; Pulmonary Fibrosis; Scleroderma, Systemic; Telangiectasis; Urine
PubMed: 14229760
DOI: No ID Found -
Molecular Medicine Reports Jan 2022Efferocytosis, the phagocytosis of apoptotic cells performed by both specialized phagocytes (such as macrophages) and non‑specialized phagocytes (such as epithelial... (Review)
Review
Efferocytosis, the phagocytosis of apoptotic cells performed by both specialized phagocytes (such as macrophages) and non‑specialized phagocytes (such as epithelial cells), is involved in tissue repair and homeostasis. Effective efferocytosis prevents secondary necrosis, terminates inflammatory responses, promotes self‑tolerance and activates pro‑resolving pathways to maintain homeostasis. When efferocytosis is impaired, apoptotic cells that could not be cleared in time aggregate, resulting in the necrosis of apoptotic cells and release of pro‑inflammatory factors. In addition, defective efferocytosis inhibits the intracellular cholesterol reverse transportation pathways, which may lead to atherosclerosis, lung damage, non‑alcoholic fatty liver disease and neurodegenerative diseases. The uncleared apoptotic cells can also release autoantigens, which can cause autoimmune diseases. Cancer cells escape from phagocytosis via efferocytosis. Therefore, new treatment strategies for diseases related to defective efferocytosis are proposed. This review illustrated the mechanisms of efferocytosis in multisystem diseases and organismal homeostasis and the pathophysiological consequences of defective efferocytosis. Several drugs and treatments available to enhance efferocytosis are also mentioned in the review, serving as new evidence for clinical application.
Topics: Animals; Apoptosis; Cytophagocytosis; Disease; Epithelial Cells; Extracellular Vesicles; Homeostasis; Humans; Immunity; Inflammation; Macrophages; Necrosis; Pathology; Phagocytes
PubMed: 34779503
DOI: 10.3892/mmr.2021.12529 -
Journal of Alzheimer's Disease : JAD 2018The study of life and living organisms and the way in which these interact and organize to form social communities have been central to my career. I have been fascinated...
The study of life and living organisms and the way in which these interact and organize to form social communities have been central to my career. I have been fascinated by biology, neurology, and neuropathology, but also by history, sociology, and art. Certain current historical, political, and social events, some occurring proximally but others affecting people in apparently distant places, have had an impact on me. Epicurus, Seneca, and Camus shared their philosophical positions which I learned from. Many scientists from various disciplines have been exciting sources of knowledge as well. I have created a world of hypothesis and experiments but I have also got carried away by serendipity following unexpected observations. It has not been an easy path; errors and wanderings are not uncommon, and opponents close to home much more abundant than one might imagine. Ambition, imagination, resilience, and endurance have been useful in moving ahead in response to setbacks. In the end, I have enjoyed my dedication to science and I am grateful to have glimpsed beauty in it. These are brief memories of a Spanish neuropathologist born and raised in Barcelona, EU.
Topics: Animals; Art; History, 20th Century; History, 21st Century; Humans; Neuropathology; Philosophy; Politics; Spain
PubMed: 29154280
DOI: 10.3233/JAD-170609