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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 -
Acta Neuropathologica May 2017Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is... (Review)
Review
Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability. The present review describes the physiological and pathophysiological properties of tau and how these relate to its distribution and functions in neurons. We highlight the post-translational modifications of tau, which are pivotal in defining and modulating tau localisation and its roles in health and disease. We include discussion of other pathologically relevant changes in tau, including mutation and aggregation, and how these aspects impinge on the propensity of tau to propagate, and potentially drive neuronal loss, in diseased brain. Finally, we describe the cascade of pathological events that may be driven by tau dysfunction, including impaired axonal transport, alterations in synapse and mitochondrial function, activation of the unfolded protein response and defective protein degradation. It is important to fully understand the range of neuronal functions attributed to tau, since this will provide vital information on its involvement in the development and pathogenesis of disease. Such knowledge will enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies.
Topics: Animals; Brain; Humans; Neurodegenerative Diseases; Neurons; Protein Processing, Post-Translational; Tauopathies; tau Proteins
PubMed: 28386764
DOI: 10.1007/s00401-017-1707-9 -
European Urology May 2022For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.
BACKGROUND
For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.
OBJECTIVE
To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.
DESIGN, SETTING, AND PARTICIPANTS
Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.
RESULTS AND LIMITATIONS
Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.
CONCLUSIONS
Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.
PATIENT SUMMARY
This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.
Topics: Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cisplatin; Cystectomy; Female; Humans; Male; Neoadjuvant Therapy; Neoplasm Invasiveness; Retrospective Studies; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 34782206
DOI: 10.1016/j.eururo.2021.10.035 -
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 -
JAMA Surgery Jun 2021An overview of rates of axillary pathologic complete response (pCR) for all breast cancer subtypes, both for patients with and without pathologically proven clinically... (Meta-Analysis)
Meta-Analysis
Axillary Pathologic Complete Response After Neoadjuvant Systemic Therapy by Breast Cancer Subtype in Patients With Initially Clinically Node-Positive Disease: A Systematic Review and Meta-analysis.
IMPORTANCE
An overview of rates of axillary pathologic complete response (pCR) for all breast cancer subtypes, both for patients with and without pathologically proven clinically node-positive disease, is lacking.
OBJECTIVE
To provide pooled data of all studies in the neoadjuvant setting on axillary pCR rates for different breast cancer subtypes in patients with initially clinically node-positive disease.
DATA SOURCES
The electronic databases Embase and PubMed were used to conduct a systematic literature search on July 16, 2020. The references of the included studies were manually checked to identify other eligible studies.
STUDY SELECTION
Studies in the neoadjuvant therapy setting were identified regarding axillary pCR for different breast cancer subtypes in patients with initially clinically node-positive disease (ie, defined as node-positive before the initiation of neoadjuvant systemic therapy).
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently selected eligible studies according to the inclusion criteria and extracted all data. All discrepant results were resolved during a consensus meeting. To identify the different subtypes, the subtype definitions as reported by the included articles were used. The random-effects model was used to calculate the overall pooled estimate of axillary pCR for each breast cancer subtype.
MAIN OUTCOMES AND MEASURES
The main outcome of this study was the rate of axillary pCR and residual axillary lymph node disease after neoadjuvant systemic therapy for different breast cancer subtypes, differentiating studies with and without patients with pathologically proven clinically node-positive disease.
RESULTS
This pooled analysis included 33 unique studies with 57 531 unique patients and showed the following axillary pCR rates for each of the 7 reported subtypes in decreasing order: 60% for hormone receptor (HR)-negative/ERBB2 (formerly HER2)-positive, 59% for ERBB2-positive (HR-negative or HR-positive), 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. No major differences were found in the axillary pCR rates per subtype by analyzing separately the studies of patients with and without pathologically proven clinically node-positive disease before neoadjuvant systemic therapy.
CONCLUSIONS AND RELEVANCE
The HR-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate. These data may help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.
Topics: Axilla; Breast Neoplasms; Female; Humans; Lymph Nodes; Neoadjuvant Therapy
PubMed: 33881478
DOI: 10.1001/jamasurg.2021.0891 -
Cell Sep 2017The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and...
The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and signaling lineage reporters to generate a spatial and transcriptional map of the lung mesenchyme. We find that each mesenchymal lineage has a distinct spatial address and transcriptional profile leading to unique niche regulatory functions. The mesenchymal alveolar niche cell is Wnt responsive, expresses Pdgfrα, and is critical for alveolar epithelial cell growth and self-renewal. In contrast, the Axin2+ myofibrogenic progenitor cell preferentially generates pathologically deleterious myofibroblasts after injury. Analysis of the secretome and receptome of the alveolar niche reveals functional pathways that mediate growth and self-renewal of alveolar type 2 progenitor cells, including IL-6/Stat3, Bmp, and Fgf signaling. These studies define the cellular and molecular framework of lung mesenchymal niches and reveal the functional importance of developmental pathways in promoting self-renewal versus a pathological response to tissue injury.
Topics: Algorithms; Animals; Epithelial Cells; Fibrosis; Gene Expression Profiling; Lung; Lung Injury; Mesoderm; Mice; Organoids; Paracrine Communication; Regeneration; Signal Transduction; Single-Cell Analysis; Stem Cells
PubMed: 28886382
DOI: 10.1016/j.cell.2017.07.034 -
Journal of Current Ophthalmology Sep 2018To summarize available literature on physiologic and pathologic ocular changes during pregnancy. (Review)
Review
PURPOSE
To summarize available literature on physiologic and pathologic ocular changes during pregnancy.
METHODS
Narrative review of literature.
RESULTS
Ocular changes occur commonly during pregnancy. Although most of these are benign physiologic responses to the metabolic, hormonal, and immunologic modifications to adopt the gestational product, there is some serious pathology that may develop, exacerbate, or even resolve over the course of pregnancy which requires prompt diagnosis and management. The pathological eye conditions can be classified into preexisting pathologies and emerging ocular diseases. Regardless of the different mechanisms by which these ocular changes occur, the key point is the establishment of an effective perinatal screening program to monitor the new development or successive progression of these ocular abnormalities. Irrespective of the visual health status of the pregnant women, regular perinatal eye examination should be scheduled in order to assure continuous surveillance of healthy eyes. Treatment of pathologic ocular conditions or functionally disturbing benign changes relies on an appropriate patient selection.
CONCLUSIONS
Discriminating pathological eye disease from physiologic ocular changes is important in order to establish an individualized treatment or preventive plan and constitutes the mainstay of obstetric ophthalmology. This individualized approach should always weigh the ocular benefits of treatment to the mother against the potential harms to the fetus.
PubMed: 30197948
DOI: 10.1016/j.joco.2017.11.012