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Neurogenetics Oct 2023Brain iron accumulation disorders (BIADs) are a group of diseases characterized by iron overload in deep gray matter nuclei, which is a common feature of...
Brain iron accumulation disorders (BIADs) are a group of diseases characterized by iron overload in deep gray matter nuclei, which is a common feature of neurodegenerative diseases. Although genetic factors have been reported to be one of the etiologies, much more details about the genetic background and molecular mechanism of BIADs remain unclear. This study aimed to illustrate the genetic characteristics of BIADs and clarify their molecular mechanisms. A total of 84 patients with BIADs were recruited from April 2018 to October 2022 at Xuanwu Hospital. Clinical characteristics including family history, consanguineous marriage history, and age at onset (AAO) were collected and assessed by two senior neurologists. Neuroimaging data were conducted for all the patients, including cranial magnetic resonance imaging (MRI) and susceptibility-weighted imaging (SWI). Whole-exome sequencing (WES) and capillary electrophoresis for detecting sequence mutation and trinucleotide repeat expansion, respectively, were conducted on all patients and part of their parents (whose samples were available). Variant pathogenicity was assessed according to the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP). The NBIA and NBIA-like genes with mutations were included for bioinformatic analysis, using Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genome (KEGG). GO annotation and KEGG pathway analysis were performed on Metascape platform. In the 84 patients, 30 (35.7%) were found to carry mutations, among which 20 carried non-dynamic mutations (missense, stop-gained, frameshift, inframe, and exonic deletion) and 10 carried repeat expansion mutations. Compared with sporadic cases, familial cases had more genetic variants (non-dynamic mutation: P=0.025, dynamic mutation: P=0.003). AAO was 27.85±10.42 years in cases with non-dynamic mutations, which was significantly younger than those without mutations (43.13±17.17, t=3.724, P<0.001) and those with repeated expansions (45.40±8.90, t=4.550, P<0.001). Bioinformatic analysis suggested that genes in lipid metabolism, autophagy, mitochondria regulation, and ferroptosis pathways are more likely to be involved in the pathogenesis of BIADs. This study broadens the genetic spectrum of BIADs and has important implications in genetic counselling and clinical diagnosis. Patients diagnosed as BIADs with early AAO and family history are more likely to carry mutations. Bioinformatic analysis provides new insights into the molecular pathogenesis of BIADs, which may shed lights on the therapeutic strategy for neurodegenerative diseases.
Topics: Humans; Brain; Mutation; Frameshift Mutation; Neurodegenerative Diseases; Iron
PubMed: 37453004
DOI: 10.1007/s10048-023-00725-9 -
JCI Insight Oct 2023Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial...
Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI) and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1-dependent apoptotic cell clearance, or efferocytosis, and this was associated with dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate the functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.
Topics: Mice; Animals; Humans; Kidney Tubules, Proximal; Tretinoin; Kidney; Acute Kidney Injury; Epithelial Cells; Mammals
PubMed: 37698919
DOI: 10.1172/jci.insight.173144 -
Trends in Cancer Nov 2023Benzodiazepines (BZDs) are commonly prescribed for pancreatic cancer patients. To investigate the correlation between BZDs and survival outcomes a recent study by...
Benzodiazepines (BZDs) are commonly prescribed for pancreatic cancer patients. To investigate the correlation between BZDs and survival outcomes a recent study by Cornwell et al. found that lorazepam (LOR) correlates with poor survival. The mechanistic study shows that LOR increases interleukin 6 (IL6) expression in cancer-associated fibroblasts via GPR68.
Topics: Humans; Anti-Anxiety Agents; Benzodiazepines; Lorazepam; Anxiety; Pancreatic Neoplasms; Receptors, G-Protein-Coupled
PubMed: 37778962
DOI: 10.1016/j.trecan.2023.09.005 -
Cancers Aug 2023Dedifferentiated chondrosarcoma (DDCS) is a rare subtype of chondrosarcoma, a primary cartilaginous malignant neoplasm. It accounts for up to 1-2% of all chondrosarcomas... (Review)
Review
Dedifferentiated chondrosarcoma (DDCS) is a rare subtype of chondrosarcoma, a primary cartilaginous malignant neoplasm. It accounts for up to 1-2% of all chondrosarcomas and is generally associated with one of the poorest prognoses among all chondrosarcomas with the highest risk of metastasis. The 5-year survival rates range from 7% to 24%. DDCS may develop at any age, but the average presentation age is over 50. The most common locations are the femur, pelvis humerus, scapula, rib, and tibia. The standard treatment for localised disease is surgical resection. Most patients are diagnosed in unresectable and advanced stages, and chemotherapy for localised and metastatic dedifferentiated DDCS follows protocols used for osteosarcoma.
PubMed: 37568740
DOI: 10.3390/cancers15153924 -
Pathology Mar 2024Lung cancer is the most common cause of cancer-related deaths globally, with the highest mortality rates among both men and women. Most lung cancers are diagnosed at... (Review)
Review
Lung cancer is the most common cause of cancer-related deaths globally, with the highest mortality rates among both men and women. Most lung cancers are diagnosed at late stages, necessitating systemic therapy. Modern clinical management of lung cancer relies heavily upon application of biomarkers, which guide the selection of systemic treatment. Here, we provide an overview of currently approved and emerging biomarkers of non-small cell lung cancer (NSCLC), including EGFR, ALK, ROS1, RET, NTRK1-3, KRAS, BRAF, MET, ERBB2/HER2, NRG1, PD-L1, TROP2, and CEACAM5. For practical purposes, we divide these biomarkers into genomic and protein markers, based on the tested substrate. We review the biology and epidemiology of the genomic and proteomic biomarkers, discuss optimal diagnostic assays for their detection, and highlight their contribution to the contemporary clinical management of NSCLC.
Topics: Male; Humans; Female; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Prognosis; Proteomics; Mutation; Proto-Oncogene Proteins; Biomarkers, Tumor
PubMed: 38199926
DOI: 10.1016/j.pathol.2023.11.006 -
ESMO Open Oct 2023Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is...
BACKGROUND
Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs).
MATERIALS AND METHODS
To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021.
RESULTS
TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme.
CONCLUSIONS
These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Laboratories; Retrospective Studies; Pandemics; Mutation; ErbB Receptors; Europe
PubMed: 37713929
DOI: 10.1016/j.esmoop.2023.101628 -
Genes Dec 2023Since the introduction of new molecular techniques, the diagnostic landscape of soft tissue and bone tumors has expanded greatly over the past few years. The use of new... (Review)
Review
Since the introduction of new molecular techniques, the diagnostic landscape of soft tissue and bone tumors has expanded greatly over the past few years. The use of new molecular techniques has led to the identification of new genetic alterations and, therefore, to a better understanding of tumorigenesis, tumor detection and classification. Furthermore, methylation profiling has emerged as a classification tool for soft tissue and bone tumors. Molecular pathology also plays an important role in the determination of patient prognosis and in the identification of targets that can be used for targeted therapy. As a result, molecular pathology has gained a more prominent role in the daily practice of the surgical pathologist. This review delves into various molecular techniques applied in the surgical pathology of soft tissue and bone tumors. It highlights their applications through the analysis of five specific cases.
Topics: Humans; Soft Tissue Neoplasms; Mutation; Bone Neoplasms; Prognosis; Pathology, Molecular
PubMed: 38137051
DOI: 10.3390/genes14122229 -
Pathologie (Heidelberg, Germany) Dec 2023Primary vitreoretinal lymphoma (PVRL) represents a subtype of intraocular lymphomas, which are a subgroup of malignant lymphomas of the eye. PVRL is considered... (Review)
Review
Primary vitreoretinal lymphoma (PVRL) represents a subtype of intraocular lymphomas, which are a subgroup of malignant lymphomas of the eye. PVRL is considered a special form of primary diffuse large cell lymphoma (DLBCL) of the CNS (central nervous system) (PCNSL) and arises primary or secondary to PCNSL. According to the cell of origin (COO) classification of DLBCL, PVRL largely belongs to the activated B‑cell (ABC) type of DLBCL. Based on a recently established genetic-biological classification of DLBCL, PCNSL and thus also PVRL belong to a group of DLBCL of the MYD88/CD79B-mutated (MCD) or cluster 5 subtype, which often shows extranodal manifestations and MYD88 and CD79A mutations as well as CDKN2A deletions.PVRL diagnostics is often complicated as it represents a classic masquerade syndrome. Due to the usually limited material with often large numbers of reactive lymphocytes and/or degenerative changes in the cells, the results of diagnostic tests are difficult to interpret. Classic diagnostic tests include cytology on vitreous aspirates, immunocytochemistry, and clonality analysis.New insights into the spectrum of genetic alterations of vitreoretinal lymphomas (VRL) confirm the close relationship to PCNSL and could significantly improve pathological diagnosis. Next-generation sequencing panel-based diagnostics allow VRL diagnosis confirmation with little DNA in almost 100% of patients in cases with insufficient cytological evidence or lack of clonality detection. PVRL, as well as secondary vitreoretinal lymphomas after PCNSL or extracerebral DLBCL, have high mutation frequencies in characteristically mutated genes in PCNSL or MCD/cluster 5 type DLBCL. Supporting diagnostics, mutation detection can also be performed on cell-free DNA from the vitreous supernatant.
Topics: Humans; Retinal Neoplasms; Myeloid Differentiation Factor 88; Pathology, Molecular; Vitreous Body; Eye Neoplasms; Lymphoma, Large B-Cell, Diffuse; Central Nervous System Neoplasms
PubMed: 37947807
DOI: 10.1007/s00292-023-01251-z -
Pathologie (Heidelberg, Germany) Mar 2024With the advancements in precision medicine, the demands on pathological diagnostics have increased, requiring standardized, quantitative, and integrated assessments of... (Review)
Review
With the advancements in precision medicine, the demands on pathological diagnostics have increased, requiring standardized, quantitative, and integrated assessments of histomorphological and molecular pathological data. Great hopes are placed in artificial intelligence (AI) methods, which have demonstrated the ability to analyze complex clinical, histological, and molecular data for disease classification, biomarker quantification, and prognosis estimation. This paper provides an overview of the latest developments in pathology AI, discusses the limitations, particularly concerning the black box character of AI, and describes solutions to make decision processes more transparent using methods of so-called explainable AI (XAI).
Topics: Artificial Intelligence; Pathology, Molecular; Hope; Precision Medicine
PubMed: 38315198
DOI: 10.1007/s00292-024-01308-7 -
Journal of Infection and Public Health Nov 2023Infectious diseases present a global challenge, requiring accurate diagnosis, effective treatments, and preventive measures. Artificial intelligence (AI) has emerged as... (Review)
Review
Infectious diseases present a global challenge, requiring accurate diagnosis, effective treatments, and preventive measures. Artificial intelligence (AI) has emerged as a promising tool for analysing complex molecular data and improving the diagnosis, treatment, and prevention of infectious diseases. Computer-aided detection (CAD) using convolutional neural networks (CNN) has gained prominence for diagnosing tuberculosis (TB) and other infectious diseases such as COVID-19, HIV, and viral pneumonia. The review discusses the challenges and limitations associated with AI in this field and explores various machine-learning models and AI-based approaches. Artificial neural networks (ANN), recurrent neural networks (RNN), support vector machines (SVM), multilayer neural networks (MLNN), CNN, long short-term memory (LSTM), and random forests (RF) are among the models discussed. The review emphasizes the potential of AI to enhance the accuracy and efficiency of diagnosis, treatment, and prevention of infectious diseases, highlighting the need for further research and development in this area.
PubMed: 37769584
DOI: 10.1016/j.jiph.2023.08.021