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European Journal of Cancer (Oxford,... Aug 2022Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk... (Review)
Review
Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk factors include advanced age, ultraviolet exposure, male sex, immunosuppression, such as AIDS/HIV infection, haematological malignancies or solid organ transplantation, and Merkel cell polyomavirus infection. MCC is an aggressive tumour with 26% of cases presenting lymph node involvement at diagnosis and 8% with distant metastases. Five-year overall survival rates range between 48% and 63%. Two subsets of MCC have been characterised with distinct molecular pathogenetic pathways: ultraviolet-induced MCC versus virus-positive MCC, which carries a better prognosis. In both subtypes, there are alterations in the retinoblastoma protein and p53 gene structure and function. MCC typically manifests as a red nodule or plaque with fast growth, most commonly on sun exposed areas. Histopathology (small-cell neuroendocrine appearance) and immunohistochemistry (CK20 positivity and TTF-1 negativity) confirm the diagnosis. The current staging systems are the American Joint Committee on Cancer/Union for international Cancer control 8th edition. Baseline whole body imaging is encouraged to rule out regional and distant metastasis. For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy is recommended in all patients with MCC without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is complete lymph nodes dissection potentially followed by post-operative RT. Immunotherapy with anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Chemotherapy can be used when patients fail to respond or are intolerant for anti-PD-(L)1 immunotherapy or clinical trials.
Topics: Carcinoma, Merkel Cell; Consensus; HIV Infections; Humans; Male; Neoplasm Staging; Sentinel Lymph Node Biopsy; Skin Neoplasms
PubMed: 35732101
DOI: 10.1016/j.ejca.2022.03.043 -
Cells Oct 2021Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).... (Review)
Review
Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR protein is known to acts as a chloride (Cl) channel expressed in the exocrine glands of several body systems where it also regulates other ion channels, including the epithelial sodium (Na) channel (ENaC) that plays a key role in salt absorption. This function is crucial to the osmotic balance of the mucus and its viscosity. However, the pathophysiology of CF is more challenging than a mere dysregulation of epithelial ion transport, mainly resulting in impaired mucociliary clearance (MCC) with consecutive bronchiectasis and in exocrine pancreatic insufficiency. This review shows that the CFTR protein is not just a chloride channel. For a long time, research in CF has focused on abnormal Cl and Na transport. Yet, the CFTR protein also regulates numerous other pathways, such as the transport of HCO, glutathione and thiocyanate, immune cells, and the metabolism of lipids. It influences the pH homeostasis of airway surface liquid and thus the MCC as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF.
Topics: Animals; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelium; Humans; Lipid Metabolism; Models, Biological
PubMed: 34831067
DOI: 10.3390/cells10112844 -
Journal of Translational Medicine Sep 2023Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in...
BACKGROUND
Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in the pathophysiology of AD. Herein, we identified the metabolism-related AD subtypes and feature genes.
METHODS
The AD datasets were obtained from the Gene Expression Omnibus database and the metabolism-relevant genes were downloaded from a previously published compilation. Consensus clustering was performed to identify the AD subclasses. The clinical characteristics, correlations with metabolic signatures, and immune infiltration of the AD subclasses were evaluated. Feature genes were screened using weighted correlation network analysis (WGCNA) and processed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, three machine-learning algorithms were used to narrow down the selection of the feature genes. Finally, we identified the diagnostic value and expression of the feature genes using the AD dataset and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis.
RESULTS
Three AD subclasses were identified, namely Metabolism Correlated (MC) A (MCA), MCB, and MCC subclasses. MCA contained signatures associated with high AD progression and may represent a high-risk subclass compared with the other two subclasses. MCA exhibited a high expression of genes related to glycolysis, fructose, and galactose metabolism, whereas genes associated with the citrate cycle and pyruvate metabolism were downregulated and associated with high immune infiltration. Conversely, MCB was associated with citrate cycle genes and exhibited elevated expression of immune checkpoint genes. Using WGCNA, 101 metabolic genes were identified to exhibit the strongest association with poor AD progression. Finally, the application of machine-learning algorithms enabled us to successfully identify eight feature genes, which were employed to develop a nomogram model that could bring distinct clinical benefits for patients with AD. As indicated by the AD datasets and qRT-PCR analysis, these genes were intimately associated with AD progression.
CONCLUSION
Metabolic dysfunction is associated with AD. Hypothetical molecular subclasses of AD based on metabolic genes may provide new insights for developing individualized therapy for AD. The feature genes highly correlated with AD progression included GFAP, CYB5R3, DARS, KIAA0513, EZR, KCNC1, COLEC12, and TST.
Topics: Humans; Alzheimer Disease; Algorithms; Citrates; Citric Acid; Cluster Analysis; Shaw Potassium Channels; Nerve Tissue Proteins
PubMed: 37715200
DOI: 10.1186/s12967-023-04324-y -
Computational and Structural... 2021Drug discovery aims at finding new compounds with specific chemical properties for the treatment of diseases. In the last years, the approach used in this search... (Review)
Review
Drug discovery aims at finding new compounds with specific chemical properties for the treatment of diseases. In the last years, the approach used in this search presents an important component in computer science with the skyrocketing of machine learning techniques due to its democratization. With the objectives set by the Precision Medicine initiative and the new challenges generated, it is necessary to establish robust, standard and reproducible computational methodologies to achieve the objectives set. Currently, predictive models based on Machine Learning have gained great importance in the step prior to preclinical studies. This stage manages to drastically reduce costs and research times in the discovery of new drugs. This review article focuses on how these new methodologies are being used in recent years of research. Analyzing the state of the art in this field will give us an idea of where cheminformatics will be developed in the short term, the limitations it presents and the positive results it has achieved. This review will focus mainly on the methods used to model the molecular data, as well as the biological problems addressed and the Machine Learning algorithms used for drug discovery in recent years.
PubMed: 34471498
DOI: 10.1016/j.csbj.2021.08.011 -
Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial.Journal of Clinical Oncology : Official... Aug 2020Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed...
PURPOSE
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC.
METHODS
In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies.
RESULTS
Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation.
CONCLUSION
Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Carcinoma, Merkel Cell; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Nivolumab; Prognosis; Skin Neoplasms; Survival Rate; Young Adult
PubMed: 32324435
DOI: 10.1200/JCO.20.00201 -
JAAPA : Official Journal of the... Nov 2023Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun... (Review)
Review
Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun exposure or via Merkel cell polyomavirus (MCV) gene expression. MCV is found in most patients with MCC and is associated with a lower recurrence rate of MCC. MCC has a wide range of clinical presentations that make diagnosis challenging. Histologic examination is performed using unique markers to differentiate it from other diagnoses. This article reviews the pathogenesis, clinical presentation, histopathology, differential diagnosis, and treatment of MCC.
Topics: Humans; Carcinoma, Merkel Cell; Polyomavirus Infections; Tumor Virus Infections; Skin Neoplasms; Merkel cell polyomavirus
PubMed: 37820270
DOI: 10.1097/01.JAA.0000979460.69305.b7 -
Der Pathologe Dec 2019Merkel-cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma named for its Merkel-cell-like ultrastructure. The neuroendocrine Merkel cell was... (Review)
Review
Merkel-cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma named for its Merkel-cell-like ultrastructure. The neuroendocrine Merkel cell was previously believed to be the cell of origin. However, Merkel cells are postmitotic and thus probably not the cell of origin of MCC. It is derived from an epidermal stem cell, which also might represent the cell of origin of MCC. Further putative cells of origin are dermal stem cells and pre/pro‑B cells, the latter showing some similar markers (e.g. PAX5).About 80% of MCCs are induced by the integration of DNA of the Merkel cell polyoma virus (MCPyV) into the genome. On the other hand, about 20% of MCCs show UV-induced mutations in numerous genes (e.g. TP53, RB1). In routine histology, MCC appears monomorphic and the diagnosis is confirmed by immunohistochemistry showing CK20 arranged in typical paranuclear plaques, together with the presence of neurofilaments and chromogranin A. Virus-positive and virus-negative MCC are not different histologically.UV-induced and viral neoantigens cause the strong immunogenicity of MCC. Moreover, over the last few years, the presence of PD-1 and PD-L1 has been demonstrated within tumor and immune cells. For the checkpoint inhibitors pembrolizumab and avelumab, responses of about 50% have been shown, independent of virus state. Circulating tumor cells (CTCs) seem to be helpful in tumor tracking. Further immunological and molecular studies are necessary for future individual therapies, also concerning immunocompromised patients.
Topics: Biomarkers, Tumor; Carcinoma, Merkel Cell; Humans; Immunohistochemistry; Merkel cell polyomavirus; Skin Neoplasms; Tumor Virus Infections
PubMed: 31820040
DOI: 10.1007/s00292-019-00705-7 -
Gene Jan 2023Glioblastoma (GBM) is the most common malignant brain tumor among adults. Cancer stem cells (CSCs) are known to drive treatment resistance and recurrence. However, a few...
Glioblastoma (GBM) is the most common malignant brain tumor among adults. Cancer stem cells (CSCs) are known to drive treatment resistance and recurrence. However, a few CSC markers have been identified as therapeutic targets for GBM. This study aimed to show highly coexpressed genes in GBM CSCs and TCGA GBM samples and to identify possible therapeutic targets for GBM. The gene expression profiles of GBM CSCs were obtained from Gene Expression Omnibus database. After the differentially upregulated genes were screened, functional enrichment analyses were performed using DAVID and Reactome databases. For upregulated genes, biological processes were mainly associated with the regulation of transcription. Subsequently, a protein-protein interaction network was constructed for upregulated genes through STRING, in which DUSP6, FGFR3, EGFR, SOX2, NES, and PLP1 were further identified as hub genes via MCC and MNC methods. Expression profiles of hub genes and their association with survival were examined in TCGA GBM dataset using GEPIA2 platform. The expression levels of four hub genes were found to be increased in TCGA GBM samples. Of these, DUSP6 and SOX2 had prognostic value for patients with GBM. Molecular compounds targeting DUSP6 were searched through PubChem database. (E/Z)-BCI and BCI were found to be inhibitors of DUSP6. The molecular docking was performed using Autodock vina 1.02. The compounds showed strong binding capacities by forming various interactions with the ERK2 binding domain of DUSP6. Hence, the current study unravels the potential of (E/Z)-BCI and BCI compounds as possible anti-cancer molecules for GBM treatment.
Topics: Adult; Brain Neoplasms; Computational Biology; ErbB Receptors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Molecular Docking Simulation; Neoplastic Stem Cells
PubMed: 36122609
DOI: 10.1016/j.gene.2022.146895 -
Frontiers in Endocrinology 2022Primary osteoporosis has long been underdiagnosed and undertreated. Currently, ferroptosis may be a promising research direction in the prevention and treatment of...
Primary osteoporosis has long been underdiagnosed and undertreated. Currently, ferroptosis may be a promising research direction in the prevention and treatment of primary osteoporosis. However, the specific mechanism of ferroptosis in primary osteoporosis remains a mystery. Differentially expressed genes (DEGs) were identified in bone mesenchymal stromal cells (BMSCs) of primary osteoporosis and heathy patients from the GEO databases with the help of bioinformatics analysis. Then, we intersected these DEGs with the ferroptosis dataset and obtained 80 Ferr-DEGs. Several bioinformatics algorithms (PCA, RLE, Limma, BC, MCC, etc.) were adopted to integrate the results. Additionally, we explored the potential functional roles of the Ferr-DEGs GO and KEGG. Protein-protein interactions (PPI) were used to predict potential interactive networks. Finally, 80 Ferr-DEGs and 5 key Ferr-DEGs were calculated. The 5 key Ferr-DEGs were further verified in the OVX mouse model. In conclusion, through a variety of bioinformatics methods, our research successfully identified 5 key Ferr-DEGs associated with primary osteoporosis and ferroptosis, namely, sirtuin 1(), heat shock protein family A () member 5 (), mechanistic target of rapamycin kinase (), hypoxia inducible factor 1 subunit alpha () and beclin 1 (), which were verified in an animal model.
Topics: Animals; Computational Biology; Ferroptosis; Gene Expression Profiling; Mesenchymal Stem Cells; Mice; Osteoporosis
PubMed: 36093072
DOI: 10.3389/fendo.2022.980867 -
Annual Review of Pathology Jan 2021Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with two distinct etiologies. Clonal integration of Merkel cell polyomavirus DNA into... (Review)
Review
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with two distinct etiologies. Clonal integration of Merkel cell polyomavirus DNA into the tumor genome with persistent expression of viral T antigens causes at least 60% of all MCC. UV damage leading to highly mutated genomes causes a nonviral form of MCC. Despite these distinct etiologies, both forms of MCC are similar in presentation, prognosis, and response to therapy. At least three oncogenic transcriptional programs feature prominently in both forms of MCC driven by the virus or by mutation. Both forms of MCC have a high proliferative growth rate with increased levels of cell cycle-dependent genes due to inactivation of the tumor suppressors RB and p53, a strong MYC signature due to MYCL activation by the virus or gene amplification, and an attenuated neuroendocrine differentiation program driven by the ATOH1 transcription factor.
Topics: Carcinogenesis; Carcinoma, Merkel Cell; Humans; Merkel cell polyomavirus; Mutation; Polyomavirus Infections; Skin Neoplasms; Tumor Virus Infections
PubMed: 33228463
DOI: 10.1146/annurev-pathmechdis-012419-032817