RESUMO
Cancer cells edit gene expression to evade immunosurveillance. However, genome-wide studies of gene editing during early tumorigenesis are lacking. Here we used single-cell RNA sequencing in a breast cancer genetically engineered mouse model (GEMM) to identify edited genes without bias. Late tumors repressed antitumor immunity genes, reducing infiltrating immune cells and tumor-immune cell communications. Innate immune genes, especially interferon-stimulated genes, dominated the list of downregulated tumor genes, while genes that regulate cell-intrinsic malignancy were mostly unedited. Naive and activated CD8+ T cells in early tumors were replaced with exhausted or precursor-exhausted cells in late tumors. Repression of immune genes was reversed by inhibiting DNA methylation using low-dose decitabine, which suppressed tumor growth and restored immune control, increasing the number, functionality and memory of tumor-infiltrating lymphocytes and reducing the number of myeloid suppressor cells. Decitabine induced important interferon, pyroptosis and necroptosis genes, inflammatory cell death and immune control in GEMM and implanted breast and melanoma tumors.
RESUMO
OBJECTIVES: This review aimed to compare the effectiveness of three treatments: BTX A, CBZ, and OXB, in managing trigeminal neuralgia (TN). MATERIAL AND METHODS: We conducted a thorough search for research articles related to our issue using specific keywords on several databases, including Cochrane Central Register of Controlled Trials, Science Direct, Scopus, PubMed, Elsevier, Springer Journals, Ovid Medline, EBSCO, and Web of Science. Our focus was on publications from 1965 to 2023. RESULTS: We retrieved 46 articles from the search and reviewed them carefully. Out of these, we selected 29 articles that met the inclusion criteria. Among the selected articles, 11 investigated the effects of CBZ and OXB, while 18 explored the impact of BTX A on the improvement of TN symptoms. The response rate ranged between 56% and 90.5% for CBZ and between 90.9% and 94% for OXB. The response rate for BTX A ranged between 51.4% and 100%. All these three treatments had a remarkable effect on the improvement of TN. Importantly, findings highlighted that side effects of CBZ and OXB could lead to treatment discontinuation in some cases, whereas BTX A's side effects have been minimal and less frequent. CONCLUSIONS: Consequently, BTX A emerges as a promising alternative for TN treatment. However, additional clinical trials are necessary to validate this finding, and further research is required to establish a standardized protocol for administering BTX A in TN.
Assuntos
Toxinas Botulínicas Tipo A , Carbamazepina , Oxcarbazepina , Neuralgia do Trigêmeo , Neuralgia do Trigêmeo/tratamento farmacológico , Humanos , Carbamazepina/uso terapêutico , Oxcarbazepina/uso terapêutico , Toxinas Botulínicas Tipo A/uso terapêutico , Toxinas Botulínicas Tipo A/administração & dosagem , Resultado do Tratamento , Fármacos Neuromusculares/uso terapêutico , Fármacos Neuromusculares/administração & dosagem , Anticonvulsivantes/uso terapêuticoRESUMO
Symptoms of temporomandibular disorders (TMD) could be present as otologic symptoms like earache and dizziness in some patients. In most cases, these symptoms are not recognized because otolaryngologists fail to diagnose TMD as a source of the problem. This investigation was conducted to evaluate the effect of TMD treatments on the otologic symptoms which after taking history and clinical examinations seemed to be related to TMD. In the present study, the patients who were complaining of otalgia, ear fullness, tinnitus, hearing loss, and dizziness were evaluated by an ear fellow. Forty patients who had no known otologic or other primary causes to explain their symptoms, were referred to the orofacial pain clinic with the possible diagnosis of TMD. If the diagnosis was confirmed by an orofacial pain specialist, a combination of TMD treatments was administered to each case and the patients were followed up. The results showed that following implementation of treatment protocols for TMD, more than 50% of the patients reported complete or partial recovery in the second follow-up (p < 0.05). The most common otologic symptom of the referred cases was earache, and the most common associated complaint was neck pain. All the patients had one or more parafunctional habits. This study showed that TMD treatments were significantly efficient in improving otologic symptoms partially or completely and the authors concluded that for the patients with otolaryngologic unexplained symptoms, an overhaul examination is needed to assess TMD as a possible cause of the patient complaint. It is recommended that in cases with unexplained otologic symptoms, otolaryngologists care more about the neck trigger points (TP) and ask about the patient's parafunctional habits. Otolaryngologists and dentists need to be aware of the risk of developing otologic symptoms caused by these habits or cervical TPs.
Assuntos
Otopatias , Transtornos da Articulação Temporomandibular , Zumbido , Humanos , Otopatias/diagnóstico , Otopatias/etiologia , Otopatias/terapia , Dor de Orelha/etiologia , Dor de Orelha/terapia , Tontura/complicações , Zumbido/complicações , Vertigem/complicações , Transtornos da Articulação Temporomandibular/terapia , Transtornos da Articulação Temporomandibular/complicações , Dor Facial/etiologia , Dor Facial/terapiaRESUMO
Charting microRNA (miRNA) regulation across pathways is key to characterizing their function. Yet, no method currently exists that can quantify how miRNAs regulate multiple interconnected pathways or prioritize them for their ability to regulate coordinate transcriptional programs. Existing methods primarily infer one-to-one relationships between miRNAs and pathways using differentially expressed genes. We introduce PanomiR, an in silico framework for studying the interplay of miRNAs and disease functions. PanomiR integrates gene expression, mRNA-miRNA interactions and known biological pathways to reveal coordinated multi-pathway targeting by miRNAs. PanomiR utilizes pathway-activity profiling approaches, a pathway co-expression network and network clustering algorithms to prioritize miRNAs that target broad-scale transcriptional disease phenotypes. It directly resolves differential regulation of pathways, irrespective of their differential gene expression, and captures co-activity to establish functional pathway groupings and the miRNAs that may regulate them. PanomiR uses a systems biology approach to provide broad but precise insights into miRNA-regulated functional programs. It is available at https://bioconductor.org/packages/PanomiR.
Assuntos
MicroRNAs , MicroRNAs/metabolismo , Biologia de Sistemas , Perfilação da Expressão Gênica/métodos , Biologia Computacional/métodos , Redes Reguladoras de GenesRESUMO
The use of graph theory models is widespread in biological pathway analyses as it is often desired to evaluate the position of genes and proteins in their interaction networks of the biological systems. In this article, we argue that the common standard graph centrality measures do not sufficiently capture the informative topological organizations of the pathways, and thus, limit the biological inference. While key pathway elements may appear both upstream and downstream in pathways, standard directed graph centralities attribute significant topological importance to the upstream elements and evaluate the downstream elements as having no importance.We present a directed graph framework, Source/Sink Centrality (SSC), to address the limitations of standard models. SSC separately measures the importance of a node in the upstream and the downstream of a pathway, as a sender and a receiver of biological signals, and combines the two terms for evaluating the centrality. To validate SSC, we evaluate the topological position of known human cancer genes and mouse lethal genes in their respective KEGG annotated pathways and show that SSC-derived centralities provide an effective framework for associating higher positional importance to the genes with higher importance from a priori knowledge. While the presented work challenges some of the modeling assumptions in the common pathway analyses, it provides a straight-forward methodology to extend the existing models. The SSC extensions can result in more informative topological description of pathways, and thus, more informative biological inference.