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1.
Braz. j. biol ; 84: e253616, 2024. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1355880

RESUMO

Abstract This study evaluated the effect of the volatile oil of Alpinia zerumbet (VOAz) on caveolin-1 gene expression and muscular fibrosis. The rats were immobilized to induce fibrosis of the gastrocnemius muscle, and they were treated with VOAz. Collagen quality was assessed by histology and the expression of the caveolin-1 (CAV-1) gene was evaluated using qPCR. Histomorphological analysis indicated a significant reduction in the perimeter, width, and intensity of collagen in the treated groups, thus showing that the oil was effective in regulating the quality of collagen at the three concentrations. The results of expression levels suggested a decrease in the lesioned group and in two treatment groups (0.0115 µg/g and 0.009 µg/g). However, with the lowest concentration (0.0065 µg/g), no significant difference was observed, with levels similar to those found in healthy tissue. Therefore, the results showed that VOAz has the potential to be a non-invasive and low-cost alternative to aid in the treatment of muscular fibrosis.


Resumo Este estudo avaliou o efeito do óleo volátil de Alpinia zerumbet (OVAz) na expressão do gene da caveolina-1 e na fibrose muscular. Os ratos foram imobilizados para induzir a fibrose do músculo gastrocnêmio, e foram tratados com OVAz. A qualidade do colágeno foi avaliada com histologia e à expressão do gene caveolina-1 (CAV-1) foi avaliada usando qPCR. A análise histomorfológica indicou uma redução significativa no perímetro, largura e intensidade do colágeno nos grupos tratados. Os resultados dos níveis de expressão sugeriram diminuição nos grupos de lesão e em dois grupos de tratamento (0,0115 µg/g e 0,009 µg/g). No entanto, com a menor concentração (0,0065 µg/g), não foi observada diferença significativa, apresentando níveis semelhantes aos encontrados em tecido saudável. O uso do OVAz foi eficaz para reverter as alterações do colágeno causadas pela fibrose, e sua menor concentração apresentou uma possível tendência de aumento na expressão do CAV-1. Portanto, os resultados mostraram que o OVAz tem potencial para ser uma alternativa não invasiva e de baixo custo para auxiliar no tratamento da fibrose muscular.


Assuntos
Animais , Ratos , Óleos Voláteis/farmacologia , Colágeno/metabolismo , Alpinia/química , Caveolina 1/metabolismo , Músculos/efeitos dos fármacos , Fibrose , Óleos Vegetais/farmacologia , Brasil , Ratos Wistar , Modelos Animais de Doenças , Músculos/patologia
2.
Ned Tijdschr Geneeskd ; 1672023 Jan 04.
Artigo em Holandês | MEDLINE | ID: mdl-36633055

RESUMO

PSMA PET/CT is a diagnostic technique for patients with prostate cancer. It makes use of a radioligand that specifically binds to 'prostate specific membrane antigen' (PSMA), expressed by the prostate cancer cells. PSMA PET has proven to be highly effective in prostate cancer diagnostics in both primary staging and re-staging. PSMA PET/CT has a much higher accuracy than traditional CT and skeletal scintigraphy for the detection of metastases, allowing metastases to be detected in an earlier stage. The clinical relevance of the improved detection is now under investigation. Staging with PSMA PET/CT sometimes leads to avoiding surgery because distant metastases are found that were not detected with conventional imaging. In the Netherlands, PSMA PET/CT is now indicated both in primary prostate cancer diagnostics for the detection of metastases and for the detection of biochemical recurrence after prostatectomy or after radiotherapy.


Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico por imagem , Antígeno Prostático Específico , Prostatectomia
3.
Ned Tijdschr Geneeskd ; 1672023 Jan 11.
Artigo em Holandês | MEDLINE | ID: mdl-36633084

RESUMO

A 83-year-old man presented with a large tumour on his head. He had been postponing his visit due to COVID. Physical examination revealed an ulcerating, bleeding tumour of 5.5x5x3 cm. Histologic analyses showed a poorly differentiated squamous cell carcinoma. Additional imaging displayed damage of the tabula externa without pathological lymph nodes.


Assuntos
COVID-19 , Carcinoma , Masculino , Humanos , Idoso de 80 Anos ou mais , Couro Cabeludo , Carcinoma/patologia , Linfonodos/patologia
4.
Cancer Discov ; 13(1): 17-18, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36620882

RESUMO

SUMMARY: Chronic infection by several "high-risk" human papillomavirus (HPV) types has been causally implicated in several forms of anogenital and oropharyngeal cancers. Now, HPV42, which is usually classified as a "low-risk" type, can be listed as the main cause of digital papillary adenocarcinoma, an uncommon malignant tumor of the fingers and toes. See related article by Leiendecker et al., p. 70 (3).


Assuntos
Adenocarcinoma Papilar , Neoplasias Ósseas , Neoplasias da Mama , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Feminino , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Neoplasias Orofaríngeas/virologia , Células Germinativas/patologia
6.
BMC Cancer ; 23(1): 20, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609243

RESUMO

BACKGROUND: Tumor-associated neutrophils (TANs) in the tumor microenvironment are prognostic biomarkers in many malignancies. However, it is unclear whether TANs can serve as a prognostic marker for clinical outcomes in patients with glioblastoma (GBM), as classified according to World Health Organization Classification of Tumors of the Central Nervous System, fifth edition (CNS5). In the present study, we analyzed correlations of TANs and peripheral blood neutrophils prior to radiotherapy with overall survival (OS) in GBM (CNS5). METHODS: RNA-seq expression profiles of patients with newly diagnosed GBM (CNS5) were extracted from The Cancer Genome Atlas (TCGA), and The Chinese Glioma Genome Atlas (CGGA). TAN infiltration was inferred using CIBERSORTx algorithm. Neutrophil counts prior to radiotherapy in newly diagnosed GBM (CNS5) were obtained from the First Affiliated Hospital of Fujian Medical University. The prognostic value of TANs and peripheral blood neutrophils before radiotherapy was investigated using Kaplan-Meier analysis and Cox proportional hazards models. The robustness of these findings was evaluated by sensitivity analysis, and E values were calculated. RESULTS: A total of 146 and 173 individuals with GBM (CNS5) were identified from the TCGA and CGGA cohorts, respectively. High infiltration of TANs was of prognostic of poor OS in TCGA (HR = 1.621, 95% CI: 1.004-2.619) and CGGA (HR = 1.546, 95% CI: 1.029-2.323). Levels of peripheral blood neutrophils before radiotherapy (HR = 2.073, 95% CI: 1.077-3.990) were independently associated with poor prognosis. Sensitivity analysis determined that the E-value of high TANs infiltration was 2.140 and 2.465 in the TCGA and CGGA cohorts. CONCLUSIONS: TANs and peripheral blood neutrophil levels before radiotherapy are prognostic of poor outcomes in GBM (CNS5).


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Prognóstico , Glioblastoma/patologia , Neutrófilos/patologia , Modelos de Riscos Proporcionais , Estimativa de Kaplan-Meier , Neoplasias Encefálicas/patologia , Microambiente Tumoral
7.
BMC Urol ; 23(1): 6, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609261

RESUMO

BACKGROUND: To evaluate the incidence of lymph node degeneration and its association with nodal metastatic pattern in prostate cancer. METHODS: A retrospective analysis of the submitted lymph node specimen of 390 prostatectomies in 2011 was performed. All lymph nodes were histologically re-evaluated and the degree of lymph node degeneration e.g. lipomatous atrophy, capsular and framework fibrosis, and calcifications as well as the lymph node size were recorded. Lymph node degeneration was compared in the anatomic regions of the pelvis as well as in lymph nodes with and without metastases of prostatic cancer. RESULTS: Eighty-one of 6026 lymph nodes demonstrated metastases. Complete histologic examination with analysis of a complete cross-section was possible in 5173 lymph nodes including all lymph nodes with metastases. The incidence of lymph node degeneration was different across the various landing sites. Lymph node metastases were primarily detected in less degenerative and therefore more functional lymph nodes. In metastatic versus non-metastatic lymph nodes low lipomatous atrophy was reported in 84.0% versus 66.7% (p = 0.004), capsular fibrosis in 14.8% versus 35.4% (p < 0.001), calcifications in 35.8% versus 46.1% (p = 0.072) and framework fibrosis in 69.8% versus 75.3% (p = 0.53). Metastases were also identified more frequently in larger than in smaller lymph nodes (63.0% vs. 47.5%; p = 0.007). CONCLUSIONS: Degenerative changes in pelvic lymph nodes are commonly detectable but occur with variable frequency in the various nodal landing sites in the pelvis. The degree of lymph node degeneration of single lymph nodes has a significant influence on whether a lymph node is infiltrated by tumor cells and may harbour metastases.


Assuntos
Linfonodos , Neoplasias da Próstata , Masculino , Humanos , Estudos Retrospectivos , Linfonodos/patologia , Neoplasias da Próstata/patologia , Pelve/patologia , Fibrose , Excisão de Linfonodo
8.
Lipids Health Dis ; 22(1): 1, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609276

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH) increases the risk for liver cirrhosis. Noninvasive tests for NAFLD/NASH exist, but they are unreliable and thus liver biopsy remains the standard for diagnosis and new noninvasive diagnostic approaches are of great interest. The aim of this study was to test whether the serum levels of fatty acid-binding protein-4 (FABP4) and matrix metalloproteinase-9 (MMP9) could be used as a diagnostic tool for NASH. METHODS: Patients who underwent bariatric surgery and simultaneous liver biopsy were identified. Biopsies were assigned a NAFLD activity score (NAS). MMP9- and FABP4- Enzyme-linked Immunosorbent Assays (ELISAs) on serum samples were performed. The serum levels of FABP4/MMP9 were compared and different models to predict NASH were developed. RESULTS: A total of 84 patients were included, 28 patients (33.3%) were diagnosed with NASH. Higher concentrations of MMP9 in NASH patients (p < 0.01) were detected. FABP4 concentrations were not significantly increased. A moderate correlation between the NAS and MMP9 concentrations (r = 0.32, P < 0.01) was observed. The neural network model fit best with the dataset, with an area under the curve (AUC) of 83% and an accuracy of 88%. CONCLUSION: Serum MMP9 levels are increased in patients with NASH and should routinely be measured in patients with obesity, but further investigations are needed to improve noninvasive NASH diagnosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Metaloproteinase 9 da Matriz , Cirrose Hepática/patologia , Obesidade/patologia , Proteínas de Ligação a Ácido Graxo , Biópsia , Fígado/patologia , Biomarcadores
9.
BMC Cancer ; 23(1): 23, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609281

RESUMO

BACKGROUND: The breast-conserving surgery and reconstruction rate in China is relatively low when compared with those in Western countries. Moreover, predictors of surgical choices for women with breast cancer in China have not yet been explored. This study aims to explore differences in the surgical choices of women with different demographic and clinical characteristics and the predictors that influence surgical choices of women with early-stage breast cancer. METHODS: This retrospective study included women with early-stage (0-II) breast cancer who underwent surgeries at one of two Xiamen University-affiliated hospitals between 2009 and 2017. Using medical records, eleven variables were collected: the woman's age, year of diagnosis, hospital, marital status, payment method, cancer stage, presence of positive axillary lymph node, histology, neoadjuvant chemotherapy, radiotherapy, and the type(s) of surgery they chose. Binary logistic regression was used to analyse predictors of surgical choice. RESULTS: A total of 1,787 cases were included in this study. Of the total number of women with breast cancer, 61.3% underwent mastectomy without breast reconstruction, 26.4% underwent mastectomy with breast reconstruction, and the remaining 12.2% chose breast-conserving surgery. Women with different demographic and clinical characteristics underwent different types of surgery. Cancer stage, neoadjuvant chemotherapy, radiotherapy, and the choice of hospital were found to be predictors of breast-conserving surgery. Meanwhile, age, year of diagnosis, payment method, neoadjuvant chemotherapy, and the choice of hospital were found to be predictors of reconstruction after mastectomy in women with early-stage breast cancer. CONCLUSIONS: In China, surgical choices for women with breast cancer have diversified. Healthcare workers should understand the surgical preferences of women of different ages. For early detection of breast cancer, knowledge of breast self-examination and breast cancer screening should be provided. Adequate information about the safety of reconstruction and advocacy for medical insurance coverage of reconstruction should be offer. Breast surgeons need specialised training and standardising protocols towards different types of breast surgery. These actions will help women make better, well-informed decisions about their breast surgeries.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Mastectomia/métodos , Estudos Retrospectivos , Mastectomia Segmentar , China/epidemiologia
10.
J Cardiothorac Surg ; 18(1): 5, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609288

RESUMO

BACKGROUND: Pulmonary sequestration is a rare congenital lung anomaly, presenting mostly in childhood and adolescence. CASE PRESENTATION: We report the case of a 26-year-old male patient presenting with pleuritic left sided chest pain and haemoptysis. Computed tomography of the chest showed features of intralobar pulmonary sequestration involving the left lower lobe, with arterial supply arising from the descending thoracic aorta above the diaphragm and normal venous drainage. Video assisted thoracic surgery was planned to perform a left lower lobectomy. Considering the risk of bleeding from the large artery supplying the sequestered segment, a posterolateral thoracotomy incision was made and left lower lobectomy was completed, with successful division of the arterial feeder. The patient was discharged home without complications. Pathologic examination of the specimen grossly revealed partial division of the lobe by two fissures with extensive adhesions into an upper and lower portion with no clear demarcation and a large vessel which enters the lower portion at the posterior inferior aspect, separate from the hilum with a diameter 10 mm. Microscopically, both portions of the lobe showed normally alveolated lung tissue with patchy recent intra-alveolar haemorrhage and evidence of chronic inflammation in the sequestered segment. There was no evidence of malignancy. CONCLUSION: This case highlights the rare presentation of pulmonary sequestration in adulthood and the importance of imaging to identify anomalous arterial supply to the sequestered segment in the left lower lobe of the lung. The use of safe surgical techniques to control the anomalous systemic arterial feeding vessel cannot be overemphasized.


Assuntos
Sequestro Broncopulmonar , Masculino , Adolescente , Humanos , Adulto , Sequestro Broncopulmonar/diagnóstico por imagem , Sequestro Broncopulmonar/cirurgia , Pulmão/diagnóstico por imagem , Pulmão/cirurgia , Pulmão/irrigação sanguínea , Hemoptise/etiologia , Artérias/patologia , Tomografia Computadorizada por Raios X
11.
Mol Cancer ; 22(1): 2, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609320

RESUMO

BACKGROUND: According to current guidelines, more than 70% of patients with invasive submucosal colorectal cancer (T1 CRC) undergo a radical operation with lymph node dissection, even though only ~ 10% have lymph node metastasis (LNM). Hence, there is imperative to develop biomarkers that can help robustly identify LNM-positive patients to prevent such overtreatments. Given the emerging interest in exosomal cargo as a source for biomarker development in cancer, we examined the potential of exosomal miRNAs as LNM prediction biomarkers in T1 CRC. METHODS: We analyzed 200 patients with high-risk T1 CRC from two independent cohorts, including a training (n = 58) and a validation cohort (n = 142). Cell-free and exosomal RNAs from pre-operative serum were extracted, followed by quantitative reverse-transcription polymerase chain reactions for a panel of miRNAs. RESULTS: A panel of four miRNAs (miR-181b, miR-193b, miR-195, and miR-411) exhibited robust ability for detecting LNM in the exosomal vs. cell-free component. We subsequently established a cell-free and exosomal combination signature, successfully validated in two independent clinical cohorts (AUC, 0.84; 95% CI 0.70-0.98). Finally, we developed a risk-stratification model by including key pathological features, which reduced the false positive rates for LNM by 76% without missing any true LNM-positive patients. CONCLUSIONS: Our novel exosomal miRNA-based liquid biopsy signature robustly identifies T1 CRC patients at risk of LNM in a preoperative setting. This could be clinically transformative in reducing the significant overtreatment burden of this malignancy.


Assuntos
Neoplasias Colorretais , Exossomos , MicroRNAs , Humanos , Metástase Linfática , Exossomos/genética , Exossomos/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Biomarcadores Tumorais/genética , Biópsia Líquida
12.
Biol Sex Differ ; 14(1): 2, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609358

RESUMO

RATIONALE: Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of oral contraceptives decreased the onset of asthma in women of reproductive age. In the current study, we hypothesized that steady-state levels of estrogen would reduce airway inflammation and airway hyperresponsiveness to methacholine challenge. METHODS: Ovariectomized BALB/c mice (Ovx) were implanted with subcutaneous hormone pellets (estrogen, OVX-E2) that deliver consistent levels of estrogen [68 ± 2 pg/mL], or placebo pellets (OVX-Placebo), followed by ovalbumin sensitization and challenge. In conjunction with methacholine challenge, immune phenotyping was performed to correlate inflammatory proteins and immune populations with better or worse pulmonary outcomes measured by invasive pulmonary mechanics techniques. RESULTS: Histologic analysis showed an increase in total cell infiltration and mucus staining around the airways leading to an increased inflammatory score in ovarectomized (OVX) animals with steady-state estrogen pellets (OVX-E2-OVA) as compared to other groups including female-sham operated (F-INTACT-OVA) and OVX implanted with a placebo pellet (OVX-Pl-OVA). Airway resistance (Rrs) and lung elastance (Ers) were increased in OVX-E2-OVA in comparison to F-INTACT-OVA following aerosolized intratracheal methacholine challenges. Immune phenotyping revealed that steady-state estrogen reduced CD3+ T cells, CD19+ B cells, ILC2 and eosinophils in the BAL across all experiments. While these commonly described allergic cells were reduced in the BAL, or airways, we found no changes in neutrophils, CD3+ T cells or CD19+ B cells in the remaining lung tissue. Similarly, inflammatory cytokines (IL-5 and IL-13) were also decreased in OVX-E2-OVA-treated animals in comparison to Female-INTACT-OVA mice in the BAL, but in the lung tissue IL-5, IL-13 and IL-33 were comparable in OVX-E2-OVA and F-INTACT OVA mice. ILC2 were sorted from the lungs and stimulated with exogenous IL-33. These ILC2 had reduced cytokine and chemokine expression when they were isolated from OVX-E2-OVA animals, indicating that steady-state estrogen suppresses IL-33-mediated activation of ILC2. CONCLUSIONS: Therapeutically targeting estrogen receptors may have a limiting effect on eosinophils, ILC2 and potentially other immune populations that may improve asthma symptoms in those females that experience perimenstrual worsening of asthma, with the caveat, that long-term use of estrogens or hormone receptor modulators may be detrimental to the lung microenvironment over time.


Assuntos
Asma , Interleucina-33 , Feminino , Animais , Camundongos , Interleucina-33/uso terapêutico , Estradiol/farmacologia , Estradiol/uso terapêutico , Imunidade Inata , Interleucina-13/uso terapêutico , Cloreto de Metacolina/farmacologia , Cloreto de Metacolina/uso terapêutico , Alérgenos/uso terapêutico , Resistência das Vias Respiratórias , Interleucina-5/uso terapêutico , Líquido da Lavagem Broncoalveolar , Linfócitos/metabolismo , Linfócitos/patologia , Pulmão/metabolismo , Asma/tratamento farmacológico , Asma/metabolismo , Citocinas , Estrogênios/uso terapêutico
13.
Cell Death Dis ; 14(1): 9, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609391

RESUMO

Esophageal squamous cell carcinoma (ESCC) is characterized by high morbidity and mortality. Circular RNAs (circRNAs) play an important role in tumor progression. We discovered an aberrantly expressed circRNA (hsa_circ_0021727) in patients with ESCC. However, the mechanism of action of hsa_circ_0021727 in tumors is unclear. The present study aimed to investigate the biological role of hsa_circ_0021727 and its mechanism in ESCC progression. We screened for the expression of hsa_circ_0021727 in ESCC patients. Patients with ESCC with high expression of hsa_circ_0021727 had shorter survival than those with low expression. Hsa_circ_0021727 promoted the proliferation, invasion, and migration of ESCC cells. However, miR-23b-5p inhibited this ability of hsa_circ_0021727. MiR-23b-5p acts by targeting TAK1-binding protein 1 (TAB1). Upregulation of TAB1 can activate the nuclear factor kappa B (NFκB) pathway. Hsa_circ_0021727 promoted ESCC progression by activating TAB1/NFκB pathway by sponging miR-23b-5p. In addition, in vivo experiments also confirmed that hsa_circ_0021727 could promote the proliferation, invasion, and migration of ESCC cells. In short, hsa_circ_0021727 promotes ESCC progression by targeting miR-23b-5p to activate the TAB1/NFκB pathway. These findings might provide potential targets to treat ESCC.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Humanos , MicroRNAs/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/genética , Linhagem Celular Tumoral , RNA Circular/genética , RNA Circular/metabolismo , Proliferação de Células/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Receptores de Hialuronatos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
14.
J Exp Clin Cancer Res ; 42(1): 10, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609396

RESUMO

BACKGROUND: Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway.  METHODS: A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells.  RESULTS: We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. CONCLUSIONS: In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Metilação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Fatores de Transcrição/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo
15.
Mol Neurodegener ; 18(1): 2, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609403

RESUMO

BACKGROUND: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aß40, Aß42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. METHODS: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. RESULTS: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. CONCLUSIONS: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Estudo de Associação Genômica Ampla , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Placa Amiloide/patologia , Fenótipo , Apolipoproteínas E/metabolismo , Proteínas tau/metabolismo
16.
Nat Commun ; 14(1): 95, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609402

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood clinical heterogeneity, underscored by significant differences in patient age at onset, symptom progression, therapeutic response, disease duration, and comorbidity presentation. We perform a patient stratification analysis to better understand the variability in ALS pathology, utilizing postmortem frontal and motor cortex transcriptomes derived from 208 patients. Building on the emerging role of transposable element (TE) expression in ALS, we consider locus-specific TEs as distinct molecular features during stratification. Here, we identify three unique molecular subtypes in this ALS cohort, with significant differences in patient survival. These results suggest independent disease mechanisms drive some of the clinical heterogeneity in ALS.


Assuntos
Esclerose Amiotrófica Lateral , Córtex Motor , Doenças Neurodegenerativas , Humanos , Esclerose Amiotrófica Lateral/patologia , Doenças Neurodegenerativas/patologia , Comorbidade , Córtex Motor/patologia , Variação Biológica da População
17.
Sci Rep ; 13(1): 273, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609438

RESUMO

Recent evidence has shown an increase in recurrence and a decrease in overall survival in patients treated with laparoscopic radical hysterectomy (LRH) and robotic assisted radical hysterectomy (RRH) open techniques (ORH). In addition, several high quality trials were recently published regarding the laparoscopic treatment of early stage cervical cancer. We sought out to reassess the recurrence rates, overall survival, complications and outcomes associated with laparoscopic radical hysterectomy (LRH) techniques against open techniques (ORH) when robotic assisted techniques were excluded. We searched PubMed, Medline, Cochrane CENTRAL, SCOPUS, ClinicalTrials.Gov and Web of Science for relevant clinical trials and observational studies. We included all studies that compared with early stage cervical cancer receiving LRH compared with ORH. We included randomized clinical trials, prospective cohort, and retrospective cohort trials. We included studies that included LRH and RRH as long as data was available to separate the two arms. We excluded studies that combined LRH and RRH without supplying data to differentiate. Of 1244 total studies, we used a manual three step screening process. Sixty studies ultimately met our criteria. We performed this review in accordance with PRISMA guidelines. We analyzed continuous data using mean difference (MD) and a 95% confidence interval (CI), while dichotomous data were analyzed using odds ratio (OR) and a 95% CI. Review Manager and Endnote software were utilized in the synthesis. We found that when excluding RRH, the was no significant difference regarding 5-year overall Survival (OR = 1.24 [0.94, 1.64], (P = 0.12), disease free survival (OR = 1.00 [0.80, 1.26], (P = 0.98), recurrence (OR = 1.01 [0.81, 1.25], (P = 0.95), or intraoperative complications (OR = 1.38 [0.94, 2.04], (P = 0.10). LRH was statistically better than ORH in terms of estimated blood loss (MD = - 325.55 [- 386.16, - 264.94] (P < 0.001), blood transfusion rate (OR = 0.28 [0.14, 0.55], (P = 0.002), postoperative complication rate (OR = 0.70 [0.55, 0.90], (P = 0.005), and length of hospital stay (MD = - 3.64[- 4.27, - 3.01], (P < 0.001). ORH was superior in terms of operating time (MD = 20.48 [8.62, 32.35], (P = 0.007) and number of resected lymph nodes (MD = - 2.80 [- 4.35, - 1.24], (P = 0.004). The previously seen increase recurrence and decrease in survival is not seen in LRH when robotic assisted techniques are included and all new high quality is considered. LRH is also associated with a significantly shorter hospital stay, less blood loss and lower complication rate.Prospero Prospective Registration Number: CRD42022267138.


Assuntos
Laparoscopia , Procedimentos Cirúrgicos Robóticos , Neoplasias do Colo do Útero , Feminino , Humanos , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Prospectivos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Histerectomia/efeitos adversos , Histerectomia/métodos , Estadiamento de Neoplasias
18.
Cell Death Dis ; 14(1): 7, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609444

RESUMO

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate cancer through the N6-methyladenosine (m6A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate cancer (NEPC) progression and poor survival in prostate cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m6A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate cancer to apply the neurological disorder drug SLC12A5 inhibitors.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Simportadores , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Simportadores/genética , Simportadores/metabolismo , Cloretos/metabolismo , Cloretos/uso terapêutico , Castração , Potássio/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Fatores de Processamento de RNA/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
19.
J Med Case Rep ; 17(1): 5, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609451

RESUMO

BACKGROUND: Collagenous fibroma or desmoplastic fibroblastoma is a rare benign fibrous tissue tumor. It usually presents as a painless, slowly growing mass. Collagenous fibroma arises ordinarily inside the subcutaneous tissues or skeletal muscles. Histopathologically, the tumor consists of scattered stellate and spindle cells in a hypovascular collagenous stroma without atypia or infiltration. The oral cavity is a very uncommon site for desmoplastic fibroblastoma. Only 15 published articles in the literature reported the intraoral location. We present a case of collagenous fibroma with a bilateral distribution on the hard palate. This is the second case of bilateral collagenous fibroma after a previously reported one in literature; however, our case was larger, occupying almost the whole palate. We discuss the management of this rare tumor and how we can reach definite diagnosis. CASE PRESENTATION: A 37-year-old Caucasian female patient had a huge bilateral firm palatal mass that caused breathing problems. There was no history of trauma and the patient had no relevant medical history Total surgical excision under general anesthesia was carried out and histopathological examination suggested a benign mesenchymal tumor. Immunohistochemistry was necessary to confirm the tumor origin and to exclude aggressive fibromatosis. A diagnosis of bilateral collagenous fibroma was reached. Six months after surgery, there was no recurring lesion and the patient's health was good. CONCLUSIONS: Collagenous fibroma is a benign fibrous tissue tumor of unknown cause that is treated with simple excision. The prognosis is good with no recurrence. Reaching an accurate diagnosis is mandatory to avoid aggressive treatment since collagenous fibroma may be misdiagnosed as aggressive fibromatosis in case of massive size. Clinicians and pathologists should be aware of this unusual tumor for conservative management without side effects.


Assuntos
Fibroma Desmoplásico , Fibroma , Fibromatose Agressiva , Neoplasias de Tecidos Moles , Humanos , Feminino , Adulto , Fibroma Desmoplásico/diagnóstico por imagem , Fibroma Desmoplásico/cirurgia , Palato Duro/diagnóstico por imagem , Palato Duro/cirurgia , Palato Duro/patologia , Fibroma/patologia , Fibroma/cirurgia , Neoplasias de Tecidos Moles/cirurgia
20.
Nat Commun ; 14(1): 108, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609505

RESUMO

Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.


Assuntos
DNA Mitocondrial , Miosite , Humanos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Receptor Toll-Like 9/metabolismo , Dinâmica Mitocondrial/genética , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , Inflamação/patologia
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