RESUMO
BACKGROUND: Crossed renal ectopia (CRE) occurs when one kidney crosses the midline from the primary side to the contralateral side while the ureter remains on the primary side. Rectal cancer, one of the most common malignant tumors of the digestive tract, refers to cancer from the dentate line to the rectosigmoid junction. The concurrent presentation of CRE alongside rectal cancer is an uncommon clinical observation. CASE SUMMARY: Herein, we report a 69-year-old male patient with rectal cancer who was diagnosed with CRE via computed tomography during hospitalization. Following thorough preoperative evaluations, the patient underwent Dixon surgery. CONCLUSION: We performed laparoscopic radical resection of rectal cancer and adequate lymph node removal in a patient with CRE with no postoperative discomfort.
RESUMO
OBJECTIVE: Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits from novel biological agents. We performed a drug-targeted Mendelian randomization (MR) study to identify novel therapeutic targets of MG. METHODS: Cis-expression quantitative loci (cis-eQTL), which proxy expression levels for 2176 druggable genes, were used for MR analysis. Causal relationships between genes and disease, identified by eQTL MR analysis, were verified by comprehensive sensitivity, colocalization, and protein quantitative loci (pQTL) MR analyses. The protein-protein interaction (PPI) analysis was also performed to extend targets, followed by enzyme-linked immunosorbent assay (ELISA) to explore the serum level of drug targets in MG patients. A phenome-wide MR analysis was then performed to assess side effects with a clinical trial review assessing druggability. RESULTS: The eQTL MR analysis has identified eight potential targets for MG, one for early-onset MG and seven for late-onset MG. Further colocalization analyses indicated that CD226, CDC42BPB, PRSS36, and TNFSF12 possess evidence for colocalization with MG or late-onset MG. pQTL MR analyses identified the causal relations of TNFSF12 and CD226 with MG and late-onset MG. Furthermore, PPI analysis has revealed the protein interaction between TNFSF12-TNFSF13(APRIL) and TNFSF12-TNFSF13B(BLyS). Elevated TNFSF13 serum level of MG patients was also identified by ELISA experiments. This study has ultimately proposed three promising therapeutic targets (TNFSF12, TNFSF13, TNFSF13B) of MG. CONCLUSIONS: Three drug targets associated with the BLyS/APRIL pathway have been identified. Multiple biological agents, including telitacicept and belimumab, are promising for MG therapy.
Assuntos
Análise da Randomização Mendeliana , Miastenia Gravis , Locos de Características Quantitativas , Humanos , Miastenia Gravis/genética , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/patologia , Miastenia Gravis/sangue , Locos de Características Quantitativas/genética , Mapas de Interação de Proteínas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by rapidly developing and painful skin ulcers with distinctive features. As far as we are concerned, there is no previous case report on facial PG in East-Asia. In this case, we describe a case of a 79-year-old man with a 3-month history of progressive painful ulcers on his cheek and upper lip. Initial suspicion of atypical mycobacterium infection led to an ineffective treatment regimen. Comprehensive infectious testing yielded negative results, and a positive pathergy test indicated a potential diagnosis of PG. A skin biopsy confirmed the diagnosis, and the patient showed significant improvement with intravenous methylprednisolone and oral cyclosporine treatment. After three months, complete resolution of the lesions was achieved without recurrence. The case highlights the diagnostic challenges associated with PG, which is often misdiagnosed due to its resemblance to other conditions. Thorough evaluation is crucial to exclude alternative diagnoses, particularly cutaneous infections. Clinical morphology, tissue biopsy, and culture are essential for accurate diagnosis. The presence of pathergy, the development of new lesions following minor trauma, can also be a diagnostic clue.
RESUMO
OBJECTIVE: Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank(UKB). METHODS: To avoid immortal-time-biases in pharmacoepidemiologic studies, Mendelian randomisation was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with HbA1c, serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% confidence interval (CI). RESULTS: A total of 407 159 participants were analyzed, including 9,126 EOP and 3,324 LOP. The AMPK-genetic-risk-score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022-1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062-1.395) in male psoriasis patients. CONCLUSIONS: AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed.
RESUMO
Objectives: To describe the demographics and phenotypes of malignancies-associated dermatomyositis (MADM) in east China and pinpoint potential factors indicative of malignancies in patients with dermatomyositis and establish a predictive model. Methods: We retrospectively analyzed clinical data from 134 patients with adult-onset dermatomyositis hospitalized between January 2019 and May 2022 in one comprehensive hospital. Clinical data including disease course, initial symptoms and signs, and demographic information were retrieved from the Electronic Medical Records System. Other parameters including myositis-specific autoantibodies profiles, ferritin, sedimentation, etc. were all referable. Multivariable multinomial logistic regression was employed to simulate a model to predict cancer risks. Receiver operating characteristic curve was adopted to evaluate the potency of the model. Results: 134 patients with adult-onset dermatomyositis were aptly enrolled in this study based on inclusive and exclusive criteria: 12 (8.96%) with malignancies, 57 (42.53%) with aberrant tumor biomarkers but no malignancies, 65 (48.51%) with neither malignancies nor abnormal tumor biomarkers. Senior diagnostic age, higher LDH, higher ferritin, positive anti-TIF1γ and anti-Mi2 rather than anti-NXP2 autoantibodies were positive indicators of malignancies. Additionally, neither initial complaints nor signs were found to be correlated to a tendency towards malignancies. Digestive system, nasopharyngeal, and lung malignancies were mostly documented in east China. One multivariable multinomial logistic regression model was established to predict the phenotypes of dermatomyositis on the basis of potential malignancies and the overall sensitivity and specificity was satisfactory. Conclusion: Positivity of anti-TIF1γ and anti-Mi2 autoantibodies are highly indicative of malignancies while the role of anti-NXP2 autoantibody in MADM in the Chinese population remains unclear. The phenotypes of malignancies can be predicted through the model and the predictive power is sufficient. More attention should be paid to malignancies screening in patients with aberrant tumor biomarkers but no malignancies, particularly digestive system, nasopharyngeal, and lung malignancies in patients with dermatomyositis but without malignancies.
RESUMO
Nasopharyngeal carcinoma (NPC) is a rare head and neck tumor that threatens people's health. Radiotherapy is a major treatment for NPC, however, radioresistance of the NPC cells may contribute to treatment failure. LncRNA SNHG16 was upregulated in NPC; however, the function of SNHG16 in radioresistant NPC cells remains unexplored. RT-qPCR was applied for detecting SNHG16, miR-31-5p and SFN levels. MTT assay and colony formation assay were applied to assess the cell viability and proliferation. Dual luciferase was applied for assessing the relation among SNHG16, miR-31-5p and SFN. SFN level in NPC cells was examined by Western blot. The level of SNHG16 and SFN in NPC cells was significantly upregulated by exposure to radiation. In addition, silencing of SNHG16 or miR-31-5p mimics notably attenuated radioresistance of NPC cells. SNHG16 could positively regulate the expression of SFN in NPC cells through binding with miR-31-5p. Furthermore, SNHG16 downregulation obviously attenuated the proliferation and radioresistance of NPC cells by regulation of miR-31-5p/SFN axis. Knockdown of lncRNA SNHG16 attenuates radioresistance of nasopharyngeal carcinoma cells by miR-31-5p/SFN axis. Thus, our research data show a novel method for improving the efficacy of radiotherapy for NPC.
Assuntos
MicroRNAs , Neoplasias Nasofaríngeas , RNA Longo não Codificante , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/patologia , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: The prognosis of wild-type BRAF cutaneous melanoma (WT Bf-CM) patients remains poor due to the lack of therapeutic options. However, few studies have investigated the factors contributing to the prognosis of WT Bf-CM patients. METHODS: In this paper, we proposed and validated a novel 7-RNA based signature to predict the prognosis of WT Bf-CM by analyzing the information from TCGA database. RESULTS: Dependence of this signature to other clinical factors were verified and a nomogram was also drawn to promote its application in clinical practice. Functional analysis suggested that the predictive function of this signature might attribute to the prediction of the up-regulation of RNA splicing, transcription, and cellular proliferation in the high-risk group, which have been demonstrated to be linked to malignancy of cancer. Moreover, functional analysis and therapy response analysis supported that the prognosis is highly related to PI3K/Akt/mTOR pathway among WT Bf-CM patients. CONCLUSION: Collectively, this study will provide a preliminary bioinformatics evidence for the molecular mechanism and potential drug targets that could improving WT Bf-CM prognosis.
RESUMO
Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as TNC, MMP2, and VEGFA, and cytokine genes CSF1 and CXCL1, which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB-mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.
Assuntos
Neoplasias da Mama , NF-kappa B , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Terapia de Imunossupressão , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Metástase Neoplásica/patologia , Fator de Transcrição RelA/metabolismo , Fatores de TranscriçãoRESUMO
BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia with poorly understood mechanisms. We aimed to investigate the biological mechanism of AF and to discover feature genes by analyzing multi-omics data and by applying a machine learning approach. METHODS: At the transcriptomic level, four microarray datasets (GSE41177, GSE79768, GSE115574, GSE14975) were downloaded from the Gene Expression Omnibus database, which included 130 available atrial samples from AF and sinus rhythm (SR) patients with valvular heart disease. Microarray meta-analysis was adopted to identified differentially expressed genes (DEGs). At the proteomic level, a qualitative and quantitative analysis of proteomics in the left atrial appendage of 18 patients (9 with AF and 9 with SR) who underwent cardiac valvular surgery was conducted. The machine learning correlation-based feature selection (CFS) method was introduced to selected feature genes of AF using the training set of 130 samples involved in the microarray meta-analysis. The Naive Bayes (NB) based classifier constructed using training set was evaluated on an independent validation test set GSE2240. RESULTS: 863 DEGs with FDR < 0.05 and 482 differentially expressed proteins (DEPs) with FDR < 0.1 and fold change > 1.2 were obtained from the transcriptomic and proteomic study, respectively. The DEGs and DEPs were then analyzed together which identified 30 biomarkers with consistent trends. Further, 10 features, including 8 upregulated genes (CD44, CHGB, FHL2, GGT5, IGFBP2, NRAP, SEPTIN6, YWHAQ) and 2 downregulated genes (TNNI1, TRDN) were selected from the 30 biomarkers through machine learning CFS method using training set. The NB based classifier constructed using the training set accurately and reliably classify AF from SR samples in the validation test set with a precision of 87.5% and AUC of 0.995. CONCLUSION: Taken together, our present work might provide novel insights into the molecular mechanism and provide some promising diagnostic and therapeutic targets of AF.
Assuntos
Fibrilação Atrial/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Átrios do Coração/metabolismo , Aprendizado de Máquina , Mapas de Interação de Proteínas , Proteômica , Transcriptoma , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Teorema de Bayes , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Estudos de Associação Genética , Átrios do Coração/cirurgia , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de SinaisRESUMO
Prostate specific antigen (PSA) is one of the most common biomarkers for the management of prostate cancer. However, it still remains urgent to develop highly sensitive, cost-effective and selective strategies for PSA assay. In this paper, we developed a low-cost, highly sensitive and specific analytical strategy for the detection of PSA by using a fluorescence sensor based on Pb2+-dependent DNAzyme. We designed a DNA sequence called cmMB with a hairpin structure, containing PSA-specific aptamers and Pb2+-dependent DNAzyme chains. Also, a fluorophore-labelled DNA sequence called Sub-FAM, which contains a cleavage site of Pb2+-dependent DNAzyme and serves as substrate, is also designed for the signal generation. In the presence of PSA, interaction between aptamer and PSA blocks the hairpin structure of cmMB, resulting in the formation of Pb2+-dependent DNAzyme with Pb2+. Then, Pb2+-dependent DNAzyme can cleavage Sub-FAM and produce a high fluorescence. In the absence of PSA, since Sub-FAM remains to be ssDNA and can be absorbed by GO, only low fluorescence can be detected. Under optimal experimental conditions, a good linear relationship in the range of 1-100 pg mL-1 was exhibited, with a limit of detection (LOD) of 0.76 pg mL-1. In addition, the proposed method has potential value in the diagnosis and monitoring of prostate cancer because of its good selectivity and practical application in biological samples.
Assuntos
Técnicas Biossensoriais/métodos , DNA Catalítico/química , Corantes Fluorescentes/química , Antígeno Prostático Específico/sangue , Eletroforese em Gel de Poliacrilamida , Humanos , Limite de Detecção , Masculino , Espectrometria de FluorescênciaRESUMO
Purines, among most influential molecules, are reported to have essential biological function by regulating various cell types. A large number of studies have led to the discovery of many biological functions of the purine nucleotides such as ATP, ADP, and adenosine, as signaling molecules that engage G protein-coupled or ligand-gated ion channel receptors. The role of purines in the regulation of cellular functions at the gene or protein level has been well documented. With the advances in multiomics, including those from metabolomic and bioinformatic analyses, metabolic reprogramming was identified as a key mechanism involved in the regulation of cellular function under physiological or pathological conditions. Recent studies suggest that purines or purine-derived products contribute to important regulatory functions in many fundamental biological and pathological processes related to metabolic reprogramming. Therefore, this review summarizes the role and potential mechanism of purines in the regulation of metabolic reprogramming. In particular, the molecular mechanisms of extracellular purine- and intracellular purine-mediated metabolic regulation in various cells during disease development are discussed. In summary, our review provides an extensive resource for studying the regulatory role of purines in metabolic reprogramming and sheds light on the utilization of the corresponding peptides or proteins for disease diagnosis and therapy.