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OBJECTIVE: In this study, we examined the reason and prognosis of unplanned excision on synovial sarcoma. METHODS: We retrospectively analyzed 54 patients diagnosed with synovial sarcoma between March 2013 and February 2021, including 26 cases of unplanned excision surgery. Patients were divided into two groups based on whether they underwent unplanned excision. Then, factors such as gender, age, tumor size, tumor location, American Joint Committee on Cancer (AJCC) staging, unplanned excision, time of onset, duration of disease, radiotherapy, chemotherapy, amputation, local recurrence factors, and death were statistically evaluated. RESULTS: The results of a multivariate analysis revealed that the AJCC staging is an independent factor for patient prognosis. When patients were divided into two groups, those who had undergone unplanned excision and those who had not, statistical analysis revealed that there was no difference of survival between two groups, but tumor size and AJCC staging had statistical difference. To further explore the influences of unplanned excision, we performed propensity score analysis with 1:1 matching using the nearest neighbor matching method to balance the covariates between the two groups. There was no difference of survival between two groups after propensity score matching. CONCLUSION: Unplanned excision is commonly performed in synovial sarcoma and do not impact the prognosis after extensive resection.
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Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.
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BACKGROUND: Mazabraud's syndrome (MS) is a rare and slowly progressive benign disease characterized by the concurrent presence of fibrous dysplasia of bone and intramuscular myxoma, and is thought to be associated with mutations of the GNAS gene. To date, only about 100 cases of MS have been reported in the literature, but its standard treatment strategy remains unclear. CASE SUMMARY: We report two cases of MS in young women who underwent different treatments based on their symptoms and disease manifestations. The first patient, aged 37, received internal fixation and intravenous bisphosphonate for a pathological fracture of the right femoral neck, excision of a right vastus medialis myxoma was subsequently performed for pain control, and asymptomatic psoas myxomas were monitored without surgery. Genetic testing confirmed a GNAS gene mutation in this patient. The second patient, aged 24, underwent right vastus intermedius muscle myxoma resection, and conservative treatment for fibrous dysplasia of the ilium. These patients were followed-up for 17 months and 3 years, respectively, and are now in a stable condition. CONCLUSION: Various treatments have been selected for MS patients who suffer different symptoms. The main treatment for myxomas is surgical resection, while fibrous dysplasia is selectively treated if the patient experiences pathological fracture or severe pain. However, given the documented instances of malignant transformation of fibrous dysplasia in individuals with MS, close follow-up is necessary.
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Feline chronic gingivostomatitis (FCGS) is an ulcerative and/or proliferative disease that typically affects the palatoglossal folds. Because of its unknown pathogenesis and long disease course, it is difficult to treat and has a high recurrence rate. Most of the bacteria in the oral microbiota exist in the mouth symbiotically and maintain a dynamic balance, and when the balance is disrupted, they may cause disease. Disturbance of the oral microbiota may play an important role in the development of FCGS. In this study, the medical records of 3109 cats in three general pet hospitals in Xi 'an were collected. Sixty-one cats with FCGS were investigated via questionnaires, routine oral examinations and laboratory examinations. Oral microbiota samples were collected from 16 FCGS-affected cats, and microbial species were identified by 16S rDNA sequencing. The results showed that the incidence of FCGS had no significant correlation with age, sex or breed. However, the incidence of FCGS was associated with immunization, a history of homelessness and multicat rearing environments. The number of neutrophils and the serum amyloid A concentration were increased, and the percentage of cells positive for calicivirus antigen was high in all cases. All the cats had different degrees of dental calculus, and there were problems such as loss of alveolar bone or tooth resorption. Compared with those in healthy cats, the bacterial diversity and the abundance of anaerobic bacteria were significantly increased in cats with FCGS. Porphyromonas, Treponemas and Fusobacterium were abundant in the mouths of the affected cats and may be potential pathogens of FCGS. After tooth extraction, a shift could be seen in the composition of the oral microbiota in cats with FCGS. An isolated bacteria obtained from the mouths of the affected cats was homologous to P. gulae. Both the identified oral microbiota and the isolated strain of the cats with FCGS had high sensitivity to enrofloxacin and low sensitivity to metronidazole. This study provides support to current clinical criteria in diagnosing FCGS and proposes a more suitable antibiotic therapy.
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The MUC1 gene evolved in mammals for adaptation of barrier tissues in response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA in response to loss of homeostasis. There is no known intersection of MUC1 with NEAT1 or paraspeckles. Here, we demonstrate that the MUC1-C subunit plays an essential role in regulating NEAT1 expression. MUC1-C activates the NEAT1 gene with induction of the NEAT1_1 and NEAT1_2 isoforms by NF-κB- and MYC-mediated mechanisms. MUC1-C/MYC signaling also induces expression of the SFPQ, NONO and FUS RNA binding proteins (RBPs) that associate with NEAT1_2 and are necessary for paraspeckle formation. MUC1-C integrates activation of NEAT1 and RBP-encoding genes by recruiting the PBAF chromatin remodeling complex and increasing chromatin accessibility of their respective regulatory regions. We further demonstrate that MUC1-C and NEAT1 form an auto-inductive pathway that drives common sets of genes conferring responses to inflammation and loss of homeostasis. Of functional significance, we find that the MUC1-C/NEAT1 pathway is of importance for the cancer stem cell (CSC) state and anti-cancer drug resistance. These findings identify a previously unrecognized role for MUC1-C in the regulation of NEAT1, RBPs, and paraspeckles that has been co-opted in promoting cancer progression.
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Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Mucina-1 , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Mucina-1/genética , Mucina-1/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Camundongos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , NF-kappa B/metabolismo , NF-kappa B/genética , Fator de Processamento Associado a PTB/genética , Fator de Processamento Associado a PTB/metabolismo , Transdução de Sinais/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Proteínas de Ligação a DNARESUMO
The long non-coding RNA X-inactive specific transcript (lncRNA XIST) and MUC1 gene are dysregulated in chronic inflammation and cancer; however, there is no known interaction of their functions. The present studies demonstrate that MUC1-C regulates XIST lncRNA levels by suppressing the RBM15/B, WTAP and METTL3/14 components of the m6A methylation complex that associate with XIST A repeats. MUC1-C also suppresses the YTHDF2-CNOT1 deadenylase complex that recognizes m6A sites and contributes to XIST decay with increases in XIST stability and expression. In support of an auto-regulatory pathway, we show that XIST regulates MUC1-C expression by promoting NF-κB-mediated activation of the MUC1 gene. Of significance, MUC1-C and XIST regulate common genes associated with inflammation and stemness, including (i) miR-21 which is upregulated across pan-cancers, and (ii) TDP-43 which associates with the XIST E repeats. Our results further demonstrate that the MUC1-C/XIST pathway (i) is regulated by TDP-43, (ii) drives stemness-associated genes, and (iii) is necessary for self-renewal capacity. These findings indicate that the MUC1-C/XIST auto-regulatory axis is of importance in cancer progression.
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Regulação Neoplásica da Expressão Gênica , Mucina-1 , RNA Longo não Codificante , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Progressão da Doença , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , MicroRNAs/metabolismo , MicroRNAs/genética , Mucina-1/metabolismo , Mucina-1/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: In recent years, exoskeleton robot technology has developed rapidly. Exoskeleton robots that can be worn on a human body and provide additional strength, speed or other abilities. Exoskeleton robots have a wide range of applications, such as medical rehabilitation, logistics and disaster relief and other fields. OBJECTIVE: The study goal is to propose a lower limb assistive exoskeleton robot to provide extra power for wearers. METHODS: The mechanical structure of the exoskeleton robot was designed by using bionics principle to imitate human body shape, so as to satisfy the coordination of man-machine movement and the comfort of wearing. Then a gait prediction method based on neural network was designed. In addition, a control strategy according to iterative learning control was designed. RESULTS: The experiment results showed that the proposed exoskeleton robot can produce effective assistance and reduce the wearer's muscle force output. CONCLUSION: A lower limb assistive exoskeleton robot was introduced in this paper. The kinematics model and dynamic model of the exoskeleton robot were established. Tracking effects of joint angle displacement and velocity were analyzed to verify feasibility of the control strategy. The learning error of joint angle can be improved with increase of the number of iterations. The error of trajectory tracking is acceptable.
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Desenho de Equipamento , Exoesqueleto Energizado , Extremidade Inferior , Humanos , Extremidade Inferior/fisiologia , Fenômenos Biomecânicos , Robótica/instrumentação , Marcha/fisiologia , Redes Neurais de ComputaçãoRESUMO
The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCC). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCC). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and IFN regulatory factors, and (iii) downstream IFN-stimulated genes. MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity, and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by single-cell RNA sequencing analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression. SIGNIFICANCE: This work reports a previously unrecognized role for MUC1-C in driving STAT1-mediated chronic inflammation with the progression of HNSCC and identifies MUC1-C as a druggable target for advanced HNSCC treatment.
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Progressão da Doença , Neoplasias de Cabeça e Pescoço , Mucina-1 , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Mucina-1/genética , Mucina-1/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Camundongos , Animais , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Receptor Notch3/genética , Receptor Notch3/metabolismoRESUMO
Among the primary threats to human health worldwide, nonsmall cell lung cancer (NSCLC) remains a significant factor and is a leading cause of cancer-related deaths. Due to subtle early symptoms, NSCLC patients are diagnosed at advanced stages, resulting in low survival rates. Herein, novel Au-Se bond nanoprobes (NPs) designed for the specific detection of Calpain-2 (CAPN2) and Human Neutrophil Elastase (HNE), pivotal biomarkers in NSCLC, were developed. The NPs demonstrated exceptional specificity and sensitivity toward CAPN2 and HNE, enabling dual-color fluorescence imaging to distinguish between NSCLC cells and normal lung cells effectively. The NPs' performance was consistent across a wide pH range (6.2 to 8.0), and it exhibited remarkable resistance to biological thiol interference, indicating its robustness in complex physiological environments. These findings suggest the nanoprobe is a promising tool for early NSCLC diagnosis, offering a novel approach for enhancing the accuracy of cancer detection.
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Carcinoma Pulmonar de Células não Pequenas , Corantes Fluorescentes , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Corantes Fluorescentes/química , Imagem Óptica , Ouro/química , Calpaína/metabolismo , Calpaína/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Linhagem Celular TumoralRESUMO
Novel Au-Se bond-based nanoprobes were designed for concurrent detection of PSA and PSMA in serum samples, aiming to enhance the early diagnosis of prostate cancer. These probes demonstrate robust stability, specificity and accuracy, underscoring their potential as non-invasive tools for diagnosis.
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Antígenos de Superfície , Corantes Fluorescentes , Glutamato Carboxipeptidase II , Ouro , Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Masculino , Antígeno Prostático Específico/sangue , Glutamato Carboxipeptidase II/sangue , Corantes Fluorescentes/química , Antígenos de Superfície/sangue , Ouro/químicaRESUMO
BACKGROUND: In a multi-institutional clinical study, we assessed the prognostic significance of a novel indicator preoperative peripheral blood immune (PBIS) scores that combined ratios of preoperative lymphocyte, monocyte, and neutrophil of renal cell carcinoma (RCC) patients undergoing laparoscopic nephrectomy. METHODS: Between January 2014 and December 2019, 438 patients with RCC were retrospectively analyzed in three centers. We used X-tile software to obtain the optimum cut-off values for neutrophils, monocytes, and lymphocytes to classify the patients. To assess the relationship between PBIS score and overall survival (OS), and cancer-specific survival (CSS) in patients with RCC by Kaplan-Meier survival curves and Cox regression analyses. In addition, predictive OS and CSS nomograms were constructed. The discriminative ability of nomogram and predictive performance accuracy were verified with consistency index (C-index), calibration curves, receiver operating curve (ROC) curves, decision curve analysis (DCA) curves, and time-dependent ROC curves. RESULTS: The optimum cutoff values for monocytes, lymphocytes, and neutrophils were 0.46, 1.01, and 4.50, respectively. We divided patients into four subgroups according to PBIS scores, which were significantly associated with M-stage (p = 0.008), T-stage (p < 0.001), N-stage (p = 0.006), and AJCC stage (p < 0.001). Multivariate Cox regression analysis revealed that RCC patients with lower PBIS scores showed a worse postoperative prognosis and served as an independent predictor of OS (p = 0.002) and CSS (p < 0.001). Ultimately, the nomograms based on PBIS scores demonstrated excellent predictive performance for OS (C-index: 0.770) and CSS (C-index: 0.828) through the analysis of calibration curves, ROC curves, DCA curves, and time-dependent ROC curves. CONCLUSION: PBIS score served as novel and effective predictor to accurately predict OS and CSS in patients with RCC receiving laparoscopic nephrectomy.
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Carcinoma de Células Renais , Neoplasias Renais , Laparoscopia , Linfócitos , Monócitos , Nefrectomia , Neutrófilos , Nomogramas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Estimativa de Kaplan-Meier , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Linfócitos/patologia , Nefrectomia/métodos , Neutrófilos/patologia , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos , Curva ROCRESUMO
Aims: Radiotherapy is a well-known local treatment for spinal metastases. However, in the presence of postoperative systemic therapy, the efficacy of radiotherapy on local control (LC) and overall survival (OS) in patients with spinal metastases remains unknown. This study aimed to evaluate the clinical outcomes of post-surgical radiotherapy for spinal metastatic non-small-cell lung cancer (NSCLC) patients, and to identify factors correlated with LC and OS. Methods: A retrospective, single-centre review was conducted of patients with spinal metastases from NSCLC who underwent surgery followed by systemic therapy at our institution from January 2018 to September 2022. Kaplan-Meier analysis and log-rank tests were used to compare the LC and OS between groups. Associated factors for LC and OS were assessed using Cox proportional hazards regression analysis. Results: Overall, 123 patients with 127 spinal metastases from NSCLC who underwent decompression surgery followed by postoperative systemic therapy were included. A total of 43 lesions were treated with stereotactic body radiotherapy (SBRT) after surgery and 84 lesions were not. Survival rate at one, two, and three years was 83.4%, 58.9%, and 48.2%, respectively, and LC rate was 87.8%, 78.8%, and 78.8%, respectively. Histological type was the only significant associated factor for both LC (p = 0.007) and OS (p < 0.001). Treatment with targeted therapy was significantly associated with longer survival (p = 0.039). The risk factors associated with worse survival were abnormal laboratory data (p = 0.021), lesions located in the thoracic spine (p = 0.047), and lumbar spine (p = 0.044). This study also revealed that postoperative radiotherapy had little effect in improving OS or LC. Conclusion: Tumour histological type was significantly associated with the prognosis in spinal NSCLC metastasis patients. In the presence of post-surgical systemic therapy, radiotherapy appeared to be less effective in improving LC, OS, or quality of life in spinal NSCLC metastasis patients.
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Background: Metamycoplasma orale (M.orale), a symbiotic bacterium observed in the human oral cavity, is generally regarded as non-pathogenic to humans. Although infrequent, symptomatic infections caused by M.orale may occur in individuals with compromised humoral immunity. Accurate identification and early diagnosis of M.orale still present significant challenges due the limitations associated with conventional detection methods. Although metagenomic next-generation sequencing (mNGS) is currently widely utilized in clinical practices and exhibits a remarkable specificity and sensitivity for detecting various pathogens, its application in the diagnosis of M.orale-induced osteomyelitis remains largely unexplored. Case description: In this report, we present a case study of osteonecrosis caused by M.orale in a 20-year-old female patient with nephrotic syndrome and other comorbidities. She was administered long-term hormone therapy and immunosuppressants, leading to her admission to the hospital due to recurrent fever, hip abscess and left thigh pain. Imaging examination revealed bilateral mid-femoral lesions, with the extensive nature of the left femoral lesion suggesting a potential secondary infection. Although no pathogen was detected in pus culture, mNGS analysis identified M.orale in the sample. Following treatment with doxycycline and levofloxacin, the patient's symotoms improved and she was discharged with favorable outcomes. Conclusion: mNGS enables rapid identification of etiology in patients with osteomyelitis caused by the rare pathogen M.orale. This case accentuate the strength of mNGS for early detection and targeted clinical treatment of infectious diseases caused by uncommon pathogens.
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PURPOSE: Segmentation of orbital tumors in CT images is of great significance for orbital tumor diagnosis, which is one of the most prevalent diseases of the eye. However, the large variety of tumor sizes and shapes makes the segmentation task very challenging, especially when the available annotation data is limited. METHODS: To this end, in this paper, we propose a multi-scale consistent self-training network (MSCINet) for semi-supervised orbital tumor segmentation. Specifically, we exploit the semantic-invariance features by enforcing the consistency between the predictions of different scales of the same image to make the model more robust to size variation. Moreover, we incorporate a new self-training strategy, which adopts iterative training with an uncertainty filtering mechanism to filter the pseudo-labels generated by the model, to eliminate the accumulation of pseudo-label error predictions and increase the generalization of the model. RESULTS: For evaluation, we have built two datasets, the orbital tumor binary segmentation dataset (Orbtum-B) and the orbital multi-organ segmentation dataset (Orbtum-M). Experimental results on these two datasets show that our proposed method can both achieve state-of-the-art performance. In our datasets, there are a total of 55 patients containing 602 2D images. CONCLUSION: In this paper, we develop a new semi-supervised segmentation method for orbital tumors, which is designed for the characteristics of orbital tumors and exhibits excellent performance compared to previous semi-supervised algorithms.
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Processamento de Imagem Assistida por Computador , Neoplasias Orbitárias , Tomografia Computadorizada por Raios X , Neoplasias Orbitárias/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Aprendizado de Máquina SupervisionadoRESUMO
The oncogenic MUC1-C transmembrane protein is a critical effector of the cancer stem cell (CSC) state. Addiction to MUC1-C for self-renewal in the progression of human cancers has emphasized the need for development of anti-MUC1-C agents. However, there are presently no approved small molecules for targeting MUC1-C-dependent CSCs. In screening for small molecules, we identified salinomycin (SAL), an inducer of ferroptosis, as a potent inhibitor of MUC1-C signaling. We demonstrate that SAL suppresses MUC1-C expression by disrupting a NF-κB/MUC1-C auto-inductive circuit that is necessary for ferroptosis resistance. Our results show that SAL-induced MUC1-C suppression downregulates a MUC1-CâMYC pathway that activates genes encoding (i) glutathione-disulfide reductase (GSR), and (ii) the LDL receptor related protein 8 (LRP8), which inhibit ferroptosis by generating GSH and regulating selenium levels, respectively. GSR and LRP8 contribute to the function of glutathione peroxidase 4 (GPX4), an essential negative regulator of ferroptotic cell death. We demonstrate that targeting MUC1-C genetically or with the GO-203 peptide inhibitor suppresses GPX4 expression and GPX activity in association with the induction of ferroptosis. Studies of CSCs enriched by serial passage as tumorspheres further demonstrate that the effects of SAL are mediated by downregulation of MUC1-C and thereby overcoming resistance to ferroptosis. As confirmation of these results, rescue of MUC1-C downregulation with the MUC1-C cytoplasmic domain (i) reversed the suppression of GSR, LRP8 and GPX4 expression, and (ii) attenuated the induction of ferroptosis. These findings identify SAL as a unique small molecule inhibitor of MUC1-C signaling and demonstrate that MUC1-C is an important effector of resistance to ferroptosis.
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BACKGROUND: Topical photodynamic therapy (PDT) has demonstrated encouraging results in the treatment of oral leukoplakia (OLK). However, data on the clinical efficacy of PDT in Chinese patients with OLK are still limited. METHODS: Fifty patients diagnosed with OLK were enrolled, including patients with various dysplastic tissues. All patients received topical PDT with 5-aminolevulinic acid (5-ALA) as a photosensitizer. Clinical efficacy was evaluated 4 weeks after treatment. Follow-up was performed every 3 months during the first year and every 6 months during the second year. RESULTS: The overall response rate was 68% (34/50): 12% (n = 6) complete and 56% (n = 28) partial responses. Aneuploidy was reduced in the patients with dysplastic lesions. Oral pain and local ulcers developed in 52% of the patients (n = 26). Patients with a long history of OLK including hyperplasia and dysplastic lesions, as well as those with non-homogenous lesions, were more likely to develop pain and ulcer. During follow-up, the recurrence rate of hyperplasia and dysplastic lesions was 32% (n = 16) and the malignant transformation rate of dysplastic lesions was 4% (n = 2). Lesions on the buccal mucosa were associated with recurrence (P = 0.044; OR: 0.108, 95% CI: 0.013-0.915). CONCLUSION: Topical 5-ALA-mediated PDT is an effective treatment for OLK, particularly for homogenous leukoplakia, with few side effects. The buccal mucosa may be a protective factor that can reduce recurrence.
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Fotoquimioterapia , Humanos , Estudos Retrospectivos , Fotoquimioterapia/efeitos adversos , Fotoquimioterapia/métodos , Hiperplasia/tratamento farmacológico , Hiperplasia/etiologia , Leucoplasia Oral/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Ácido Aminolevulínico/uso terapêutico , Dor/etiologiaRESUMO
INTRODUCTION: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance. METHODS: H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity. RESULTS: We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs. CONCLUSIONS: Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.
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Acrilamidas , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores ErbB/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-akt/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Compostos de Anilina/farmacologia , Mucina-1/genéticaRESUMO
Prostate cancer (PC) is a prevalent malignancy in males, characterized by high morbidity and mortality. Despite MLC1 being established as a key mediator in tumor progression, its role in PC remains unexplored. This study aims to validate MLC1's anti-tumor effects and uncover potential mechanisms. MLC1's clinical significance is assessed using data from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. MLC1 expression is significantly reduced in PC samples compared with the adjacent normal tissues. MLC1 expression correlates negatively with tumor metastasis and positively with the survival of patients with PC. In vitro, up-regulating MLC1 effectively inhibits tumor progression by curtailing proliferation, infestation, and migration through the deactivation of the PI3K/AKT signaling pathway. Conversely, down-regulating MLC1 promotes PC progression, a phenomenon alleviated by the PI3K/AKT inhibitor, Gefitinib. Furthermore, the anti-tumor function of MLC1 is corroborated by a reduction in tumor volume compared with the negative control in vivo. This study confirms the anti-tumor effects of MLC1 via in vitro and in vivo experiments, demonstrating its potential mechanism of inhibiting the PI3K/AKT signaling pathway.
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Neoplasias da Próstata , Proteínas Proto-Oncogênicas c-akt , Masculino , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Linhagem Celular Tumoral , Transdução de Sinais/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas de Membrana/farmacologiaRESUMO
Docetaxel is the preferred chemotherapeutic agent in patients with castrate-resistant prostate cancer (CRPC). However, patients eventually develop docetaxel resistance and in the absence of effective treatment options. Consequently, it is essential to investigate the mechanisms generating docetaxel resistance and develop novel alternative therapeutic targets. RNA sequencing was undertaken on docetaxel-sensitive and docetaxel-resistant prostate cancer (PCa) cells. Subsequently, chemoresistance, cancer stemness, and lipid metabolism were investigated. To obtain insight into the precise activities and action mechanisms of NOTCH3 in docetaxel-resistant PCa, immunoprecipitation, mass spectrometry, ChIP, luciferase reporter assay, cell metabolism, and animal experiments were performed. Through RNA sequencing analysis, we found that NOTCH3 expression was markedly higher in docetaxel-resistant cells relative to parental cells, and that this trend was continued in docetaxel-resistant PCa tissues. Experiments in vitro and in vivo revealed that NOTCH3 enhanced stemness, lipid metabolism, and docetaxel resistance in PCa. Mechanistically, NOTCH3 is bound to TUBB3 and activates the MAPK signaling pathway. Moreover, NOTCH3 was directly regulated by MEF2A in docetaxel-resistant cells. Notably, targeting NOTCH3 and the MEF2A/TUBB3 signaling axis was related to docetaxel chemoresistance in PCa. Overall, these results demonstrated that NOTCH3 fostered stemness, lipid metabolism, and docetaxel resistance in PCa via the TUBB3 and MAPK signaling pathways. Therefore, NOTCH3 may be employed as a prognostic biomarker in PCa patients. NOTCH3 could be a therapeutic target for PCa patients, particularly those who have developed docetaxel resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias da Próstata , Masculino , Animais , Humanos , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transdução de Sinais/genética , Tubulina (Proteína)/metabolismo , Receptor Notch3/genéticaRESUMO
BACKGROUND: A20 may be a neuroprotective factor. Herein, we aimed to investigate whether serum A20 levels were associated with disease severity, delayed cerebral ischemia (DCI), and outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In this prospective cohort study containing 112 aSAH patients and 112 controls, serum A20 levels were quantified. At 90 d poststroke, Modified Rankin Scale (MRS) scores ≥3 were defined as a poor outcome. All correlations and associations were assessed using multivariate analysis. RESULTS: Compared with controls, there was a significant elevation of serum A20 levels in patients (median 123.7 pg/mL vs. 25.8 pg/mL; P<0.001). Serum A20 levels were independently correlated with Hunt-Hess scores (ß 9.854; 95% confidence interval [95% CI] 2.481-17.227, P=0.009) and modified Fisher scores (ß 10.349, 95% CI 1.273-19.424, P=0.026). Independent associations were found between serum A20 levels and poor outcome (odds ratio [OR] 1.015, 95% CI 1.000-1.031, P=0.047) and DCI (OR 1.018, 95% CI 1.001-1.035, P=0.042). Areas under the curve for predicting poor outcome and DCI were 0.771 (95% CI 0.682-0.845) and 0.777 (95% CI 0.688-0.850), respectively. Serum A20 levels ≥128.15 pg/mL predicted poor outcome, with a sensitivity of 73.9% and specificity of 74.2%, and A20 levels ≥160.55 pg/mL distinguished the risk of DCI with 65.5% sensitivity and 89.2% specificity. Its ability to predict poor outcome and DCI was similar to those of Hunt-Hess scores and modified Fisher scores (both P>0.05). CONCLUSION: Enhanced serum A20 levels are significantly associated with stroke severity and poor clinical outcome after aSAH, implying that serum A20 may be a potential prognostic biomarker for aSAH.