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Asthma is a heterogeneous disease that can be broadly classified into type 2, which is primarily steroid-sensitive and eosinophilic, and non-type 2, which is primarily steroid-resistant and neutrophilic. While the mechanisms leading to the development of molecular-targeted therapies for type 2 asthma are being elucidated, much remains to be learned about non-type 2 asthma. To investigate the role of oxidative stress in refractory allergic airway inflammation, we compared asthma models generated by immunizing wild-type and nuclear factor erythroid-2-related factor 2 (Nrf2)-deficient mice with the house dust mite antigen. Both asthma models had similar levels of airway inflammation and hyperresponsiveness, but the Nrf2-deficient mice had increased oxidative stress and exacerbated neutrophilic airway inflammation compared with the wild-type mice. Type 2 cytokines and the expression of GATA3, a transcription factor that is important for Th2 cell differentiation, had decreased in Nrf2-deficient mice compared with the wild-type mice, whereas helper T (Th) 17 cytokines and the expression of RORγt, which is important for Th17 cell differentiation, had increased. Furthermore, the neutrophilic airway inflammation caused by Nrf2 deficiency was ameliorated by interleukin (IL)-17 neutralization. We have concluded that the disruption of the Nrf2-mediated antioxidant defense system contributed to the induction of Th17 differentiation and exacerbated allergic neutrophilic airway inflammation.
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Background: To facilitate robotic radical prostatectomy (RP), we developed a novel anterior approach that utilizes a peritoneal incision between the umbilical ligaments to develop the Retzius space without contacting the internal inguinal rings, followed by closure of this space prior to prostatectomy and vesicourethral anastomosis. This approach could decrease the incidence of postoperative inguinal hernia (IH), similar to a Retzius-sparing RP (RS-RP). We compared the incidence of IH following this novel approach with that following conventional anterior RP and RS-RP. Methods: We retrospectively reviewed 532 patients who underwent robotic RP from September 2017 to August 2022. We compared the incidence of IH following novel anterior RP (n = 153) to that following conventional anterior RP (n = 284) and RS-RP (n = 95). We also assessed the independent factors associated with postoperative IH using Cox hazard models. Results: The 12- and 24-month cumulative incidences of postoperative IH following novel anterior RP were 1.3% and 1.3%, significantly lower than those associated with conventional anterior RP (8.0% and 12.6%, p = 0.009) but not significantly different from those following RS-RP (1.1% and 2.1%, p = 0.782). In multivariate analysis, use of the novel anterior RP approach, RS-RP, and body mass index were independent factors negatively associated with the occurrence of postoperative IH. Conclusions: This novel anterior approach involves developing the Retzius space between the umbilical ligaments and closure of this space following prostatectomy and vesicourethral anastomosis. It can decrease the incidence of IH compared to the conventional anterior approach. Prospective comparative studies are necessary to confirm the benefits of this approach.
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A 69-year-old woman was referred to our hospital for the treatment of a left renal tumor found by computed tomography (CT) during examination for microscopic hematuria. Contrast-enhanced CT showed a 5 cm tumor in the inferior pole of the left kidney. Left renal cell carcinoma (RCC) (cT1bN0M0) was suspected. In addition, the left renal and gonadal veins were dilated and enhanced in an arterial phase; renal arteriovenous fistula (RAVF) was suspected. Moreover, there were multiple focal arterial dilatations, suggesting the presence of multiple vascular malformation. Hereditary aortic disease, including vascular Ehlers-Danlos syndrome (vEDS), was a concern. In general, surgery is not recommended for patients with vEDS, due to vascular fragility. As such, a panel analysis of genes for hereditary aortic diseases, including vEDS, was performed; no pathogenic variants in candidate genes including COL3A1 were identified. After detailed discussions with the patient, she underwent a left nephrectomy, following transcatheter arterial embolization (TAE) of the left renal artery. We prepared a balloon catheter for aortic occlusion as a preventative measure for massive bleeding; this was not the case, as only a small amount of intraoperative bleeding occurred. Thus, the nephrectomy was performed successfully without using the balloon catheter. The patient recovered uneventfully and was discharged on day 8. Pathological examination showed clear-cell RCC (pT1a) and a RAVF near the tumor. Herein we report this case of left RCC with RAVF and multiple arterial malformation, which was successfully managed by evaluating preoperative risks with a genetic test, followed by TAE of the renal artery and open nephrectomy.
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Fístula Arteriovenosa , Carcinoma de Células Renales , Embolización Terapéutica , Neoplasias Renales , Femenino , Humanos , Anciano , Carcinoma de Células Renales/cirugía , Riñón , Fístula Arteriovenosa/complicaciones , Fístula Arteriovenosa/diagnóstico por imagen , Fístula Arteriovenosa/cirugía , Nefrectomía/métodos , Neoplasias Renales/cirugía , Embolización Terapéutica/métodos , HemorragiaRESUMEN
BACKGROUND: Elongation of very-long-chain fatty acids protein 6 (ELOVL6), an enzyme regulating elongation of saturated and monounsaturated fatty acids with C12 to C16 to those with C18, has been recently indicated to affect various immune and inflammatory responses; however, the precise process by which ELOVL6-related lipid dysregulation affects allergic airway inflammation is unclear. OBJECTIVES: This study sought to evaluate the biological roles of ELOVL6 in allergic airway responses and investigate whether regulating lipid composition in the airways could be an alternative treatment for asthma. METHODS: Expressions of ELOVL6 and other isoforms were examined in the airways of patients who are severely asthmatic and in mouse models of asthma. Wild-type and ELOVL6-deficient (Elovl6-/-) mice were analyzed for ovalbumin-induced, and also for house dust mite-induced, allergic airway inflammation by cell biological and biochemical approaches. RESULTS: ELOVL6 expression was downregulated in the bronchial epithelium of patients who are severely asthmatic compared with controls. In asthmatic mice, ELOVL6 deficiency led to enhanced airway inflammation in which lymphocyte egress from lymph nodes was increased, and both type 2 and non-type 2 immune responses were upregulated. Lipidomic profiling revealed that the levels of palmitic acid, ceramides, and sphingosine-1-phosphate were higher in the lungs of ovalbumin-immunized Elovl6-/- mice compared with those of wild-type mice, while the aggravated airway inflammation was ameliorated by treatment with fumonisin B1 or DL-threo-dihydrosphingosine, inhibitors of ceramide synthase and sphingosine kinase, respectively. CONCLUSIONS: This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-sphingosine-1-phosphate biosynthesis and indicates that ELOVL6 may be a novel therapeutic target for asthma.
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Asma , Ceramidas , Animales , Ratones , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Ovalbúmina/efectos adversosRESUMEN
INTRODUCTION: This study aimed to evaluate whether it is useful for junior physicians to use a three-dimensional (3D) kidney model when evaluating the R.E.N.A.L. nephrometry score. MATERIALS AND METHODS: An expert and four urology residents retrospectively evaluated the R.E.N.A.L. nephrometry scores of 64 renal tumors (62 patients) that underwent robot-assisted partial nephrectomy at our hospital. The expert evaluated 64 R.E.N.A.L. nephrometry scores with computed tomography (CT), whereas four residents evaluated 32 cases using CT alone and the other 32 cases using CT and a 3D kidney model. The consistency between the expert and residents was assessed by Cohen's kappa score. Patient-specific 3D kidney models were created in a gird style using a 3D printer based on CT or magnetic resonance imaging of the patient. RESULTS: For all four residents, the accuracy of the overall R.E.N.A.L. nephrometry score was significantly higher with the 3D model and CT than with CT alone (P < .001). Regarding the individual components of the R.E.N.A.L. nephrometry score, the accuracy rates of "E," "N," "A," and "L" scores were higher with the 3D model and CT than with the CT alone (P = .020-.089). CONCLUSION: Patient-specific 3D-printed kidney models could improve the resident's understanding of the renal tumor complexity and could be an important educational tool for residents.
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Neoplasias Renales , Riñón , Humanos , Estudios Retrospectivos , Riñón/diagnóstico por imagen , Riñón/cirugía , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/cirugía , Nefrectomía/métodos , Impresión TridimensionalRESUMEN
Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells transform to acquire mesenchymal phenotypes. Accumulating evidence indicate the involvement of EMT in the progression of malignant diseases. Notch signaling mediates TGF-ß1-induced EMT through direct transcriptional activation of Snai1. The molecular mechanism how TGF-ß1 activates Notch signaling, however, remains unknown. In this study, we show a pivotal role for reactive oxygen species (ROS)-Nrf2 pathway in TGF-ß1-induced Notch signaling activation and EMT development. TGF-ß1 induces Nrf2 activation through ROS production. Inhibiting Nrf2 activation either by reducing ROS levels by N-acetylcysteine or by knocking down of Nrf2 by small interfering RNA attenuated both Notch signaling activation and EMT development. TGF-ß1 induced the transcription of Notch4 via Nrf2-dependent promoter activation. In conclusion, our study indicates the ROS-Nrf2 pathway mediates the development of TGF-ß1-induced EMT through the activation of Notch signaling.
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Transición Epitelial-Mesenquimal , Factor de Crecimiento Transformador beta1 , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno , Transducción de SeñalRESUMEN
Bronchial anthracofibrosis is a rare disease defined as bronchial stenosis with black pigmentation and usually not associated with artery occlusion. The patient was an 81-year-old man with silicosis. He presented with dyspnea on exertion, and pulmonary hypertension due to right upper pulmonary artery occlusion without thromboembolism was diagnosed on the basis of the results of right heart catheterization and pulmonary angiography. Bronchoscopy demonstrated bronchial anthracofibrosis in the right upper lobe. These findings suggested that the cause of PH was silicosis and pulmonary artery occlusion with bronchial anthracofibrosis. He has been treated with home oxygen therapy and tadalafil, and his symptom and 6MWD remain stable.
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The programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) pathway could affect antimicrobial immune responses by suppressing T cell activity. Several recent studies demonstrated that blocking of the PD-1/PD-L1 pathway exacerbated Mycobacterium tuberculosis infection. However, the effect of blocking this pathway in pulmonary Mycobacterium avium-intracellulare complex (MAC) infection is not fully understood. Wild-type, PD-1-deficient mice, and PD-L1-deficient mice were intranasally infected with Mycobacterium avium bacteria. Depletion of PD-1 or PD-L1 did not affect mortality and bacterial burden in MAC-infected mice. However, marked infiltration of CD8-positive T lymphocytes was observed in the lungs of PD-1 and PD-L1-deficient mice compared to wild-type mice. Comprehensive transcriptome analysis showed that levels of gene expressions related to Th1 immunity did not differ according to the genotypes. However, genes related to the activity of CD8-positive T cells and related chemokine activity were upregulated in the infected lungs of PD-1 and PD-L1-deficient mice. Thus, the lack of change in susceptibility to MAC infection in PD-1 and PD-L1-deficient mice might be explained by the absence of obvious changes in the Th1 immune response. Furthermore, activated CD8-positive cells in response to MAC infection in these mice seemed to not be relevant in the control of MAC infection.
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Antígeno B7-H1/genética , Linfocitos T CD8-positivos/inmunología , Mycobacterium avium/inmunología , Receptor de Muerte Celular Programada 1/genética , Células TH1/inmunología , Tuberculosis/genética , Animales , Antígeno B7-H1/deficiencia , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/microbiología , Movimiento Celular , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genotipo , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Activación de Linfocitos , Ratones , Ratones Noqueados , Mycobacterium avium/patogenicidad , Receptor de Muerte Celular Programada 1/deficiencia , Receptor de Muerte Celular Programada 1/inmunología , Análisis de Supervivencia , Células TH1/microbiología , Transcriptoma , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/mortalidadRESUMEN
A 71-year-old man presented with neck pain. He was diagnosed with renal cell carcinoma of the left kidney with lung and bone metastases. After laparoscopic left nephrectomy, nivolumab plus ipilimumab was introduced as a first-line therapy for intermediate risk metastatic renal cell carcinoma based on the IMDC risk classification. After four cycles of nivolumab plus ipilimumab, he experienced dyspnea and was diagnosed with interstitial pneumonitis. Corticosteroid therapy was initiated, after which the symptoms of interstitial pneumonitis subsided. Corticosteroid therapy was tapered and discontinued after two months of treatment. The patient experienced fatigue at one week after the discontinuation of corticosteroid therapy and was diagnosed with isolated ACTH deficiency due to hypophysitis. He recovered after hydrocortisone treatment. This case involved two different immune-related adverse events (irAE), interstitial pneumonitis and hypophysitis, that occurred asynchronously following nivolumab plus ipilimumab therapy. It is important to observe the patient's condition carefully whether additional irAEs arise when corticosteroid therapy is tapered or discontinued.
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Carcinoma de Células Renales , Hipofisitis , Neoplasias Renales , Enfermedades Pulmonares Intersticiales , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Ipilimumab/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/inducido químicamente , Masculino , Nivolumab/efectos adversosRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease. Although high-resolution computed tomography (HRCT) is important for the diagnosis of IPF, the changes in the HRCT findings in IPF are not fully understood. The patient was a 66-year-old man. His HRCT findings had atypically developed from a probable usual interstitial pneumonia pattern to a nonspecific interstitial pneumonia (NSIP) like pattern over 6 years. On the basis of the histologic examination and multidisciplinary discussion, IPF was diagnosed, and nintedanib, administered. This case can be useful for the differential diagnosis of IPF and NSIP.
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Nrf2 is a redox-sensitive transcription factor that is thought to be important in protection against intracellular pathogens. To determine the protective role of Nrf2 in the host defense against Mycobacterium avium complex (MAC), both wild-type and Nrf2-deficient mice were intranasally infected with MAC bacteria. Nrf2-deficient mice were highly susceptible to MAC bacteria compared with wild-type mice. There were no significant changes in the levels of oxidative stress and Th1 cytokine production between genotypes. Comprehensive transcriptome analysis showed that the expressions of Nramp1 and HO-1 were much lower in the infected lungs, and the expression of Nramp1 was especially lower in alveolar macrophages of Nrf2-deficient mice than of wild-type mice. Electron microscopy showed that many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes, compared with those from wild-type mice. Treatment with sulforaphane, an activator of Nrf2, increased resistance to MAC with increased lung expression of Nramp1 and HO-1 in wild-type mice. These results indicate that Nramp1 and HO-1, regulated by Nrf2, are essential in defending against MAC infection due to the promotion of phagolysosome fusion and granuloma formation, respectively. Thus, Nrf2 is thought to be a critical determinant of host resistance to MAC infection.IMPORTANCE Nontuberculous mycobacteria (NTM) are an important cause of morbidity and mortality in pulmonary infections. Among them, Mycobacterium avium complex (MAC) is the most common cause of pulmonary NTM disease worldwide. It is thought that both environmental exposure and host susceptibility are required for the establishment of pulmonary MAC disease, because pulmonary MAC diseases are most commonly observed in slender, postmenopausal women without a clearly recognized immunodeficiency. However, host factors that regulate MAC susceptibility have not been elucidated until now. This study shows that Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively. The Nrf2 system is activated in alveolar macrophages, the most important cells during MAC infection, as both the main reservoir of infection and bacillus-killing cells. Thus, augmentation of Nrf2 might be a useful therapeutic approach for protection against pulmonary MAC disease.
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Proteínas de Transporte de Catión/genética , Regulación de la Expresión Génica/inmunología , Granuloma/microbiología , Hemo-Oxigenasa 1/genética , Interacciones Microbiota-Huesped , Proteínas de la Membrana/genética , Factor 2 Relacionado con NF-E2/genética , Animales , Proteínas de Transporte de Catión/inmunología , Femenino , Granuloma/inmunología , Hemo-Oxigenasa 1/inmunología , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/inmunología , Activación de Macrófagos/inmunología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/microbiología , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Complejo Mycobacterium avium/inmunología , Factor 2 Relacionado con NF-E2/inmunología , Estrés OxidativoRESUMEN
HAS2 is a member of the gene family encoding the hyaluronan synthase 2, which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for increased susceptibility to adult asthma. However, whether HAS2 dysfunction affects airway remodeling and steroid insensitivity is still limited. Therefore, this study aimed to clarify the Has2 dysfunction, triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Has2 heterozygous-deficient (Has2+/-) mice and their wild-type littermates have been evaluated in a model of chronic ovalbumin (OVA) sensitization and challenge. Mice present a higher sensitivity to OVA and higher IL-17 release as well as eosinophilic infiltration. RNA sequencing demonstrated the downregulation of EIF2 signaling pathways, TGF-ß signaling pathways, and heat shock proteins with Th17 bias in Has2+/--OVA mice. The combined treatment with anti-IL-17A antibody and dexamethasone reduces steroid insensitivity in Has2+/--OVA mice. Has2 attenuation worsens eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling and could potentially be exploited for their therapeutic benefits in patients with asthma.
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Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma/inmunología , Resistencia a Medicamentos/inmunología , Hialuronano Sintasas/inmunología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Remodelación de las Vías Aéreas (Respiratorias)/genética , Animales , Asma/inducido químicamente , Asma/genética , Resistencia a Medicamentos/genética , Hialuronano Sintasas/genética , Ratones , Ratones Noqueados , Ovalbúmina/toxicidad , Esteroides/farmacologíaRESUMEN
INTRODUCTION: Tumor lysis syndrome is a rare and potentially fatal complication of oncological treatment. It is characterized by biochemical changes associated with the rapid lysis of malignant cells, usually after chemotherapy. Tumor lysis syndrome is typically noted in patients with hematological malignancies, and it rarely occurs in patients with solid tumors. CASE PRESENTATION: We report a case of tumor lysis syndrome after cabazitaxel administration for metastatic castration-resistant prostate cancer. To our knowledge, tumor lysis syndrome after cabazitaxel therapy has not been reported previously. The patient was a 77-year-old man who developed clinical tumor lysis syndrome after a single dose of cabazitaxel for metastatic castration-resistant prostate cancer. He was treated with hydration and the recombinant uricolytic agent rasburicase, and his condition improved. CONCLUSION: It is extremely important to assess the risk factors for tumor lysis syndrome and to perform active prevention procedures in order to avoid fatal outcomes. It may be beneficial to use rasburicase in patients with established tumor lysis syndrome.
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A 39-year-old woman received a seasonal influenza vaccine in November 2015 and subsequently experienced malaise, low-grade fever, and chest discomfort. A chest X-ray performed 2 weeks after vaccination showed multiple nodular shadows in both lungs and ground-glass shadows in both lower lung fields. Her bronchoalveolar lavage fluid contained an unusually high number of lymphocytes, and a drug-induced lymphocyte stimulation test for seasonal influenza vaccine was positive. Transbronchial lung biopsy revealed the presence of granulomatous inflammation. Thereafter her abnormal chest shadow spontaneously improved. Based on these findings, the patient was diagnosed with drug-induced pneumonitis due to an influenza vaccine.
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Vacunas contra la Influenza/efectos adversos , Nódulos Pulmonares Múltiples/inducido químicamente , Neumonía/inducido químicamente , Adulto , Biopsia , Líquido del Lavado Bronquioalveolar , Femenino , Fiebre/inducido químicamente , Humanos , Gripe Humana/prevención & control , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Neumonía/diagnóstico por imagen , Estaciones del AñoRESUMEN
Partial or complete spontaneous cancer regression is a rare phenomenon, particularly in patients with lung cancer. This is the case report of a patient with lung cancer who exhibited spontaneous regression of the primary as well as metastatic lesions, without receiving any treatment. Spontaneous regression commenced within a week of obtaining pathological specimens by transbronchial and percutaneous biopsies from the primary lesion and metastatic lymph nodes of the left side of the neck. The reason for this phenomenon is unknown; however, we hypothesized that there may be an immunological association between the stimulus of the biopsies and the spontaneous regression. This patient should be closely followed up to monitor the clinical course of this unusual case.