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Sea slugs of the family Chromodorididae (Nudibranchia, Gastropoda, Mollusca) have garnered attention by researchers and hobbyists alike for their bright and variable color patterns. However, the chromodorid life cycle has yet to be fully elucidated as there exist no reports of their rearing in the laboratory. Here, we report the rearing of Hypselodoris festiva from eggs to adults, where we categorized their post-settlement growth patterns from juvenile to adult stages. Body coloration appeared around 36 days, and organogenesis of vital adult organs began within 42 days after hatching. The anus of H. festiva was observed to change from a ventral to dorsal position during juvenile growth. Individuals reached sexual maturity after six months post-hatching, with successful mating and spawning observed ex situ. This study outlines comprehensive rearing methods and life cycle staging that could be applied to other chromodorid species. We propose H. festiva as a model organism for chromodorid research, with this research contributing to the progress of developmental and evolutionary research on sea slugs.
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Gastrópodos , Estadios del Ciclo de Vida , Animales , Gastrópodos/crecimiento & desarrolloRESUMEN
Redox reactions control fundamental biochemical processes, including energy production, metabolism, respiration, detoxification, and signal transduction. Cancer cells, due to their generally active metabolism for sustained proliferation, produce high levels of reactive oxygen species (ROS) compared to normal cells and are equipped with antioxidant defense systems to counteract the detrimental effects of ROS to maintain redox homeostasis. The KEAP1-NRF2 system plays a major role in sensing and regulating endogenous antioxidant defenses in both normal and cancer cells, creating a bivalent contribution of NRF2 to cancer prevention and therapy. Cancer cells hijack the NRF2-dependent antioxidant program and exploit a very unique metabolism as a trade-off for enhanced antioxidant capacity. This work provides an overview of redox metabolism in cancer cells, highlighting the role of the KEAP1-NRF2 system, selenoproteins, sulfur metabolism, heme/iron metabolism, and antioxidants. Finally, we describe therapeutic approaches that can be leveraged to target redox metabolism in cancer.
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Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Glutamina/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Inhibidores Enzimáticos/uso terapéutico , MutaciónRESUMEN
The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.
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Factor 2 Relacionado con NF-E2 , Neoplasias , Animales , Humanos , Ratones , Cromatina , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Reprogramación Metabólica , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Evasión Inmune , Línea Celular Tumoral , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/terapia , Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Inmunoterapia , Microambiente TumoralRESUMEN
Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We have previously shown that KEAP1 mutant tumors have increased glutamine consumption to support the metabolic rewiring associated with NRF2 activation. Here, using patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the novel glutamine antagonist DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumor growth by inhibiting glutamine-dependent nucleotide synthesis and promoting anti-tumor CD4 and CD8 T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we discover that DRP-104 reverses T cell exhaustion and enhances the function of CD4 and CD8 T cells culminating in an improved response to anti-PD1 therapy. Our pre-clinical findings provide compelling evidence that DRP-104, currently in phase 1 clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer. Furthermore, we demonstrate that by combining DRP-104 with checkpoint inhibition, we can achieve suppression of tumor intrinsic metabolism and augmentation of anti-tumor T cell responses.
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Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect how LKB1 mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling of LKB1 -mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1 + interstitial macrophages and SiglecF Hi neutrophils. We discovered a novel mechanism whereby autocrine LIF signaling in Lkb1 -mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling in Lkb1 -mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1 + interstitial macrophages and SiglecF Hi neutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment of LKB1 -mutant tumors.
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Interplay between metabolism and chromatin signaling have been implicated in cancer initiation and progression. However, whether and how metabolic reprogramming in tumors generates specific epigenetic vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor mutations that cause aberrant activation of the NRF2 antioxidant pathway and drive aggressive and chemo-resistant disease. We performed a chromatin-focused CRISPR screen and report that NRF2 activation sensitized LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association was consistently observed across cultured cells, syngeneic mouse models and patient-derived xenografts. HDAC inhibition causes widespread increases in histone H4 acetylation (H4ac) at intergenic regions, but also drives re-targeting of H4ac reader protein BRD4 away from promoters with high H4ac levels and transcriptional downregulation of corresponding genes. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that these chromatin changes are associated with reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest that metabolic alterations such as NRF2 activation could serve as biomarkers for effective repurposing of HDAC inhibitors to treat solid tumors.
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Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Factor 2 Relacionado con NF-E2 , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Pulmonares/metabolismo , NAD/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/genética , Transducción de SeñalRESUMEN
The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance. SIGNIFICANCE: Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.
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Factor 2 Relacionado con NF-E2 , Neoplasias , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
We herein report an unusual case of granulomatosis with polyangiitis (GPA) in a 65-year-old man in whom relapsed disease manifested as an anterior cheek nodule. Magnetic resonance imaging indicated the differential diagnoses of the subcutaneous nodule in the patient's anterior cheek to be inflammatory granulomatous lesions with GPA, malignancy, or infectious disease. A histopathological examination ruled out malignancy and infectious diseases, and necrotizing vasculitis was suspected. The subcutaneous nodule was successfully treated using rituximab, suggesting that it was associated with GPA, secondary to vasculitis. Clinicians should be aware of the possibility of such a rare manifestation of GPA.
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Granulomatosis con Poliangitis , Anciano , Mejilla , Granuloma , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Imagen por Resonancia Magnética , Masculino , RituximabRESUMEN
The transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers. Here we addressed whether targeting Nrf2 activation in the microenvironment can suppress the progression of Nrf2-activated tumors. We combined two types of Keap1-flox mice expressing variable levels of Keap1 with a Kras-driven adenocarcinoma model to generate Keap1-deficient lung tumors surrounded by normal or Keap1-knockdown host cells. In this model system, activation of Nrf2 in the microenvironment prolonged the survival of Nrf2-activated tumor-bearing mice. The Nrf2-activated microenvironment suppressed tumor burden; in particular, preinvasive lesion formation was significantly suppressed. Notably, loss of Nrf2 in bone marrow-derived cells in Nrf2-activated host cells appeared to counteract the suppression of Nrf2-activated cancer progression. Thus, these results demonstrate that microenvironmental Nrf2 activation suppresses the progression of malignant Nrf2-activated tumors and that Nrf2 activation in immune cells at least partially contributes to these suppressive effects. SIGNIFICANCE: This study clarifies the importance of Nrf2 activation in the tumor microenvironment and in the host for the suppression of malignant Nrf2-activated cancers and proposes new cancer therapies utilizing inducers of Nrf2.
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Adenocarcinoma del Pulmón/metabolismo , Progresión de la Enfermedad , Proteína 1 Asociada A ECH Tipo Kelch/deficiencia , Neoplasias Pulmonares/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Microambiente Tumoral , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/terapia , Alelos , Animales , Secuencia de Bases , Trasplante de Médula Ósea/métodos , Linfocitos T CD8-positivos , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Genes ras , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/deficiencia , Factor 2 Relacionado con NF-E2/genética , Especificidad de Órganos , ARN Mensajero/metabolismo , Recombinación Genética , Estrés Fisiológico , Transcripción Genética , Activación Transcripcional , Carga Tumoral , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
PURPOSE: Cancer treatment can alter patient appearance, leading to psychological, social, and behavioral issues. This study aimed to investigate distress and difficulties related to appearance concerns in Japanese cancer patients and to identify information and support needs among them. METHODS: We conducted a questionnaire survey using the Derriford Appearance Scale 59 (DAS59) among cancer patients with a prior history of chemotherapy, molecular targeted therapy, or immunotherapy, who were recruited from the Departments of Medical Oncology and Psychosomatic Medicine, Kindai University Hospital. RESULTS: Participants were 114 patients with a mean age of 62.9 years; 70.2% were female, 86.0% had metastatic or locally advanced unresectable cancer, and 78.1% had concerns about some aspect of their appearance. Mean DAS59 full-scale score was 77.7 ± 36.4. Younger and female participants were found to have higher full-scale scores in univariate analysis (P < .05 for both), and younger participants were found to have higher full-scale scores in multivariate analysis (P < .05). CONCLUSIONS: DAS59 scores had a wide distribution, suggesting that psychological distress due to appearance changes showed large individual differences. Young and female patients tended to have high DAS59 full-scale scores, but some older and male patients also had high scores. Basic information regarding appearance changes should be provided to all patients before initiating cancer treatment. Both information provision prior to treatment and care at the time of actual appearance changes are important, and should be handled through a multidisciplinary approach.
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Neoplasias/terapia , Cuidados Paliativos/métodos , Calidad de Vida/psicología , Estrés Psicológico/psicología , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Neoplasias/psicología , Encuestas y CuestionariosRESUMEN
Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via ß-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD.
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Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.
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Disección Aórtica/genética , Inflamación/genética , Transactivadores/genética , Transcriptoma/genética , Disección Aórtica/inducido químicamente , Disección Aórtica/patología , Angiotensina II/toxicidad , Animales , Apoptosis/efectos de los fármacos , Quimiocina CCL2/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Interleucina-6/genética , Ratones , Estrés Mecánico , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
OBJECTIVE: Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. Although high salt intake is a proposed risk factor for cardiovascular diseases, the relationship between AD and high salt intake has not been clarified. We examined the effect of high-salt challenge on a mouse AD model. Approach and Results: AD was induced in male mice by continuous infusion of ß-aminopropionitrile and Ang II (angiotensin II). High-salt challenge exacerbated aortic wall destruction in AD. Deletion of Il17a (IL-17KO [IL (interleukin)-17A knockout]) did not affect the AD phenotype at baseline, but it abolished the high salt-induced worsening of the aortic destruction. Unexpectedly, aortas of IL-17KO mice exhibited global changes in ECM (extracellular matrix)-related genes without alteration of proinflammatory genes, altered architecture of collagen fibers, and reduced stiffness before AD induction. The aortas of IL-17KO mice were less sensitive to AD-inducing stimuli, as shown by the induction of phenotypic modulation markers SMemb and vimentin, suggesting a reduced stress response. The aortas of IL-17KO mice had a higher population of smooth muscle cells with nuclear-localized phosphorylated Smad2, indicative of TGFß (transforming growth factor-beta) signal activation. Consistently, pretreatment of smooth muscle cells in culture with IL-17A blunted the activation of Smad2 by TGFß1. CONCLUSIONS: These findings indicate that high salt intake has a worsening effect on AD in the context of high aortic wall stiffness, which is under the control of IL-17A through ECM metabolism. Therefore, salt restriction may represent a low-cost and practical way to reduce AD risk.
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Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Interleucina-17/genética , Músculo Liso Vascular/metabolismo , Sodio en la Dieta/efectos adversos , Disección Aórtica/metabolismo , Disección Aórtica/patología , Animales , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Matriz Extracelular/patología , Interleucina-17/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/patología , ARN/genética , Transducción de SeñalRESUMEN
RATIONALE: The ancient infectious diseases, Lemierre's Syndrome and Bezold's Abscesses are rare. PATIENT CONCERNS: A 70-year-old Japanese woman with a 15-year history of Parkinson's disease was referred to our hospital due to fever, occipital headache and bilateral shoulder pain that had continued for three months. She had been prescribed prednisolone due to a diagnosis of polymyalgia rheumatica. DIAGNOSES: A blood culture revealed bacteremia of Streptococcus constellatus. In addition, computed tomography revealed Bezold's abscesses and Lemierre's syndrome. INTERVENTIONS: We administered ceftriaxone for 31 days, followed by oral amoxicillin. OUTCOMES: The patient recovered and the abscesses improved. LESSONS: This case underscores the importance of blood culture tests and cross-referencing with radiological imagings in the diagnoses of these rare critical infectious diseases that mimic polymyalgia rheumatica.
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Absceso/complicaciones , Síndrome de Lemierre/complicaciones , Infecciones Estreptocócicas/complicaciones , Streptococcus constellatus/aislamiento & purificación , Absceso/microbiología , Anciano , Amoxicilina/uso terapéutico , Antibacterianos/uso terapéutico , Cultivo de Sangre/métodos , Ceftriaxona/uso terapéutico , Comorbilidad , Femenino , Humanos , Síndrome de Lemierre/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. METHODS AND RESULTS: We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B-cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B-cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B-cell-deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase-9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin-6 and metalloproteinase-9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. CONCLUSIONS: From these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue-destructive activities. Finally, we identified Syk as a potential therapeutic target.
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Aorta Abdominal/enzimología , Aneurisma de la Aorta Abdominal/enzimología , Linfocitos B/enzimología , Inmunoglobulina G/metabolismo , Inmunoglobulina M/metabolismo , Quinasa Syk/metabolismo , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/inmunología , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/inmunología , Aneurisma de la Aorta Abdominal/prevención & control , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Cloruro de Calcio , Modelos Animales de Enfermedad , Activación Enzimática , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/deficiencia , Inmunoglobulina M/genética , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/inmunología , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibidores de Proteínas Quinasas/farmacología , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/genética , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin-6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin-6 in macrophages in pathogenesis of AD. METHODS AND RESULTS: We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild-type (WT) mice, but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction. CONCLUSIONS: These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.