RESUMEN
Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Hepatitis , Neoplasias Hepáticas , Ratones , Animales , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Hígado , Fibrosis , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Línea Celular , Oligonucleótidos Antisentido/metabolismo , Hepatitis/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismoRESUMEN
BACKGROUND: Securing a professional baseball career is a formidable task, and only a unique few can overcome the obstacles necessary to become a Major League player in the Korea Baseball Organization (KBO). When achieving a spot in a KBO Major League team, a player's technical aspect may be influenced by their initial neuropsychological status. HYPOTHESIS: Personality and neurocognitive functions influence long-term pro-baseball league success. STUDY DESIGN: Cohort observational study. LEVEL OF EVIDENCE: Level 3. METHODS: From the start of each player's career, we monitored the status and course of 153 baseball players in the KBO from 2009 to 2019 who agreed to participate in this study. The Korean versions of the Temperament and Character Inventory (TCI) and the State-Trait Anxiety Inventory-Y (STAI-KY) analyzed traits and estimated state and trait anxiety levels, respectively. The Trail Making Test (TMT) (parts A and B) assessed attention shifting, and, in the Wisconsin Card Sorting Test (WCST), perseverative errors determined cognitive flexibility. Hierarchical logistic regression models were used to predict player status variables, with TCI and neurocognitive function variables as covariates. RESULTS: High novelty-seeking scores, low state anxiety, and short TMT A results reliably predict KBO Major League participation in a player's third year. Similarly, low state anxiety scores and high harm avoidance, reward dependence, and self-transcendence scores accurately predict KBO Major League participation in a player's fifth year. Lastly, short TMT A results, low perseverative error scores, and high novelty-seeking, harm avoidance, reward dependence, and self-transcendence efficiently predict KBO Major League participation in a player's seventh year. CONCLUSION: Draft ranking, personality, and neurocognitive function are associated with pro-baseball league achievement. In particular, personality and neuropsychological functions are associated with long-term success. CLINICAL RELEVANCE: Clinically, sound personality and neuropsychological functions determine KBO Major League success.
Asunto(s)
Béisbol , Humanos , Ansiedad , Temperamento , Carácter , Inventario de PersonalidadRESUMEN
This study focused on evaluating the effectiveness of stabilizer/binding agents in immobilizing arsenic (As) in contaminated soil using both geochemical and geophysical monitoring methods. The effluent from the stabilizer/binding agent's application and control columns was analyzed, and the status of the columns was monitored using electrical resistivity (ER) and induced polarization (IP) methods. As stabilizers/binder, acid mine drainage sludge (AMDS) and steel slag (SS) were used, which delayed As and Ca leaching time and significantly reduced As leaching amount. Determination coefficients for As and Fe leaching exhibited elevated values (control column, R2 = 0.955; AMDS column, R2 = 0.908; and SS column, R2 = 0.833). A discernible decline in the concentration of leached Fe was accompanied by a corresponding reduction in IP. The determination coefficients correlating IP and Fe leaching remained substantial (control column, R2 = 0.768; AMDS column, R2 = 0.807; and SS column, R2 = 0.818). Such IP measurements manifest as instrumental tools in monitoring and assessing the retention capacity of applied stabilizer/binding agents in As-affected soils, thereby furnishing crucial data for the enduring surveillance of stabilization/solidification locales. This research posits a swift and continuous monitoring method for solidification/stabilization locales in situ.
Asunto(s)
Arsénico , Restauración y Remediación Ambiental , Contaminantes del Suelo , Arsénico/análisis , Contaminantes del Suelo/análisis , Contaminación Ambiental , Suelo , Aguas del Alcantarillado , AceroRESUMEN
This study investigated the association between maximum standardized uptake values (SUVmax) on preoperative 18-FDG PET-CT and next-generation sequencing (NGS) results in post-surgical ovarian malignant tissue in patients with advanced ovarian cancer. Twenty-five patients with stage IIIC or IV ovarian cancer who underwent both preoperative 18-FDG PET-CT and postoperative NGS for ovarian malignancies were retrospectively enrolled. Two patients had no detected variants, 21 of the 23 patients with any somatic variant had at least one single nucleotide variant (SNV) or insertion/deletion (indel), 10 patients showed copy number variation (CNV), and two patients had a fusion variant. SUVmax differed according to the presence of SNVs/indels, with an SUVmax of 13.06 for patients with ≥ 1 SNV/indel and 6.28 for patients without (p = 0.003). Seventeen of 20 patients with Tier 2 variants had TP53 variants, and there was a statistically significant association between SUVmax and the presence of TP53 variants (13.21 vs. 9.35, p = 0.041). Analysis of the correlation between the sum of the Tier 1 and Tier 2 numbers and SUVmax showed a statistically significant correlation (p = 0.002; Pearson's r = 0.588). In conclusion, patients with advanced ovarian cancer with SNVs/indels on NGS, especially those with TP53 Tier 2 variants, showed a proportional association with tumor SUVmax on preoperative PET-CT.
RESUMEN
Renal fibrosis is a common feature of chronic kidney disease and is a promising therapeutic target. However, there is still limited treatment for renal fibrosis, so the development of new anti-fibrotic agents is urgently needed. Accumulating evidence suggest that oxidative stress and endoplasmic reticulum (ER) stress play a critical role in renal fibrosis. Carnosol (CS) is a bioactive diterpene compound present in rosemary plants and has potent antioxidant and anti-inflammatory properties. In this study, we investigated the potential effects of CS on renal injury and fibrosis in a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6J mice underwent sham or UUO surgery and received intraperitoneal injections of CS (50 mg/kg) daily for 8 consecutive days. CS improved renal function and ameliorated renal tubular injury and interstitial fibrosis in UUO mice. It suppressed oxidative injury by inhibiting pro-oxidant enzymes and activating antioxidant enzymes. Activation of ER stress was also attenuated by CS. In addition, CS inhibited apoptotic and necroptotic cell death in kidneys of UUO mice. Furthermore, cytokine production and immune cell infiltration were alleviated by CS. Taken together, these findings indicate that CS can attenuate renal injury and fibrosis in the UUO model.
RESUMEN
Vaccination with tumor peptide epitopes associated with MHC class I molecules is an attractive approach directed at inducing tumor-specific CTLs. However, challenges remain in improving the therapeutic efficacy of peptide epitope vaccines, including the low immunogenicity of peptide epitopes and insufficient stimulation of innate immune components in vivo. To overcome this, we aimed to develop and test an innovative strategy that elicits potent CTL responses against tumor epitopes. The essential feature of this strategy is vaccination using tumor epitope-loaded nanoparticles (NPs) in combination with polyinosinic-polycytidylic acid (poly-IC) and anti-PD1 mAb. Carboxylated NPs were prepared using poly(lactic-co-glycolic acid) and poly(ethylene/maleic anhydride), covalently conjugated with anti-H-2Kb mAbs, and then attached to H-2Kb molecules isolated from the tumor mass (H-2b). Native peptides associated with the H-2Kb molecules of H-2Kb-attached NPs were exchanged with tumor peptide epitopes. Tumor peptide epitope-loaded NPs efficiently induced tumor-specific CTLs when used to immunize tumor-bearing mice as well as normal mice. This activity of the NPs significantly was increased when co-administered with poly-IC. Accordingly, the NPs exerted significant anti-tumor effects in mice implanted with EG7-OVA thymoma or B16-F10 melanoma, and the anti-tumor activity of the NPs was significantly increased when applied in combination with poly-IC. The most potent anti-tumor activity was observed when the NPs were co-administered with both poly-IC and anti-PD1 mAb. Immunization with tumor epitope-loaded NPs in combination with poly-IC and anti-PD1 mAb in tumor-bearing mice can be a powerful means to induce tumor-specific CTLs with therapeutic anti-tumor activity.
RESUMEN
Streptococcus pyogenes (S. pyogenes) bacteria cause almost all primary skin infections in humans. Bee venom (BV) and melittin (Mel) have multiple effects, including antibacterial and anti-inflammatory activities. This study aims to demonstrate their effects on bacterial mouse skin infection using S. pyogenes. The dorsal skin was tape-stripped, then S. pyogenes was topically applied. BV or Mel were topically applied to the lesion. The tissues were stained with hematoxylin and eosin, while immunohistochemical staining was performed with anti-neutrophil. S. pyogenes-infected skin revealed increased epidermal and dermal layers, but it was reduced in the BV and Mel groups. Finding increased neutrophils in the mice infected with S. pyogenes, but the BV and Mel mice showed decreased expression. These results suggest that BV and Mel treatments could reduce the inflammatory reactions and help improve lesions induced by S. pyogenes skin infection. This study provides additional assessment of the potential therapeutic effects of BV and Mel in managing skin infection caused by S. pyogenes, further suggesting that it could be a candidate for developing novel treatment alternative for streptococcal skin infections.
Asunto(s)
Venenos de Abeja , Enfermedades Cutáneas Bacterianas , Humanos , Ratones , Animales , Meliteno/farmacología , Meliteno/uso terapéutico , Venenos de Abeja/farmacología , Venenos de Abeja/uso terapéutico , Streptococcus pyogenes , Eosina Amarillenta-(YS) , Hematoxilina , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Antibacterianos/uso terapéuticoRESUMEN
The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site-targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several diseases. We designed ring-type non-coding RNAs (ncRNAs), also called mTOR ODNs to suppress mammalian target rapamycin (mTOR) translation. mTOR signaling is associated with excessive cell proliferation and fibrogenesis. In this study, we examined the effects of mTOR suppression on chronic renal injury. To explore the regulation of fibrosis and inflammation in unilateral ureteral obstruction (UUO)-induced injury, we injected synthesized ODNs via the tail vein of mice. The expression of inflammatory-related markers (interleukin-1ß, tumor necrosis factor-α), and that of fibrosis (α-smooth muscle actin, fibronectin), was decreased by synthetic ODNs. Additionally, ODN administration inhibited the expression of autophagy-related markers, microtubule-associated protein light chain 3, Beclin1, and autophagy-related gene 5-12. We confirmed that ring-type ODNs inhibited fibrosis, inflammation, and autophagy in a UUO mouse model. These results suggest that mTOR may be involved in the regulation of autophagy and fibrosis and that regulating mTOR signaling may be a therapeutic strategy against chronic renal injury.
Asunto(s)
Insuficiencia Renal Crónica , Obstrucción Ureteral , Actinas/metabolismo , Animales , Autofagia/genética , Beclina-1/metabolismo , Modelos Animales de Enfermedad , Fibronectinas/metabolismo , Fibrosis , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Riñón/metabolismo , Mamíferos/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Oligonucleótidos/farmacología , ARN no Traducido/metabolismo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/genética , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/genética , Obstrucción Ureteral/metabolismoRESUMEN
Despite emerging evidence suggesting that autophagy occurs during renal interstitial fibrosis, the role of autophagy activation in fibrosis and the mechanism by which autophagy influences fibrosis remain controversial. Transcription factor EB (TFEB) is a master regulator of autophagy-related gene transcription, lysosomal biogenesis, and autophagosome formation. In this study, we examined the preventive effects of TFEB suppression on renal fibrosis. We injected synthesized TFEB decoy oligonucleotides (ODNs) into the tail veins of unilateral ureteral obstruction (UUO) mice to explore the regulation of autophagy in UUO-induced renal fibrosis. The expression of interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), and collagen was decreased by TFEB decoy ODN. Additionally, TEFB ODN administration inhibited the expression of microtubule-associated protein light chain 3 (LC3), Beclin1, and hypoxia-inducible factor-1α (HIF-1α). We confirmed that TFEB decoy ODN inhibited fibrosis and autophagy in a UUO mouse model. The TFEB decoy ODNs also showed anti-inflammatory effects. Collectively, these results suggest that TFEB may be involved in the regulation of autophagy and fibrosis and that regulating TFEB activity may be a promising therapeutic strategy against kidney diseases.
Asunto(s)
Insuficiencia Renal Crónica , Obstrucción Ureteral , Animales , Autofagia/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Riñón/metabolismo , Ratones , Oligonucleótidos/farmacología , Insuficiencia Renal Crónica/metabolismo , Obstrucción Ureteral/metabolismoRESUMEN
The use of cisplatin, a chemotherapy drug, is often limited due to its renal side effects such as acute kidney injury (AKI). However, there are no validated medications to prevent or treat cisplatin-induced AKI. Oridonin is the major bioactive component of Isodon rubescens (Rabdosia rubescens) and exhibits anticancer, antioxidative, and anti-inflammatory effects. Recent studies have shown that oridonin alleviated a variety of inflammatory diseases, including renal diseases, in rodents. This study was aimed at investigating the potential renoprotective effect of oridonin on cisplatin-induced AKI. Male C57BL/6 mice were administered with cisplatin (20 mg/kg) with or without oridonin (15 mg/kg). Oridonin administration to mice after cisplatin injection attenuated renal dysfunction and histopathological changes. Upregulation of tubular injury markers was also suppressed by oridonin. Mechanistically, oridonin suppressed lipid peroxidation and reversed the decreased ratio of reduced to oxidized glutathione in cisplatin-injected mice. The increase in cisplatin-induced apoptosis was also alleviated by the compound. Moreover, oridonin inhibited cytokine overproduction and attenuated immune cell infiltration in cisplatin-injected mice. Altogether, these data demonstrated that oridonin alleviates cisplatin-induced kidney injury via inhibiting oxidative stress, apoptosis, and inflammation.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Animales , Apoptosis , Cisplatino/farmacología , Diterpenos de Tipo Kaurano , Femenino , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés OxidativoRESUMEN
Acne vulgaris is the most common disease of the pilosebaceous unit. The pathogenesis of this disease is complex, involving increased sebum production and perifollicular inflammation. Understanding the factors that regulate sebum production is important in identifying novel therapeutic targets for the treatment of acne. Bee Venom (BV) and melittin have multiple effects including antibacterial, antiviral, and anti-inflammatory activities in various cell types. However, the anti-lipogenic mechanisms of BV and melittin have not been elucidated. We investigated the effects of BV and melittin in models of Insulin-like growth factor-1 (IGF-1) or Cutibacterium acnes (C. acnes)-induced lipogenic skin disease. C. acnes or IGF-1 increased the expression of sterol regulatory element-binding protein-1 (SREBP-1) and proliferator-activated receptor gamma (PPAR-γ), transcription factors that regulate numerous genes involved in lipid biosynthesis through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/SREBP signaling pathway. In this study using a C. acnes or IGF-1 stimulated lipogenic disease model, BV and melittin inhibited the increased expression of lipogenic and pro-inflammatory factor through the blockade of the Akt/mTOR/SREBP signaling pathway. This study suggests for the first time that BV and melittin could be developed as potential natural anti-acne agents with anti-lipogenesis, anti-inflammatory, and anti-C. acnes activity.
Asunto(s)
Acné Vulgar , Venenos de Abeja , Acné Vulgar/tratamiento farmacológico , Antiinflamatorios/farmacología , Venenos de Abeja/farmacología , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Meliteno/farmacología , Propionibacterium acnes , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Sirolimus/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The purpose of this study was to investigate whether the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) can be used as supplementary tools to differentiate between benign, borderline, and malignant ovarian tumors. The ratio of patients with benign to borderline to malignant tumors was planned as 3:1:2 considering the incidence of each disease. Consecutive patients were enrolled retrospectively. Preoperative complete blood counts with differentials were investigated, and calculated NLRs and PLRs were analyzed. A total of 630 patients with ovarian tumors were enrolled in this study. The final histopathological results revealed that 318 patients had benign, 108 patients had epithelial borderline, and 204 patients had epithelial malignant ovarian tumors. The NLR and PLR were significantly higher in malignant than in benign or borderline ovarian tumors, and they did not differ significantly between benign and borderline ovarian tumors. The diagnostic cut-off value of NLR for differentiating between benign or borderline and malignant tumors was 2.36, whereas that of PLR for differentiating between benign/borderline and malignancy was 150.02. High preoperative NLR and PLR indicate that the likelihood of epithelial ovarian cancer is higher than that of benign or borderline tumors.
RESUMEN
Renal fibrosis is a common process of various kidney diseases. Autophagy is an important cell biology process to maintain cellular homeostasis. In addition, autophagy is involved in the pathogenesis of various renal disease, including acute kidney injury, glomerular diseases, and renal fibrosis. However, the functional role of autophagy in renal fibrosis remains poorly unclear. The mammalian target of rapamycin (mTOR) plays a negative regulatory role in autophagy. Signal transducer and activator of transcription 3 (STAT3) is an important intracellular signaling that may regulate a variety of inflammatory responses. In addition, STAT3 regulates autophagy in various cell types. Thus, we synthesized the mTOR/STAT3 oligodeoxynucleotide (ODN) to regulate the autophagy. The aim of this study was to investigate the beneficial effect of mTOR/STAT3 ODN via the regulation of autophagy appearance on unilateral ureteral obstruction (UUO)-induced renal fibrosis. This study showed that UUO induced inflammation, tubular atrophy, and tubular interstitial fibrosis. However, mTOR/STAT3 ODN suppressed UUO-induced renal fibrosis and inflammation. The autophagy markers have no statistically significant relation, whereas mTOR/STAT3 ODN suppressed the apoptosis in tubular cells. These results suggest the possibility of mTOR/STAT3 ODN for preventing renal fibrosis. However, the role of mTOR/STAT3 ODN on autophagy regulation needs to be further investigated.
Asunto(s)
Autofagia/efectos de los fármacos , Fibrosis/prevención & control , Riñón/lesiones , Oligodesoxirribonucleótidos/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Modelos Animales de EnfermedadRESUMEN
We propose multimodal machine translation (MMT) approaches that exploit the correspondences between words and image regions. In contrast to existing work, our referential grounding method considers objects as the visual unit for grounding, rather than whole images or abstract image regions, and performs visual grounding in the source language, rather than at the decoding stage via attention. We explore two referential grounding approaches: (i) implicit grounding, where the model jointly learns how to ground the source language in the visual representation and to translate; and (ii) explicit grounding, where grounding is performed independent of the translation model, and is subsequently used to guide machine translation. We performed experiments on the Multi30K dataset for three language pairs: English-German, English-French and English-Czech. Our referential grounding models outperform existing MMT models according to automatic and human evaluation metrics.
RESUMEN
Follicular bronchiolitis is a rare pulmonary disorder characterized by the presence of multiple hyperplastic lymphoid follicles with a peribronchiolar distribution. An 11-year-old girl with total atelectasis of the right middle lobe (RML) and diffuse multiple small nodules at both lung bases presented to our hospital with frequent upper respiratory infections and pneumonia. The disease progressed during a 3-month period of macrolide therapy, and thoracoscopic biopsy with lobectomy of the atelectatic RML was performed. The histopathologic diagnosis was follicular bronchiolitis. The patient's pulmonary function improved dramatically after oral steroid treatment. It can be difficult to diagnose follicular bronchiolitis based solely on clinical, laboratory, and radiologic findings; the disorder must be confirmed histopathologically. A patient with longstanding irreversible atelectasis and resulting recurrent respiratory infection may require lobectomy for the diagnosis and treatment of follicular bronchiolitis.
RESUMEN
RATIONALE: Simultaneous occurrence of anti-glomerular basement membrane (anti-GBM) disease and thin basement membrane nephropathy (TBMN), both of which invade the type IV collagen subunits, is very rare. Here, we present the case of a 20-year-old male patient diagnosed with both anti-GBM disease and TBMN upon presenting dyspnea and hemoptysis. PATIENT CONCERNS: No laboratory abnormalities, except arterial hypoxemia (PaO275.4âmmHg) and microscopic hematuria, were present. Chest computed tomography revealed bilateral infiltrations in the lower lung fields; thus, administration of empirical antibiotics was initiated. Gross hemoptysis persisted nonetheless, and bronchoscopy revealed diffuse pulmonary hemorrhage with no endobronchial lesions. Broncho-alveolar lavage excluded bacterial pneumonia, tuberculosis, and fungal infection. DIAGNOSIS: Enzyme-linked immunosorbent assay of his serum was positive for anti-GBM antibody (95.1âU/mL). Human leukocyte antigen (HLA) test was positive for both HLA-DR15/-DR04. Other than diffuse thinning of the GBM (average thickness, 220ânm), index kidney biopsy did not demonstrate any specific abnormalities such as crescent formation. INTERVENTIONS: Methylprednisolone was administered intravenously for 7 consecutive days (500âmg/day), followed by the daily dose of oral prednisolone (80âmg). Cyclophosphamide was also orally administered every day for 3 months (250âmg/day). Following 6 sessions of plasmapheresis, the anti-GBM antibody in serum became negative. OUTCOMES: There was no clinical evidence suggesting recurrence of pulmonary hemorrhage or azotemia during hospitalization and 12-month follow-up period. Twelve months after hospital discharge, oral prednisolone was discontinued. LESSONS: The patients with concurrent anti-GBM disease and TBMN will have a favorable prognosis after proper therapy. However, further research is needed to elucidate the pathogenesis and long-term outcome of the comorbidity of these 2 diseases.
Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular/complicaciones , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/diagnóstico , Enfermedades Renales/complicaciones , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/terapia , Membrana Basal Glomerular/diagnóstico por imagen , Membrana Basal Glomerular/patología , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/terapia , Masculino , Adulto JovenRESUMEN
Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting. Here, we report that NSrp70 is selectively expressed in developing thymocytes, highest at the double-positive (DP) stage. Global splicing and transcriptional profiling revealed that NSrp70 regulates the cell cycle and survival of thymocytes by controlling the alternative processing of various RNA splicing factors, including the oncogenic splicing factor SRSF1. A conditional-knockout of Nsrp1 (NSrp70-cKO) using CD4Cre developed severe defects in T cell maturation to single-positive thymocytes, due to insufficient T cell receptor (TCR) signaling and uncontrolled cell growth and death. Mice displayed severe peripheral lymphopenia and could not optimally control tumor growth. This study establishes a model to address the function of lymphoid-lineage-specific alternative splicing factor NSrp70 in a thymic T cell developmental pathway.
Asunto(s)
Empalme Alternativo/genética , Carcinogénesis/metabolismo , Desarrollo Embrionario/genética , Hematopoyesis/genética , Melanoma/metabolismo , Timocitos/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Apoptosis/genética , Carcinogénesis/genética , Proliferación Celular/genética , Genómica , Células HEK293 , Humanos , Lectinas Tipo C/metabolismo , Linfopenia/genética , Linfopenia/metabolismo , Melanoma/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa , RNA-Seq , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Antígenos de Linfocitos T/metabolismo , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismo , Timo/embriología , Timo/metabolismoRESUMEN
Keloid and hypertrophic scars are skin fibrosis-associated disorders that exhibit an uncontrollable proliferation of fibroblasts and their subsequent contribution to the excessive accumulation of extracellular matrix (ECM) in the dermis. In this study, to elucidate the underlying mechanisms, we investigated the pivotal roles of epidermal growth factor (EGF) in modulating fibrotic phenotypes of keloid and hypertrophic dermal fibroblasts. Our initial findings revealed the molecular signatures of keloid dermal fibroblasts and showed the highest degree of skin fibrosis markers, ECM remodeling, anabolic collagen-cross-linking enzymes, such as lysyl oxidase (LOX) and four LOX-like family enzymes, migration ability, and cell-matrix traction force, at cell-matrix interfaces. Furthermore, we observed significant EGF-mediated downregulation of anabolic collagen-cross-linking enzymes, resulting in amelioration of fibrotic phenotypes and a decrease in cell motility measured according to the cell-matrix traction force. These findings offer insight into the important roles of EGF-mediated cell-matrix interactions at the cell-matrix interface, as well as ECM remodeling. Furthermore, the results suggest their contribution to the reduction of fibrotic phenotypes in keloid dermal fibroblasts, which could lead to the development of therapeutic modalities to prevent or reduce scar tissue formation.
Asunto(s)
Factor de Crecimiento Epidérmico/farmacología , Matriz Extracelular/efectos de los fármacos , Fibroblastos/patología , Queloide/patología , Adulto , Movimiento Celular , Células Cultivadas , Cicatriz Hipertrófica/patología , Módulo de Elasticidad , Enzimas/metabolismo , Matriz Extracelular/patología , Femenino , Fibrosis , Humanos , Hidrogeles/química , Masculino , Persona de Mediana Edad , Piel/patologíaRESUMEN
We report a rare case of metachronous lymphoma with two distinct cell lineages in a 75-year-old man. The patient complained about having nasal obstruction for 2 years and extranodal natural killer (NK)/T-cell lymphoma of the nasal type was diagnosed from a biopsy. The immunohistochemical staining for CD56 and in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNA (EBER-ISH) were positive and the tumor cells were negative for CD20. After 13 months of concurrent chemoradiotherapy, the patient presented with swelling of the left testis. Positron emission tomography scan detected an abnormal uptake in the testis. A diffuse large B-cell lymphoma, not otherwise specified, was diagnosed from subsequent radical orchiectomy. The immunohistochemical staining revealed to be positive for CD20, BCL2, BCL6, and MYC and negative for CD10 and EBER-ISH.
RESUMEN
Aortic dissection (AD) is a fatal disease characterized by a ruptured intima that leads to the complete rupture of the aorta. The aim of this study is to examine the immunohistochemical expression of inflammation/fibrosis-associated chemical mediators in AD patients. Surgical specimens of aortic tissues were obtained from 37 patients who underwent an open thoracic aortic repair. AD was detected with histological staining. Local congestion and hemorrhage as well as chronic inflammatory cells infiltrations were observed at the dissection. Moreover, extensive disarrangement and disruption of elastic fibers were observed in the medial layer of the aorta with dissection. In summary, our study revealed that the apoptotic rate of vascular SMCs (VSMCs) in the vascular middle layer is higher in the dissected aortas than in the control aortas, suggesting that abnormally elevated apoptosis is correlated with AD pathogenesis. Functional studies of key genes identified in the apoptotic pathways as well as in extracellular matrix would be critical in thoroughly understanding the underlying mechanisms of AD development. Targeting the mediators related to TGF-ß1, the Smad family proteins, and caspase 3 or anti-apoptotic agents may provide diagnostic markers and therapeutic targets that could be used to prevent AD.