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Fibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies that target fibrosis remain limited3. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.
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Linfócitos T CD8-Positivos , Fibrose Endomiocárdica/terapia , Imunoterapia Adotiva , Animais , Antígenos de Superfície/imunologia , Linfócitos T CD8-Positivos/imunologia , Fibrose Endomiocárdica/imunologia , Fibroblastos/imunologia , Humanos , Masculino , Camundongos , Ovalbumina/imunologia , CicatrizaçãoRESUMO
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Spermatid production is a complex regulatory process in which coordination between hormonal control and apoptosis plays a pivotal role in maintaining a balanced number of sperm cells. Apoptosis in spermatogenesis is controlled by pro-apoptotic and anti-apoptotic molecules. Hormones involved in the apoptotic process during spermatogenesis include gonadotrophins, sex hormones, and glucocorticoid (GC). GC acts broadly as an apoptosis inducer by binding to its receptor (glucocorticoid receptor: GR) during organ development processes, such as spermatogenesis. However, the downstream pathway induced in GC-GR signaling and the apoptotic process during spermatogenesis remains poorly understood. We reported previously that GC induces full-length glucocorticoid-induced transcript 1 (GLCCI1-long), which functions as an anti-apoptotic mediator in thymic T cell development. Here, we demonstrate that mature murine testis expresses a novel isoform of GLCCI1 protein (GLCCI1-short) in addition to GLCCI1-long. We demonstrate that GLCCI1-long is expressed in spermatocytes along with GR. In contrast, GLCCI1-short is primarily expressed in spermatids where GR is absent; instead, the estrogen receptor is expressed. GLCCI1-short also binds to LC8, which is a known mediator of the anti-apoptotic effect of GLCCI1-long. A luciferase reporter assay revealed that ß-estradiol treatment synergistically increased Glcci1-short promotor-driven luciferase activity in Erα-overexpressing cells. Together with the evidence that the conversion of testosterone to estrogen is preceded by aromatase expression in spermatids, we hypothesize that estrogen induces GLCCI1-short, which, in turn, may function as a novel anti-apoptotic mediator in mature murine testis.
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Glucocorticoides , Sêmen , Masculino , Camundongos , Animais , Espermatogênese , Espermátides , EstrogêniosRESUMO
BACKGROUND: Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. METHODS: We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. RESULTS: Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. CONCLUSIONS: FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.
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Adenocarcinoma de Pulmão , Progressão da Doença , Endopeptidases , Neoplasias Pulmonares , Proteínas de Membrana , Humanos , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Proteínas de Membrana/metabolismo , Idoso , Gelatinases/metabolismo , Serina Endopeptidases/metabolismo , Serina Endopeptidases/genética , Actinas/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Biomarcadores Tumorais/metabolismo , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Estadiamento de Neoplasias , Adenocarcinoma in Situ/patologia , Adenocarcinoma in Situ/metabolismo , AdultoRESUMO
PURPOSE: Single lung transplantation (SLT) is a viable option for patients with end-stage pulmonary parenchymal and vascular diseases. However, various diseases can occur in native lungs after SLT. METHODS: Between January 2000 and December 2021, 35 patients underwent cadaveric SLT and survived for more than 30 days in our hospital. Among these 35 patients, 10 required surgery for diseases that developed in their native lungs. The clinical characteristics of these 10 patients and the outcomes of native lung surgery (NLS) were investigated. RESULTS: Among these ten patients, the indications for lung transplantation were chronic obstructive pulmonary disease and idiopathic interstitial pneumonia in three patients each, and lymphangioleiomyomatosis and collagen vascular disease-related interstitial pneumoniain two patients each. The causes of NLS included pneumothorax (n = 4), primary lung cancer (n = 2), native lung hyperinflation (n = 2), and pulmonary aspergilloma (n = 2). The surgical procedures were pneumonectomy (n = 7), lobectomy (n = 2), and alveolar-pleural fistula repair (n = 1). Only one postoperative complication, empyema, was treated with antibiotics. The 5-year overall survival rates after transplantation with and without NLS were 70.0% and 80.0%, respectively, and did not differ to a statistically extent (p = 0.56). CONCLUSION: NLS is an effective treatment option for diseases that develop in the native lungs after SLT.
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PURPOSE: The hemiclamshell (HCS) approach provides a comprehensive view of the anterior mediastinum, whereas the transmanubrial osteomuscular sparing approach (TMA) allows sufficient exposure of the cervico-thoracic transition. We assessed the effectiveness and the outcomes of the combined HCS plus TMA approach to resect thoracic malignant tumors. METHODS: We reviewed five patients with thoracic malignant tumors invading the thoracic outlet who underwent surgery using an HCS and TMA approach between 2018 and 2021. RESULTS: The preoperative diagnosis was myxofibrosarcoma, lung cancer, thymic cancer, thymoma, and neurofibromatosis type1 in one patient each, respectively. Cardiovascular reconstruction was done on the aortic arch in two patients, on the descending aorta in one, and on the superior vena cava in one, combined with resection of the vagus nerve in three patients, of the phrenic nerve in two, and of vertebra in one, with overlap in some cases. The TMA was added because all patients required dissection of the periphery of the subclavian artery, and two had tumor extension to the neck. Macroscopic complete resection was achieved in four patients. There was no postoperative mortality. CONCLUSION: The combination of the HCS and TMA approaches at the same operation provides a comprehensive view of the mediastinum, lung, and cervico-thoracic transition and allows safe access to the thoracic great vessels and subclavian vessels.
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BACKGROUND: The cause of podocyte injury in idiopathic nephrotic syndrome (INS) remains unknown. Although recent evidence points to the role of B cells and autoimmunity, the lack of animal models mediated by autoimmunity limits further research. We aimed to establish a mouse model mimicking human INS by immunizing mice with Crb2, a transmembrane protein expressed at the podocyte foot process. METHODS: C3H/HeN mice were immunized with the recombinant extracellular domain of mouse Crb2. Serum anti-Crb2 antibody, urine protein-to-creatinine ratio, and kidney histology were studied. For signaling studies, a Crb2-expressing mouse podocyte line was incubated with anti-Crb2 antibody. RESULTS: Serum anti-Crb2 autoantibodies and significant proteinuria were detected 4 weeks after the first immunization. The proteinuria reached nephrotic range at 9-13 weeks and persisted up to 29 weeks. Initial kidney histology resembled minimal change disease in humans, and immunofluorescence staining showed delicate punctate IgG staining in the glomerulus, which colocalized with Crb2 at the podocyte foot process. A subset of mice developed features resembling FSGS after 18 weeks. In glomeruli of immunized mice and in Crb2-expressing podocytes incubated with anti-Crb2 antibody, phosphorylation of ezrin, which connects Crb2 to the cytoskeleton, increased, accompanied by altered Crb2 localization and actin distribution. CONCLUSION: The results highlight the causative role of anti-Crb2 autoantibody in podocyte injury in mice. Crb2 immunization could be a useful model to study the immunologic pathogenesis of human INS, and may support the role of autoimmunity against podocyte proteins in INS.
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Nefrose Lipoide , Síndrome Nefrótica , Podócitos , Camundongos , Humanos , Animais , Podócitos/metabolismo , Síndrome Nefrótica/metabolismo , Nefrose Lipoide/patologia , Camundongos Endogâmicos C3H , Proteinúria/metabolismo , Modelos Animais de Doenças , Imunização , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismoRESUMO
PURPOSES: Some predictive markers of death have been reported for patients on the waiting list for lung transplantation (LTx). We assessed whether or not the preoperative psoas muscle index (PMI) correlates with waitlist mortality. METHODS: In 81 patients with end-stage lung disease on the waiting list for LTx between 2011 and 2020 at Osaka University Hospital, we examined the association between baseline characteristics, including the diagnosis, respiratory function test results, blood collection items, steroid use, and psoas muscle mass on computed tomography, and survival during the waiting period using Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS: Thirty-three patients (41%) died during follow-up. Univariate and multivariate analyses showed that patients with a low PMI had a higher rate of death during follow-up than those with a high PMI (p < 0.0001 and 0.0002, respectively). In addition, a diagnosis of interstitial pneumonia (hazard ratio 3.30, 95% confidence interval 1.52-7.17, p = 0.0025) and low albumin level (hazard ratio 2.21, 95% confidence interval 1.02-4.80, p = 0.0449) were also significant predictors of survival. CONCLUSION: A low PMI at registration is associated with a decreased survival time among LTx candidates and it may be a predictive factor of mortality in patients waiting for LTx.
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Our department has been performing uniportal thoracoscopic lobectomy since April 2019 and now also performs segmentectomy for small malignant tumors. A skin incision of approximately 4 cm is created between the anterior fifth intercostal space on the left and right sides. Based on our experience, uniportal segmentectomy does not follow the learning curve unique to segmentectomy. For dissection of segmental surface, an automatic suture is used to prevent pulmonary fistulas. If the cutting line between the segments is straight, dissection can be performed easily even in uniportal surgery, in which the automatic suturing device is inserted from one direction. For inter-area identification, we use an air-containing collapsed line with normal ventilation, after which thoracoscopic indocyanine green( ICG) imaging is introduced. However, there have been cases in which a difference in inter-area identification occurred between ICG identification and the air-containing collapsed line. As such, it is better to utilize both methods in cases with masses close to the inter-areas.
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Neoplasias Pulmonares , Cirurgia Torácica Vídeoassistida , Humanos , Pneumonectomia/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Verde de IndocianinaRESUMO
Podocyte damage is a major pathological lesion leading to focal segmental glomerulosclerosis (FSGS). Podocytes damaged by cellular stress undergo hypertrophy to compensate for podocytopenia. It is known that cyclin-dependent kinase inhibitors induced by p53 ensure podocytes hypertrophy; however, its precise mechanism remains to be further investigated. In this study, we found that ubiquitin specific protease 40 (USP40) is a novel regulator of p53. Although USP40 knockout mice established in the present study revealed no abnormal kidney phenotype, intermediate filament Nestin was upregulated in the glomeruli, and was bound to and colocalized with USP40. We also found that USP40 deubiquitinated histidine triad nucleotide-binding protein 1 (HINT1), an inducer of p53. Gene knockdown experiments of USP40 in cultured podocytes revealed the reduction of HINT1 and p53 protein expression. Finally, in glomerular podocytes of mouse FSGS, upregulation of HINT1 occurred in advance of the proteinuria, which was followed by upregulation of USP40, p53 and Nestin. In conclusion, USP40 bound to Nestin deubiquitinates HINT1, and in consequence upregulates p53. These results provide additional insight into the pathological mechanism of podocyte hypertrophy in FSGS.
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Glomerulosclerose Segmentar e Focal , Proteínas do Tecido Nervoso , Nestina , Podócitos , Proteína Supressora de Tumor p53 , Proteases Específicas de Ubiquitina , Animais , Enzimas Desubiquitinantes/genética , Enzimas Desubiquitinantes/metabolismo , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Hipertrofia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nestina/genética , Nestina/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Podócitos/fisiologia , Proteína Quinase C/antagonistas & inibidores , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo , Ubiquitinação , Regulação para CimaRESUMO
BACKGROUND AND AIM: Chronic enteropathy associated with the solute carrier organic anion transporter family member 2A1 (SLCO2A1), or CEAS, causes anemia and hypoalbuminemia in young people. Dysfunction of the SLCO2A1 transporter protein is thought to involve genetic mutation, but mutant proteins have not been functionally characterized. We examined the prostaglandin E2 (PGE2 ) transport ability of recombinant SLCO2A1 proteins containing 11 SLCO2A1 mutations found in CEAS patients. METHODS: Wild-type and mutant SLCO2A1 proteins were forcibly expressed in Xenopus laevis oocytes, and measurements of PGE2 uptake and transport capacity were compared. The membrane protein topology and functionality of the eight SLCO2A1 mutations involving single-nucleotide substitutions were predicted using computer analysis. RESULTS: The extent of functional disruption of the 11 SLCO2A1 mutations identified in CEAS patients was variable, with 10 mutations (421GT, 547GA, 664GA, 770GA, 830dupT, 830delT, 940 + 1GA, 1372GT, 1647GT, and 1807CT) resulting in loss or reduction of PGE2 transport, excluding 97GC. CONCLUSION: PGE2 transport ability of recombinant SLCO2A1 in X. laevis oocytes was hindered in 10/11 SLCO2A1 mutations identified in patients with CEAS. Further studies on the relationships between the different mutations and PGE2 transport and clinical features, such as severity, are needed.
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Doenças Inflamatórias Intestinais , Transportadores de Ânions Orgânicos , Dinoprostona/genética , Dinoprostona/metabolismo , Humanos , Mutação , Transportadores de Ânions Orgânicos/genéticaRESUMO
PURPOSE: We evaluated the impact of omitting mediastinal lymph node dissection (MLND) from the surgical treatment of non-small cell lung cancer (NSCLC) in older patients. METHODS: We collected data retrospectively on 2475 patients who underwent pulmonary resection for NSCLC at our hospital between June, 2006 and December 2018. The subjects of this analysis were 209 patients aged ≥ 75 years who underwent lobectomy for cN0-1 NSCLC. The patients were divided into two groups based on whether they underwent MLND (ND2 group) or not (group ND0-1). RESULTS: There were more patients aged ≥ 80 years in the ND0-1 group than in the ND2 group (p < 0.001). Patients in the ND0-1 group had clinically earlier stage lung cancers than those in the ND2 group (p = 0.053). We matched patient characteristics in the ND0-1 and ND2 groups by age, tumor diameter, cN, histology, and radiological findings. There were no significant differences in overall survival between the groups (p = 0.295). More patients in the ND2 group suffered complications (41.6% vs. 27.3%, p = 0.061) and arrhythmia episodes than those in the ND0-1 group (14.3% vs. 3.9%, p = 0.021). CONCLUSION: MLND in older patients may not extend survival but it could lead to complications. Thus, the omission of MLND may be considered for patients of advanced age.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Excisão de Linfonodo/efeitos adversos , Linfonodos/patologia , Mediastino/cirurgia , Estadiamento de Neoplasias , Pneumonectomia/efeitos adversos , Estudos RetrospectivosRESUMO
PURPOSE: The optimal extent of lymph node dissection (LND) during segmentectomy is unclear. During segmentectomy, it is more challenging to dissect the non-adjacent interlobar lymph node (non-aiLN) away from the primary tumor than to dissect the adjacent interlobar lymph node (aiLN), as injury to the preserved parenchyma and bronchus may occur. We examined whether dissection of non-aiLNs was required during intentional segmentectomy. METHODS: This retrospective cohort study included 310 patients who underwent lobectomy and mediastinal LND for non-small cell lung cancer of ≤ 2 cm at the Osaka International Cancer Institute during January 2006 to December 2015. We investigated LN metastasis distribution and evaluated metastases in non-aiLNs distant from the primary lesion. RESULTS: Six (1.9%) patients had iLN metastasis. Patients with iLN metastasis did not have primary lesions in the right upper lobe or left upper segment. Of the six patients with iLN metastasis, three had non-aiLN metastasis with a tumor diameter of ≥ 15 mm, with high positron emission tomography standard uptake values (> 3.5). Two patients had multiple LN metastases, and one had solitary LN metastasis. CONCLUSION: Non-aiLN dissection may be unnecessary during segmentectomy of the right upper lobe or left upper segment; however, it should be considered during lower-lobe segmentectomy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Metástase Linfática/patologia , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Estadiamento de Neoplasias , Linfonodos/patologia , Excisão de Linfonodo/métodos , Doença Crônica , PneumonectomiaRESUMO
BACKGROUND: Allergic rhinitis (AR) is caused by allergic reaction to allergens such as pollen. Galanin (GAL), a neuropeptide that regulates inflammatory processes, is widely expressed in the central and peripheral nervous systems. Although neuropeptides are implicated in arthritis and chemically induced ileitis, their roles in AR remain unclear. METHODS: We developed a murine model of AR and generated control, systemic sensitization, mild AR, and severe AR groups. We examined GAL and GAL receptor (GALR) mRNA and protein levels and localization patterns in each group using reverse transcription PCR, western blotting, and immunohistochemical analyses. Additionally, we evaluated the effects of M871, a GALR2 antagonist, on mice with severe AR. RESULTS: Gal and Galr2 are expressed in nasal mucosa and brain (control) samples from control and AR mice. GAL and GALR2 were expressed at similar levels and localized to ciliated epithelial and submucosal gland cells of the nasal mucosa in all four groups. Intranasal M871 administration significantly reduced the incidence of nose rubbing behaviors and sneezing (p < 0.001 in 30 min, respectively) in severe AR mice relative to that in controls. Mechanistically, we postulate that GALR2 is expressed in B cells, and M871 administration reduces IgE production, as well as the number of B cells in tissues. CONCLUSIONS: GAL signaling may not change progressively with increasing nasal sensitization, suggesting that this signaling process exacerbates, rather than directly trigger, AR. GAL-GALR2 signaling likely mediates AR development, suggesting that its inhibition represents a novel therapeutic strategy for AR.
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Galanina/metabolismo , Receptor Tipo 2 de Galanina/metabolismo , Rinite Alérgica/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Galanina/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , RNA Mensageiro/metabolismo , Receptor Tipo 2 de Galanina/genética , Rinite Alérgica/genética , Transdução de SinaisRESUMO
BACKGROUND & AIMS: Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. METHODS: We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). RESULTS: HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. CONCLUSIONS: We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Proteínas Fetais , Humanos , Cirrose Hepática , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , alfa-FetoproteínasRESUMO
The stability of a zirconium (Zr)-substituted face-centered cubic (FCC) yttrium (Y) hydride (Y1-xZrx hydride) phase was investigated experimentally and theoretically. Two possible sites for hydrogen atoms exist in the FCC structure, namely, T- and O-sites, where hydrogen is present at the center of the tetrahedron and the octahedron composed of Y and/or Zr metals. The P-C isotherms revealed that the hydrogen content per metal (H/M) with 33% Zr-substituted YH3-δ was 2.2-2.3, which was lower than the expected value calculated from the starting composition of YH3-33% ZrH2 (Y0.67Zr0.33H2.67, H/M = 2.67). Hydrogen at the O-site in Y1-xZrx hydride mainly reacted during hydrogen desorption/absorption. On the basis of theoretical analyses, the hydrogen atoms do not occupy the center of the octahedron, when at least two of the six vertices of the octahedron were composed of Zr. The O-sites, where more than two Zr atoms coordinate, nonlinearly increased with the Zr content, and when the Zr content was >50%, almost no hydrogen atoms occupy the O-sites. The theoretical discussion supported the experimental results, and the Zr substitution was confirmed to reduce the occupancy of H at the O-site in the FCC YH3 significantly.
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The adhesion between the visceral and parietal pleura makes video-assisted thoracoscopic surgery (VATS) difficult or impossible. When performing VATS without conversion to thoracotomy due to pleural adhesion, it is important to( â °) evaluate the presence and extent of the adhesion preoperatively, (â ±) carefully perform detachment, and( â ²) adequately repair the injured visceral pleura. We evaluate visceral sliding with the help of chest ultrasonography and plan the best approach to make utility inci-sions, camera port, and third-port incisions. Considering the difficulty in repairing the injured visceral pleura under VATS, we perform extra-pleural detachment of adhesions around the injured visceral pleura, which can facilitate the repair of the pleural injury. For repairing pleural injury, we use free mediastinal fat tissue as biological pledgets to support suturing. In this report, we present the approaches and techniques we follow to perform VATS for patients with pleural adhesion.
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Doenças Pleurais , Cirurgia Torácica Vídeoassistida , Humanos , Pleura/diagnóstico por imagem , Pleura/cirurgia , Doenças Pleurais/diagnóstico por imagem , Doenças Pleurais/cirurgia , Toracotomia , Aderências Teciduais/cirurgiaRESUMO
BACKGROUND: The optimal sequential therapy for castration-resistant prostate cancer (CRPC) remains unknown. In recent years, some doubts have emerged regarding the clinical benefit of sequential therapy with androgen receptor axis-targeted agents (ART) such as abiraterone (ABI) or enzalutamide (ENZ) for patients with CRPC. We compared the effect of ART-to-ART (AA) sequential therapy after castration resistance with that of docetaxel (DTX)-combined sequential therapy (ART to DTX or DTX to ART) in patients with CRPC. METHODS: We retrospectively identified and analyzed the data of 315 patients with CRPC treated in our seven affiliated institutions between 2009 and 2019. All patients received either DTX or ART (ABI or ENZ) as the first- or second-line therapy after castration resistance. We compared the overall survival (OS) and the second progression-free survival (PFS2), calculated from the initiation of first-line therapy after castration resistance, between the AA sequence group and the DTX-combined sequence group. PFS2 was defined as the period from the start of first-line treatment after castration resistance to progression on second-line treatment. To minimize selection bias from possible confounders, we performed propensity score matching using one-to-one nearest neighbor matching without replacement. RESULTS: Overall, 106 and 209 patients were administered the AA sequential therapy and DTX-combined sequential therapy, respectively. The clinicopathological variables of patients were well balanced after propensity score matching, and there were no significant differences between the two groups. In the propensity score-matched cohort, OS was not significantly different between the two groups (median, 37.9 vs. 45.4 months; hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.68-1.79; p = .701), while PFS2 was significantly shorter in the AA group than in the DTX-combined group (median, 12.9 vs. 21.6 months; HR, 1.70; 95% CI, 1.16-2.48; p = .007). CONCLUSIONS: Certain patients with CRPC can benefit from ART-to-ART sequential therapy in a daily clinical setting.
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Antagonistas de Receptores de Andrógenos/uso terapêutico , Androstenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Progressão da Doença , Quimioterapia Combinada , Humanos , Masculino , Nitrilas , Feniltioidantoína/uso terapêutico , Intervalo Livre de Progressão , Pontuação de Propensão , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: AminoIndex™ Cancer Screening (AICS (lung)) was developed as a screening test for lung cancer using a multivariate analysis of plasma-free amino acid (PFAA) profiles. According to the developed index composed of PFAA, the probability of lung cancer was categorized into AICS (lung) ranks A, B, and C in order of increasing risk. The aim of the present study was to investigate the relationship between the preoperative AICS (lung) rank and surgical outcomes in patients who underwent curative resection for non-small cell lung cancer (NSCLC). METHODS: Preoperative blood samples were collected from 297 patients who underwent curative resection for NSCLC between 2006 and 2015. PFAA concentrations were measured. The relationship between the preoperative AICS (lung) rank and clinicopathological factors was examined. The effects of the preoperative AICS (lung) rank on postoperative outcomes were also analyzed. RESULTS: The AICS (lung) rank was A in 93 patients (31.3%), B in 82 (27.6%), and C in 122 (41.1%). The AICS (lung) rank did not correlate with any clinicopathological factors, except for age. Based on follow-up data (median follow-up period of 6 years), postoperative recurrence was observed in 22 rank A patients (23.7%), 15 rank B (18.3%) and 49 rank C (40.2%). In the univariate analysis, preoperative AICS (lung) rank C was a worse factor of recurrence-free survival (p = 0.0002). The multivariate analysis identified preoperative AICS (lung) rank C (HR: 2.17, p = 0.0005) as a significant predictor of postoperative recurrence, particularly in patients with early-stage disease or adenocarcinoma. CONCLUSION: Preoperative AICS (lung) rank C is a high-risk predictor of postoperative recurrence in patients undergoing curative resection for NSCLC.
Assuntos
Aminoácidos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Detecção Precoce de Câncer/métodos , Recidiva Local de Neoplasia/diagnóstico , Pneumonectomia/mortalidade , Complicações Pós-Operatórias/diagnóstico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/epidemiologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/epidemiologia , Cuidados Pré-Operatórios , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Glucocorticoids (GCs) potently induce T-cell apoptosis in a GC receptor (GR)-dependent manner and are used to control lymphocyte function in clinical practice. However, its downstream pathways remain controversial. Here, we showed that GC-induced transcript 1 (GLCCI1) is a novel downstream molecule of the GC-GR cascade that acts as an antiapoptotic mediator in thymic T cells. GLCCI1 was highly phosphorylated and colocalized with microtubules in GLCCI1-transfected human embryonic kidney QBI293A cells. GR-dependent up-regulation of GLCCI1 was associated with GC-induced proapoptotic events in a cultured thymocyte cell line. However, GLCCI1 knockdown in a thymocyte cell line led to apoptosis. Consistently, transgenic mice overexpressing human GLCCI1 displayed enlarged thymi that consisted of larger numbers of thymocytes. Further molecular characterization showed that GLCCI1 bound to both dynein light chain LC8-type 1 (LC8) and its functional kinase, p21-protein activated kinase 1 (PAK1), thereby inhibiting the kinase activity of PAK1 toward LC8 phosphorylation, a crucial event in apoptotic signaling. GLCCI1 induction facilitated LC8 dimer formation and reduced Bim expression. Thus, GLCCI1 is a candidate factor involved in apoptosis regulation of thymic T cells.-Kiuchi, Z., Nishibori, Y., Kutsuna, S., Kotani, M., Hada, I., Kimura, T., Fukutomi, T., Fukuhara, D., Ito-Nitta, N., Kudo, A., Takata, T., Ishigaki, Y., Tomosugi, N., Tanaka, H., Matsushima, S., Ogasawara, S., Hirayama, Y., Takematsu, H., Yan, K. GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells.