RESUMO
Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. PAF (platelet-activating factor), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases such as bronchial asthma and COPD. We focused on LPLAT9 (lysophospholipid acyltransferase 9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophages (AMs). LPLAT9 was predominant and upregulated in AMs, particularly monocyte-derived AMs, in patients with COPD. To identify the function of LPLAT9/PAF in AMs in the pathogenesis of COPD, we exposed systemic LPLAT9-knockout (LPALT9-/-) mice to cigarette smoke (CS). CS increased the number of AMs, especially the monocyte-derived fraction, which secreted MMP12 (matrix metalloprotease 12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophages and, subsequently, PAF synthesis in the lung. The LPLAT9-/- mouse lung showed reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AMs by increasing MCP1 (monocyte chemoattractant protein-1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9-/- mice compared with LPLAT9+/+ mice. Notably, these phenotypes were again worsened by LPLAT9+/+ bone marrow transplantation in LPALT9-/- mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AMs aggravated pulmonary emphysema via PAF-induced further accumulation of AMs. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD.
Assuntos
1-Acilglicerofosfocolina O-Aciltransferase , Macrófagos Alveolares , Camundongos Knockout , Fator de Ativação de Plaquetas , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Animais , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Humanos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Enfisema Pulmonar/genética , Fator de Ativação de Plaquetas/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferase/genética , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 12 da Matriz/genética , Pulmão/metabolismo , Pulmão/patologia , Fumar Cigarros/efeitos adversos , Fumar Cigarros/metabolismo , FemininoRESUMO
BACKGROUND: A higher number of tumor buds in the invasive front of colorectal cancer (CRC) specimens has been shown to contribute to a poor prognosis in CRC patients. Because macrophages (Mφs) have been demonstrated to alter the phenotype of cancer cells, we hypothesized that the phenotype of CRC cells in the tumor budding (TB) area might be changed by the interaction between CRC cells and Mφs. METHODS: We assessed the expression of topoisomerase 1 in CRC cells to estimate the acquisition of chemoresistance in CRC. To demonstrate the tumor-stromal interaction between CRC cells and Mφs, we assessed two histological findings, the number of Mφs per single CRC cell and the proximity between CRC cells and Mφs by histological spatial analysis using HALO software. RESULTS: The expression levels of topoisomerase 1 in CRC cells were decreased in deeper areas, especially in the TB area, compared to the surface area. Our histological spatial analysis revealed that 2.6 Mφs located within 60 µm of a single CRC cell were required to alter the phenotype of the CRC cell. Double-immunofluorescence staining revealed that higher Mφs were positive for interleukin-6 (IL-6) in the TB area and that AE1/AE3-positive CRC cells were also positive for phospho-STAT3 (pSTAT3) in the TB area; thus, the IL-6 receptor (IL-6R)/STAT3 signaling pathway in CRC cells was upregulated by IL-6 derived from neighboring Mφs. CONCLUSION: IL-6 secreted from the neighboring Mφs would alter the phenotype of CRC cells via IL-6R/STAT3 signaling pathway.
RESUMO
BACKGROUND: Mucoid degeneration of the anterior cruciate ligament is a pathological condition that may impair knee mechanics and contribute to the symptomatology of osteoarthritis. This study aimed to evaluate whether preoperative magnetic resonance imaging can predict anterior cruciate ligament degeneration, specifically mucoid degeneration, and to elucidate the histopathological characteristics of mucoid degeneration in knee osteoarthritis patients. METHODS: We evaluated a total of 95 knees of osteoarthritis patients (23 males, 72 females; mean age: 72.7 ± 7.5) scheduled for total knee arthroplasty. The relationship between preoperative magnetic resonance imaging findings and the histopathological evidence of anterior cruciate ligament mucoid degeneration was examined. Immunohistochemical analysis was employed for collagen types (COL-I, COL-II), chondrogenesis (SOX9), and vascularity (CD31). RESULTS: High signal intensity on magnetic resonance imaging showed a positive correlation with Alcian Blue staining areas (rs = 0.59, p < 0.01) and the swelling index (rs = 0.62, p < 0.01), indicating advanced mucoid degeneration. The absence of synovial lining around the anterior cruciate ligament was associated with more severe degeneration. In the histological evaluations, advanced degeneration was characterized by an increase in chondroid metaplasia and collagen disorientation. The Alcian Blue and SOX9 correlation was positive (rs = 0.69, p < 0.01), but negative with COL-I (rs = -0.38, p = 0.03) and vascularity (CD31) (rs = -0.60, p < 0.01). CONCLUSIONS: Preoperative magnetic resonance imaging is an effective tool in assessing the severity of anterior cruciate ligament degeneration; it influences surgical decisions. High signal intensity on magnetic resonance images denotes advanced mucoid degeneration. The absence of synovial lining around the anterior cruciate ligament is associated with more severe degeneration and may accelerate degenerative changes. Chondroid metaplasia and collagen disorientation mark advanced degeneration. Magnetic resonance imaging can be used to gauge the degree of anterior cruciate ligament degeneration in osteoarthritis.
RESUMO
BACKGROUND: Carbon-ion radiotherapy(CIRT)has an advantage over conventional radiotherapy by its dose distribution and biological effect for locally advanced unresectable pancreatic cancer(UR-PC). Conversion surgery(CS)might be attempted for UR-PC with favorable response by chemotherapy and radiotherapy. CASE PRESENTATION: A 67-year-old female who have a history of distal gastrectomy. CT scan revealed locally advanced UR-PC with invasion to celiac artery, 60 mm in size. Systemic chemotherapy with gemcitabine and nab-paclitaxel was continued for 15 months, showing decrease of tumor markers and radiological shrinkage of the tumor. The patient was referred to our hospital for surgical consultation. Since there was no metastasis in staging laparoscopy, CIRT with gemcitabine was administered for 3 weeks. After completion of CIRT, distal pancreatectomy with celiac axis resection and total remnant gastrectomy for direct invasion of the tumor was performed as CS, resulting R0 resection. Her postoperative course was uneventful with 17 days of hospital stay. DISCUSSION: CS after CIRT was safely performed. Clinical trial of total neoadjuvant therapy with systemic chemotherapy, CIRT, followed by CS for locally advanced CIRT is ongoing in our hospital. CIRT could be an effective treatment in locally advanced UR-PC in the context of multi-modal treatment including CS.
Assuntos
Gencitabina , Neoplasias Pancreáticas , Humanos , Feminino , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pâncreas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Carbono/uso terapêuticoRESUMO
Background: Although mutations in telomerase reverse transcriptase (TERT) promoter (TERTp) are the most common alterations in glioblastoma (GBM), predicting TERTp mutation status by preoperative imaging is difficult. We determined whether tumour-surrounding hyperintense lesions on fluid-attenuated inversion recovery (FLAIR) were superior to those of contrast-enhanced lesions (CELs) in assessing TERTp mutation status using magnetic resonance imaging (MRI). Methods: This retrospective study included 114 consecutive patients with primary isocitrate dehydrogenase (IDH)-wild-type GBM. The apparent diffusion coefficient (ADC) and volume of CELs and FLAIR hyperintense lesions (FHLs) were determined, and the correlation between MRI features and TERTp mutation status was analyzed. In a subset of cases, FHLs were histopathologically analyzed to determine the correlation between tumor cell density and ADC. Results: TERTp mutations were present in 77 (67.5%) patients. The minimum ADC of FHLs was significantly lower in the TERTp-mutant group than in the TERTp-wild-type group (mean, 958.9 × 10-3 and 1092.1 × 10-3 mm2/s, respectively, P < 0.01). However, other MRI features, such as CEL and FHL volumes, minimum ADC of CELs, and FHL/CEL ratio, were not significantly different between the two groups. Histopathologic analysis indicated high tumor cell density in FHLs with low ADC. Conclusion: The ADC of FHLs was significantly lower in IDH-wild-type GBM with TERTp mutations, suggesting that determining the ADC of FHLs on preoperative MRI might be helpful in predicting TERTp mutation status and surgical planning.
RESUMO
Obg-like ATPase 1 (OLA1) is a binding protein of Breast cancer gene 1 (BRCA1), germline pathogenic variants of which cause hereditary breast cancer. Cancer-associated variants of BRCA1 and OLA1 are deficient in the regulation of centrosome number. Although OLA1 might function as a tumor suppressor, the relevance of OLA1 deficiency to carcinogenesis is unclear. Here, we generated Ola1 knockout mice. Aged female Ola1+/- mice developed lymphoproliferative diseases, including malignant lymphoma. The lymphoma tissues had low expression of Ola1 and an increase in the number of cells with centrosome amplification. Interestingly, the proportion of cells with centrosome amplification in normal spleen from Ola1+/- mice was higher in male mice than in female mice. In human cells, estrogen stimulation attenuated centrosome amplification induced by OLA1 knockdown. Previous reports indicate that prominent centrosome amplification causes cell death but does not promote tumorigenesis. Thus, in the current study, the mild centrosome amplification observed under estrogen stimulation in Ola1+/- female mice is likely more tumorigenic than the prominent centrosome amplification observed in Ola1+/- male mice. Our findings provide a possible sex-dependent mechanism of the tumor suppressor function of OLA1.