Osteoclast activity is enhanced in acidic environments following systemic or local inflammation. However, the regulatory mechanism of receptor activator of NF-κB ligand (RANKL) expression in ...osteoblasts under acidic conditions is not fully understood. In the present paper, we detected the mRNA expression of the G-protein-coupled receptor (GPR) proton sensors GPR4 and GPR65 (T-cell death-associated gene 8, TDAG8), in osteoblasts. RANKL expression and the cyclic AMP (cAMP) level in osteoblasts were up-regulated under acidic culture conditions. Acidosis-induced up-regulation of RANKL was abolished by the protein kinase A inhibitor H89. To clarify the role of GPR4 in RANKL expression, GPR4 gain and loss of function experiments were performed. Gene knockdown and forced expression of GPR4 caused reduction and induction of RANKL expression, respectively. These results suggested that, at least in part, RANKL expression by osteoblasts in an acidic environment was mediated by cAMP/PKA signaling resulting from GPR4 activation. A comprehensive microarray analysis of gene expression of osteoblasts revealed that, under acidic conditions, the phenotype of osteoblasts was that of an osteoclast supporting cell rather than that of a mineralizing cell. These findings will contribute to a molecular understanding of bone disruption in an acidic environment.
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•RANKL expression was increased in osteoblasts under acidosis via cAMP/PKA pathway.•GRP4 knockdown resulted in decrease of RANKL expression.•GRP4 overexpression resulted in increase of RANKL expression.•Osteoblast mineralization was reduced under acidic condition.
Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined ...chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma.
This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry.
The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1–positive groups than in TTF-1–negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1–positive groups than in TTF-1–negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1–positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02).
TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.
Immunotherapy using immune checkpoint inhibitors and CAR‐T cells has revolutionized treatment for patients with malignant tumors. However, measuring tumor cell cytotoxicity mediated by immune ...effector cells in clinical laboratories has been difficult due to the requirement for radioactive substances. In this study, a series of novel terpyridine derivative proligands were synthesized, and a non‐radioactive cellular cytotoxicity assay using the newly synthesized compounds was developed for use in preclinical and clinical studies for cancer immunotherapy. Once internalized into target cells, the compounds are hydrolyzed by esterases, resulting in the intracellular accumulation of the negatively charged terpyridine derivatives. When the labeled target cells are recognized and killed by immune effector cells, the integrity of the cell membrane is disrupted, and the terpyridine derivatives are released. Upon combining the culture supernatant with europium (Eu3+), the cytotoxicity of immune effector cells for the target cells can be quantitatively determined by measuring the intensity of the Eu3+/ligand‐derived time‐resolved fluorescence. Thus, the assay developed in this study would facilitate the development of novel cancer immunotherapies.
Gauging the effectors: Immune checkpoint inhibitors have revolutionized the treatment of cancer patients. Although many clinical trials have been conducted to develop novel immunotherapies, measuring cellular cytotoxicity has been difficult. In this study, a series of chelate‐forming proligands were synthesized to improve non‐radioactive cytotoxicity assays. This assay is ideal for measuring the effector functions of immune cells in clinical laboratories.
Skin-related adverse events (AEs) occur frequently in adult T-cell leukemia-lymphoma (ATL) patients treated with mogamulizumab, a humanized anti-CCR4 monoclonal antibody. This study was undertaken to ...elucidate the mechanisms of mogamulizumab-induced skin-related AEs. We analyzed the T-cell receptor β chain repertoire in ATL patients' peripheral blood mononuclear cells (PBMCs) before and after mogamulizumab. Skin-related AEs were present in 16 patients and were absent in 8 patients. Additionally, we included 11 patients before and after chemotherapy without mogamulizumab. Immune-related gene expression in PBMCs before and after mogamulizumab was also assessed (n = 24). Mogamulizumab treatment resulted in CCR4+ T-cell depletion, and the consequent lymphopenia provoked homeostatic CD8+ T-cell proliferation, as evidenced by increased expressions of CD8B and CD8A, which were significantly greater in patients with skin-related AEs than in those without them. We hypothesize that proliferation is driven by the engagement of self-antigens, including skin-related antigens, in the face of regulatory T-cell depletion. Together with the observed activated antigen presentation function, this resulted in T-cell diversification that was significantly greater in patients with skin-related AEs than in those without. We found that the CD8+ T cells that proliferated and diversified after mogamulizumab treatment were almost entirely newly emerged clones. There was an inverse relationship between the degree of CCR4+ T-cell depletion and increased CD8+ T-cell proliferation and diversification. Thus, lymphocyte-depleting mogamulizumab treatment provokes homeostatic CD8+ T-cell proliferation predominantly of newly emerging clones, some of which could have important roles in the pathogenesis of mogamulizumab-induced skin-related AEs.
•Mogamulizumab treatment provokes homeostatic CD8+ T-cell proliferation, along with diversification, of PBMCs in ATL patients.
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The thyroid gland is resistant to microbial infection, because of its organ characteristics such as encapsulation, iodine content, and rich blood supply. Therefore, acute suppurative thyroiditis ...(AST), as a bacterial infection of the thyroid gland, is rarely seen. AST typically takes places on the left side the neck region in children, because of the coincidence of the left piriform sinus fistula, as a most common route of infection. AST is also usually seen in immunocompromised hosts. Herein, we report a rare case of AST in the right thyroid lobe of adult woman without any immunocompromised condition.
A 59-year-old woman was introduced to our hospital for the further examination with fever, sore throat, and right anterior neck swelling. The patient appeared not to be immunodeficient. Neck ultrasonography showed a 47-mm, hypoechoic, heterogeneous nodule with ill-defined margins and irregular form, suggesting a right thyroid malignant nodule. Fine needle aspiration (FNA) biopsy specimen revealed numerous number of neutrophils in the background without nuclear atypia. Based on the clinical course and cytology, AST was confirmed to be diagnosed. Complete response was obtained by an intravenous administration of antimicrobial agents within a week. Image findings such as CT scan did not show any piriform sinus fistula. Four months later, neck ultrasonography showed a significant decrease in size of the nodule in the right thyroid gland to 27 mm, but the lesion still resembled a malignant nodule. So, FNA was repeated again and cytological examination confirmed papillary thyroid carcinoma (PTC). The patient subsequently underwent total thyroidectomy and bilateral level D1 lymph node dissection. Histological findings revealed a 20-mm PTC in the right lobe with sternothyroid muscle invasion of the tumor.
This report represents a rare case of AST associated with PTC on the right side of thyroid gland, found in a healthy adult woman. The reason why AST coincided with malignant thyroid tumor is unclear. We have to take it into our account that malignant tumor may exist in the background when AST is identified on the right side of thyroid gland with a healthy subject.
The plant chondriome confers a complex nature. The atp4 gene (formerly called orf25) of Aegilops crassa (CR) harbors the promoter sequence of the rps7 gene from common wheat (Triticum aestivum cv. ...Chinese Spring, CS). The rps7 gene of CR has the promoter sequence of CS atp6. The atp6 gene of CR contains an unknown sequence inside of its coding region. Since repeat sequences have been found around the breaking points, these structural alterations are most likely generated through homologous recombination. In this study, PCR analysis was performed to detect structural alterations in each of three lines: euplasmic lines of Ae. crassa, Chinese Spring, and alloplasmic Chinese Spring wheat with the cytoplasm of Ae. crassa ((cr)-CS). We found that each of these lines contained both genotypes, although mitochondrial genotypes of CR in Chinese Spring wheat and CS genotypes in Ae. crassa were still retained as minor fractions (less than 10%). On the other hand, CS mitochondrial gene frequencies in ((cr)-CS) were shown to be ca. 30%. SNP analysis after DNA sequencing of these genes indicated that minor types of all three mitochondrial genes in alloplasmic wheat contained the mitochondrial gene types from pollens. Since the frequencies of paternal mitochondrial gene types in F1 were about 20%, successive backcrossing increased the frequencies of paternal mitochondrial gene types to around 30% in alloplasmic wheat. Expression profiles of these mitochondrial genes were quantitatively analyzed by RT-PCR. Transcripts of paternal mitochondrial gene types were scarcely found. This suggests that minor fractions including paternal mitochondrial gene types are maintained and silenced in the descendants.
Extracellular vesicles (EVs) including exosomes act as intercellular communicators by transferring protein and microRNA cargoes, yet the role of EV lipids remains unclear. Here, we show that the ...pro-tumorigenic action of lymphoma-derived EVs is augmented via secreted phospholipase A
(sPLA
)-driven lipid metabolism. Hydrolysis of EV phospholipids by group X sPLA
, which was induced in macrophages of Epstein-Barr virus (EBV) lymphoma, increased the production of fatty acids, lysophospholipids, and their metabolites. sPLA
-treated EVs were smaller and self-aggregated, showed better uptake, and increased cytokine expression and lipid mediator signaling in tumor-associated macrophages. Pharmacological inhibition of endogenous sPLA
suppressed lymphoma growth in EBV-infected humanized mice, while treatment with sPLA
-modified EVs reversed this phenotype. Furthermore, sPLA
expression in human large B cell lymphomas inversely correlated with patient survival. Overall, the sPLA
-mediated EV modification promotes tumor development, highlighting a non-canonical mechanistic action of EVs as an extracellular hydrolytic platform of sPLA
.
The goal of palliative care is to support the ideal life of cancer patients and their partners, but the medical staff does not listen to all the needs of cancer patients and their partners. Cancer ...patients choose opponents and situations and express their suffering. Additionally, the typical problem of hidden suffering is not the issues of sexuality ? The suffering from sexuality of cancer patients is not expected to be expressed unless there is a suitable opponent. Are we the medical staff ready to respond to the suffering from sexuality of terminal cancer patients ? In this study, we thought that it was necessary to investigate the preparation of medical staff for the suffering from sexuality of terminal cancer patients, through a relationship with the hospitalized inpatient who reported suffering from sexuality.
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