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1.
Biol Pharm Bull ; 45(4): 429-437, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370267

RESUMO

Cancer immunotherapies are powerful therapeutic options for cancer patients. To enhance the therapeutic effects of cancer immunotherapies, we plan to develop novel immunostimulatory drugs for use in combination with cancer immunotherapy. In the present study, we focused on tetracyclines, the effects of which are controversial for immunotherapy. We examined the effects of tetracyclines on human T cells in the peripheral blood of healthy donors and the tumor tissues of non-small cell lung cancer (NSCLC) patients. By using bispecific T-cell engager technology to assess the cytotoxicity of peripheral T cells against tumor cells, we showed that tetracyclines (minocycline, tetracycline, doxycycline, meclocycline, chlortetracycline, and demeclocycline) enhanced T-cell cytotoxicity through granzyme B expression and CD4+ and CD8+ T-cell proliferation. In analyses of the peripheral blood mononuclear cells (PBMCs) and lung tumor-infiltrated cells of NSCLC patients, we found that demeclocycline enhanced T-cell cytotoxicity not only in PBMCs, but also in lung tumor tissues. These results support the further application of tetracyclines to combination cancer immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Leucócitos Mononucleares , Neoplasias Pulmonares/tratamento farmacológico , Minociclina , Linfócitos T
2.
Sci Rep ; 12(1): 5377, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35354899

RESUMO

Regulatory T cells (Tregs) suppress the host immune response and maintain immune homeostasis. Tregs also promote cancer progression and are involved in resistance to immune checkpoint inhibitor treatments. Recent studies identified selective CCR8 expression on tumor-infiltrating Tregs; CCR8+ Tregs have been indicated as a possible new target of cancer immunotherapy. Here, we investigated the features of CCR8+ Tregs in lung cancer patients. CCR8+ Tregs were highly activated and infiltration of CCR8+ Tregs in tumors was associated with poor prognosis in lung cancer patients. We also investigated their immune suppressive function, especially the influence on cytotoxic T lymphocyte cell function. The Cancer Genome Atlas analysis revealed that CD8 T cell activities were suppressed in high CCR8-expressing tumors. Additionally, depletion of CCR8+ cells enhanced CD8 T cell function in an ex vivo culture of lung tumor-infiltrating cells. Moreover, CCR8+ Tregs, but not CCR8- Tregs, induced from human PBMCs markedly suppressed CD8 T cell cytotoxicity. Finally, we demonstrated the therapeutic effect of targeting CCR8 in a murine model of lung cancer. These findings reveal the significance of CCR8+ Tregs for immunosuppression in lung cancer, especially via cytotoxic T lymphocyte cell suppression, and suggest the potential value of CCR8-targeted therapy for cancer treatment.


Assuntos
Neoplasias Pulmonares , Linfócitos T Reguladores , Animais , Humanos , Tolerância Imunológica , Imunoterapia , Neoplasias Pulmonares/patologia , Camundongos , Receptores CCR8/metabolismo , Linfócitos T Citotóxicos
3.
Cancer Med ; 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35343095

RESUMO

Postoperative recurrence of colorectal cancer (CRC) eventually leads to therapeutic failure; therefore, treatment strategies based on accurate prediction of recurrence are urgently required. To identify biomarkers that can predict treatment outcomes, we compared the mutational profiles of surgically resected specimens from patients with recurrent cancer with those from patients with non-recurrent cancer. Target sequencing, whole-exome sequencing (WES), or whole-genome sequencing (WGS) was performed on 89 and 58 tumors from recurrent and non-recurrent cases, respectively. WGS revealed the driver mutations that were not detected with target sequencing or WES, including the structural variations affecting ZFP36L2. Loss of function of ZFP36L2 was frequently observed in primary tumors from recurrent cases. Furthermore, the recurrence-free survival of patients with loss of function of ZFP36L2 was significantly shorter relative to patients with no loss of ZFP36L2 function. In summary, the study demonstrated that detailed genomic analysis could help improve precision medicine for CRC.

4.
Gastroenterology ; 162(3): 799-812, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34687740

RESUMO

BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Genes MHC Classe I/genética , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Microglobulina beta-2/genética , Alelos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Metilação de DNA , Epigênese Genética , Expressão Gênica , Antígenos HLA-A/genética , Antígenos HLA-A/metabolismo , Humanos , Imunogenética , Linfócitos do Interstício Tumoral , Instabilidade de Microssatélites , Complexo de Endopeptidases do Proteassoma/genética , Fatores de Transcrição de Fator Regulador X/genética , Taxa de Sobrevida , Microglobulina beta-2/metabolismo
5.
J Clin Neurosci ; 94: 244-249, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34863446

RESUMO

The prevalence of chronic subdural hematoma (CSDH) associated with dural metastasis is uncertain, and appropriate treatment strategies have not been established. This study aimed to investigate the characteristics of and appropriate treatment strategies for CSDH associated with dural metastasis. We retrospectively reviewed the charts of 214 patients who underwent surgery for CSDH. The patients were divided into the dural metastasis group (DMG; n = 5, 2.3%) and no dural metastasis group (No-DMG; n = 209, 97.3%). Patient characteristics, treatment, and outcomes were compared between the two groups. Active cancer was detected in 31 out of 214 patients, 5 of whom (16.1%) had dural metastasis. In-hospital death (80.0% vs. 0%; p < 0.001) and recurrence within 14 days (80.0% vs. 2.9%; p < 0.001) and 60 days (80.0% vs. 13.9%; p = 0.002) were significantly prevalent in the DMG. All patients in the DMG developed subdural hematoma re-accumulation requiring emergent surgery because of brain herniation, and patients in the DMG had significantly worse recurrence-free survival (p < 0.001). This relationship remained significant (p < 0.001) even when the analysis was limited to the active cancer cohort (n = 31). CSDH associated with dural metastasis leads to early recurrence and death because of the difficulty in controlling subdural hematoma re-accumulation by common drainage procedures. Depending on the primary cancer status, withdrawal of active treatment and change to palliative care should be discussed after diagnosing CSDH associated with dural metastasis.


Assuntos
Hematoma Subdural Crônico , Neoplasias , Estudos de Coortes , Hematoma Subdural Crônico/diagnóstico por imagem , Hematoma Subdural Crônico/etiologia , Hematoma Subdural Crônico/cirurgia , Mortalidade Hospitalar , Humanos , Recidiva , Estudos Retrospectivos
6.
Artigo em Inglês | MEDLINE | ID: mdl-34574371

RESUMO

Reports on the expenditure of cancer treatments per patient using comprehensive data remain unavailable in Japan. This study aimed to use Japan's cancer registry data and health service utilization data for evaluating the disease-specific, per-patient costs of five major cancers-stomach, lung, colorectal, liver, and breast cancers. We used a database linking the 2017 data from a hospital-based cancer registry and the health service utilization data from the Diagnosis Procedure Combination survey. All patients who started their first treatment course at each hospital were included. The costs were calculated using the total volume of the health services provided and the unit fee information included in the data. We analyzed 304,698 patients. Lung cancer had the highest healthcare cost per-patient for the first year of diagnosis and the longest median hospitalization duration. Conversely, breast cancer showed the lowest cost and the shortest median hospitalization duration. However, in the first month after diagnosis, colorectal cancer showed the highest cost. Subsequently, the gaps between the costs of the five common cancers drastically diminished. The cancer type having the longest hospitalization duration had the highest overall healthcare resource utilization costs. This information is essential for care planning and research studies.


Assuntos
Neoplasias da Mama , Custos de Cuidados de Saúde , Feminino , Gastos em Saúde , Hospitalização , Humanos , Japão/epidemiologia , Estudos Retrospectivos
8.
Surg Neurol Int ; 12: 347, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345487

RESUMO

BACKGROUND: The treatment of internal carotid artery (ICA) - posterior communicating artery aneurysms (ICPC aneurysms) is challenging when a fetal posterior cerebral artery (PCA) arises from the saccular neck. This complex angioarchitecture renders endovascular approaches difficult. Giant thrombosed IC-PC aneurysms are also hard to treat by endovascular coiling because its flow-diversion effect is insufficient. CASE DESCRIPTION: We report the first case of a ruptured giant thrombosed IC-PC aneurysm associated with a fetal PCA that was successfully treated by coil embolization with retrograde overlap horizontal stenting using low-profile stents introduced through the contralateral ICA. The aneurysm was completely occluded and follow-up MRI scans demonstrated the reduction of the aneurysmal size. CONCLUSION: Our technique is advantageous because low-profile stents can be used to treat lesions not accessible with flow-diverter stents due their presence in complex angioarchitectures, and overlap stenting may have flow-diversion effects that can result in the complete occlusion of giant thrombosed aneurysms.

9.
Plant Cell Physiol ; 62(9): 1460-1477, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34184745

RESUMO

Aluminum (Al)-tolerant tobacco cell line ALT301 derived from SL (wild-type) hardly exhibits Al-triggered reactive oxygen species (ROS) compared with SL. Molecular mechanism leading to this phenotype was investigated comparatively with SL. Under normal growth condition, metabolome data suggested the activation of glycolysis and lactate fermentation but the repression of the tricarboxylic acid (TCA) cycle in ALT301, namely aerobic fermentation, which seemed to be transcriptionally controlled partly by higher expression of genes encoding lactate dehydrogenase and pyruvate dehydrogenase kinase. Microarray and gene ontology analyses revealed the upregulation of the gene encoding related to APETALA2.3 (RAP2.3)-like protein, one of the group VII ethylene response factors (ERFVIIs), in ALT301. ERFVII transcription factors are known to be key regulators for hypoxia response that promotes substrate-level ATP production by glycolysis and fermentation. ERFVIIs are degraded under normoxia by the N-end rule pathway of proteolysis depending on both oxygen and nitric oxide (NO), and NO is produced mainly by nitrate reductase (NR) in plants. In ALT301, levels of the NR gene expression (NIA2), NR activity and NO production were all lower compared with SL. Consistently, the known effects of NO on respiratory pathways were also repressed in ALT301. Under Al-treatment condition, NO level increased in both lines but was lower in ALT301. These results suggest that the upregulation of the RAP2.3-like gene and the downregulation of the NIA2 gene and resultant NO depletion in ALT301 coordinately enhance aerobic fermentation, which seems to be related to a higher capacity to prevent ROS production in mitochondria under Al stress.


Assuntos
Alumínio/farmacologia , Fermentação , Tabaco/fisiologia , Tolerância a Medicamentos , Fermentação/efeitos dos fármacos , Fermentação/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tabaco/genética
10.
Microb Cell Fact ; 20(1): 54, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653319

RESUMO

BACKGROUND: Linalool, an acyclic monoterpene alcohol, is extensively used in the flavor and fragrance industries and exists as two enantiomers, (S)- and (R)-linalool, which have different odors and biological properties. Linalool extraction from natural plant tissues suffers from low product yield. Although linalool can also be chemically synthesized, its enantioselective production is difficult. Microbial production of terpenes has recently emerged as a novel, environmental-friendly alternative. Stereoselective production can also be achieved using this approach via enzymatic reactions. We previously succeeded in producing enantiopure (S)-linalool using a metabolically engineered Pantoea ananatis, a member of the Enterobacteriaceae family of bacteria, via the heterologous mevalonate pathway with the highest linalool titer ever reported from engineered microbes. RESULTS: Here, we genetically modified a previously developed P. ananatis strain expressing the (S)-linalool synthase (AaLINS) from Actinidia arguta to further improve (S)-linalool production. AaLINS was mostly expressed as an insoluble form in P. ananatis; its soluble expression level was increased by N-terminal fusion of a halophilic ß-lactamase from Chromohalobacter sp. 560 with hexahistidine. Furthermore, in combination with elevation of the precursor supply via the mevalonate pathway, the (S)-linalool titer was increased approximately 1.4-fold (4.7 ± 0.3 g/L) in comparison with the original strain (3.4 ± 0.2 g/L) in test-tube cultivation with an aqueous-organic biphasic fermentation system using isopropyl myristate as the organic solvent for in situ extraction of cytotoxic and semi-volatile (S)-linalool. The most productive strain, IP04S/pBLAAaLINS-ispA*, produced 10.9 g/L of (S)-linalool in "dual-phase" fed-batch fermentation, which was divided into a growth-phase and a subsequent production-phase. Thus far, this is the highest reported titer in the production of not only linalool but also all monoterpenes using microbes. CONCLUSIONS: This study demonstrates the potential of our metabolically engineered P. ananatis strain as a platform for economically feasible (S)-linalool production and provides insights into the stereoselective production of terpenes with high efficiency. This system is an environmentally friendly and economically valuable (S)-linalool production alternative. Mass production of enantiopure (S)-linalool can also lead to accurate assessment of its biological properties by providing an enantiopure substrate for study.


Assuntos
Monoterpenos Acíclicos/metabolismo , Fermentação , Engenharia Metabólica , Pantoea/metabolismo , Actinidia/enzimologia , Monoterpenos Acíclicos/química , Hidroliases/metabolismo , Conformação Molecular , Estereoisomerismo
11.
Yonago Acta Med ; 64(1): 46-56, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33642903

RESUMO

BACKGROUND: The purpose of this study was to elucidate the factors which affect the achievement of clinical nursing competency. METHODS: A survey was conducted on 717 nurses using an anonymous self-administered questionnaire. Their clinical nursing competency was assessed using the Clinical Nursing Competence Self-Assessment Scale (CNCSS). This study examined the factors affecting clinical nursing competency using regression analyses. A simple regression analysis was performed with the CNCSS as the objective variable. A multiple regression analysis was performed using the items for which the relationship was clarified as explanatory variables. RESULTS: The factors affecting the "basic nursing competency" were age, ease of taking time off, workplace with a clear vision, and good interpersonal relationships. The factors affecting the "competency in providing assistance commensurate with the patient's health status" were total years of experience, workplace with a clear vision, ease of taking time off, and use of acquired certifications. The factors affecting the "coordinating care environment and teamwork" were total years of experience, workplace with a clear vision, use of acquired certifications, and ease of taking time off. The factors affecting the "ability for professional growth in nursing practice" were use of acquired certifications, workplace with a clear vision, total years of experience, and ease of taking time off. CONCLUSION: For improvement of clinical nursing competency, the factors elucidated to be necessary were accumulation of experience as a nurse, a clear vision of goals, and a work environment with good interpersonal relationships and ease of getting days off. The way nurses make their nursing practice experience meaningful contributed toward their growth as nurses. It is important to train nurses through basic education and continued education with awareness of achievement and improvement of clinical nursing competency. Basic education should promote the ability to make clinical training experience meaningful and continuing education should enable nurses to continue to grow independently through reflection.

12.
NMC Case Rep J ; 8(1): 295-300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35079478

RESUMO

Intravenous indocyanine green (ICG) videoangiography is reportedly useful for vascular neurosurgery, and for treating hemangioblastoma due to its high vascularity. Videoangiography obtained after intra-arterial ICG injection has emerged as a more useful option than that after intravenous injection. This report offers the first description of a case of hemangioblastoma successfully treated using intra-arterial ICG videoangiography, and describes the efficacy of this technique. A 20-year-old man presented with progressive cerebellar ataxia and dysphagia. Magnetic resonance imaging (MRI) revealed an enhanced solid tumor in the medulla oblongata. Digital subtraction angiography (DSA) showed a highly vascularized tumor. Surgery was performed to remove the tumor in a hybrid operating room. A catheter was introduced into the vertebral artery (VA) for intra-arterial ICG videoangiography. Superficial feeders and drainers were identified and flow dynamic changes in the tumor were assessed by intra-arterial ICG videoangiography. The tumor was removed after confirming lack of flow in the drainer. Intra-arterial ICG videoangiography was more useful than intravenous ICG videoangiography in hemangioblastoma surgery for identifying feeders and drainers and assessing flow dynamics in the tumor. Use of Flow 800 made these findings simpler and easier to evaluate.

13.
Endocrinology ; 161(11)2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32987399

RESUMO

We previously reported that daily administration of a pharmacological dose of eldecalcitol, an analog of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], increased bone mass by suppressing bone resorption. These antiresorptive effects were found to be mediated by the vitamin D receptor (VDR) in osteoblast-lineage cells. Using osteoblast-lineage-specific VDR conditional knockout (Ob-VDR-cKO) mice, we examined whether proresorptive activity induced by the high-dose 1α,25(OH)2D3 was also mediated by VDR in osteoblast-lineage cells. Administration of 1α,25(OH)2D3 (5 µg/kg body weight/day) to wild-type mice for 4 days increased the number of osteoclasts in bone and serum concentrations of C-terminal crosslinked telopeptide of type I collagen (CTX-I, a bone resorption marker). The stimulation of bone resorption was concomitant with the increase in serum calcium (Ca) and fibroblast growth factor 23 (FGF23) levels, and decrease in body weight. This suggests that a toxic dose of 1α,25(OH)2D3 can induce bone resorption and hypercalcemia. In contrast, pretreatment of wild-type mice with neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody inhibited the 1α,25(OH)2D3-induced increase of osteoclast numbers in bone, and increase of CTX-I, Ca, and FGF23 levels in serum. The pretreatment with anti-RANKL antibody also inhibited the 1α,25(OH)2D3-induced decrease in body weight. Consistent with observations in mice conditioned with anti-RANKL antibody, the high-dose administration of 1α,25(OH)2D3 to Ob-VDR-cKO mice failed to significantly increase bone osteoclast numbers, serum CTX-I, Ca, or FGF23 levels, and failed to reduce the body weight. Taken together, this study demonstrated that the proresorptive, hypercalcemic, and toxic actions of high-dose 1α,25(OH)2D3 are mediated by VDR in osteoblast-lineage cells.


Assuntos
Reabsorção Óssea/genética , Linhagem da Célula/genética , Osteoblastos/metabolismo , Receptores de Calcitriol/fisiologia , Vitamina D/análogos & derivados , Animais , Reabsorção Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Feminino , Hipercalcemia/genética , Hipercalcemia/metabolismo , Hipercalcemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Osteoblastos/citologia , Receptores de Calcitriol/genética , Vitamina D/farmacologia
14.
Brain Sci ; 10(9)2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32942724

RESUMO

The diagnosis and treatment of functional movement disorders are challenging for clinicians who manage patients with movement disorders. The borderline between functional and organic dystonia is often ambiguous. Patients with functional dystonia are poor responders to pallidal deep brain stimulation (DBS) and are not good candidates for DBS surgery. Thus, if patients with medically refractory dystonia have functional features, they are usually left untreated with DBS surgery. In order to investigate the outcome of functional dystonia in response to pallidal DBS surgery, we retrospectively included five patients with this condition. Their dystonia was diagnosed as organic by dystonia specialists and also as functional according to the Fahn and Williams criteria or the Gupta and Lang Proposed Revisions. Microelectrode recordings in the globus pallidus internus of all patients showed a cell-firing pattern of bursting with interburst intervals, which is considered typical of organic dystonia. Although their clinical course after DBS surgery was incongruent to organic dystonia, the outcome was good. Our results question the possibility to clearly differentiate functional dystonia from organic dystonia. We hypothesized that functional dystonia can coexist with organic dystonia, and that medically intractable dystonia with combined functional and organic features can be successfully treated by DBS surgery.

16.
Sci Rep ; 10(1): 4064, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132638

RESUMO

Indications for current immune checkpoint inhibitors are expanding and now include thymic epithelial tumors (TETs). Although clinical trials on immune checkpoint inhibitors for TETs are ongoing, a rationale has not yet been established for immunotherapy for TETs. Therefore, we herein performed phenotypic and functional analyses of T cells in surgically resected TET tissues with a focus on the anti-tumor properties of T cells to TETs as a step towards establishing a rationale for immunotherapy for TETs. We examined T-cell profiles in surgically resected TET tissues, particularly CD4 and CD8 single-positive T cells, using flow cytometry. In the functional analysis of T cells in TETs, we investigated not only cytokine production by T cells, but also their cytotoxicity using bispecific T-cell engager technology. The cluster analysis of T-cell profiles based on flow cytometric data revealed that type B3 thymoma and thymic carcinoma (B3/C) belonged to the hot cluster characterized by a high proportion of Tim-3+ and CD103+ in CD4 and CD8 single-positive T cells. Enhancements in cytokine production and the cytotoxicity of T cells by the anti-PD-1 antibody were significantly greater in B3/C. These results indicate the potential of immunotherapy for patients with B3/C.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Celular , Imunoterapia , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias do Timo/imunologia , Neoplasias do Timo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias do Timo/patologia
17.
Biol Pharm Bull ; 43(3): 399-403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115500

RESUMO

Immune checkpoint inhibitors (ICIs) exert beneficial effects in non-small cell lung cancer (NSCLC) patients. However, ICIs are only advantageous for a limited population of NSCLC patients. Therefore to enhance their effects, combination therapies with ICIs have been developed. To identify preferable chemotherapy to combine with ICIs against lung cancer, we examined immunological effects of docetaxel compared with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We found no difference in peripheral lymphocyte counts and ratio of their subpopulations in lung cancer patients before and after both treatments. On the other hand, plasma levels of high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, showed significant increase after docetaxel treatment. Furthermore, we investigated effects of HMGB1 on tumor-infiltrating immune cells obtained from surgically resected tumor tissue from NSCLC patients. When the tumor infiltrating cells were stimulated with HMGB1, CD11c+ cells showed increased expression of activation markers. These findings imply that docetaxel could be involved in anti-tumor immunity via HMGB1. Therefore docetaxel might be a candidate for combination treatment with ICIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/farmacologia , Fator de Crescimento Epidérmico/antagonistas & inibidores , Receptores ErbB/antagonistas & inibidores , Proteína HMGB1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Antineoplásicos , Antígenos CD11/metabolismo , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Terapia Combinada , Citocinas/metabolismo , Feminino , Proteína HMGB1/sangue , Humanos , Cadeias alfa de Integrinas/metabolismo , Masculino , Mutação , Proteínas Tirosina Quinases/antagonistas & inibidores , Ativação Transcricional/efeitos dos fármacos
18.
Int Immunol ; 32(6): 397-405, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32009163

RESUMO

Persistent exposure to tumor antigens results in exhausted tumor-infiltrating T cells (TILs) that express the immune checkpoint molecules, PD-1 and Tim3, and lack anti-tumor immunity. To examine the exhausted status of TILs in ovarian cancer, the potential for cytokine production, proliferation and cytotoxicity by purified PD-1+ Tim3+ CD8 TILs was assessed. The production of IFN-γ and TNF-α by PD-1+ Tim3+ CD8 TILs remained the same in an intracellular cytokine staining assay and was higher in a cytokine catch assay than that by PD-1- Tim3- and PD-1+ Tim3- CD8 TILs. %Ki67+ was higher in PD-1+ Tim3+ CD8 TILs than in PD-1- Tim3- CD8 TILs. However, patients with high PD-1+ Tim3+ CD8 TILs had a poor prognosis. The potential for cytotoxicity was then examined. %Perforin+ and %granzyme B+ were lower in PD-1+ Tim3+ CD8 TILs than in PD-1- Tim3- and PD-1+ Tim3- CD8 TILs. To observe the potential for direct cytotoxicity by T cells, a target cell line expressing membrane-bound anti-CD3scFv was newly established and a cytotoxic assay targeting these cells was performed. The cytotoxicity of PD-1+ Tim3+ CD8 TILs was significantly lower than that of PD-1- Tim3- and PD-1+ Tim3- CD8 TILs. Even though PD-1+ Tim3+ CD8 TILs in ovarian cancer showed a sustained potential for cytokine production and proliferation, cytotoxicity was markedly impaired, which may contribute to the poor prognosis of patients with ovarian cancer. Among the impaired functions of exhausted TILs, cytotoxicity may be an essential target for cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Interferon gama/biossíntese , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/imunologia , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Feminino , Receptor Celular 2 do Vírus da Hepatite A/deficiência , Humanos , Imunoterapia , Interferon gama/imunologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Receptor de Morte Celular Programada 1/deficiência
19.
J Affect Disord ; 265: 453-459, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32090772

RESUMO

BACKGROUND: In the treatment of depression, improvements in both clinical symptoms and social adaptation are important. Previous studies have shown that cognitive distortion and depressive symptoms are mutually related, and that depressive symptoms and social adaptation are related to each other. However, it is unknown how these three factors interrelate. Therefore, this study examined the relationship between cognitive distortion, depressive symptoms, and social adaptation. METHODS: The final analyzed sample consisted of 430 employees of a manufacturing company in Japan (74.2% male, 24.7% female, 1.2% unknown). Participants completed the Worker's Cognitive Distortion Scale (WCDS), Beck Depression Inventory-Second Edition (BDI-II), and Social Adaptation Self-Evaluation Scale (SASS). The WCDS was further divided into two subscales: self-contained cognitive distortion (WCDS-S) and environment-dependent cognitive distortion (WCDS-E). We used a covariance structure analysis for the main analysis and examined the relationship between these three variables' scores. RESULTS: The results revealed that both the WCDS-S and WCDS-E affected social adaptation indirectly via depressive symptoms, and that the WCDS-S additionally affected social adaptation directly. It was further revealed that the WCDS-S exerted a greater effect on depressive symptoms than the WCDS-E. LIMITATIONS: The participants were healthy cases. As such, one must be cautious about applying the results of healthy cases to clinical cases. CONCLUSIONS: This study indicates that cognitive distortion affects social adaptation directly and that it is indirectly mediated by depressive symptoms. Thus, professionals are required to attempt to treat depressive symptoms and improve social adaptation by considering that interventions in cognitive distortion may be effective.


Assuntos
Depressão , Ajustamento Social , Cognição , Depressão/epidemiologia , Feminino , Humanos , Japão , Masculino , Escalas de Graduação Psiquiátrica
20.
Int Immunol ; 32(5): 347-357, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31950169

RESUMO

OBJECTIVE: CD4+CD8+ T cells are expressed in some cancer patients including those with renal cell carcinoma (RCC). However, no reports have mentioned the clinical importance of this expression. We evaluated the expression of CD4+CD8+ T cells in patients with various cancer types to clarify clinical characteristics and prognostic importance significantly correlating with these T cells. METHODS: Expression of CD4+CD8+ T cells was evaluated using flowcytometry in tissue-infiltrating lymphocytes extracted from 260 cancer tissues including 104 RCC samples. RNA sequencing and characterization and regression (Citrus) was used to determine characteristics. The prognostic importance of CD4+CD8+ T cells was evaluated by Cox regression analysis. RESULTS: Among eight cancer types, expression of CD4+CD8+ T cells was significantly highest in RCC patients. According to the expression of CD4+CD8+ T cells in adjacent normal tissue-infiltrating lymphocytes, 24 patients (23.1%) were defined as being positive for CD4+CD8+ with an expression higher than 9.29% in RCC patients. Citrus showed CD8+PD-1+TIM-3+CD103- T cells to be a specific subpopulation of CD4+CD8+ T cells. RNA sequencing revealed that CD4+CD8+ T cells had significantly lower diversity than the other T cells and shared most T-cell receptor clones with CD8+ not CD4+ T cells. Expression of CD4+CD8+ T cells was identified as an independent predictor of overall survival (hazard ratio: 0.11, 95% confidence interval: 0.01-0.86, P = 0.035) in multivariate analysis. CONCLUSIONS: The expression of CD4+CD8+ T cells was significantly up-regulated in RCC patients and correlated significantly with prognostic importance in surgically treated RCC patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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