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Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4+ T cells and triads are required for CD8+ T cell cytotoxicity during the effector phase and tumor elimination.
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Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Humanos , Linfócitos T CD8-Positivos/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Camundongos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos C57BL , Imunoterapia Adotiva/métodos , Células Dendríticas/imunologia , Linhagem Celular Tumoral , Microambiente Tumoral/imunologiaRESUMO
Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By integrating this dataset with the Cancer Genome Atlas MPM RNA-seq data, we selected 29 prognostic genes displaying high variability across different tumors but low ITH, which named PRACME (Prognostic Risk Associated Clonal Mesothelioma Expression). We evaluated PRACME in two independent MPM datasets and demonstrated its prognostic values. Patients with high signature scores are associated with poor prognosis after adjusting established clinical factors. Interestingly, the PRACME and the ORACLE signatures defined respectively from MPM and lung adenocarcinoma cross-predict prognosis between the two cancer types. Further investigation indicated that the cross-prediction ability might be explained by the high similarity between the two cancer types in their genomic regions with copy number variation, which host many clonal genes. Overall, our clonal signature PRACME provided prognostic stratification in MPM and this study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.
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This study presents a novel nondestructive analysis method for precise characterization of corroded copper oxidation using optical coherence microscopy (OCM). By exploiting the partial light transmission through metallic oxide layers, we employed a specialized OCM system with a wavelength of 1700nm and enhanced the analysis accuracy compared to conventional optical coherence tomography (OCT). The developed OCM system featured a numerical aperture (NA) of 0.15, providing improved surface profiling and higher lateral resolution than OCT. we developed a peak-finding algorithm to accurately determine the thickness of the copper oxide layer from the acquired interference data with zero padding. Our method was validated by comparing the measured thickness profiles with those obtained from scanning electron microscope (SEM) images of corroded metals. The copper oxidation specimens were prepared after heat treatment for 1, 2, 4, and 8â h in an alumina tube furnace at a temperature of 900 °C to find the correlation between the OCM thickness measurement. Additionally, the acquired enface 3D images enabled the identification of local corrosion distribution within a 4 mm × 4 mm area. The en-face mapping images are utilized to analyze the uniformity of the metal oxidation process across the imaging area of the copper oxidation specimens. With an increase in heat treatment time, the median value of the thickness histogram for the copper oxide within the area consistently remained around 10â µm. However, the thickness variation ranged from -2â µm to 5â µm. This indicates that as the heat treatment time progresses, the thickness of the copper oxide becomes more non-uniform. Our technique holds great potential for nondestructive and noncontact detection of metal corrosion and assessment of corrosion rates in various industrial applications. Future research efforts could focus on expanding the application of OCM to different metals and exploring its commercialization prospects for practical implementation in diverse industries.
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Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.
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Adenocarcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Proteômica , Herpesvirus Humano 4 , Genômica , Adenocarcinoma/genética , Adenocarcinoma/terapia , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapiaRESUMO
PURPOSE: We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551). PATIENTS AND METHODS: The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses. RESULTS: Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells. CONCLUSIONS: These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Antígeno B7-H1 , Antígeno CTLA-4 , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Terapia Neoadjuvante , Neoplasias Pleurais/patologia , Microambiente TumoralRESUMO
PURPOSE: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. EXPERIMENTAL DESIGN: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. RESULTS: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti-programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69-CD44+CD62L- T cells, reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. CONCLUSIONS: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010.
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Mesotelioma Maligno , Mesotelioma , Camundongos , Animais , Antígeno B7-H1/imunologia , Interleucina-2/administração & dosagem , Citocinas , Mesotelioma/patologia , Imunidade InataRESUMO
SIGNIFICANCE: Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy. See related commentary by Lee et al., p. 2515.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Macrófagos , Microambiente TumoralRESUMO
BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent ß-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Masculino , Feminino , Carcinoma Hepatocelular/patologia , beta Catenina/genética , Neoplasias Hepáticas/patologia , Consenso , Proteômica , Genômica , FenótipoRESUMO
BACKGROUND: Robotic transthoracic first rib resection (R-FRR) has advantages over traditional approaches; however, its impact on postoperative neurogenic thoracic outlet syndrome (nTOS) outcomes is unknown. Our primary objective was to determine improvement of patient-reported outcome measures (PROMs) of pain and disability after R-FRR in nTOS. Our secondary objective was to compare improvement of patient-reported pain between R-FRR and supraclavicular FRR (SC-FRR) in nTOS. METHODS: We queried a prospectively maintained, single-surgeon, single-institution database for patients with nTOS undergoing R-FRR or SC-FRR with available preoperative and postoperative PROMs. PROMs included the Disability of the Arm, Hand, and Shoulder (DASH) questionnaire and visual analog scale (VAS) for pain. RESULTS: Cohort 1 included 37 patients (32 women) undergoing 40 R-FRRs, with an average age of 36 years. Preoperative VAS and DASH (6.0 and 64.2, respectively) improved significantly at the first (2.8 and 35.0; P < .001 for both) and second postoperative visits (1.4 and 30.2; P < .01 for both) which occurred at 2.6 and 15.3 weeks, respectively. Cohort 2 included 57 R-FRRs performed in 53 patients and 35 SC-FRRs performed in 34 patients. The R-FRR and SC-FRR groups did not significantly differ in sex, age, hand dominance, TOS laterality, or preoperative VAS. At the first postoperative visit (2.4 weeks), R-FRR was associated with lower VAS scores (P = .023) and greater VAS improvement than SC-FRR (53% and 27% decrease, respectively; P = .008). CONCLUSIONS: R-FRR results in significant improvement in disability and pain in nTOS and may have a greater impact on patient-reported pain than SC-FRR in the early postoperative period.
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Procedimentos Cirúrgicos Robóticos , Síndrome do Desfiladeiro Torácico , Adulto , Descompressão Cirúrgica/métodos , Feminino , Humanos , Dor/cirurgia , Estudos Retrospectivos , Costelas/cirurgia , Síndrome do Desfiladeiro Torácico/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with programmed cell death 1 (PD-1) blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM. METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 nonresponders). We used The Cancer Genome Atlas MPM cohort (n = 73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model. RESULTS: Immunogenomic analysis by applying our anti-PD-1 resistance signature to The Cancer Genome Atlas cohort revealed that deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by cyclin dependent kinase 4/6 (CDK4/6) inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a-/- AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth compared with anti-PD-1 or CDK4/6 inhibitor alone. CONCLUSIONS: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.
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Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Camundongos , Animais , Quinase 4 Dependente de Ciclina , Nivolumabe , Inibidor p16 de Quinase Dependente de Ciclina/genética , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Mesotelioma/metabolismo , Apoptose , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologiaRESUMO
BACKGROUND: The prognostic role of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) is incompletely understood. Our objectives were to evaluate the evidence for tumor PD-L1 as a prognostic biomarker in MPM through meta-analysis and to determine whether tumor PD-L1 expression is associated with survival in MPM patients undergoing macroscopic complete resection. METHODS: Meta-analysis was performed to determine the association of PD-L1 with overall survival in MPM (n = 1655) from 14 studies containing overall survival and tumor PD-L1 expression. Univariable and multivariable analyses tested the relationship of tumor PD-L1 with overall survival and recurrence-free survival in an institutional cohort of MPM patients treated by macroscopic complete resection (n = 75). To validate the association of PD-L1 with overall survival, we utilized two independent MPM cohorts (n = 284). RESULTS: Meta-analysis demonstrated that high tumor PD-L1 expression was associated with poor overall survival. Among 75 patients undergoing macroscopic complete resection, 49 tumors (65%) expressed PD-L1 (1% or more), and high PD-L1 (50% or greater) was more commonly expressed on nonepithelial (29%) compared with epithelial tumors (14%). High tumor PD-L1 expression was independently associated with poor overall survival (P < .001, hazard ratio 5.67) and recurrence-free survival (P = .003, hazard ratio 3.28). The association of PD-L1 overexpression with unfavorable survival was more significant in epithelial MPMs than nonepithelial MPMs. These findings were validated in RNA sequencing analyses in two independent cohorts. Exploratory transcriptome analysis revealed that MPM tumors with PD-L1 overexpression displayed coexpression of other immune regulatory molecules, programmed cell death 1 ligand 2 and T-cell immunoglobulin mucin receptor 3. CONCLUSIONS: Tumor PD-L1 expression is a prognostic biomarker in patients undergoing surgical resection for MPM and may be useful in perioperative decision making.
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Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/biossíntese , Mesotelioma/metabolismo , Mesotelioma/mortalidade , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/mortalidade , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Humanos , Mesotelioma/química , Mesotelioma/cirurgia , Neoplasias Pleurais/química , Neoplasias Pleurais/cirurgia , Prognóstico , Taxa de SobrevidaRESUMO
nc886 is a regulatory non-coding RNA (ncRNA) whose expression is frequently silenced in malignancies. In the case of esophageal squamous cell carcinoma (ESCC), nc886 silencing is associated with shorter survival of patients, suggesting nc886's tumor suppressor role in ESCC. However, this observation has not been complemented by an in-detail study about nc886's impact on gene expression and cellular phenotypes. Here we have shown that nc886 inhibits AKT, a key protein in a renowned pro-survival pathway in cancer. nc886-silenced cells (nc886- cells) have activated AKT and altered expression of cell cycle genes. nc886- cells tend to have lower expression of CDKN2A and CDKN2C, both of which are inhibitors for cyclin-dependent kinase (CDK), and higher expression of CDK4 than nc886-expressing cells. As a result, nc886- cells are hyperactive in the progression of the G1 to S cell cycle phase, proliferate faster, and are more sensitive to palbociclib, which is a cancer therapeutic drug that targets CDK4/6. Experimentally by nc886 expression and knockdown, we have determined the AKT target genes and cell cycle genes that are controlled by nc886 (nc886-associated gene sets). These gene sets, in combination with pathologic staging and nc886 expression levels, are a vastly superior predictor for the survival of 108 ESCC patients. In summary, our study has elucidated in ESCC how nc886 inhibits cell proliferation to explain its tumor suppressor role and identified gene sets that are of future clinical utility, by predicting patient survival and responsiveness to a therapeutic drug.
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Ciclo Celular/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA não Traduzido/genética , Transdução de Sinais , Sequência de Bases , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Fase G1/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Prognóstico , RNA não Traduzido/metabolismo , Análise de SobrevidaRESUMO
OBJECTIVES: We set out to investigate whether transcriptome-based molecular subtypes in lung adenocarcinoma and lung squamous cell carcinoma are predictive of the response to programmed cell death 1 blockade. METHODS: Molecular classification of non-small cell lung cancer was performed by unsupervised clustering of mRNA sequencing data from 87 lung adenocarcinoma and 101 lung squamous cell carcinoma specimens, and molecular subtypes were characterized according to their immunogenomic determinants. A prediction algorithm of molecular subtypes was applied to 35 patients with non-small cell lung cancer treated with programmed cell death 1 blockade to test its association with treatment response (GSE93157; the Barcelona cohort). RESULTS: Unsupervised hierarchical clustering of transcriptome sequencing data in lung adenocarcinoma and lung squamous cell carcinoma revealed 3 and 2 distinct clusters, respectively. Cluster 1 in each histology had a higher expression of immune regulatory molecules, increased cytolytic activity, higher interferon-γ signature, and more abundant infiltration of immune cells. Cluster 1 and other cluster(s) in lung adenocarcinoma and lung squamous cell carcinoma had immunologically-hot and immunologically-cold tumor-immune microenvironments, respectively. Immunologically-hot cluster 1 subtype is hereafter referred to as "good-tumor-immune microenvironments" and the other subtypes as "bad-tumor-immune microenvironments." The "good-tumor-immune microenvironments" subtype in lung adenocarcinoma included a high fraction of CD8 T cells and memory B cells, but a low fraction of regulatory CD4 T cells and tumor-associated myeloid cells. Forward and backward application of our molecular subtyping to the Barcelona cohort revealed that transcriptome-based molecular subtyping is significantly associated with response to programmed cell death 1 blockade. CONCLUSIONS: Molecular stratification by transcriptome sequencing data in non-small cell lung cancer identifies distinct immunomolecular subtypes that predict the response to programmed cell death 1 blockade.
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Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Transcriptoma/genética , Algoritmos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Imunoterapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente TumoralRESUMO
Essential to development, primary cilia are microtubule-based cellular organelles that protrude from the surface of cells. Acting as cellular antenna, primary cilia play central roles in transducing or regulating several signaling pathways, including Sonic hedgehog (Shh) and Wnt signaling. Defects in primary cilia contribute to a group of syndromic disorders known as "ciliopathies" and can adversely affect development of the brain and other essential organs, including the kidneys, eyes, and liver. The molecular mechanisms of how defective primary cilia contribute to neurological defects, however, remain poorly understood. In this mini review, we summarize recent advances in understanding of the interactions between primary cilia and signaling pathways essential to cellular homeostasis and brain development.
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OBJECTIVES: Hyperthermic pleural lavage with povidone-iodine (PVP-I) is utilized to control micrometastatic disease following cytoreductive surgery for thymic epithelial tumours (TETs). Our objective was to investigate whether PVP-I demonstrates direct cytotoxicity against human TET cells. METHODS: Human Met-5A (immortalized mesothelial cell), IU-TAB-1 (thymoma) and Ty-82 (thymic carcinoma) cell lines were treated with serial dilutions of PVP-I (0.01-10%) for 5, 30 and 60 min at 37°C and 42°C. MTT assays and flow cytometry were used to evaluate cell death and apoptosis. Membrane permeability was assayed by intracellular staining of cleaved poly-ADP-ribose polymerase. Cellular fixation was evaluated by membrane disruption of dead cells by dimethylsulphoxide and by comparing cleaved poly-ADP-ribose polymerase staining following PVP-I with known fixatives. RESULTS: MTT assays demonstrated that PVP-I concentrations greater than 0.5% led to rapid cell death in both TET cell lines regardless of temperature. IC50 values following 5 min of exposure to PVP-I were 8.4 mM (0.3%) and 13.3 mM (0.48%) for IU-TAB-1 and Ty-82, respectively and 8.9 mM (0.32%) for MeT-5A. Flow cytometry demonstrated that 5-min exposure of either cell line to 1% PVP-I resulted in profound cell death: 74% and 58% at 5 min and 97% and 95% at 30 min, for IU-TAB-1 and Ty-82 cells, respectively. Resistance of PVP-I-treated cells to dimethylsulphoxide lysis and similar cleaved poly-ADP-ribose polymerase expression following PVP-I and known fixatives revealed cellular fixation as the mechanism of death following PVP-I exposure. CONCLUSIONS: PVP-I results in rapid death of human TET cells and normal mesothelial cells through a cellular fixation mechanism and may, therefore, favourably impact the control of micrometastatic disease following resection of TETs with pleural dissemination.
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Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Povidona-Iodo/farmacologia , Neoplasias do Timo/tratamento farmacológico , Anti-Infecciosos Locais/farmacologia , Apoptose , Linhagem Celular Tumoral , Humanos , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias do Timo/patologiaRESUMO
Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.
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Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica , Mesoderma/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/metabolismo , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Instabilidade de Microssatélites , Mutação , Prognóstico , Proteômica , Receptor IGF Tipo 1/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismoRESUMO
We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides.
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Antígenos de Neoplasias/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Pulmonares/imunologia , Mesotelioma/imunologia , Neoplasias Pleurais/imunologia , Transcriptoma/imunologia , Antígenos de Neoplasias/genética , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Espectrometria de Massas/métodos , Mesotelioma/genética , Mesotelioma/mortalidade , Mesotelioma/terapia , Mesotelioma Maligno , Pleura/patologia , Pleura/cirurgia , Neoplasias Pleurais/genética , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/terapia , Prognóstico , Estudos Prospectivos , Proteogenômica/métodos , Estudos Retrospectivos , Análise de Célula Única/métodos , Transcriptoma/genética , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
PURPOSE: To identify effects of menstrual attitude, premenstrual syndrome, and stress response on quality of life of nursing students. METHODS: Subjects were 135 nursing students who agreed to participate in this study. Data were analyzed using descriptive statistics, t-test, ANOVA, Pearson correlation, and stepwise multiple regression. RESULTS: Premenstrual syndrome, younger than 20 years of age, and habit of eating bland food in everyday life were factors influencing quality of life of nursing students. These factors accounted for 17.6% of quality of life. Premenstrual syndrome toward quality of life was the most influential factor. CONCLUSION: Premenstrual syndrome is the most significant factor affecting the quality of life of nursing students. To increase their quality of life, it is important to develop and apply educational programs using factors influencing quality of life of the nursing students. Results of this study will be useful as basic data for improving quality of life of nursing students. Additional study is needed to test its effect in the future.
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Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials.