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Martins, A. M. C. R. P. da F. "METABOLISMO DA GLUTAMINA NA CÉLULA TUMORAL". Arquivos do Instituto Biológico 70, n.º 2 (abril de 2003): 231–37. http://dx.doi.org/10.1590/1808-1657v70p2312003.
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RESUMO Neoplasias são doenças com alterações no DNA, provocadas por diversos eventos.Sua origem é monoclonal e com desenvolvimento e instabilidade gênica, novos clones surgem. Os atributos neoplásicos (cariótipo, invasibilidade, suscetibilidade a anti-neoplásicos, ritmo de crescimento, suscetibilidade hormonal, capacidade metastática) são heterogêneos, exigindo fluxo energético alto, macromoléculas e nitrogênio. Assim, as vias metabólicas nessas células garantem-lhes precursores para a síntese de lipídeos estruturais e reguladores, DNA e RNA. Célula tumoral usa qualquer substrato como fonte energética: glicose, lipídeos, corpos cetônicos e aminoácidos, competindo com o hospedeiro pela glicose. Glutamina e alanina são dois transportadores de nitrogênio e esqueleto carbônico entre os diferentes tecidos.O íon amônio é extremamente tóxico às células devendo ser carreadas por aminoácido.Portanto, a glutamina torna-se a principal fonte de nitrogênio das células tumorais, acarretando profundas mudanças no metabolismo do hospedeiro pelas crescentes necessidades de glutamina pelas células. Glicólise e glutaminólise não são essenciais a neoplasias, são antes oportunidades estratégicas favoráveis á sobrevivência e proliferação em circunstâncias de carência de nutrientes e oxigênio. Nas células tumorais ocorre a expressão de glutaminase P-dependente mitocondrial e de malato-NAD(P)-dependente descaboxilase mitocondrial,enzimas que oxidam piruvato e acetil CoA. Conversão de glutamina à lactato, é chamada glutaminólise e tem a função de produzir energia, glutamato,citrato e aspartato.A concentração da glutamina é inversamente proporcional ao crescimento da neoplasia, com aumento da glutaminase e diminuição, prescindível nos tumores, da glutamina sintetase. O estudo das vias metabólicas das células tumorais oferece subsídios ao combate às neoplasias. Como os tumores também sintetizam menos aminoácidos que as células normais e (necessitam receber suplementos em aminoácidos do fluido extracelular e carbono,) tornam-se vulneráveis aos bloqueadores de transporte de aminoácidos sendo esta uma base de terapia contra o câncer.
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Quinelato, Ayra Daneluzzi, Murilo Bonatelli, Patrik Da Silva Vital, Eduardo Caetano Albino da Silva, Paula Roberta Pastrez, Adhemar Longatto-Filho y Céline Pinheiro. "O Efeito Warburg em carcinoma de pulmão de pequenas células: caracterização da expressão de proteínas relacionadas ao metabolismo glicolítico em amostras preservadas em meio líquido". Manuscripta Médica 5 (28 de diciembre de 2022): 3–16. http://dx.doi.org/10.59255/mmed.2022.73.
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Introdução: O câncer de pulmão de pequenas células (CPPC) afeta, em média,200.000 pessoas no mundo, anualmente, correspondendo a 15-20% de todos os cânceres de pulmão. Em geral, tumores sólidos reprogramam seu metabolismo aumentando a dependência na glicólise, mesmo em condições aeróbias (efeito Warburg), sendo uma das características fundamentais do câncer. Objetivo: Avaliar a expressão de proteínas relacionadas ao metabolismo glicolítico em amostras de CPPC preservadas em meio líquido. Material e Métodos: Foram incluídos 45 pacientes diagnosticados com CPPC, submetidos a lavagem brônquica em ambos os pulmões, cujas amostras (normal e tumoral) foram armazenadas em meio líquido (BD SurePathÒ). A expressão das proteínas MCT1, MCT4, GLUT1 e CA9 foi avaliada por imunocitoquímica (ICQ) em cell blocks, seguida de avaliação por patologista e, por fim, análise estatística. Resultados: Foi observada uma perda importante de amostras durante a construção dos cell blocks, na ICQ e por falta de representatividade celular. Das remanescentes, 1 amostra tumoral (12,5%) foi positiva para MCT1, 2 amostras normais (9,1%) e 2 tumorais (14,3%) foram positivas para MCT4, 1 amostra normal (4,2%) e 3 amostras tumorais (21,4%) foram positivas para GLUT1 (p=0,043) e 1 amostra tumoral (7,1%) foi positiva para CA9. Devido ao reduzido número de casos positivos, não foi possível verificar possíveis associações com os dados clínicos e patológicos dos pacientes. Conclusão: A expressão de MCT1, MCT4 e CA9 foi observada em poucas amostras, não sendo observada diferença entre amostras normais e tumorais. Para GLUT1, observou-se um aumento significativo da expressão citoplasmática nas amostras tumorais, comparando às normais.
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He, Z., Z. Meng, P. Liang, L. Xing, X. Zheng y G. Wang. "P13.15 Pre-clinical trial of T601 oncolytic virus for high grade glima via intra-tumoral injection". Neuro-Oncology 23, Supplement_2 (1 de septiembre de 2021): ii35—ii36. http://dx.doi.org/10.1093/neuonc/noab180.122.
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Abstract BACKGROUND An effective therapeutic method still hasn’t been devised for lethal high grade glioma. Thus, a method with high anti-tumoral efficiency, tumoral targeting, and acceptable side effect needs to be designed. Oncolytic virotherapy which can specifically lyse tumor cells via mass replication and deleting nucleotide metabolism related gene, like TK, required in viral replication and overexpressed in tumor cells, provides hope for patients. However, the virus only contained TK deletion is unable to show sufficient specificity of anti-tumoral response in tumor cells. Here, the adapted strain of vaccinia virus with high tumoral specificity due to TK and RR deletion and FUC1 insertion, named T601, is chosen in this project. In clinical application, intra-tumoral injection showed improved anti-tumoral efficiency and acceptable side effect. However, intra-tumoral viral injection in orthotropic glioma model is rare. In this project, various biosafety and antitumoral efficiency parameter would be tested for confirming the biosafety and reliability of intra-tumoral T601 viral injection for future clinical trials. MATERIAL AND METHODS For measuring the IC50 of T601, 10 different amounts of virus was tested in vitro via calculating cell viability with CCK-8(cell counting kit-8). For measuring the further antitumoral response of FCU1, different concentration of the 5-FC was added into the medium with IC50 viral amount. To ensure the biosafety of T601, MTD (maximum tolerance dose) was measured. Based on the MTD result, for evaluating the anti-tumoral efficiency, 106 pfu,105 pfu,104 pfu of virus was intra-tumoral injected in orthotopic GBM bearing mice. Tumor size was measured once a week through in vivo bioimaging system. RESULTS 0.022 MOI, the IC50 of T601, showed high cytotoxicity of T601. Moreover, the significantly decreased cell viability under the combined treatment of 5-FC and 0.22MOI T601 showed intact anti-tumoral function. In MTD assay, except for 107 group, no significant weight loss was found. However, in 107 pfu group, mean body weight decreased around 10% and animal fatality happened on day 9. According to the MTD result, certain amount of virus was intra-tumorally injected. In all treatment group, the tumor size was significantly shrined. At the same time, the survival rate of mice under viral treatment was significantly extended. CONCLUSION In summary, T601 exhibited efficient anti-tumoral function and acceptable side effect. T601 treatment prolonged the survival period of GBM mice with acceptable neurotoxicity, demonstrating that T601 contains necessary criterial for intra-tumoral injection. Ultimately, this project provided basic reference information of dose for future clinical trial.
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Shah, Sumedh, Garima Yagnik, Alan Nguyen, Harsh Wadhwa, Jordan Spatz, Michael Safaee, Justin Cheng y Manish Aghi. "TMIC-57. PRO-TUMORAL EFFECTS OF INTRA-TUMORAL NEUTROPHILS IN THE GLIOBLASTOMA MICROENVIRONMENT". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi260. http://dx.doi.org/10.1093/neuonc/noz175.1091.
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Abstract While macrophage enrichment and lymphocyte depletion have been described in glioblastoma, intratumoral neutrophils and their effect on glioblastoma have been under-characterized. While tumor-associated neutrophils (TANs) were initially regarded as passive bystanders due to their short-lived nature, investigation of TANs in other cancer types revealed pro-tumoral roles. Therefore, we sought to characterize TANs in the glioblastoma microenvironment using transcriptomic analysis and define their oncologic effects. Flow cytometric analysis of patient samples for neutrophils (CD11b+/CD15+/CD66b+) revealed higher percentages of TANs in glioblastoma compared to low-grade gliomas (1.76% [n=13] vs. 0.33% [n=6], p=0.03). Using the Transwell migration assay with glioblastoma tumor conditioned-media (CM), we found that recruitment of circulating neutrophils to tumor sites is mediated by leukotriene-B4 chemoattraction and that this interaction can be blocked with the addition of LtB4 receptor antagonist, LY293111. TANs were morphologically activated, unlike circulating neutrophils from GBM patients (P< 0.05) and, while not intravascular, were close to blood vessels. We performed single-cell RNA sequencing of isolated TANs and found a distinct transcriptomic profile relative to circulating neutrophils from these patients, particularly upregulated osteopontin. Osteopontin concentration was significantly higher in TAN CM than in patient-matched peripheral blood neutrophil CM (3.2ng/mL [n=3] vs. 0.02ng/mL [n=3], p< 0.05). Because osteopontin is linked to GBM stem cell-like phenotype maintenance and TANs localized to the perivascular niche where GBM stem cells reside, we investigated TAN-GBM stem cell interactions and osteopontin as a potential mediator. We found TAN CM increased proliferation and stem cell markers (Nanog, Oct4, Sox2) of stem cell-containing GBM neurospheres (p< 0.01). These effects were blocked by osteopontin-neutralizing antibodies (p< 0.01). Our work defines neutrophil-mediated pro-tumoral effects and their mechanisms and identifies a novel approach to target GBM stem cells—by disrupting the immune cell mediators that create their supportive microenvironment in the perivascular niche.
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Derakhshani, Afshin, Zeinab Rostami, Hossein Safarpour, Mahdi Abdoli Shadbad, Niloufar Sadat Nourbakhsh, Antonella Argentiero, Sina Taefehshokr et al. "From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy". Molecules 26, n.º 8 (14 de abril de 2021): 2278. http://dx.doi.org/10.3390/molecules26082278.
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Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.
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Chih, Y., K. Sahm, A. Sadik, T. Bunse, N. Trautwein, S. Pusch, S. Stevanovic et al. "KS01.3.A Tumoral MHC class II expression in gliomas drives T cell exhaustion". Neuro-Oncology 23, Supplement_2 (1 de septiembre de 2021): ii3. http://dx.doi.org/10.1093/neuonc/noab180.007.
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Abstract BACKGROUND Neoepitopes are presented on major histocompatibility class II (MHCII) molecules. In glioma, for instance, the recurrent driver mutation IDH1R132H was shown to bear an MHCII-restricted epitope in preclinical and clinical vaccine studies. The general relevance of MHCII expression in glioma for antitumor immunity, however, remains unknown. Here we evaluate stromal and tumoral MHCII expression, functionality, and its association with survival in gliomas. MATERIAL AND METHODS Immunostaining of human glioma tissues was used to identify tumoral, endothelial, and microglial MHCII expression and to enumerate T cell infiltrates. To gain insights into tumoral MHCII expression, bulk transcriptomic data from TCGA and single-cell transcriptomic data from publicly available datasets were analyzed. MHC ligandome analyses of an MHCII+ glioma cell line and human glioma tissues were used to determine the functionality of MHCII in vitro and ex vivo. Functional in vitro co-culture assays with an HLA-DR-matched tetanus toxoid (TT) epitope-overexpressing glioma cell line and in vitro-expanded TT-reactive T cells from healthy donors were used to examine direct target recognition by T helper cells. CRISPR-Cas9-mediated knockout of MHCII in preclinical hypermutant glioblastoma cell line GL261 was employed to further validate the consequences of tumoral MHCII expression and to probe potential clinical intervention with existing therapies. RESULTS MHCII is expressed in the majority of gliomas and associated with increased infiltration of T cells. In 10% of the analyzed glioma tissues and a subset of single cells, tumoral MHCII expression is detected. Clinical and transcriptomic data reveal that tumoral MHCII is associated with poor prognosis, cytokine responses, immune inhibition and T cell differentiation. Ligandome analyses evidence presentation of peptides by MHCII molecules on glioma cells. In in vitro assays, TT-reactive T helper cells specifically produce IFNg when co-cultured with MHCII+ glioma cells upon the presence of co-stimulation. In agreement with the clinical data, preclinical murine models demonstrate that tumoral MHCII expression leads to reduced survival. Co-culture assay shows that tumoral MHCII results in upregulation of PD-1 on T helper cells antigen-specifically. Concordantly, immune checkpoint blockade (ICB) therapy slows the disease progression of mice carrying MHCII+ tumors. CONCLUSION MHCII is expressed in gliomas by a subset of tumor cells. Although tumoral MHCII is functional, it is associated with poor survival in both clinical data and preclinical models. T cell exhaustion induced by tumoral MHCII expression can, in part, be overcome by ICB in vivo. Further experiments are required to decipher tumor cell intrinsic and microenvironmental consequences of tumoral MHCII expression.
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Montes, Marta y Maite Huarte. "8G modifications rewire tumoral microRNAs". Nature Cell Biology 25, n.º 9 (septiembre de 2023): 1243–44. http://dx.doi.org/10.1038/s41556-023-01179-9.
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Masetti, Michela, Federica Portale, Roberta Carriero, Bianca Partini, Nicolò Morina, Andrea Ponzetta, Piergiuseppe Colombo et al. "High-dimensional single cell-based immune profiling of the tumor immune microenvironment in prostate cancer." Journal of Clinical Oncology 38, n.º 6_suppl (20 de febrero de 2020): 376. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.376.
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376 Background: Genetic lesions that drive prostate cancer (PCa) development are able to modify the immune response and tumor infiltrating immune subsets, resulting in tumor progression. We investigated the profile of the immune microenvironment in PCa by high dimensional single cell analysis. Methods: We conducted an immune profiling study based on integrated RNA single cell sequencing and multiparametric flow cytometry in order to dissect the immune landscape of PCa. CD45+ immune cells infiltrating tumoral and adjacent non tumoral tissues were isolated from patients with PCa who underwent software assisted fusion biopsy, based on MRI, and/or radical prostatectomy, and analyzed by single cell sequencing. The primary endpoint was to evaluate the effectiveness of single cell RNA sequencing on CD45+ cell sorted from tumoral and adjacent non-tumoral tissues. Secondary endpoint was the identification of tumor-driven immune changes in prostatic lesions. Results: The cohort consisted of 3 patients who underwent radical prostatectomy (RP) and 45 patients with positive prostate biopsy; the negative control was checked by pathological assessment. In patients who underwent RP the gene expression analysis identified a modulation in the abundance of several immune subsets infiltrating the tumoral tissue, when compared with the non tumoral, evident for Tumor associated macrophages (TAMs), Natural Killer cells (NK) and T regulatory cells. We then implemented a 22 parameters flow cytometry panel that we tested on fresh prostatic tissue and peripheral blood from positive PCa biopsies. We identified a subset of tumor infiltrating macrophages showing an altered gene expression profile when compared with macrophages infiltrating the non-tumoral tissue. Importantly we derived a genetic signature from this subset of tumoral TAMs that resulted to be associated with cancer progression. Conclusions: Our findings support the effectiveness of single cell RNA sequencing in the dissection of the immune landscape in PCa and identified immune changes in patients when comparing neoplastic tissue with non tumoral areas. Such data may be useful for understanding the role of immune system in PCa carcinogenesis.
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Lombardo, Dominique, Carole Siret y Sadia Beloribi-Djefaflia. "Exosomal lipids impact on tumoral cell behavior". Cell Cycle 14, n.º 4 (16 de febrero de 2015): 461–62. http://dx.doi.org/10.1080/15384101.2015.1006538.
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Rennó, Magdalena N., Gleyce M. Barbosa, Patricia Zancan, Venicio F. Veiga, Celuta S. Alviano, Mauro Sola-Penna, Fábio S. Menezes y Carla Holandino. "Crude ethanol extract from babassu (Orbignya speciosa): cytotoxicity on tumoral and non-tumoral cell lines". Anais da Academia Brasileira de Ciências 80, n.º 3 (septiembre de 2008): 467–76. http://dx.doi.org/10.1590/s0001-37652008000300008.
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Plant-derived substances have been considered as important sources of drugs, including antineoplasic agents. Babassu mesocarp is popularly used in Brazil as a food additive, and in popular medicine against several conditions, such as inflammations, menstrual pains and leukaemia. From babassu Orbignya speciosa (Mart.) Barb. Rodr. [Arecaceae (Palmae)] epicarp/mesocarp, an ethanol extract was prepared and named OSEME, which was tested on the viability,morphology and metabolism of several cell lines, such as the leukaemic cell lines, HL-60, K562 and the latter multidrug resistant counterpart K562-Lucena 1, the human breast cancer cell line MCF-7, the mouse fibroblast cell line 3T3-L1 and fresh human lymphocytes. OSEME promoted a dose-dependent decrease on the viability of all cells. This effect was much more pronounced on the tumoral cell lines than on non-tumoral cells, a phenomenon revealed by the dose of OSEME which promotes half of maximal effect (ID50). The decrease on viability was followed by shrinkage of cells, alteration on their morphology, and a markedly nuclear condensation. Curiously, stimulation of 6-phosphofructokinase activity (6.6-times) was observed on HL-60 cells, treated with OSEME, when compared to control treated with ethanol (vehicle). These results support evidences to suggest OSEME as a promising source of novel antineoplasic agents.
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Rennert, Charlotte, Catrin Tauber, Pia Fehrenbach, Kathrin Heim, Dominik Bettinger, Özlem Sogukpinar, Anita Schuch et al. "Adaptive Subsets Limit the Anti-Tumoral NK-Cell Activity in Hepatocellular Carcinoma". Cells 10, n.º 6 (2 de junio de 2021): 1369. http://dx.doi.org/10.3390/cells10061369.
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Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the anti-tumoral activity of NK cells in HCC associated with different etiologies, and the impact of the heterogeneous NK cell subset, e.g., adaptive and conventional subsets, are not understood in detail. By comparatively analyzing the NK-cell repertoire in 60 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD), we show in this study that the NK-cell repertoire is linked to HCC etiology, with increased frequencies of adaptive NK cells in Hepatitis B virus (HBV)-associated HCC. Adaptive NK cells exhibited limited anti-tumoral activity toward liver cancer cells; however, this was not a result of a specific NK-cell impairment in HCC but rather represented an intrinsic feature, since the characteristics of circulating and intra-tumoral adaptive NK cells were conserved between HD, HCC and liver cirrhosis patients. Hence, the expansion of adaptive NK cells with reduced anti-tumoral activity, detectable in HBV-associated HCC, may have implications for tumor surveillance and therapy.
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Sriram, Ganapathy, Lauren Milling, Jung-Kuei Chen, Wuhbet Abraham, Darrell J. Irvine y Michael B. Yaffe. "Intratumoral administration of DNA-damaging chemotherapy-treated tumor cells to enhance therapeutic benefit of systemic immune checkpoint blockade in mouse cancer models." Journal of Clinical Oncology 38, n.º 5_suppl (10 de febrero de 2020): 77. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.77.
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77 Background: Immune checkpoint inhibition or ICI (antibodies to PD-1 and CTLA4), has shown promise in the treatment of some tumor types, especially in inducing durable remissions in advanced stage cancer patients. However, the majority of patients do not respond to ICI. Identifying combinations to enhance response to ICI is an urgent medical need. Methods: Murine tumor cell lines B16-Ova and MC-38-Ova were treated with DNA-damaging chemotherapeutic drugs, co-cultured with primary murine bone marrow derived dendritic cells (BMDC) followed by addition of OT-1 CD8+ T-cells and flow cytometric analysis of IFN-γ+ CD8+ T-cells. Mice bearing B16-Ova or MC-38 flank tumors were injected intra-tumorally with ex vivo chemotherapy-treated B16-Ova cells with or without systemic ICI. Tumor cross-sectional area was measured using calipers. Intra-tumoral DC and circulating H2-Kb/SIINFEKL-specific CD8+ T-cells were analyzed by flow cytometry. Results: Etoposide and mitoxantrone-treated B16-Ova and MC-38-Ova tumor cells, when co-cultured with BMDC, efficiently promote IFN- γ induction in OT-1 CD8+ T-cells. This was abrogated by co-treatment of tumor cells with Necrostatin-1 but not ZVAD-FMK. Intra-tumoral injection of ex vivo etoposide-treated tumor cells, with systemic ICI, increases the numbers of intra-tumoral CD103+ DC, the frequency of circulating H2-Kb/SIINFEKL-specific CD8+ T-cells and significantly improves survival. The tumor cell vaccine/systemic ICI combination, but not ICI alone, induced complete tumor regressions in a subset of mice. This is abrogated in BATF3-deficient mice. Conclusions: Etoposide and mitoxantrone-treated tumor cells efficiently promote BMDC-mediated CD8+ T-cell priming, in a tumor cell RIPK1 activity-dependent but caspase-independent manner. Intra-tumoral administration of the DNA-damage induced tumor cell vaccine in vivo, in combination with systemic ICI, enhances anti-tumor CD8+ T-cell responses, tumor-free and overall survival, and anti-tumor immunological memory. This enhancement in therapeutic efficacy is dependent on BATF3+ DC in vivo.
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Lequerica-Fernández, Paloma, Julián Suárez-Canto, Tania Rodriguez-Santamarta, Juan Pablo Rodrigo, Faustino Julián Suárez-Sánchez, Verónica Blanco-Lorenzo, Francisco Domínguez-Iglesias, Juana María García-Pedrero y Juan Carlos de Vicente. "Prognostic Relevance of CD4+, CD8+ and FOXP3+ TILs in Oral Squamous Cell Carcinoma and Correlations with PD-L1 and Cancer Stem Cell Markers". Biomedicines 9, n.º 6 (8 de junio de 2021): 653. http://dx.doi.org/10.3390/biomedicines9060653.
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This study investigates the relevance of tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis of stromal/tumoral CD4+, CD8+ and FOXP3+ TILs is performed in 125 OSCC patients. Potential relationships with the expression of tumoral PD-L1 and cancer stem cell (CSC) markers (NANOG, SOX2, OCT4, Nestin and Podoplanin (PDPN)) are assessed. CD4+ and CD8+ TILs are significantly associated with smoking and alcohol habits. CD4+ and CD8+ TILs show an inverse relationship with NANOG and SOX2 expression, and FOXP3+ TILs is significantly correlated with Nestin and PDPN expression. High infiltration of CD4+ and CD8+ TILs and a high tumoral CD8+/FOXP3+ ratio are significantly associated with tumors harboring positive PD-L1 expression. Infiltration of stromal/tumoral FOXP3+ TILs and a low stromal CD8+/FOXP3+ ratio are significantly associated with better disease-specific survival. Multivariate analysis reveals that the stromal CD8+/FOXP3+ TILs ratio is a significant independent prognostic factor. Regarding OSCC patient survival, the CD8+/FOXP3+ TILs ratio is an independent prognostic factor. TILs may act as biomarkers and potential therapeutic targets for OSCC.
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Elahi, Maryam y Vahid Rakhshan. "Clinical and Histopathological Factors Associated with the Tumoral Expression of TGF-β1, MED15, CD16, and CD57 in Oral Squamous Cell Carcinoma". Advances in Preventive Medicine 2022 (27 de octubre de 2022): 1–11. http://dx.doi.org/10.1155/2022/3145117.
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Introduction. Factors associated with the expression of oral squamous cell carcinoma (OSCC) biomarkers “CD16, CD57, TGF-β1, and MED15” are not assessed, except in few controversial studies of some of these biomarkers. This study aimed to highlight factors that can correlate with tumoral overexpression of these biomarkers. Methods. In this genetically-matched case-control study, biomarker expressions in all available OSCC tissues and their adjacent normal tissues at the National Tumor Center (n = 384 (4 biomarkers × (48 cancers + 48 controls))) were measured using qRT-PCR. Factors associated with tumoral overexpression of CD16, CD57, TGF-β1, and MED15 (compared to the benign control) were evaluated, using log-level multiple linear regressions and Spearman (α = 0.05). Results. Tumoral CD16 upregulation was observed in younger patients (β = −0.284, P = 0.040 ) and cigarette smokers (β = 0.397, P = 0.005 ). Tumoral CD57 was upregulated in males (β = 0.341, P = 0.008 ), smokers (β = 0.401, P = 0.002 ), and cases without vascular invasion (β = −0.242, P = 0.042 ). Tumoral TGF-β1 was elevated in smokers (β = 0.452, P = 0.001 ) and smaller tumors (β = −0.322, P = 0.045 ). Tumoral MED15 was overexpressed in smokers (β = 0.295, P = 0.036 ) and cases lacking perineural invasion (β = −0.394, P = 0.007 ). Conclusion. As the most consistent finding, smoking might be positively associated with tumoral overexpression of all biomarkers. Tumoral increase in CD57 might be positively associated with metastasis while being negatively correlated with vascular and lymphatic invasion. Tumor size might be negatively associated with tumoral TGF-β1 expression.
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Bertagnolo, Valeria, Federica Brugnoli, Silvia Grassilli, Ervin Nika y Silvano Capitani. "Vav1 in differentiation of tumoral promyelocytes". Cellular Signalling 24, n.º 3 (marzo de 2012): 612–20. http://dx.doi.org/10.1016/j.cellsig.2011.11.017.
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Rodríguez-Antona, Cristina, Susanna Leskelä, Magdalena Zajac, Marta Cuadros, Javier Alvés, Maria Victoria Moneo, Carmen Martín et al. "Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas". Blood 110, n.º 9 (1 de noviembre de 2007): 3345–51. http://dx.doi.org/10.1182/blood-2007-02-075036.
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Abstract Peripheral T-cell lymphomas (PTCLs) are aggressive tumors in which the current therapy based on multiagent chemotherapy is not successful. Since cytochrome P450 3A subfamily (CYP3A) enzymes are involved in the inactivation of chemotherapy drugs, we hypothesized that CYP3A and P-glycoprotein (MDR1) expression in these lymphomas could result in a poor clinical response. We measured tumoral CYP3A and MDR1 mRNA content in 44 T-cell lymphomas, finding a large variation in CYP3A expression. Multiplex polymerase chain reaction (PCR) analysis and fluorescence in situ hybridization (FISH) analysis showed genomic gains affecting CYP3A and MDR1 genes in T-cell lines and primary tumors, suggesting that this could be the mechanism underlying the tumoral expression variation. To test whether the tumoral expression of CYP3A and/or MDR1 could influence PTCL treatment outcome, their expression levels were compared with the clinical response and survival of the patients, finding that a high tumoral expression of CYP3A4 was significantly associated with a lower complete remission rate. This was further investigated with cell lines stably expressing CYP3A4 that exhibited an increased resistance to doxorubicin and etoposide. In conclusion, a high CYP3A4 tumoral expression could be useful to predict poor response to the standard PTCL chemotherapy; in these cases alternative chemotherapy combinations or doses should be explored.
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Lau, Hannah Si Hui, Veronique Kiak Mien Tan, Benita Kiat Tee Tan, Yirong Sim, Jelmar Quist, Aye Aye Thike, Puay Hoon Tan, Shazib Pervaiz, Anita Grigoriadis y Kanaga Sabapathy. "Abstract P64: Adipose-enriched Peri-tumoral Stroma Prognosticates Poorer Survival in Breast Cancers". Cancer Research 84, n.º 8_Supplement (15 de abril de 2024): P64. http://dx.doi.org/10.1158/1538-7445.fcs2023-p64.
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Abstract Background: Breast cancers display a large degree of diversity between and within tumors. Intra-tumoral heterogeneity is contributed by variations in tumor cells and non-malignant stromal and immune cells of the tumor microenvironment (TME). So far, studies on the TME have focused on intra-tumoral stroma, whereas little attention has been given to the peri-tumoral microenvironment, extending beyond the tumor margins into the surrounding histologically normal-appearing tissues. Here, we hypothesized that intrinsic intra-tumoral heterogeneity impacts the more distal peri-tumoral stroma, which may in turn affect tumor growth and development. Methods: A systematic, multi-regional transcriptomic profiling analysis of the tumor and peri-tumoral regions from 8 ER+/PR+/HER2− invasive breast carcinomas was performed using the human Clariom™ S Assay. For each patient, 5 spatially distinct tumor samples were obtained, while peri-tumoral samples were collected from 4 different sides and at varying distances up to 7 cm from tumor margins. Pathway enrichment analyses and cellular deconvolution were performed to determine their molecular characteristics and cell type compositions. Gene expression signatures identified from peri-tumoral samples were applied to tumor-adjacent normal RNA-seq samples from 50 TCGA ER+/PR+/HER2− breast cancer patients to determine their prognostic value. Results: The 8 tumors displayed varying levels of spatial diversity in their biological properties, including 3 tumors with basal-classified regions. Four peri-tumoral clusters with distinct pathway activities and cell compositions were identified, but were independent of distance and location to the tumor. Two clusters reflect the major breast peri-tumoral states – a pro-inflammatory, adipose-enriched phenotype which was significantly associated with poorer overall survival (HR=4.28, p-value=0.02), and an adaptive immune cell- and myofibroblast-enriched phenotype. Conclusion: This suggests that the peri-tumoral stroma may be an important determinant in cancer progression. Moreover, independent of spatially-defined patterns, the peri-tumoral phenotype appears to be driven by inter-individual variations in the proportion of fibroglandular and fat tissue of the breast. Citation Format: Hannah Si Hui Lau, Veronique Kiak Mien Tan, Benita Kiat Tee Tan, Yirong Sim, Jelmar Quist, Aye Aye Thike, Puay Hoon Tan, Shazib Pervaiz, Anita Grigoriadis, Kanaga Sabapathy. Adipose-enriched Peri-tumoral Stroma Prognosticates Poorer Survival in Breast Cancers [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P64.
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Royo, Felix, Clara Garcia-Vallicrosa, Maria Azparren-Angulo, Guillermo Bordanaba-Florit, Silvia Lopez-Sarrio y Juan Manuel Falcon-Perez. "Three-Dimensional Hepatocyte Spheroids: Model for Assessing Chemotherapy in Hepatocellular Carcinoma". Biomedicines 12, n.º 6 (28 de mayo de 2024): 1200. http://dx.doi.org/10.3390/biomedicines12061200.
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BACKGROUND: Three-dimensional cellular models provide a more comprehensive representation of in vivo cell properties, encompassing physiological characteristics and drug susceptibility. METHODS: Primary hepatocytes were seeded in ultra-low attachment plates to form spheroids, with or without tumoral cells. Spheroid structure, cell proliferation, and apoptosis were analyzed using histological staining techniques. In addition, extracellular vesicles were isolated from conditioned media by differential ultracentrifugation. Spheroids were exposed to cytotoxic drugs, and both spheroid growth and cell death were measured by microscopic imaging and flow cytometry with vital staining, respectively. RESULTS: Concerning spheroid structure, an active outer layer forms a boundary with the media, while the inner core comprises a mass of cell debris. Hepatocyte-formed spheroids release vesicles into the extracellular media, and a decrease in the concentration of vesicles in the culture media can be observed over time. When co-cultured with tumoral cells, a distinct distribution pattern emerges over the primary hepatocytes, resulting in different spheroid conformations. Tumoral cell growth was compromised upon antitumoral drug challenges. CONCLUSION: Treatment of mixed spheroids with different cytotoxic drugs enables the characterization of drug effects on both hepatocytes and tumoral cells, determining drug specificity effects on these cell types.
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Diab, Maria y Bassel F. El-Rayes. "The heterogeneity of CAFs and immune cell populations in the tumor microenvironment of pancreatic adenocarcinoma". Journal of Cancer Metastasis and Treatment 8 (2022): 42. http://dx.doi.org/10.20517/2394-4722.2022.60.
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Over the past decade, researchers have identified and characterized the diverse cell populations within the tumor microenvironment of pancreatic cancer. The interplay between these cells in the TME either promotes or inhibits the malignant behavior of pancreatic cancer cells. Cancer-associated fibroblasts, previously thought to be one main subset, can now be broadly subclassified into three main types: inflammatory, myofibroblastic, and antigen-presenting, with the former and the latter two exerting pro-tumoral and anti-tumoral functions, respectively. Myeloid cells include myeloid-derived suppressor cells and tumor-associated macrophages. Myeloid-derived suppressor cells can be further divided into polymorphonuclear and monocytic and exhibit pro-tumoral activities. Tumor-associated macrophages exhibit M1 (anti-tumoral) or M2 (pro-tumoral) phenotypes, which are present in a dynamic fashion between the two phenotypes. Other constituents of the immune make-up of the tumor microenvironment include T and B cells and less described subsets which include natural killer cells, γδ T cells, and group 2 innate lymphoid cells. This review provides an overview of the studies that lead to the discovery of those cellular populations and highlights the recent efforts to utilize them as therapeutic targets in pancreatic cancer.
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Christophe, J. "Pancreatic tumoral cell line AR42J: an amphicrine model". American Journal of Physiology-Gastrointestinal and Liver Physiology 266, n.º 6 (1 de junio de 1994): G963—G971. http://dx.doi.org/10.1152/ajpgi.1994.266.6.g963.
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AR42J cells derive from azaserine-induced malignant nodules from the rat pancreas. They differ from normal acinar cells for at least three reasons: 1) they proliferate rapidly; 2) they synthesize, store, and secrete digestive enzymes but the regulation of their exocrine function is abnormal, from the emergence of atypical receptors (e.g., cholecystokinin octapeptide type B and pituitary adenylate cyclase-activating polypeptide type I receptors) to unusual inositol phosphate metabolism and cytoskeleton disorganization; and 3) they possess an added neuroendocrine-regulated pathway characterized by voltage-sensitive ionic currents, post-translational processing of peptidic prohormones (and possibly autocriny), and the release of small neurotransmitters (gamma-aminobutyric acid, glycine, and glutamic acid). These amphicrine cells represent, therefore, a cancerous version of the primordial pancreatic ductular epithelium. Dexamethasone favors their differentiation toward the exocrine phenotype. The mitogenic pathway is favored by the occupancy of receptor tyrosine kinases, adenosine 3',5'-cyclic monophosphate, ornithine decarboxylase expression, and Na(+)-H+ exchange. Somatostatin opposes proliferation through protein phosphatases.
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Shadbad, Mahdi Abdoli, Sahar Safaei, Oronzo Brunetti, Afshin Derakhshani, Parisa Lotfinejad, Ahad Mokhtarzadeh, Nima Hemmat et al. "A Systematic Review on the Therapeutic Potentiality of PD-L1-Inhibiting MicroRNAs for Triple-Negative Breast Cancer: Toward Single-Cell Sequencing-Guided Biomimetic Delivery". Genes 12, n.º 8 (4 de agosto de 2021): 1206. http://dx.doi.org/10.3390/genes12081206.
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The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various intracellular singling pathways in TNBC. Therefore, we conducted the current systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to provide a comprehensive and unbiased synthesis of currently available evidence regarding the effect of PD-L1-inhibiting miRs restoration on TNBC development and tumor microenvironment. For this purpose, we systematically searched the Cochrane Library, Embase, Scopus, PubMed, ProQuest, Web of Science, Ovid, and IranDoc databases to obtain the relevant peer-reviewed studies published before 25 May 2021. Based on the current evidence, the restoration of miR-424-5p, miR-138-5p, miR-570-3p, miR-200c-3p, miR-383-5p, miR-34a-5p, miR-3609, miR-195-5p, and miR-497-5p can inhibit tumoral PD-L1 expression, transform immunosuppressive tumor microenvironment into the pro-inflammatory tumor microenvironment, inhibit tumor proliferation, suppress tumor migration, enhance chemosensitivity of tumoral cells, stimulate tumor apoptosis, arrest cell cycle, repress the clonogenicity of tumoral cells, and regulate various oncogenic signaling pathways in TNBC cells. Concerning the biocompatibility of biomimetic carriers and the valuable insights provided by the single-cell sequencing technologies, single-cell sequencing-guided biomimetic delivery of these PD-L1-inhibiting miRs can decrease the toxicity of traditional approaches, increase the specificity of miR-delivery, enhance the efficacy of miR delivery, and provide the affected patients with personalized cancer therapy.
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Vanier, M. T., P. Neuville, L. Michalik y J. F. Launay. "Expression of specific tau exons in normal and tumoral pancreatic acinar cells". Journal of Cell Science 111, n.º 10 (15 de mayo de 1998): 1419–32. http://dx.doi.org/10.1242/jcs.111.10.1419.
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Tau is a neuron-specific microtubule-associated protein (MAP) that is required for the development and maintaining neuronal cell polarity. Tau is encoded by a single gene, while its transcript undergoes a complex and regulated alternative splicing. We have recently reported that tau-like MAPs of 48–55 kDa, corresponding to 6 kb mRNA on northern blots, are expressed in pancreatic acinar cells. In the present study, the expression of tau exons in normal and tumoral pancreatic acinar cells was investigated by RT-PCR and cDNA sequencing. Tau isoforms with four tubulin-binding motifs containing either none, one or two N-terminal inserts (exons 2, 3) are indiscriminately expressed in normal and tumoral cells. However, tau transcripts containing the sequence encoded by exon 6 are specifically expressed in pancreatic tumoral cells from exocrine origin. By immunofluorescence and electron microscopy, we have identified in cellular extensions of tumoral cells, tau-decorated microtubules arranged in bundles like those found in neuronal processes. Tau antisense oligonucleotides inhibit the development of these cellular processes and the expression of the 55 kDa tau isoform.
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Zare Marzouni, Hadi, Matineh Barati Bagherabad, Simin Sharaf, Mohammad Zarrinkamar, Shahabeddin Shaban, Hoda Aryan y Ehsan Saburi. "Thioredoxin Reductase Activity and Its Tissue Distribution in the Pathologic Specimens of Patients with Laryngeal Squamous Cell Carcinoma". Galen Medical Journal 5, n.º 3 (20 de septiembre de 2016): 153–59. http://dx.doi.org/10.31661/gmj.v5i3.682.
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Background: Squamous Cell Carcinoma (SCC) is the second most common malignancy of the respiratory tract. Recently, researchers believe that thioredoxin system is effective in the cancerization of some tissues. Thus, this study has been conducted with the aim of measuring of thioredoxin reductase (TrxR) enzyme activity and tissue distribution in the pathologic specimens of patients with laryngeal SCC.Materials and Methods: This study was performed on 40 pathologic blocks (20 healthy and 20 tumoral) from 20 patients with laryngeal SCC who were candidates for laryngectomy surgery. The TrxR enzyme activity was measured by the commercial kit. Also, the tissue distribution of TrxR was determined by immunohistochemical staining and the percentage of staining cells (SC%) and staining intensity were calculated. Data were analyzed by using SPSS13 and significant level was set at P≤0.05.Results: The average the TrxR enzyme activity in the healthy and tumoral tissues was 0.004±0.003µM/min/ml and 0.006±0.003µM/min/ml, respectively (ranged 0.0009 to 0.0104 vs. 0.001 to 0.011 ). However, there was no relationship between the TrxR enzyme activity in the tumoral and healthy tissues (P=0.084). The total score of IHC staining in the healthy tissue was 4.45±1.09 whereas the total of these scores in the tumoral tissue 6.25±0.63. The both scores of SC% and staining intensity in the tumoral tissue was significantly higher than the healthy tissue (P<0.001).Conclusion: Based on the results, although the TrxR enzyme activity has not the significant differences in tumoral tissue compare to healthy tissue, but the tissue distribution in tumoral tissue was higher than healthy tissue.[GMJ.2016;5(3):153-159]
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Colombo, F., A. Cattaneo, S. Mazzucchelli, I. Martin-Padura, G. Rossi, L. Caccamo, V. Mazzaferro, C. Battiston, D. Prati y L. Porretti. "Hepatic stem cell characterization in tumoral and non-tumoral liver specimens from patients with hepatocellular carcinoma". Digestive and Liver Disease 41, n.º 5 (mayo de 2009): A3—A4. http://dx.doi.org/10.1016/j.dld.2009.02.016.
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Vaqué, José P., Gonzalo Gómez-López, Verónica Monsálvez, Ignacio Varela, Nerea Martínez, Cristina Pérez, Orlando Domínguez et al. "PLCG1 mutations in cutaneous T-cell lymphomas". Blood 123, n.º 13 (27 de marzo de 2014): 2034–43. http://dx.doi.org/10.1182/blood-2013-05-504308.
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Key Points Activating mutations in PLCG1 are a frequent finding in tumoral CTCL samples. This raises the possibility of targeted therapies against PLCG1 signaling pathway, using calcineurin inhibitors.
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Singh, Brij M. K., Varun K. Singh y Shyamala Guruvare. "Leiomyoma with Isolated Foam Cell Vasculopathy: A Case Report". Medical Journal of Dr. D.Y. Patil Vidyapeeth 17, n.º 1 (2 de junio de 2023): 228–30. http://dx.doi.org/10.4103/mjdrdypu.mjdrdypu_634_22.
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ABSTRACT Foam cell vasculopathy is an obliterating type of vasculitis characterized by fibrinoid necrosis, sub-intimal foam cell deposition, vessel wall hyalinosis, and lymphocytic infiltrate. Isolated intra-tumoral foam cell vasculitis is rare and similar changes have been reported in a leiomyoma attributed to treatment with tranexamic acid and gonadotropin-releasing hormone (GnRH) analogs. A 68-year-old hypertensive and diabetic female (P2L2) presented with vaginal spotting and vague abdominal pain. An ultrasound abdomen showed an anterior wall fibroid measuring 5 × 4 cm. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Microscopic sections from the leiomyoma showed multiple foci of obliterating vasculitis, along with fibrinoid necrosis, sub-intimal foam cell deposition, and hyalinosis. There was no involvement of the endometrium, cervix, or ovaries. There were no pulmonary, skin, or renal lesions, or history of systemic vasculitis, and treatment by tranexamic acid or GnRH analogs. This prompted a diagnosis of idiopathic intra-tumoral foam cell vasculitis. This finding has been documented previously in three instances, namely, within a renal angiomyolipoma, cerebral Hodgkin’s lymphoma, and a gastrointestinal stromal tumor; the present case provides the first-ever documentation of isolated intra-tumoral acute atherosis-like/foam cell vasculopathy in leiomyoma.
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Greco, Federico, Andrea Panunzio, Caterina Bernetti, Alessandro Tafuri, Bruno Beomonte Zobel y Carlo Augusto Mallio. "The Radiogenomic Landscape of Clear Cell Renal Cell Carcinoma: Insights into Lipid Metabolism through Evaluation of ADFP Expression". Diagnostics 14, n.º 15 (1 de agosto de 2024): 1667. http://dx.doi.org/10.3390/diagnostics14151667.
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This study aims to explore the relationship between radiological imaging and genomic characteristics in clear cell renal cell carcinoma (ccRCC), focusing on the expression of adipose differentiation-related protein (ADFP) detected through computed tomography (CT). The goal is to establish a radiogenomic lipid profile and understand its association with tumor characteristics. Data from The Cancer Genome Atlas (TCGA) and the Cancer Imaging Archive (TCIA) were utilized to correlate imaging features with adipose differentiation-related protein (ADFP) expression in ccRCC. CT scans assessed various tumor features, including size, composition, margin, necrosis, and growth pattern, alongside measurements of tumoral Hounsfield units (HU) and abdominal adipose tissue compartments. Statistical analyses compared demographics, clinical–pathological features, adipose tissue quantification, and tumoral HU between groups. Among 197 patients, 22.8% exhibited ADFP expression significantly associated with hydronephrosis. Low-grade ccRCC patients expressing ADFP had higher quantities of visceral and subcutaneous adipose tissue and lower tumoral HU values compared to their high-grade counterparts. Similar trends were observed in low-grade ccRCC patients without ADFP expression. ADFP expression in ccRCC correlates with specific imaging features such as hydronephrosis and altered adipose tissue distribution. Low-grade ccRCC patients with ADFP expression display a distinct lipid metabolic profile, emphasizing the relationship between radiological features, genomic expression, and tumor metabolism. These findings suggest potential for personalized diagnostic and therapeutic strategies targeting tumor lipid metabolism.
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YÜCE, Melek, Esra ALBAYRAK y Çağrı GÜMÜŞKAPTAN. "Conditioned media of tonsil derived mesenchymal stem cells shows different rates of cytotoxicity on solid cancer cells". Anatolian Current Medical Journal 5, n.º 4 (27 de octubre de 2023): 503–10. http://dx.doi.org/10.38053/acmj.1359905.
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Aims: Mesenchymal stem cells (MSCs) are the apple of the eye of cancer studies. It was indicated that the secreted factors, especially released by MSCs, have tumoral or anti-tumoral effects on tumor progression. MSCs obtained from different sources show different anti-tumoral effects, while MSCs originating from the same source also show different tumoral effects in different cancer cells. Here, we investigated the anti-tumor effects of soluble factors secreted from palatine tonsil MSCs (TMSC) as a new source of MSC on human lung carcinoma (A549) and pancreatic cancer (PANC-1) cell lines.
Methods: Conditioned medium (CM) was obtained from TMSCs isolated from palatine tonsil tissue, and the cytotoxic effect of CM on the growth of A549 and PANC-1 in a dose-dependent manner was demonstrated by MTT analysis. In addition, the function of CM treatment on the cell cycle status of cancer cells and the apoptosis process were investigated through cell cycle analysis with propidium iodide (PI) and Annexin-V/PI detection method by flow cytometry analysis, respectively.
Results: We demonstrated that TMSC-CM treatment significantly decreased the viability of A549 and PANC-1 cell lines in a dose-dependent manner post-48 hours. In addition, CM treatment differentially induced the apoptosis on A549 and PANC-1 cells and also, caused G2/M arrest in the cells.
Conclusion: In light of these findings, our study is the first to show that TMSC-CM has an anti-tumoral effect by stimulating apoptosis on A549 and PANC-1 cells. These findings reveal that the usage of CM has a cell-free cellular therapeutic potential.
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Gisina, Alisa, Irina Kholodenko, Yan Kim, Maxim Abakumov, Alexey Lupatov y Konstantin Yarygin. "Glioma Stem Cells: Novel Data Obtained by Single-Cell Sequencing". International Journal of Molecular Sciences 23, n.º 22 (17 de noviembre de 2022): 14224. http://dx.doi.org/10.3390/ijms232214224.
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Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the inter-tumoral heterogeneity of gliomas, resulting in the updated 2021 WHO classification of gliomas. Thorough understanding of inter-tumoral heterogeneity has already improved the prognosis and treatment outcomes of some types of gliomas. Currently, the challenge for researchers is to study the intratumoral cell heterogeneity of newly defined glioma subtypes. Cancer stem cells (CSCs) present in gliomas and many other tumors are an example of intratumoral heterogeneity of great importance. In this review, we discuss the modern concept of glioma stem cells and recent single-cell sequencing-driven progress in the research of intratumoral glioma cell heterogeneity. The particular emphasis was placed on the recently revealed variations of the cell composition of the subtypes of the adult-type diffuse gliomas, including astrocytoma, oligodendroglioma and glioblastoma. The novel data explain the inconsistencies in earlier glioma stem cell research and also provide insight into the development of more effective targeted therapy and the cell-based immunotherapy of gliomas. Separate sections are devoted to the description of single-cell sequencing approach and its role in the development of cell-based immunotherapies for glioma.
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Wickenhauser, Claudia, Daniel Bethmann, Matthias Kappler, Alexander Walter Eckert, André Steven, Jürgen Bukur, Bernard Aloysius Fox, Jana Beer y Barbara Seliger. "Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma". Cancers 13, n.º 4 (4 de febrero de 2021): 620. http://dx.doi.org/10.3390/cancers13040620.
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Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient’s outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells were found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN-γ signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.
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Russell, Daniel Hugh. "Granulomata in Clear Cell Renal Cell Carcinoma: An Uncommon Presentation of a Common Cancer, Not Two Separate Entities". Clinical Pathology 13 (enero de 2020): 2632010X2095421. http://dx.doi.org/10.1177/2632010x20954215.
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Sarcoidal-like granulomata (SLG) are known to occur as a response to a variety of tumor types, including lymphomas, prominently seminoma, other miscellaneous carcinomas, and rarely in renal cell carcinoma. There have been a handful of previously reported cases in the literature of SLG occurring in association with RCC. Of those previously reported, none were associated with infection and only 3 patients had a history of sarcoidosis. The prognostic significance of SLG in RCC is unsettled and somewhat complicated by the relative rarity of its occurrence and the paucity of data therein. A case is presented of an otherwise histologically typical clear cell renal cell carcinoma with peri-tumoral and intra-tumoral SLG. Special stains were negative for organisms and past medical history was negative for sarcoidosis and connective tissue disease.
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Hussain, Zainab, Jeremy Nigri y Richard Tomasini. "The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer". Cancers 13, n.º 12 (18 de junio de 2021): 3040. http://dx.doi.org/10.3390/cancers13123040.
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Deciphering the interactions between tumor and stromal cells is a growing field of research to improve pancreatic cancer-associated therapies and patients’ care. Indeed, while accounting for 50 to 90% of the tumor mass, many pieces of evidence reported that beyond their structural role, the non-tumoral cells composing the intra-tumoral microenvironment influence tumor cells’ proliferation, metabolism, cell death and resistance to therapies, among others. Simultaneously, tumor cells can influence non-tumoral neighboring or distant cells in order to shape a tumor-supportive and immunosuppressive environment as well as influencing the formation of metastatic niches. Among intercellular modes of communication, extracellular vesicles can simultaneously transfer the largest variety of signals and were recently reported as key effectors of cell–cell communication in pancreatic cancer, from its development to its evolution as well as its ability to resist available treatments. This review focuses on extracellular vesicles-mediated communication between different cellular components of pancreatic tumors, from the modulation of cellular activities and abilities to their biological and physiological relevance. Taking into consideration the intra-tumoral microenvironment and its extracellular-mediated crosstalk as main drivers of pancreatic cancer development should open up new therapeutic windows.
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Miura, Isamu, Motoo Kubota, Kento Takebayashi, Oji Momosaki, Koichi Honma, Takakazu Kawamata y Masahito Yuzurihara. "Tumoral Calcinosis of Thoracic Spine Associated with Vertebral Fracture and Inflammatory Reactions". Case Reports in Orthopedics 2020 (25 de julio de 2020): 1–5. http://dx.doi.org/10.1155/2020/8881698.
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Tumoral calcinosis involving the spine is rare. The involvement of the thoracic spine is rarer than that of the cervical or lumbar spine. We report a case of thoracic tumoral calcinosis accompanied by vertebral fracture with increased concentrations of inflammatory markers and no abnormalities in serum calcinosis and phosphorus concentration. A 60-year-old woman presented with complete paraplegia. Her white blood cell count and C-reactive protein (CRP) concentration were elevated. The thoracic magnetic resonance imaging revealed vertebral fracture and an epidural mass that demonstrated low intensity on both T2- and T1-weighted images at the T9/10 dorsal side of the central canal. This lesion is larger in size than that observed in the previous 2 months. Her laboratory data showed signs of infection, and only decompression surgery without fixation for treatment and diagnosis was performed. Histopathological examination was consistent with tumoral calcinosis. Postoperatively, the patient’s white cell count and CRP concentration were normalized. We found that tumoral calcinosis can occur at the thoracic level on the basis of the spinal instability due to the vertebral compression fracture and the accompanying increase in inflammation indicated by increased white blood cell count and CRP concentration.
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Jiménez-Cárcamo, Danae, Carlos García y Héctor R. Contreras. "Toxins of Okadaic Acid-Group Increase Malignant Properties in Cells of Colon Cancer". Toxins 12, n.º 3 (13 de marzo de 2020): 179. http://dx.doi.org/10.3390/toxins12030179.
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Diarrhetic shellfish poisoning (DSP) is a syndrome caused by the intake of shellfish contaminated with a group of lipophilic and thermostable toxins, which consists of okadaic acid (OA), dinophysistoxin-1 (DTX-1) and dinophysistoxin-2 (DTX-2). These toxins are potent protein Ser/Thr phosphatase inhibitors, mainly type 1 protein phosphatase (PP1) and type 2A protein phosphatase (PP2A). Different effects have been reported at the cellular, molecular and genetic levels. In this study, changes in cell survival and cell mobility induced by OA, DTX-1 and DTX-2 were determined in epithelial cell lines of the colon and colon cancer. The cell viability results showed that tumoral cell lines were more resistant to toxins than the nontumoral cell line. The results of the functional assays for testing cell migration, evaluation of cell death and the expression of proteins associated with cell adhesion showed a dual effect of toxins since in the nontumoral cell line, a greater induction of cell death, presumably by anoikis, was detected. In the tumoral cell lines, there was an induction of a more aggressive phenotype characterized by increased resistance to toxins, increased migration and increased FAK activation. In tumoral cell lines of colon cancer, OA, DTX-1/DTX-2 induce a more aggressive phenotype.
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Cioplea, Mirela, Luciana Nichita, Daniela Georgescu, Liana Sticlaru, Alexandra Cioroianu, Roxana Nedelcu, Gabriela Turcu et al. "FOXP3 in Melanoma with Regression: Between Tumoral Expression and Regulatory T Cell Upregulation". Journal of Immunology Research 2020 (23 de octubre de 2020): 1–8. http://dx.doi.org/10.1155/2020/5416843.
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Cutaneous melanoma is a significant immunogenic tumoral model, the most frequently described immune phenomenon being tumor regression, as a result of the interaction of tumoral antigens and stromal microenvironment. We present a retrospective cohort study including 52 cases of melanoma with regression. There were evaluated correlations of the most important prognostic factors (Breslow depth and mitotic index) with FOXP3 expression in tumor cells and with the presence of regulatory T cells and dendritic cells in the tumoral stroma. FOXP3 expression in tumor cells seems an independent factor of poor prognosis in melanoma, while regression areas are characterized by a high number of dendritic cells and a low number of regulatory T cells. FOXP3 is probably a useful therapeutical target in melanoma, since inhibition of FOXP3-positive tumor clones and of regulatory T cells could eliminate the ability of tumor cells to escape the immune defense of the host.
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Hajihoseini, Mohsen, Arian Karimi, Saeed Sadr y Hanieh Tahermohammadi. "Possible effect of great plantain on tumoral cell angiogenesis". TMR Integrative Medicine 6 (2022): e22004. http://dx.doi.org/10.53388/tmrim202206004.
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Kimura, Yasushi, Atsushi Kasamatsu, Dai Nakashima, Masanobu Yamatoji, Yasuyuki Minakawa, Kazuyuki Koike, Kazuaki Fushimi et al. "ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma". Journal of Cancer 7, n.º 6 (2016): 702–10. http://dx.doi.org/10.7150/jca.14208.
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García-Ramírez, Idoia, Lucía Ruiz-Roca, Alberto Martín-Lorenzo, Óscar Blanco, María Begoña García-Cenador, Francisco Javier García-Criado, Carolina Vicente-Dueñas y Isidro Sánchez-García. "Genetic background affects susceptibility to tumoral stem cell reprogramming". Cell Cycle 12, n.º 15 (agosto de 2013): 2505–9. http://dx.doi.org/10.4161/cc.25544.
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Corsi, Lorenzo, Rossana Guagliumi, Rossella Avallone, Maria Luisa Zeneroli y Mario Baraldi. "Nuclear peripheral benzodiazepine receptors (PBRS) and tumoral cell proliferation". Journal of Hepatology 36 (abril de 2002): 215. http://dx.doi.org/10.1016/s0168-8278(02)80767-x.
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Sipos, Ferenc y Györgyi Műzes. "Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment". Biomedicines 11, n.º 1 (11 de enero de 2023): 189. http://dx.doi.org/10.3390/biomedicines11010189.
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Inflammatory processes and cancer stem cells (CSCs) are increasingly recognized as factors in the development of tumors. Emerging evidence indicates that CSCs are associated with cancer properties such as metastasis, treatment resistance, and disease recurrence. However, the precise interaction between CSCs and the immune microenvironment remains unexplored. Although evasion of the immune system by CSCs has been extensively studied, new research demonstrates that CSCs can also control and even profit from the immune response. This review provides an overview of the reciprocal interplay between CSCs and tumor-infiltrating immune cells, collecting pertinent data about how CSCs stimulate leukocyte reprogramming, resulting in pro-tumor immune cells that promote metastasis, chemoresistance, tumorigenicity, and even a rise in the number of CSCs. Tumor-associated macrophages, neutrophils, Th17 and regulatory T cells, mesenchymal stem cells, and cancer-associated fibroblasts, as well as the signaling pathways involved in these pro-tumor activities, are among the immune cells studied. Although cytotoxic leukocytes have the potential to eliminate CSCs, immune evasion mechanisms in CSCs and their clinical implications are also known. We intended to compile experimental findings that provide direct evidence of interactions between CSCs and the immune system and CSCs and the inflammatory milieu. In addition, we aimed to summarize key concepts in order to comprehend the cross-talk between CSCs and the tumor microenvironment as a crucial process for the effective design of anti-CSC therapies.
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Sánchez-Beato, Margarita. "PD-1 loss and T-cell exhaustion in CTCL tumoral T cells". Blood 138, n.º 14 (7 de octubre de 2021): 1201–3. http://dx.doi.org/10.1182/blood.2021012676.
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Talari, Mojtaba, Enayatollah Seydi, Ahmad Salimi, Zhaleh Mohsenifar, Mohammad Kamalinejad y Jalal Pourahmad. "Dracocephalum: Novel Anticancer Plant Acting on Liver Cancer Cell Mitochondria". BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/892170.
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Dracocephalum kotschyiBoiss. (Labiatae) is a native Iranian medicinal plant which has been used in combination withPeganum harmalaL. as a remedy for many forms of human cancer especially leukemia and gastrointestinal malignancies. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. In this investigation HCC was induced by a single intraperitoneal injection of diethylnitrosamine (DEN) in corn oil at 200 mg/kg body weight to rats. Two weeks after DEN administration, cancer development was promoted with dietary 2-acetylaminofluorene (2-AAF) (0.02%, w/w) for 2 weeks. Serum alpha-fetoprotein (AFP) concentration, serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) activities were also determined for confirmation of hepatocellular carcinoma induction. Then rat hepatocytes were isolated with collagen perfusion technique and tumoral hepatocytes were sorted by flow cytometry. Finally isolated mitochondria obtained from both tumoral and nontumoral hepatocytes were used for any probable toxic effect ofDracocephalum kotschyiethanolic extract. Our results showed thatD. kotschyiextract (250 µg/mL) induced reactive oxygen species (ROS) formation, mitochondrial membrane permeabilization (MMP), and mitochondrial swelling and cytochrome c release only in tumoral but not nontumoral hepatocyte. These findings proposeDracocephalum kotschyias a promising candidate for future anticancer research.
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Donizy, Piotr, Cheng-Lin Wu, Janusz Kopczynski, Malgorzata Pieniazek, Przemyslaw Biecek, Janusz Ryś y Mai P. Hoang. "Prognostic Role of Tumoral PD-L1 and IDO1 Expression, and Intratumoral CD8+ and FoxP3+ Lymphocyte Infiltrates in 132 Primary Cutaneous Merkel Cell Carcinomas". International Journal of Molecular Sciences 22, n.º 11 (23 de mayo de 2021): 5489. http://dx.doi.org/10.3390/ijms22115489.
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The association of immune markers and clinicopathologic features and patient outcome has not been extensively studied in Merkel cell carcinoma (MCC). We correlated tumoral PD-L1 and IDO1 expression, and intratumoral CD8+ and FoxP3+ lymphocytes count with clinicopathologic variables, Merkel cell polyomavirus (MCPyV) status, and patient outcomes in a series of 132 MCC. By univariate analyses, tumoral PD-L1 expression >1% and combined tumoral PD-L1 >1% and high intratumoral FoxP3+ lymphocyte count correlated with improved overall survival (OS) (p = 0.016, 0.0072), MCC-specific survival (MSS) (p = 0.019, 0.017), and progression-free survival (PFS) (p = 0.043, 0.004, respectively). High intratumoral CD8+ and FoxP3+ lymphocyte count correlated with longer MSS (p = 0.036) and improved PFS (p = 0.047), respectively. Ulceration correlated with worse OS and worse MSS. Age, male gender, and higher stage (3 and 4) significantly correlated with worse survival. MCPyV positivity correlated with immune response. By multivariate analyses, only ulceration and age remained as independent predictors of worse OS; gender and stage remained for shorter PFS. Tumoral PD-L1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP+ lymphocytes may represent favorable prognosticators in a subset of MCCs. Tumoral PD-L1 expression correlated with intratumoral CD8+ and FoxP3+ lymphocytes, which is supportive of an adaptive immune response.
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Ipek, Volkan, I. Taci Cangul y Ahmet Akkoc. "Comparative Evaluation of the Cytological, Histopathological and Immunohistochemical Findings of Canine Cutaneous and Subcutaneous Masses". Acta Veterinaria 71, n.º 1 (1 de marzo de 2021): 61–84. http://dx.doi.org/10.2478/acve-2021-0005.
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Abstract In this study, we compared the cytological, histopathological, and immunohistochemical diagnoses of 71 canine cutaneous and subcutaneous masses. Cytological diagnoses included 56 tumors (21 mesenchymal, 15 epithelial, 16 round cell, four melanocytic), 13 inflammatory reactions, and two cysts. Of the 21 cytologically diagnosed mesenchymal tumors, three were later confirmed non-tumoral (hematoma, granulation tissue, fibroepithelial polyp). Thirteen out of 15 epithelial tumors were correctly diagnosed cytologically, whereas two cases were confirmed to be non-tumoral (fibroepithelial polyp, granulation tissue) after histopathological examination. One mast cell tumor was later confirmed as fibrous hyperplasia; diagnoses were correct in other round cell tumors. Cytological diagnoses were correct for all melanocytic tumors and cystic lesions. Five cases which had been cytologically diagnosed as inflammatory reactions were diagnosed as tumors (lymphoma, papilloma, sebaceous adenoma, and squamous cell carcinoma) after histopathological examination. Immunohistochemistry confirmed the histopathological diagnoses of all epithelial and round cell tumors, while the diagnoses of six mesenchymal tumors were changed after the immunohistochemical examination. The total accuracy of cytology in the diagnosis of tumoral/non-tumoral masses was 84.5%, and the accuracy in the determination of benign/malignant behavior was 83%. Diagnostic accordance between histopathology and immunohistochemistry was 86.6%. High success rates obtained with cytological diagnoses prove that cytology is a reliable diagnostic tool. The main diagnostic challenge remains with mesenchymal tumors and tumors accompanied by inflammatory reactions. The results suggest that immunohistochemistry is fundamental for diagnoses of most mesenchymal tumors.
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Bertagnolo, Valeria, Federica Brugnoli, Carlo Mischiati, Alessia Sereni, Alberto Bavelloni, Cinzia Carini y Silvano Capitani. "Vav promotes differentiation of human tumoral myeloid precursors". Experimental Cell Research 306, n.º 1 (mayo de 2005): 56–63. http://dx.doi.org/10.1016/j.yexcr.2004.12.001.
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Zanoni, Diogo Sousa, Silvia Regina Kleeb y José Guilherme Xavier. "Emprego do cell block de agarose como método complementar no diagnóstico citológico de tumores mamários caninos". Ciência Rural 43, n.º 3 (19 de febrero de 2013): 489–95. http://dx.doi.org/10.1590/s0103-84782013005000010.
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Os tumores mamários são neoplasias comuns em diversas espécies, sendo os processos oncológicos de maior incidência em cães. A elevada frequência e agressividade desses processos justificam a busca de métodos diagnósticos e prognósticos rápidos, de custo reduzido e menor invasividade, visando a uma abordagem cirúrgica e terapêutica adequada. O presente estudo avaliou a adequação da utilização da técnica de cell block de agarose como método diagnóstico complementar aos esfregaços tradicionais no diagnóstico desses processos. Para tanto, foram obtidas 51 amostras citológicas de tumores mamários de 30 cadelas que passaram por excisão tumoral no HOVET-UMESP, comparando-se os resultados obtidos a partir dos esfregaços, de cell blocks, e de sua associação (esfregaços cell blocks-1) com o diagnóstico histopatológico. Os melhores resultados foram obtidos mediante a associação dos métodos, reduzindo os resultados falso-negativos e elevando a correlação cito-histológica, reforçando a importância da citologia na rotina oncológica veterinária.
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Silva, Saulo Luis da, Patrícia Maria Figueiredo y Tomomasa Yano. "Cytotoxic evaluation of essential oil from Zanthoxylum rhoifolium Lam. leaves". Acta Amazonica 37, n.º 2 (junio de 2007): 281–86. http://dx.doi.org/10.1590/s0044-59672007000200015.
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Zanthoxylum rhoifolium Lam is a plant popularly used as antimicrobial, for malaria and inflammatory treatment. The essential oil of Z. rhoifolium was extracted and its cytotoxic effects against HeLa (human cervical carcinoma), A-549 (human lung carcinoma), HT-29 (human colon adenocarcinoma), Vero (monkey kidney) cell lines and mice macrophages were evaluated. Some of the terpenes of its essential oil (ß-caryophyllene, alpha-humulene, alpha -pinene, myrcene and linalool) were also tested to verify their possible influence in the oil cytotoxic activity. The results obtained permitted to confirm that the essential oil is cytotoxic against tumoral cells (CD50 = 82.3, 90.7 and 113.6 µg/ml for A-549, HeLa e HT-29 cell lines, respectively), while it did not show cytotoxicity against non-tumoral cells (Vero and mice macrophages). Thus, the essential oil from Z. rhoifolium leaves seems to present a possible therapeuthic role due to its selective cytotoxic activity against tumoral cell lines.
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Garin, E., B. Denizot, J. Roux, N. Noiret, N. Lepareur, M. Moreau, H. Mesba et al. "Description and technical pitfalls of a hepatoma model and of intra-arterial injection of radiolabelled lipiodol in the rat". Laboratory Animals 39, n.º 3 (1 de julio de 2005): 314–20. http://dx.doi.org/10.1258/0023677054307051.
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Intra-arterial metabolic radiotherapy (using lipiodol labelled with iodine-131 or rhenium-188) is a therapeutic approach that can be used for the treatment of hepatocellular carcinomas (HCC). We propose a detailed description of the tumoral model using the N1-S1 cell line as well as a technique for intra-arterial injection of radiolabelled lipiodol in order to undertake preclinical studies necessary for the evaluation of a new molecule. We also report the principal technical pitfalls that were faced. The speed of injection of the tumoral cells is a key factor in the tumoral induction since slow injections lead to a tumoral induction rate of 36.3% compared with 76.6% ( P < 0.01) when using very slow injections. This parameter should thus be controlled carefully during the subcapsular injection of the tumoral cells. In addition, when injecting radiolabelled lipiodol, anaesthesia should not be performed with isoflurane since this leads to a reduction in tumoral uptake. Indeed, we found a 'tumour/healthy liver' uptake ratio of only 2.1 ± 0.7 with isoflurane as against 4.4 ± 2.6 ( P < 0.05) when anaesthesia was carried out by intraperitoneal injection of ketamine. Lastly, we show that the tumour size has an influence on the tumoral uptake of radiolabelled lipiodol; therefore, this parameter must also be carefully controlled.
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Rodet, Franck, Alice Capuz, Bilgehan-Aybike Ozcan, Rémy Le Beillan, Antonella Raffo-Romero, Firas Kobeissy, Marie Duhamel y Michel Salzet. "PC1/3 KD Macrophages Exhibit Resistance to the Inhibitory Effect of IL-10 and a Higher TLR4 Activation Rate, Leading to an Anti-Tumoral Phenotype". Cells 8, n.º 12 (22 de noviembre de 2019): 1490. http://dx.doi.org/10.3390/cells8121490.
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During tumorigenesis, macrophages are recruited by tumors and orientated towards a pro-tumoral phenotype. One of the main anti-tumoral immunotherapy consists of their re-polarization in an anti-tumoral phenotype. We have demonstrated that the inhibition of proprotein convertase 1/3 combined with TLR4 activation in macrophages is a promising strategy. These macrophages display pro-inflammatory and anti-tumoral phenotypes. A hallmark is a stronger activation of the pro-inflammatory NFKB pathway. We believe that this can be explained by a modification of TLR4 expression at the cell surface or MYD88 cleavage since it exhibits a potential cleavage site for proprotein convertases. We tested these hypotheses through immunofluorescence and Western blot experiments. A proteomics study was also performed to test the sensitivity of these macrophages to IL-10. We demonstrated that these macrophages treated with LPS showed a quicker re-expression of TLR4 at the cell surface. The level of MYD88 was also higher when TLR4 was internalized. Moreover, these macrophages were resistant to the pro-tumoral effect of IL-10 and still produced pro-inflammatory factors. This established that the sensitivity to anti-inflammatory molecules and the length of TLR4 desensitization were reduced in these macrophages. Therefore, during antitumoral immunotherapy, a repeated stimulation of TLR4 may reactivate PC1/3 inhibited macrophages even in an anti-inflammatory environment.
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de Laat, Vincent, Halit Topal, Jonas Dehairs, Xander Spotbeen, Ali Talebi, Frank Vanderhoydonc, Tessa Ostyn, Tania Roskams, Baki Topal y Johan Swinnen. "Abstract C077: Evidence for a tumoral temperature driven chemoresistance pathway in pancreatic cancer". Cancer Research 82, n.º 22_Supplement (15 de noviembre de 2022): C077. http://dx.doi.org/10.1158/1538-7445.panca22-c077.
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Abstract Tumor growth is inevitably accompanied by changes in the tumor-microenvironment to which cancer cells have to adapt in order to thrive. Alterations in metabolism and blood perfusion of solid tumors have been suggested to drive a spontaneous increase in tumoral temperature. However, it is currently unknown if this phenomenon affects cancer biology. We found increased temperature in human pancreatic ductal adenocarcinoma (PDAC) tumors. By mimicking this observation in PDAC cell lines, we found that cancer cells adapt to tumoral temperature by altering the cellular lipidome and accordingly evade ferroptosis, a lipid-dependent form of cell death. We found evidence that tumoral temperature-induced ferroptosis evasion depends on p38-MAPK deactivation and ultimately drives resistance to the chemotherapeutic drug gemcitabine. Collectively, our findings suggest a direct role for p38-dependend ferroptosis evasion in gemcitabine resistance, and we identify tumoral temperature as a pathophysiological driver of this process. Our discovery unveils temperature as an unexplored hallmark of the tumor-microenvironment. Citation Format: Vincent de Laat, Halit Topal, Jonas Dehairs, Xander Spotbeen, Ali Talebi, Frank Vanderhoydonc, Tessa Ostyn, Tania Roskams, Baki Topal, Johan Swinnen. Evidence for a tumoral temperature driven chemoresistance pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C077.