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1.
Curr Issues Mol Biol ; 46(10): 11282-11295, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39451550

RESUMO

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis.

2.
Int J Mol Sci ; 25(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38892242

RESUMO

Skeletal muscle atrophy (SMA) is caused by a rise in muscle breakdown and a decline in protein synthesis, with a consequent loss of mass and function. This study characterized the effect of an amino acid mixture (AA) in models of SMA, focusing on mitochondria. C57/Bl6 mice underwent immobilization of one hindlimb (I) or cardiotoxin-induced muscle injury (C) and were compared with controls (CTRL). Mice were then administered AA in drinking water for 10 days and compared to a placebo group. With respect to CTRL, I and C reduced running time and distance, along with grip strength; however, the reduction was prevented by AA. Tibialis anterior (TA) muscles were used for histology and mitochondria isolation. I and C resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio and smaller myofibers than those of CTRL. Interestingly, these alterations were lightly observed in mice treated with AA. The mitochondrial yield from the TA of I and C mice was lower than that of CTRL but not in AA-treated mice. AA also preserved mitochondrial bioenergetics in TA muscle from I and C mice. To conclude, this study demonstrates that AA prevents loss of muscle mass and function in SMA by protecting mitochondria.


Assuntos
Aminoácidos , Metabolismo Energético , Camundongos Endogâmicos C57BL , Músculo Esquelético , Atrofia Muscular , Animais , Camundongos , Metabolismo Energético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/patologia , Atrofia Muscular/etiologia , Masculino , Modelos Animais de Doenças , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos
3.
Int J Mol Sci ; 24(4)2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36835131

RESUMO

Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a useful adjunct in several scenarios, namely (1) to correctly identify flat urothelial lesions and inverted urothelial lesions in the diagnostic setting; (2) to provide prognostic hints in both non-muscle invasive (NMI) and muscle invasive (MI) tumors, thus supplementing risk stratification tools, especially when evaluating higher-risk tumors such as those with variant morphology; (3) to improve antibody panels as a surrogate marker of BC molecular subtyping. Furthermore, the potential of HER2 as a therapeutic target has been only partly explored so far, in light of the ongoing development of novel target therapies.


Assuntos
Receptor ErbB-2 , Neoplasias da Bexiga Urinária , Humanos , Biomarcadores Tumorais/metabolismo , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
4.
Int J Mol Sci ; 24(3)2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36768260

RESUMO

Redox homeostasis is determinant in the modulation of quiescence/self-renewal/differentiation of stem cell lines. The aim of this study consisted of defining the impact of redox modifications on cell fate in a human hepatic progenitor line. To achieve this, the HepaRG cell line, which shows oval ductular bipotent characteristics, was used. The impact of redox status on the balance between self-renewal and differentiation of HepaRG cells was investigated using different methodological approaches. A bioinformatic analysis initially proved that the trans-differentiation of HepaRG toward bipotent progenitors is associated with changes in redox metabolism. We then exposed confluent HepaRG (intermediate differentiation phase) to oxidized (H2O2) or reduced (N-acetylcysteine) extracellular environments, observing that oxidation promotes the acquisition of a mature HepaRG phenotype, while a reduced culture medium stimulates de-differentiation. These results were finally confirmed through pharmacological modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2), a principal modulator of the antioxidant response, in confluent HepaRG. NRF2 inhibition led to intracellular pro-oxidative status and HepaRG differentiation, while its activation was associated with low levels of reactive species and de-differentiation. In conclusion, this study shows that both intra- and extracellular redox balance are crucial in the determination of HepaRG fate. The impact of redox status in the differentiation potential of HepaRG cells is significant on the utilization of this cell line in pre-clinical studies.


Assuntos
Peróxido de Hidrogênio , Fator 2 Relacionado a NF-E2 , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Linhagem Celular , Células-Tronco/metabolismo , Diferenciação Celular/fisiologia , Oxirredução , Hepatócitos/metabolismo
5.
Int J Mol Sci ; 24(17)2023 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-37686069

RESUMO

To the current data, there have been 6,955,141 COVID-19-related deaths worldwide, reported to WHO. Toll-like receptors (TLRs) implicated in bacterial and virus sensing could be a crosstalk between activation of persistent innate-immune inflammation, and macrophage's sub-population alterations, implicated in cytokine storm, macrophage over-activation syndrome, unresolved Acute Respiratory Disease Syndrome (ARDS), and death. The aim of this study is to demonstrate the association between Toll-like-receptor-4 (TLR-4)-induced inflammation and macrophage imbalance in the lung inflammatory infiltrate of lethal COVID-19 disease. Twenty-five cases of autopsy lung tissues were studied by digital pathology-based immunohistochemistry to evaluate expression levels of TLR-4 (CD 284), pan-macrophage marker CD68 (clone KP1), sub-population marker related to alveolar macrophage Galectin-3 (GAL-3) (clone 9C4), and myeloid derived CD163 (clone MRQ-26), respectively. SARS-CoV-2 viral persistence has been evaluated by in situ hybridation (ISH) method. This study showed TLR-4 up-regulation in a subgroup of patients, increased macrophage infiltration in both Spike-1(+) and Spike-1(-) lungs (p < 0.0001), and a macrophage shift with important down-regulation of GAL-3(+) alveolar macrophages associated with Spike-1 persistence (p < 0.05), in favor of CD163(+) myeloid derived monocyte-macrophages. Data show that TLR-4 expression induces a persistent activation of the inflammation, with inefficient resolution, and pathological macrophage shift, thus explaining one of the mechanisms of lethal COVID-19.


Assuntos
COVID-19 , Galectina 3 , Humanos , Receptor 4 Toll-Like , SARS-CoV-2 , Macrófagos
6.
Int J Med Sci ; 17(1): 112-124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929745

RESUMO

Background: HPV-positive oral squamous cell carcinomas (OSCCs) are specific biological and clinical entities, characterized by a more favorable prognosis compared to HPV-negative OSCCs and occurring generally in non-smoking and non-drinking younger individuals. However, poor information is available on the molecular and the clinical behavior of HPV-positive oral cancers occurring in smoking/drinking subjects. Thus, this study was designed to compare, at molecular level, two OSCC cell lines, both derived from drinking and smoking individuals and differing for presence/absence of HPV infection. Methods: HPV-negative UPCI-SCC-131 and HPV16-positive UPCI-SCC-154 cell lines were compared by whole genome gene expression profiling and subsequently studied for activation of Wnt/ßCatenin signaling pathway by the expression of several Wnt-target genes, ßCatenin intracellular localization, stem cell features and miRNA let-7e. Gene expression data were validated in head and neck squamous cell carcinoma (HNSCC) public datasets. Results: Gene expression analysis identified Wnt/ßCatenin pathway as the unique signaling pathway more active in HPV-negative compared to HPV-positive OSCC cells and this observation was confirmed upon evaluation of several Wnt-target genes (i.e., Cyclin D1, Cdh1, Cdkn2a, Cd44, Axin2, c-Myc and Tcf1). Interestingly, HPV-negative OSCC cells showed higher levels of total ßCatenin and its active form, increase of its nuclear accumulation and more prominent stem cell traits. Furthermore, miRNA let-7e was identified as potential upstream regulator responsible for the downregulation of Wnt/ßCatenin signaling cascade since its silencing in UPCI-SCC-154 cell resulted in upregulation of Wnt-target genes. Finally, the analysis of two independent gene expression public datasets of human HNSCC cell lines and tumors confirmed that Wnt/ßCatenin pathway is more active in HPV-negative compared to HPV-positive tumors derived from individuals with smoking habit. Conclusions: These data suggest that lack of HPV infection is associated with more prominent activation of Wnt/ßCatenin signaling pathway and gain of stem-like traits in tobacco-related OSCCs.


Assuntos
Papillomavirus Humano 16/genética , Nicotiana/efeitos adversos , Infecções por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Idoso , Antígenos CD/genética , Proteína Axina/genética , Caderinas/genética , Linhagem Celular Tumoral , Ciclina D1/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Papillomavirus Humano 16/patogenicidade , Humanos , Receptores de Hialuronatos/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Proteínas Proto-Oncogênicas c-myc/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Via de Sinalização Wnt/genética
7.
J Oral Pathol Med ; 48(2): 108-114, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30489667

RESUMO

BACKGROUND: ADAR1 is an enzymatic protein, which catalyzes a RNA editing reaction by converting Adenosine to Inosine, and its expression has been found to be dysregulated in many cancer types. The aim of this study was to analyze the expression of ADAR1 in oral squamous cells carcinoma. METHODS: In order to analyze the ADAR1 mRNA expression, data from The Cancer Genome Atlas (TCGA) database were downloaded and analyzed. In addition, immunohistochemistry analysis was performed on an institutional database including 46 samples of oral squamous cell carcinoma in a tissue microarray (TMA). RESULTS: No statistically significant correlation linked the mRNA ADAR1 expression to any clinic-pathological variables in the TCGA database. Immunohistochemistry analysis of ADAR1 showed different expressions between normal mucosa and tumor tissue. Focusing on the subcellular localization, the nuclear expression of ADAR1 correlated with higher grading of differentiation (ρ = 0.442; P-value = 0.002); the general expression of ADAR1 either in cytoplasm or in nuclei, correlated with the Gender of patients (Cytoplasm expression: ρ = -0.295; P-value = 0.049; while for nuclear expression: ρ = +0.374; P = 0.011); cytosol expression resulted to be an independent protective prognostic factor (HR = 0.047; C.I. 95% 0.007-0.321; P-value = 0.002). CONCLUSION: Higher expression of ADAR1 into the cytoplasm resulted to be an independent prognostic factor. In order to understand ADAR1 role in cancer, further studies should be performed, in bigger cohort and under a bio-molecular point of view.


Assuntos
Adenosina Desaminase/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Citoplasma/genética , Expressão Gênica , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/genética , Proteínas de Ligação a RNA/genética , Adenosina Desaminase/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Masculino , Prognóstico , Análise Serial de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo
8.
Int J Mol Sci ; 21(1)2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878037

RESUMO

AIM: Musashi 2 (MSI2), which is an RNA-binding protein, plays a fundamental role in the oncogenesis of several cancers. The aim of this study is to investigate the expression of MSI2 in Oral Squamous Cell Carcinoma (OSCC) and evaluate its correlation to clinic-pathological variables and prognosis. MATERIALS AND METHODS: A bioinformatic analysis was performed on data downloaded from The Cancer Genome Atlas (TCGA) database. The MSI2 expression data were analysed for their correlation with clinic-pathological and prognostic features. In addition, an immmunohistochemical evaluation of MSI2 expression on 108 OSCC samples included in a tissue microarray and 13 healthy mucosae samples was performed. RESULTS: 241 patients' data from TCGA were included in the final analysis. No DNA mutations were detected for the MSI2 gene, but a hyper methylated condition of the gene emerged. MSI2 mRNA expression correlated with Grading (p = 0.009) and overall survival (p = 0.045), but not with disease free survival (p = 0.549). Males presented a higher MSI2 mRNA expression than females. The immunohistochemical evaluation revealed a weak expression of MSI2 in both OSCC samples and in healthy oral mucosae. In addition, MSI2 expression directly correlated with Cyclin-D1 expression (p = 0.022). However, no correlation has been detected with prognostic outcomes (overall and disease free survival). CONCLUSIONS: The role of MSI2 expression in OSCC seems to be not so closely correlated with prognosis, as in other human neoplasms. The correlation with Cyclin-D1 expression suggests an indirect role that MSI2 might have in the proliferation of OSCC cells, but further studies are needed to confirm such results.


Assuntos
Carcinoma de Células Escamosas , Ciclina D1/biossíntese , Bases de Dados Factuais , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais , Proteínas de Ligação a RNA/biossíntese , Caracteres Sexuais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Neoplasias Bucais/metabolismo , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Taxa de Sobrevida
9.
Int J Mol Sci ; 19(9)2018 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-30205554

RESUMO

Survivin is a well-known protein involved in the inhibition of apoptosis in many different cancer types. The aim of this study was to perform an integrated bioinformatic and histologic analysis in order to study the expression and prognostic role of Survivin and its related gene BIRC5 in oral cancer. Publicly available databases were accessed via Gene Expression Omnibus and Oncomine, in addition raw data from The Cancer Genome Atlas (TCGA) were also obtained in order to analyze the rate of gene mutation, expression and methylation in patients with oral squamous cells carcinoma (OSCC). Immunohistochemistry (IHC) was also performed in order to evaluate the nuclear and cytoplasmic expression of Survivin and their correlation with cell proliferation in samples from OSCC patients. Results of this study revealed that Survivin is rarely mutated in OSCC samples and upregulated when compared to non-cancerous tissue. A negative correlation between the methylation of the island cg25986496 and BIRC5 mRNA expression was detected from TCGA data. IHC staining revealed that cytoplasmic (and not nuclear) expression of Survivin is associated with poor overall survival in OSCC patients, while the nuclear expression correlates with higher proliferation rate. In addition, data from TCGA database revealed that BIRC5 gene expression is an independent prognostic factor for OSCC patients.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/genética , Survivina/genética , Idoso , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Biologia Computacional , Feminino , Redes Reguladoras de Genes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/patologia , Prognóstico , Survivina/análise , Regulação para Cima
10.
Br J Cancer ; 117(7): 984-993, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28797028

RESUMO

BACKGROUND: Recent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers. METHODS: The presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11ß-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8+ T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11ß-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues. RESULTS: We show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8+ T cells in vitro. 11ß-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11ß-HSDs demonstrated that 11ß-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11ß-HSD2 activity by 18ß-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11ß-HSD2 was significantly reduced in human SCCs of the skin. CONCLUSIONS: The results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Carcinoma de Células Escamosas/enzimologia , Células Epiteliais/enzimologia , Hidrocortisona/metabolismo , Melanoma/enzimologia , Neoplasias Cutâneas/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/análise , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Hormônio Adrenocorticotrópico/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/química , Adesão Celular , Proliferação de Células/efeitos dos fármacos , Cortisona/farmacologia , Meios de Cultivo Condicionados/farmacologia , Regulação para Baixo , Inativação Gênica , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Células HT29 , Humanos , Hidrocortisona/imunologia , Hidrocortisona/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Células MCF-7 , Melanoma/química , Comunicação Parácrina , Receptores de Glucocorticoides/imunologia , Receptores de Glucocorticoides/metabolismo , Neoplasias Cutâneas/química
11.
Cells ; 13(10)2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38786077

RESUMO

Patients with COVID-19 have coagulation and platelet disorders, with platelet alterations and thrombocytopenia representing negative prognostic parameters associated with severe forms of the disease and increased lethality. METHODS: The aim of this study was to study the expression of platelet glycoprotein IIIa (CD61), playing a critical role in platelet aggregation, together with TRL-2 as a marker of innate immune activation. RESULTS: A total of 25 patients were investigated, with the majority (24/25, 96%) having co-morbidities and dying from a fatal form of SARS-CoV-2(+) infection (COVID-19+), with 13 men and 12 females ranging in age from 45 to 80 years. When compared to a control group of SARS-CoV-2 (-) negative lungs (COVID-19-), TLR-2 expression was up-regulated in a subset of patients with deadly COVID-19 fatal lung illness. The proportion of Spike-1 (+) patients found by PCR and ISH correlates to the proportion of Spike-S1-positive cases as detected by digital pathology examination. Furthermore, CD61 expression was considerably higher in the lungs of deceased patients. In conclusion, we demonstrate that innate immune prolonged hyperactivation is related to platelet/megakaryocyte over-expression in the lung. CONCLUSIONS: Microthrombosis in deadly COVID-19+ lung disease is associated with an increase in the number of CD61+ platelets and megakaryocytes in the pulmonary interstitium, as well as their functional activation; this phenomenon is associated with increased expression of innate immunity TLR2+ cells, which binds the SARS-CoV-2 E protein, and significantly with the persistence of the Spike-S1 viral sequence.


Assuntos
COVID-19 , Pulmão , Megacariócitos , SARS-CoV-2 , Trombose , Receptor 2 Toll-Like , Regulação para Cima , Humanos , COVID-19/patologia , COVID-19/imunologia , COVID-19/metabolismo , Masculino , Feminino , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Megacariócitos/metabolismo , Megacariócitos/patologia , Megacariócitos/virologia , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Pulmão/patologia , Pulmão/virologia , Pulmão/metabolismo , Regulação para Cima/genética , Trombose/patologia , Integrina beta3/metabolismo , Integrina beta3/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Pneumonia Viral/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Pneumonia Viral/metabolismo , Imunidade Inata , Pandemias
12.
J Clin Med ; 12(21)2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37959281

RESUMO

BACKGROUND: Inflammatory microenvironment is an essential component of all tumors, including thyroid cancer. Autoimmune thyroid diseases are often associated with thyroid cancer. CD25, expressed in Treg cells and B cells, has been found to be associated with autoimmune thyroid diseases and the NFkB pathway is critical to tumor formation, regulating immune-related genes, and pro-inflammatory cytokine. METHODS: Protein expression of CD25 and NFkB and its phosphorylated form was analyzed by immunohistochemistry in 80 patients with thyroid cancer (10 cases of cancers with Hashimoto's thyroiditis and 70 cases without). RESULTS: CD25 was mainly detected in the nucleus of the inflammatory cells such as in the thyrocytes and neoplastic cells. Protein staining was detected in the T-lymphocytes of the outermost zone of the lymphoid follicles. Moreover, in all cancer alterations, there were a higher level of p-NFkB than in the surrounding tissues. Again, p-NFkB staining was evident in neoplastic cells but not evident in inflammatory cells. CONCLUSIONS: Strong inflammatory infiltrate in the tumor microenvironment is correlated with an invasive phenotype. CD25 and p-NFkB levels were statistically significantly overexpressed in cancer cells.

13.
Biomolecules ; 12(3)2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35327577

RESUMO

Toll-like receptors (TLRs) regulate innate and adaptive immune responses. Moreover, TLRs can induce a pro-survival and pro-proliferation response in tumor cells. This study aims to investigate the expression of TLR4 in the epithelium surrounding oral squamous cell carcinomas (OSCC) in relation to its inflammatory microenvironment. This study included 150 human samples: 30 normal oral control (NOC), 38 non-lichenoid epithelium surrounding OSCC (NLE-OSCC), 28 lichenoid epithelium surrounding OSCC (LE-OSCC), 30 OSCC ex-non oral lichenoid lesion (OSCC Ex-NOLL), and 24 OSCC ex-oral lichenoid lesion (OSCC Ex-OLL). TLR4 expression was investigated by immunohistochemistry and the percentage of positive cells was quantified. In addition, a semiquantitative analysis of staining intensity was performed. Immunohistochemical analysis revealed that TLR4 is strongly upregulated in LE-OSCC as compared to normal control epithelium and NLE-OSCC. TLR4 expression was associated with the inflammatory environment, since the percentage of positive cells increases from NOC and NLE-OSCC to LE-OSCC, reaching the highest value in OSCC Ex-OLL. TLR4 was detected in the basal third of the epithelium in NLE-OSCC, while in LE-OSCC, TLR4 expression reached the intermediate layer. These results demonstrated that an inflammatory microenvironment can upregulate TLR4, which may boost tumor development.


Assuntos
Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Receptor 4 Toll-Like , Epitélio/metabolismo , Humanos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Receptor 4 Toll-Like/metabolismo , Microambiente Tumoral
14.
NPJ Regen Med ; 6(1): 28, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039998

RESUMO

The stem cell ability to self-renew and lead regeneration relies on the balance of complex signals in their microenvironment. The identification of modulators of hepatic progenitor cell (HPC) activation is determinant for liver regeneration and may improve cell transplantation for end-stage liver disease. This investigation used different models to point out the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a key regulator of the HPC fate. We initially proved that in vivo models of biliary epithelial cells (BECs)/HPC activation show hepatic oxidative stress, which activates primary BECs/HPCs in vitro. NRF2 downregulation and silencing were associated with morphological, phenotypic, and functional modifications distinctive of differentiated cells. Furthermore, NRF2 activation in the biliary tract repressed the ductular reaction in injured liver. To definitely assess the importance of NRF2 in HPC biology, we applied a xenograft model by inhibiting NRF2 in the human derived HepaRG cell line and transplanting into SCID/beige mice administered with anti-Fas antibody to induce hepatocellular apoptosis; this resulted in effective human hepatocyte repopulation with reduced liver injury. To conclude, NRF2 inhibition leads to the activation and differentiation of liver progenitors. This redox-dependent transcription factor represents a potential target to regulate the commitment of undifferentiated hepatic progenitors into specific lineages.

15.
Tissue Eng Part A ; 27(9-10): 631-641, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32907520

RESUMO

In the context of biointeractive dressings used for enhancing wound healing, the use of stromal vascular fraction (SVF) or adipose-derived stem cells (ASCs) hereof derived has not been fully exploited yet. Noncultured SVF, a heterogeneous mesenchymal population of cells, is attractive in the field of dermal regeneration because it can be instantaneously obtained, avoids genomic alterations, and is comparatively safer than cultured ASCs. Integra® Dermal Regeneration Template (DRT) was sprinkled with ASCs in complete medium supplemented with 10% fetal bovine serum (FBS), or SVF, obtained from emulsified or nonemulsified fat, in medium supplemented with 2% platelet-rich plasma (PRP). The presence and differentiation of cells were evaluated by standard histochemistry and immunohistochemistry, whereas conditioned media were analyzed for vascular endothelial growth factors (VEGF) by ELISA. In vitro experiments were conducted to analyze ASC proliferation in the presence of either FBS or PRP. Deposition of ASCs in medium supplemented with FBS caused their integration into Integra DRT as early as 1 h. ASCs were found as aggregates until 6-10 days without forming organized structures. When seeded onto Integra DRT, SVF cells in medium supplemented with PRP formed aggregates at early times, which at 7 and 10 days organized into vascular-like structures, lined by CD31+ and smooth muscle actin-positive cells. With nonemulsified fat, the lacunar structures did not show an organized distribution of SVF cells. PRP induced ASC proliferation although at lower level than FBS. VEGF secretion was enhanced when fat emulsification was introduced into the protocol. In conclusion, the combination of SVF cells obtained from emulsified fat, PRP, and Integra DRT exhibit synergistic effect on the formation of vessel-like structures indicating a step forward aimed at regenerative surgery for chronic wound healing.


Assuntos
Tecido Adiposo , Plasma Rico em Plaquetas , Adipócitos , Células Cultivadas , Células-Tronco , Cicatrização
16.
Infect Agent Cancer ; 16(1): 34, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001199

RESUMO

Since December 2019, the global burden of the COVID-19 pandemic has increased rapidly and has impacted nearly every country in the world, affecting those who are elderly or with underlying comorbidities or immunocompromised states. Aim of this systematic review is to summarize lung histopathological characteristics of COVID-19, not only for diagnostic purpose but also to evaluate changes that can reflect pathophysiological pathways that can inform clinicians of useful treatment strategies. We identified following histopathological changes among our patients:: hyaline membranes; endothelial cells/ interstitial cells involvement; alveolar cells, type I pneumocytes/ type II pneumocytes involvement; interstitial and/ or alveolar edema; evidence of hemorrhage, of inflammatory cells, evidence of microthrombi; evidence of fibrin deposition and of viral infection in the tissue samples.The scenario with proliferative cell desquamation is typical of Acute Respiratory Distress Syndrome (ARDS) that can be classified as diffuse alveolar damage (DAD) and not DAD-ARDS. The proposed pathological mechanism concerns the role of both innate and adaptive components of the immune system. COVID-19 lethal cases present themselves as a heterogeneous disease, characterized by the different simultaneous presence of different histological findings, which reflect histological phases with corresponding different pathological pathways (epithelial, vascular and fibrotic changes), in the same patient.

17.
J Chromatogr B Analyt Technol Biomed Life Sci ; 856(1-2): 205-13, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17613287

RESUMO

The topic of this study is the impact of several pre-analytical and analytical variables on proteomic profiling of human urine by surface enhanced laser desorption/ionization time of flight-mass spectrometry (SELDI-TOF-MS) in healthy subjects. Urine storage at room temperature caused a progressive degradation of proteins, which was prevented by the addition of protease inhibitors only up to 2 h from the collection. The timing of collection over the day had only a minor impact on protein profile, although influencing the intensity of peaks. Repeated freeze/thaw cycles (up to five) did not affect either the number or the intensity of the peaks. A comparison of the protein profile from eight different healthy individuals showed fairly consistent inter-subject similarities, along with between-subject differences, which were markedly dependent on the sex and the type of ProteinChip array used. The addition of a variety of denaturing agents improved the quality of the spectra with all the chips tested (CM10, Q10 and H50), but not with the copper-coated IMAC-30 chip. Finally, SPA matrix allowed to achieve a better performance of SELDI-TOF/MS spectrum, as compared with CHCA, regardless of the ProteinChip array used and even in the low m/z range (2500-10,000). In conclusion, we suggest that a careful choice of a number of pre-analytical and analytical conditions is required to accomplish and define a unifying protocol for the analysis of human urine by SELDI-TOF/MS, in physiological and in pathological states.


Assuntos
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Urinálise/métodos , Centrifugação , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Manejo de Espécimes
18.
Oncotarget ; 8(15): 25433-25441, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28445991

RESUMO

In the present study we tested the role of Human Epidermal Growth Factor Receptor-2 (HER-2) expression, as assayed by immunohistochemistry, in predicting recurrence and progression in 67 patients with T1G3 BC having undergone transurethral resection of bladder tumor (TURBT) alone (33) or TURBT + Bacillus Calmette Guerin (BCG) instillations (34). All patients had a negative restaging TURBT within 4 months after the first TURBT. At median follow-up of 75.7 months, the overall disease-free and progression-free rates were 35.8% and 73.0%, respectively. Univariate Kaplan-Meier survival analysis showed that traditional prognostic factors (sex, tumor number/size/recurrence) failed to predict disease-free and progression free survival (DFS, PFS). BCG treatment was a significant predictor of DFS (p=0.0231) but not of PFS (p=0.6901). HER-2 overexpression was a significant predictor of DFS (p=0.0013) and PFS (p=0.0322) in the overall patients population, but failed to predict PFS when patients were stratified for treatment (BCG: p=0.1290; no BCG: p=0.1696) probably due to the limited number of events. Multivariate Cox proportional-hazards regression analysis confirmed that BCG treatment was a significant predictor of DFS (p=0.012) but not of PFS (p=0.924), whereas HER-2 overexpression was a significant predictor of DFS (p=0.001) and PFS (p=0.041). These findings suggest that HER-2 status performs better than "traditional" prognostic factors as well as of BCG treatment in predicting the outcome of T1G3 BC, thus providing grounds for further testing this marker and possibly incorporating it in a panel of molecular markers that could reliably predict the behavior of this challenging disease.


Assuntos
Vacina BCG/uso terapêutico , Receptor ErbB-2/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/terapia , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
19.
Infect Agent Cancer ; 9(1): 34, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25364378

RESUMO

The exact worldwide incidence of Burkitt's lymphoma is not known. There are three distinct clinical variants of Burkitt's lymphoma, each manifesting differences in epidemiology, clinical presentation, morphology, biology and genetic features: the endemic (African), the sporadic (non-endemic), and the immunodeficiency-associated form. In particular, we reported data regarding Burkitt's lymphoma incidence in the world and across different European countries. Finally, we described clinic-pathological data of 48 Burkitt's lymphomas occurred in Italy from 2003 to 2013, in 4 different hospitals, two of which located in east side, and the other ones located in the west-coast. Forty Burkitt's lymphomas occurs in children (age range 3-12), and 8 were adulthood Burkitt's lymphomas (age range 18-87). In the pediatric group the Male:Female ratio (M:F) was of 4:1, whereas the group of the adult patients has a M:F of 1:1.67. Immunohistochemical detection of Latent Membrane Protein 1 (LMP1) expression and Epstein-Barr virus Encoded RNA (EBER) In Situ Hybridization (ISH) procedures have been performed. Lymphocyte B monoclonal spread has been demonstrated using a Polymerase Chain Reaction (PCR) based method to amplify Fragment Restriction FR1, FR2 and FR3 immunoglobulin heavy chains DNA fragments. Only 38 cases out of 48 were analyzed for LMP-1 showing various percentage of stained cells in 47.4% of the patients. Considering ISH for EBER detection results: 1 out 2 (50%) adult analyzed cases was positive, with 50% of stained tumor cells (this patient was a 22 years old female, coming from Napoli);15 out 24 (62.5%) children analyzed Burkitt's lymphomas resulted as positive for EBER;the overall positivity has been observed in 16/26 Burkitt's lymphomas (61.53%).Finally, EBV has been detected in children and adult patients, one of them with deregulation of the oncogene c-MYC by chromosomal translocation.

20.
Infect Agent Cancer ; 7: 4, 2012 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-22376902

RESUMO

BACKGROUND: Recent emerging evidences identify Human Papillomavirus (HPV) related Head and Neck squamous cell carcinomas (HN-SCCs) as a separate subgroup among Head and Neck Cancers with different epidemiology, histopathological characteristics, therapeutic response to chemo-radiation treatment and clinical outcome. However, there is not a worldwide consensus on the methods to be used in clinical practice. The endpoint of this study was to demonstrate the reliability of a triple method which combines evaluation of: 1. p16 protein expression by immunohistochemistry (p16-IHC); 2. HPV-DNA genotyping by consensus HPV-DNA PCR methods (Consensus PCR); and 3 viral integration into the host by in situ hybridization method (ISH). This triple method has been applied to HN-SCC originated from oral cavity (OSCC) and oropharynx (OPSCC), the two anatomical sites in which high risk (HR) HPVs have been clearly implicated as etiologic factors. Methylation-Specific PCR (MSP) was performed to study inactivation of p16-CDKN2a locus by epigenetic events. Reliability of multiple methods was measured by Kappa statistics. RESULTS: All the HN-SCCs confirmed HPV positive by PCR and/or ISH were also p16 positive by IHC, with the latter showing a very high level of sensitivity as single test (100% in both OSCC and OPSCC) but lower specificity level (74% in OSCC and 93% in OPSCC).Concordance analysis between ISH and Consensus PCR showed a faint agreement in OPSCC (κ = 0.38) and a moderate agreement in OSCC (κ = 0.44). Furthermore, the addition of double positive score (ISHpositive and Consensus PCR positive) increased significantly the specificity of HR-HPV detection on formalin-fixed paraffin embedded (FFPE) samples (100% in OSCC and 78.5% in OPSCC), but reduced the sensitivity (33% in OSCC and 60% in OPSCC). The significant reduction of sensitivity by the double method was compensated by a very high sensitivity of p16-IHC detection in the triple approach. CONCLUSIONS: Although HR-HPVs detection is of utmost importance in clinical settings for the Head and Neck Cancer patients, there is no consensus on which to consider the 'golden standard' among the numerous detection methods available either as single test or combinations. Until recently, quantitative E6 RNA PCR has been considered the 'golden standard' since it was demonstrated to have very high accuracy level and very high statistical significance associated with prognostic parameters. In contrast, quantitative E6 DNA PCR has proven to have very high level of accuracy but lesser prognostic association with clinical outcome than the HPV E6 oncoprotein RNA PCR. However, although it is theoretically possible to perform quantitative PCR detection methods also on FFPE samples, they reach the maximum of accuracy on fresh frozen tissue. Furthermore, worldwide diagnostic laboratories have not all the same ability to analyze simultaneously both FFPE and fresh tissues with these quantitative molecular detection methods. Therefore, in the current clinical practice a p16-IHC test is considered as sufficient for HPV diagnostic in accordance with the recently published Head and Neck Cancer international guidelines. Although p16-IHC may serve as a good prognostic indicator, our study clearly demonstrated that it is not satisfactory when used exclusively as the only HPV detecting method. Adding ISH, although known as less sensitive than PCR-based detection methods, has the advantage to preserve the morphological context of HPV-DNA signals in FFPE samples and, thus increase the overall specificity of p16/Consensus PCR combination tests.

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