RESUMO
Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet-induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.
Assuntos
Mitocôndrias/genética , ATPases Mitocondriais Próton-Translocadoras/genética , RNA Circular/genética , Animais , Linhagem Celular , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático/fisiologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Expressão Gênica/genética , Humanos , Resistência à Insulina , Fígado/patologia , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Circular/metabolismo , Espécies Reativas de Oxigênio , Transcriptoma/genéticaRESUMO
The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor ß1 (TGF-ß1)-activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle-promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor-controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-ß/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Transformação Celular Neoplásica , Genes ras , Proteína Smad3 , Humanos , Transformação Celular Neoplásica/genética , Senescência Celular/genética , Genes Supressores de Tumor , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
BACKGROUND: Aberrant expression of m6A-related proteins contributes to the occurrence and progression of non-small cell lung cancer (NSCLC). Current studies mainly focus on single m6A regulatory genes and their underlying mechanisms, and the expression of multiple m6A regulatory proteins in NSCLC remains unclear. Therefore, it is necessary to systematically examine these proteins, particularly in clinical specimens. METHODS: Bioinformatic analysis was used to determine the expression of m6A regulatory genes and their correlation with common gene mutations, such as TP53, EGFR and KRAS, using The Cancer Genome Atlas (TCGA) and the AE-meta databases. Immunohistochemistry was employed to analyze the protein expression of m6A regulatory proteins in 61 benign lung tissues and 316 NSCLC tissues. Statistical analysis was performed to calculate the correlation between the expression of m6A regulatory proteins and clinicopathological features, survival, and common gene mutations in lung carcinoma patients. RESULTS: Analysis of the mRNA levels of 13 core m6A regulators, using information from TCGA and the AE-meta databases, revealed that YTHDF1 levels were upregulated in NSCLC compared to those in adjacent normal tissues. Immunohistochemical staining showed that the expression of METTL3, ALKBH5, YTHDC2 and YTHDF1 was significantly upregulated in NSCLC tissues. Further analyses demonstrated a positive correlation between differentially expressed m6A regulatory proteins, including METTL3, ALKBH5, YTHDC2 and YTHDF1, and the poor clinicopathological features and survival of NSCLC patients. According to the statistics of NSCLC patients enrolled in the present study, the protein levels of METTL3 in patients with EGFR exon-19 mutation were higher than those in patients with wild-type EGFR. CONCLUSIONS: Our results indicate that m6A regulators, including METTL3, ALKBH5, YTHDC2 and YTHDF1, could serve as predictive markers of NSCLC, which will facilitate the early detection and diagnosis of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenosina/genética , Adenosina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Genes Reguladores , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metiltransferases/genéticaRESUMO
It has been reported that ACBD3 is closely related to the malignant process of cells, but its role in gastric cancer has not been elucidated. This study aims to investigate the expression and function of ACBD3 in human gastric cancer. The Cancer Genome Atlas (TCGA) database were selected to analyze mRNA levels of ACBD3 in gastric cancer tissues and normal gastric epithelial tissues. qPCR and Western blot were conducted to detect the expression of ACBD3 in two normal gastric epithelial cell lines and five gastric cancer cell lines which were cultured in our laboratory. To exclude differences in individual background between different patients, we further detected the expression of ACBD3 in 8 pairs of malignant/non-malignant clinical gastric tissues. Through the establishment of stable cells, in vitro cell experiments and in vivo xenotransplantation models in mice, the role of ACBD3 in the proliferation of gastric cancer cells has been further explored. AKT inhibitors were used to deeply explore the molecular regulation mechanism of ACBD3. The results showed that the elevated ACBD3 in gastric cancer tissue were positively correlated with the clinical grade and prognosis of gastric cancer. In terms of molecular function, we found that ACBD3 can enhance the production and growth of gastric cancer cells. At the same time, the activation of AKT kinase played an important role in ACBD3's promotion of G1-to-S transition. The experiments generally indicate that ACBD3 is expected to become a potential diagnostic molecule or therapeutic target for gastric cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Fase G1 , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fase S , Neoplasias Gástricas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It is well recognized that metastasis can occur early in the course of lung adenocarcinoma (LAD) development, and yet the molecular mechanisms driving this capability of rapid metastasis remain incompletely understood. Here we reported that a long noncoding RNA, LINC00673, was up-regulated in LAD cells. Of note, we first found that LINC00673-v4 was the most abundant transcript of LINC00673 in LAD cells and its expression was associated with adverse clinical outcome of LAD. In vitro and in vivo experiments demonstrated that LINC00673-v4 enhanced invasiveness, migration, and metastasis of LAD cells. Mechanistically, LINC00673-v4 augmented the interaction between DDX3 and CK1ε and thus the phosphorylation of dishevelled, which subsequently activated WNT/ß-catenin signaling and consequently caused aggressiveness of LAD. Antagonizing LINC00673-v4 suppressed LAD metastasis in vivo. Together, our data suggest that LINC00673-v4 is a driver molecule for metastasis via constitutively activating WNT/ß-catenin signaling in LAD and may represent a potential therapeutic target against the metastasis of LAD.
Assuntos
Adenocarcinoma de Pulmão/genética , Caseína Quinase 1 épsilon/genética , RNA Helicases DEAD-box/genética , RNA Longo não Codificante/genética , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Ativação Transcricional , Via de Sinalização Wnt/genéticaRESUMO
Luminex multiplex immunoassays enable simultaneous monitoring of Abs against multiple Ags in autoimmune, inflammatory, and infectious diseases. The assays are used extensively to monitor anti-HLA Abs in transplant patients for donor organ selection, desensitization, and assessing the risk for graft rejection. To monitor IgG Abs, fluoresceinated IgG constant H chain-binding polyclonal F(ab')2 (IgHPolyFab) is used as the fluoresceinated secondary Ab (2nd-Ab), whereas IgG subclasses are monitored with Fc-specific monoclonal whole IgG (FcMonoIgG). The fluorescent signal from the 2nd-Ab is measured as mean florescence intensity (MFI). When IgHPolyFab is used, the signal is amplified as a result of the binding of multiple polyclonal Fabs to the C region of primary IgH. The reliability of such amplification for Ab measurements was not validated, nor were MFIs compared with 1:1 binding of FcMonoIgG to primary Abs. Comparing the MFIs of anti-HLA Abs obtained with IgHPolyFab and FcMonoIgG against normal human sera, IVIg, and allograft recipients' sera, it was observed that the number of HLA-Abs was notably higher with IgHPolyFab than with FcMonoIgG The MFIs of anti-HLA Abs also remained higher with IgHPolyFab in the normal sera and in IVIg, but the reverse was true when the autologous and allogeneic IgG concentrations were augmented in allograft recipients. Indeed, MFIs of the de novo allo-HLA Abs were markedly higher with FcMonoIgG than with IgHPolyFab. Serum titration established the superiority of FcMonoIgG for monitoring MFIs of de novo allo-HLA Abs in allograft recipients. Avoiding false amplifications of the number and MFIs of anti-HLA IgG with FcMonoIgG may minimize immunosuppressive therapies, maximize the number of donors for patients waiting for allografts, and enable better prediction of graft rejection.
Assuntos
Antígenos HLA/imunologia , Imunoensaio , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Separação Imunomagnética , Dessensibilização Imunológica , Seleção do Doador , Fluorescência , Rejeição de Enxerto/imunologia , Antígenos HLA/sangue , Humanos , Imunoensaio/métodos , Imunoglobulinas Intravenosas , Masculino , Reprodutibilidade dos Testes , Medição de Risco , Doadores de TecidosRESUMO
TGF-ß plays a central role in mediating epithelial-mesenchymal transition (EMT) by activating the Smad pathway. In addition, accumulating evidence suggests that TGF-ß-induced EMT is NF-κB-dependent in various cancer types. However, it is largely unclear if NF-κB mediates TGF-ß-induced EMT in breast cancer, and if this mediation occurs, the regulatory mechanisms are unknown. In our study, we found that TGF-ß activates the NF-κB pathway. Inhibition of NF-κB signaling markedly abrogates TGF-ß-induced EMT. By studying the regulatory mechanism of TGF-ß-induced NF-κB signaling, we found that lncRNA NKILA was upregulated by TGF-ß and was essential for the negative feedback regulation of the NF-κB pathway. Accordingly, overexpression of NKILA significantly reduced TGF-ß-induced tumor metastasis in vivo. Consistent with the results from mice, the expression of NKILA was negatively correlated with EMT phenotypes in clinical breast cancer samples. Collectively, our study indicated that the NKILA-mediated negative feedback affects TGF-ß-induced NF-κB activation and that NKILA may be a therapeutic molecule in breast cancer metastasis via inhibition of EMT.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Caderinas/metabolismo , Transição Epitelial-Mesenquimal , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta/farmacologia , Animais , Apoptose , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Caderinas/genética , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , NF-kappa B/genética , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
UNLABELLED: Dengue virus (DENV) is the most common mosquito-borne virus infecting humans and is currently a serious global health challenge. To establish infection in its host cells, DENV must subvert the production and/or antiviral effects of interferon (IFN). The aim of this study was to understand the mechanisms by which DENV suppresses IFN production. We determined that DENV NS4A interacts with mitochondrial antiviral signaling protein (MAVS), which was previously found to activate NF-κB and IFN regulatory factor 3 (IRF3), thus inducing type I IFN in the mitochondrion-associated endoplasmic reticulum membranes (MAMs). We further demonstrated that NS4A is associated with the N-terminal CARD-like (CL) domain and the C-terminal transmembrane (TM) domain of MAVS. This association prevented the binding of MAVS to RIG-I, resulting in the repression of RIG-I-induced IRF3 activation and, consequently, the abrogation of IFN production. Collectively, our findings illustrate a new molecular mechanism by which DENV evades the host immune system and suggest new targets for anti-DENV strategies. IMPORTANCE: Type I interferon (IFN) constitutes the first line of host defense against invading viruses. To successfully establish infection, dengue virus (DENV) must counteract either the production or the function of IFN. The mechanism by which DENV suppresses IFN production is poorly understood and characterized. In this study, we demonstrate that the DENV NS4A protein plays an important role in suppressing interferon production through binding MAVS and disrupting the RIG-I-MAVS interaction in mitochondrion-associated endoplasmic reticulum membranes (MAMs). Our study reveals that MAVS is a novel host target of NS4A and provides a molecular mechanism for DENV evasion of the host innate immune response. These findings have important implications for understanding the pathogenesis of DENV and may provide new insights into using NS4A as a therapeutic and/or prevention target.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Vírus da Dengue/imunologia , Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Interferon Tipo I/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Antivirais/metabolismo , Western Blotting , Células Cultivadas , Dengue/metabolismo , Dengue/virologia , Retículo Endoplasmático/metabolismo , Imunofluorescência , Células HEK293 , Células HeLa , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Fator Regulador 3 de Interferon/antagonistas & inibidores , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Monócitos/virologia , NF-kappa B/genética , NF-kappa B/metabolismo , Ligação Proteica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Proteínas não Estruturais Virais/genéticaRESUMO
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Acute myeloid leukemia or myelodysplastic syndrome during the course of ALL is a rare entity. Some of these cases are therapy-related while the others occur due to lineage switch. The correct diagnosis relies on comparing the immunophenotypes and cytogenetic/molecular alterations of the myeloid neoplasm and the ALL. We present the clinical, pathologic and cytogenetic features of a case of an 18-year-old male with prior treatment for B-lymphoblastic leukemia (B-ALL) who developed therapy-related myeloid neoplasm (t-MN) 4-5years after his initial diagnosis of B-ALL. CASE PRESENTATION: A 13-year-old boy with no significant past medical history presented to Harbor-UCLA Medical Center (HUMC) in November 2012 with night sweats, fevers and chills, nausea, vomiting, diarrhea, fatigue, weakness, and weight loss. Peripheral blood flow cytometric analysis disclosed B-ALL. The blasts expressed CD10, CD19, CD22 (dim), CD34, CD38, HLA-DR, and TdT, and were negative for CD20, CD13, CD33, CD117, and cytoplasmic MPO. Chromosomal analysis and a supplemental fluorescence in situ hybridization (FISH) study performed on the bone marrow aspirate showed an abnormal karyotype (47,XY,+X,del(9)(p21p21)[4]/46,XY[16]). He achieved remission after induction chemotherapy and remained in remission until March 2016 when bilateral testicular masses were noted. Biopsy of the left testicular mass showed relapsed B-ALL. Cerebrospinal fluid (CSF) contained rare TdT-positive blasts, suggestive of minimal/early involvement by B-ALL. However, there was no evidence of acute leukemia in his bone marrow at this time. He was then treated with COG protocol AALL1331 randomized to blinatumomab arm and achieved second remission. In June 2017, the patient's peripheral blood smear showed 11% circulating monoblasts. By flow cytometry, the blasts expressed CD4, CD11b, CD13, CD15, CD33, CD38, CD56, and CD64. In addition, a few TdT-positive blasts were seen in his CSF cytospin smear. Bone marrow biopsy was subsequently performed which was consistent with evolving acute myeloid leukemia. A diagnosis of myeloid neoplasm, consistent with t-MN was made. Chromosomal analysis and FISH studies performed on his bone marrow aspirate showed normal karyotype (46,XY[20]), negative FISH result for deletion 9p21 locus, and positive KMT2A (MLL) rearrangement, respectively. Despite of chemotherapy, the patient died within one month after diagnosis. DISCUSSION AND CONCLUSION: Diagnosis of t-MN should be suspected in patients with a history of receiving cytotoxic agents and/or irradiation. In this case study, we diagnosed t-MN with KMT2A rearrangement in a patient with history of B-ALL with 9p deletion and gain of X chromosome. Unusual features associated with this case are discussed.
Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Cromossomos Humanos Par 9/genética , Cromossomos Humanos X/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Quimioterapia de Indução/efeitos adversos , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas de Neoplasias/genética , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
The molecular mechanism underlying constitutive activation of AKT signaling, which plays essential roles in astrocytoma progression, is not fully characterized. Increasing numbers of studies have reported that microRNAs are involved in the malignant behavior of astrocytoma cells via directly targeting multiple oncogenes or tumor suppressors. Here, we found that microRNA (miR)-542-3p expression was decreased in glioblastoma cell lines and astrocytoma tissues, and reduced levels of miR-542-3p expression correlated with high histopathological grades and poor prognosis of astrocytoma patients. Exogenous miR-542-3p suppressed glioblastoma cell invasion through not only targeting AKT1 itself but also directly down-regulating its two important upstream regulators, namely, integrin-linked kinase and PIK3R1. Notably, overexpressing miR-542-3p decreased AKT1 phosphorylation and directly and indirectly repressed nuclear translocation and transactivation activity of ß-catenin to exert its anti-invasive effect. Furthermore, the miR-542-3p expression level negatively correlated with AKT activity as well as levels of integrin-linked kinase and PIK3R1 in human astrocytoma specimens. These findings suggest that miR-542-3p acts as a negative regulator in astrocytoma progression and that miR-542-3p down-regulation contributes to aberrant activation of AKT signaling, leaving open the possibility that miR-542-3p may be a potential therapeutic target for high grade astrocytoma.
Assuntos
Glioblastoma/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Regiões 3' não Traduzidas/genética , Sequência de Bases , Linhagem Celular Tumoral , Classe Ia de Fosfatidilinositol 3-Quinase , Progressão da Doença , Regulação para Baixo/genética , Glioblastoma/diagnóstico , Glioblastoma/genética , Humanos , Gradação de Tumores , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Regulação para Cima/genética , beta Catenina/metabolismoRESUMO
Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma arising most frequently in the oral cavity of HIV-infected patients. Rare cases of PBL have been reported in extra-oral sites, as well as in HIV-negative patients. Cardiac involvement by lymphoma is very rare. The most common primary cardiac lymphoma is diffuse large B-cell lymphoma. We report an unusual case of PBL in a 49-year-old, HIV-positive man presenting with a large intracardiac mass and bilateral pleural effusions. Histological examination of the cardiac mass biopsy and cytological evaluation of the pleural fluid demonstrated large lymphoma cells with plasmablastic differentiation. By immunohistochemistry, the large lymphoma cells expressed CD30, CD45, CD138, MUM1, and kappa light chain, were weakly positive for EMA, and were negative for T-cell and B-cell markers, lambda light chain, and human herpes virus 8 (HHV8). In situ hybridization for Epstein Barr Virus-encoded RNA (EBER) was negative in large lymphoma cells. To our knowledge, in the English literature, this is the second reported case of PBL with cardiac origin and the first reported case of PBL that presents as a combination of intracardiac mass and pleural effusions.
Assuntos
Linfoma Plasmablástico/patologia , Linfócitos B/citologia , Linfócitos B/virologia , Diagnóstico Diferencial , Herpesvirus Humano 8 , Humanos , Imuno-Histoquímica/métodos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/virologia , Linfoma Imunoblástico de Células Grandes/diagnóstico , Linfoma Imunoblástico de Células Grandes/virologia , Masculino , Pessoa de Meia-Idade , Linfoma Plasmablástico/virologia , Derrame Pleural/diagnóstico , Derrame Pleural/patologiaRESUMO
Primary hepatic peripheral T-cell lymphoma (PTCL) is exceedingly rare. We encountered such a case in a 58-year-old Hispanic female with a history of chronic sinusitis and hypothyroidism who presented with 4weeks of fever and weight loss. Laboratory studies showed altered liver function and mild pancytopenia. Hepatitis and HIV infection were excluded by negative serological tests. A computed tomography (CT) scan showed innumerable small low-density lesions throughout the liver without splenomegaly or lymphadenopathy. CT-guided liver core biopsy showed scattered small lymphoid aggregates located mainly in the portal tracts and periportal regions. Within the lymphoid aggregates, scattered large pleomorphic lymphoma cells were seen, admixed with smaller lymphoid cells and histiocytes. By immunohistochemistry, the lymphoma cells expressed CD2, CD3, CD8, CD30, CD43, CD45, granzyme B, TIA-1, and negative for CD4, CD5, CD7, CD56, ßF1, ALK-1, and B-cell markers. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was positive in some lymphoma cells. To our knowledge, this is the first reported case of primary hepatic Epstein-Barr virus-associated PTCL with CD30 expression.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/isolamento & purificação , Linfoma de Células T Periférico/virologia , Linfócitos T Citotóxicos , Linfócitos B/virologia , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-1/imunologia , Células Matadoras Naturais/metabolismo , Linfoma de Células T Periférico/imunologia , Pessoa de Meia-Idade , FenótipoRESUMO
Acute promyelocytic leukemia (APL) with t(15;17)(q22;q21)/PML-RARα is a subtype of acute myeloid leukemia (AML) with distinct morphologic and immunophenotypic characteristics. It is a highly aggressive disease that requires rapid diagnosis and early intervention. In addition to morphologic evaluation, flow cytometry has been widely used to facilitate prompt diagnosis of this disease. Compared with other types of AML, APL typically displays a triad of absent or weak CD34, absent HLA-DR, and positive CD117. HLA-DR positive APL is extremely rare and its clinical and pathological features have not been reported. A total of 45 cases of APL with t(15,17)/PML-RARα were diagnosed at Harbor-UCLA Medical Center from year 2006 to 2015. Among them, only two cases were positive for HLA-DR by flow cytometry immunophenotyping. Here we describe the clinical, morphologic, immunophenotypic, and cytogenetic features of these two cases.
Assuntos
Antígenos HLA-DR/imunologia , Leucemia Promielocítica Aguda/imunologia , Crise Blástica/patologia , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Leucemia Promielocítica Aguda/sangue , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: We have found antibodies against denatured HLA class I antigens in the serum of allograft recipients which were not significantly associated with graft failure. It is unknown whether transplant recipients also have denatured HLA class II and MICA antibodies. The effects of denatured HLA class I, class II, and MICA antibodies on long-term graft outcome were further investigated based on their ability to fix complement c1q. MATERIALS AND METHODS: In this 4-year retrospective cohort study, post-transplant sera from 975 kidney transplant recipients were tested for antibodies against denatured HLA/MICA antigens and these antibodies were further classified based on their ability to fix c1q. RESULTS: Thirty percent of patients had antibodies against denatured HLA class I, II, or MICA antigens. Among them, 8.5% and 21.5% of all patients had c1q-fixing and non c1q-fixing antibodies respectively. There was no significant difference on graft survival between patients with or without antibodies against denatured HLA/MICA. However, when these antibodies were further classified according to their ability to fix c1q, patients with c1q-fixing antibodies had a significantly lower graft survival rate than patients without antibodies or patients with non c1q-fixing antibodies (p=0.008). In 169 patients who lost renal grafts, 44% of them had c1q-fixing antibodies against denatured HLA/MICA antigens, which was significantly higher than that in patients with functioning renal transplants (25%, p<0.0001). C1q-fixing antibodies were more significantly associated with graft failure caused by AMR (72.73%) or mixed AMR/CMR (61.9%) as compared to failure due to CMR (35.3%) or other causes (39.2%) (p=0.026). CONCLUSIONS: Transplant recipients had antibodies against denatured HLA class I, II, and MICA antigens. However, only c1q-fixing antibodies were associated with graft failure which was related to antibody mediated rejection.
Assuntos
Anticorpos/imunologia , Complemento C1q/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Transplante de Rim , Adulto , Idoso , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo/métodosRESUMO
BACKGROUND: Liver is an organ that could either be involved by widespread lymphoma or rarely as a primary site of lymphoma. Although secondary involvement of liver by lymphoma is relatively common, primary hepatic lymphoma (PHL) represents only about 0.016% of all cases of non-Hodgkin lymphoma. Understanding the clinicopathological features of hepatic lymphoma would direct appropriate treatment and patient management. METHODS: We did a retrospective cohort study of 19 patients with liver biopsy-proven lymphoma, either as part of a systemic lymphoma or as a primary lesion, who were evaluated and treated at Harbor-UCLA Medical Center between 2004 and 2014. RESULTS: The 19 cases were divided into two groups. Nine of them showing systemic involvement including not only liver but also spleen and/or lymph nodes were grouped together. The other 10 cases which showed confined liver lesions without involvement of other lymphoid structures were grouped in the PHL group. Clinical features of the two groups were compared. Our study demonstrated that PHL most commonly affected middle-aged individuals (median age: 50 years), with a male-to-female ratio of about 2.3 to 1. The most frequent presenting symptom was right upper quadrant pain. In contrast, the group with systemic lymphoma involving liver most commonly affected younger patients (median age: 40 years), with a male-to-female ratio of about 8 to 1, and with abdominal pain as well as fever/chills as the most common presenting symptoms. The tumor burden at the presentation as suggested by serum lactate dehydrogenase (LDH) level was statistically significantly lower in the PHL group compared to the systemic group in this study (p<0.05). Viral infections were found in both groups, and we did not observe a clear association of any particular viral infection with PHL. Diffuse large B-cell lymphoma was identified as the major type of primary hepatic lymphoma (8 of 10 cases). Finally, the prognosis in the PHL group demonstrated by the duration of follow-up (average follow up: 50 months) was statistically significantly better than that in the systemic group (average follow up: 5.5 months), p<0.01. CONCLUSION: Patients with PHL showed different clinicopathological features from those with widespread lymphoma involving liver. The outcome of the patients with PHL appeared much more favorable than that of the patients with liver involvement by systemic lymphoma in this study.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Fígado/efeitos dos fármacos , Linfoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Citomegalovirus/fisiologia , Feminino , Seguimentos , HIV/fisiologia , Hepacivirus/fisiologia , Vírus da Hepatite B/fisiologia , Herpesvirus Humano 4/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Fígado/patologia , Fígado/virologia , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/patologia , Linfoma/classificação , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Multiple nodes in the one-carbon metabolism pathway play important regulatory roles in cancer cell growth and tumorigenesis. The specific biological functions of metabolic enzymes in regulating the signaling pathways that are associated with tumor cell growth and survival, however, remain unclear. Our current study found that phosphoserine aminotransferase 1 (PSAT1), an enzyme catalyzing serine biosynthesis, was significantly up-regulated in non-small cell lung cancer (NSCLC) and was involved in the regulation of E2F activity. Loss- and gain-of-function experiments demonstrated that PSAT1 promoted cell cycle progression, cell proliferation and tumorigenesis. Mechanistic study suggested that elevated PSAT1 led to inhibition of cyclin D1 degradation and subsequently an alteration in Rb-E2F pathway activity, which in turn enhanced G1 progression and proliferation of NSCLC cells. Moreover, phosphorylation of cyclin D1 at threonine 286 by GSK-3ß was required for PSAT1-induced blockage of cyclin D1 degradation. We also found that the activity of p70S6K mediated the effects of PSAT1 on GSK-3ß phosphorylation and cyclin D1 degradation. We further identified that PSAT1 was over-expressed in NSCLC and predicted poor clinical outcome of patients with the disease. Correlation analysis showed that PSAT1 expression positively correlated with the levels of phosphorylated GSK-3ß, cyclin D1 and phosphorylated Rb in NSCLC primary tumors. These findings uncover a mechanism for constitutive activation of E2F via which unrestrained cell cycle progression occurs in NSCLC and may represent a prognostic biomarker and therapeutic target.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Proliferação de Células , Ciclina D1/metabolismo , Neoplasias Pulmonares/enzimologia , Transaminases/fisiologia , Animais , Linhagem Celular Tumoral , Fatores de Transcrição E2F/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Prognóstico , Processamento de Proteína Pós-Traducional , Proteólise , Transdução de Sinais , Transcriptoma , Carga TumoralRESUMO
BACKGROUND: Primary effusion lymphoma (PEL) is a rare subtype of large B-cell lymphoma associated with human herpesvirus 8 (HHV8). It has the highest incidence in HIV-positive individuals. It often presents as a malignant pleural, peritoneal and/or pericardial effusion without a detectable solid mass. Most cases are co-infected with Epstein-Barr virus (EBV). Rare cases of HHV8-positive lymphoma with features similar to PEL can present as tumor masses and are considered to represent an extracavitary or solid variant of PEL. We report a case of EBV negative, extracavitary/solid variant of primary effusion lymphoma presenting as a gastric mass. CASE PRESENTATION: A 48-year-old man was admitted to an outside hospital with abdominal pain and weight loss. At the outside hospital, he was found to be HIV positive and have a 3 × 2 cm gastric mass. He was subsequently diagnosed with ALK negative anaplastic large cell lymphoma by gastric biopsy. The patient was referred to Harbor-UCLA Medical Center for further management. Review of the outside slides and additional stains performed at our hospital revealed sheets of large anaplastic lymphoma cells that were positive for CD30, CD138, MUM1 and HHV8, focally weakly positive for CD3, and negative for other T- and B-cell markers and EBER, consistent with extracavitary/solid variant of primary effusion lymphoma. Interestingly, for the first time, cyclin D1 positivity was also demonstrated in PEL. CONCLUSION: Primary effusion lymphoma, particularly the extracavitary/solid variant, is very rare, and the diagnosis can be challenging. In some cases, when CD30 is uniformly positive, this lymphoma can be misdiagnosed as ALK negative anaplastic large cell lymphoma. This lymphoma can also aberrantly express T-cell markers as seen in this case, making diagnosis even more difficult. Awareness of the existence and the features of solid variant PEL and assessment for HHV8 infection are essential for correct diagnosis.
Assuntos
Linfócitos B/patologia , Linfoma de Células B/patologia , Linfoma de Efusão Primária/patologia , Neoplasias Cutâneas/patologia , Neoplasias Gástricas/patologia , Biópsia , Diagnóstico Diferencial , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 8/isolamento & purificação , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Efusão Primária/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/diagnóstico , Neoplasias Gástricas/diagnósticoRESUMO
Non-small cell lung cancer (NSCLC) remains a highly challenging and deadly malignancy with limited improvements in prognosis over years. Further understanding the molecular events involved in NSCLC oncogenesis and progression will help develop new and effective therapeutic strategies. In this study, we identified a ubiquitous up-regulation of DEPDC1B in NSCLC cell lines and clinical specimens, as well as its inverse correlation with patient survival. Ectopic expression of DEPDC1B endowed NSCLC cells with enhanced migration and invasion, while silencing its expression suppressed these traits. Mechanistic study showed that DEPDC1B was able to activate Wnt/ß-catenin signaling, and that depletion of TCF4 or LEF1 abrogated the biological effects of DEPDC1B on cellular migration and invasion. Taken together, our data demonstrate that DEPDC1B might confer metastasis-related malignant phenotype to NSCLC in a Wnt/ß-catenin dependent manner, providing new insights in developing novel anti-NSCLC strategies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Cateninas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Movimento Celular , Humanos , Invasividade Neoplásica , Transdução de SinaisRESUMO
Graft failure and survival are the major problems for patients with aplastic anemia undergoing hematopoietic stem cell transplantation (HSCT). Previous studies showed that anti-HLA antibodies negatively impact engraftment in HSCT. This retrospective study of 51 pediatric patients with acquired aplastic anemia who underwent allogeneic HSCT at a single institution between 2006 and 2012 investigated the influence of anti-HLA antibodies on the outcome of HSCT. Serum samples collected before HSCT were tested for the presence of anti-HLA antibodies. Pre-existing anti-HLA antibodies were detected in 54.9% (28/51) of patients, among whom 39.2% (20/51) had anti-HLA class I antibodies. Anti-HLA antibodies were associated with worse five-yr survival (78.6% vs. 100%, p = 0.021) and higher treatment-related mortality (21.4% vs. 0%, p = 0.028) compared with antibody-negative patients. Anti-HLA class I antibody-positive patients had poorer five-yr survival (75.0%) than anti-HLA class I&II antibody-positive and antibody-negative patients (87.5% and 100.0%, respectively, p = 0.039). Presence of anti-HLA class I antibodies (p = 0.024) and older age (10 yr or more; p = 0.027) significantly increased the risk of post-HSCT mortality. Pre-existing anti-HLA antibodies negatively affect the outcome of HSCT in pediatric patients with aplastic anemia. Routine testing for anti-HLA antibodies concurrent with efficient treatment should be conducted prior to HSCT.
Assuntos
Anemia Aplástica/sangue , Anemia Aplástica/terapia , Anticorpos/sangue , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Anemia Aplástica/mortalidade , Criança , Pré-Escolar , Feminino , Teste de Histocompatibilidade , Humanos , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Myelofibrosis is characterized by reticulin and/or collagen fibrosis in the bone marrow stroma resulting in secondary cytopenia. In addition to clonal hematologic neoplasms, myelofibrosis may also develop in association with other clinical conditions, including hematological disorders, solid malignancies, Down syndrome, autoimmune diseases and others. We report the first case to our knowledge of myelofibrosis associated with dengue fever. We briefly describe dengue infections and hypothesize the causes of myelofibrosis in this condition.