RESUMO
Epstein-Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case-control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an "East-Asian antibody signature of EBV-positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case-control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East-Asian antibody signature of EBV-positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV-positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a "core signature of EBV-positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.
Assuntos
Anticorpos Antivirais , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Doença de Hodgkin , Humanos , Doença de Hodgkin/virologia , Doença de Hodgkin/imunologia , Herpesvirus Humano 4/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Feminino , Masculino , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Estudos de Casos e Controles , Pessoa de Meia-Idade , Adulto , Proteoma/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Idoso , Adulto Jovem , Análise Serial de ProteínasRESUMO
INTRODUCTION: Computer-aided diagnosis (CADx) of polyp histology could support endoscopists in clinical decision-making. However, this has not been validated in a real-world setting. METHODS: We performed a prospective, multicenter study comparing CADx and endoscopist predictions of polyp histology in real-time colonoscopy. Optical diagnosis based on visual inspection of polyps was made by experienced endoscopists. After this, the automated output from the CADx support tool was recorded. All imaged polyps were resected for histological assessment. Primary outcome was difference in diagnostic performance between CADx and endoscopist prediction of polyp histology. Subgroup analysis was performed for polyp size, bowel preparation, difficulty of location of the polyps, and endoscopist experience. RESULTS: A total of 661 eligible polyps were resected in 320 patients aged ≥40 years between March 2021 and July 2022. CADx had an overall accuracy of 71.6% (95% confidence interval [CI] 68.0-75.0), compared with 75.2% (95% CI 71.7-78.4) for endoscopists ( P = 0.023). The sensitivity of CADx for neoplastic polyps was 61.8% (95% CI 56.9-66.5), compared with 70.3% (95% CI 65.7-74.7) for endoscopists ( P < 0.001). The interobserver agreement between CADx and endoscopist predictions of polyp histology was moderate (83.1% agreement, κ 0.661). When there was concordance between CADx and endoscopist predictions, the accuracy increased to 78.1%. DISCUSSION: The overall diagnostic accuracy and sensitivity for neoplastic polyps was higher in experienced endoscopists compared with CADx predictions, with moderate interobserver agreement. Concordance in predictions increased this diagnostic accuracy. Further research is required to improve the performance of CADx and to establish its role in clinical practice.
Assuntos
Pólipos do Colo , Neoplasias Colorretais , Humanos , Pólipos do Colo/diagnóstico , Pólipos do Colo/patologia , Estudos Prospectivos , Valor Preditivo dos Testes , Colonoscopia/métodos , Computadores , Neoplasias Colorretais/patologia , Imagem de Banda Estreita/métodosRESUMO
Accumulation of damaged DNA in hematopoietic stem cells (HSC) is associated with chromosomal abnormalities, genomic instability, and HSC aging and might promote hematological malignancies with age. Despite this, the regulatory pathways implicated in the HSC DNA damage response have not been fully elucidated. One of the sources of DNA damage is reactive oxygen species (ROS) generated by both exogenous and endogenous insults. Balancing ROS levels in HSC requires FOXO3, which is an essential transcription factor for HSC maintenance implicated in HSC aging. Elevated ROS levels result in defective Foxo3-/- HSC cycling, among many other deficiencies. Here, we show that loss of FOXO3 leads to the accumulation of DNA damage in primitive hematopoietic stem and progenitor cells (HSPC), associated specifically with reduced expression of genes implicated in the repair of oxidative DNA damage. We provide further evidence that Foxo3-/- HSPC are defective in DNA damage repair. Specifically, we show that the base excision repair pathway, the main pathway utilized for the repair of oxidative DNA damage, is compromised in Foxo3-/- primitive hematopoietic cells. Treating mice in vivo with N-acetylcysteine reduces ROS levels, rescues HSC cycling defects, and partially mitigates HSPC DNA damage. These results indicate that DNA damage accrued as a result of elevated ROS in Foxo3-/- mutant HSPC is at least partially reversible. Collectively, our findings suggest that FOXO3 serves as a protector of HSC genomic stability and health.
Assuntos
Dano ao DNA , Proteína Forkhead Box O3/fisiologia , Células-Tronco Hematopoéticas/citologia , Estresse Oxidativo , Acetilcisteína/farmacologia , Animais , Ciclo Celular/fisiologia , Proteína Forkhead Box O3/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismoRESUMO
Bacteria of many species rely on a simple molecule, the intracellular secondary messenger c-di-GMP (Bis-(3'-5')-cyclic dimeric guanosine monophosphate), to make a vital choice: whether to stay in one place and form a biofilm, or to leave it in search of better conditions. The c-di-GMP network has a bow-tie shaped architecture that integrates many signals from the outside world-the input stimuli-into intracellular c-di-GMP levels that then regulate genes for biofilm formation or for swarming motility-the output phenotypes. How does the 'uninformed' process of evolution produce a network with the right input/output association and enable bacteria to make the right choice? Inspired by new data from 28 clinical isolates of Pseudomonas aeruginosa and strains evolved in laboratory experiments we propose a mathematical model where the c-di-GMP network is analogous to a machine learning classifier. The analogy immediately suggests a mechanism for learning through evolution: adaptation though incremental changes in c-di-GMP network proteins acquires knowledge from past experiences and enables bacteria to use it to direct future behaviors. Our model clarifies the elusive function of the ubiquitous c-di-GMP network, a key regulator of bacterial social traits associated with virulence. More broadly, the link between evolution and machine learning can help explain how natural selection across fluctuating environments produces networks that enable living organisms to make sophisticated decisions.
Assuntos
GMP Cíclico/análogos & derivados , Aprendizado de Máquina , Modelos Biológicos , Transdução de Sinais/fisiologia , Biofilmes , Movimento Celular , Biologia Computacional , GMP Cíclico/metabolismo , Fenótipo , Pseudomonas aeruginosa/fisiologiaRESUMO
Circulating red blood cells (RBCs) are essential for tissue oxygenation and homeostasis. Defective terminal erythropoiesis contributes to decreased generation of RBCs in many disorders. Specifically, ineffective nuclear expulsion (enucleation) during terminal maturation is an obstacle to therapeutic RBC production in vitro. To obtain mechanistic insights into terminal erythropoiesis we focused on FOXO3, a transcription factor implicated in erythroid disorders. Using an integrated computational and experimental systems biology approach, we show that FOXO3 is essential for the correct temporal gene expression during terminal erythropoiesis. We demonstrate that the FOXO3-dependent genetic network has critical physiological functions at key steps of terminal erythropoiesis including enucleation and mitochondrial clearance processes. FOXO3 loss deregulated transcription of genes implicated in cell polarity, nucleosome assembly and DNA packaging-related processes and compromised erythroid enucleation. Using high-resolution confocal microscopy and imaging flow cytometry we show that cell polarization is impaired leading to multilobulated Foxo3-/- erythroblasts defective in nuclear expulsion. Ectopic FOXO3 expression rescued Foxo3-/- erythroblast enucleation-related gene transcription, enucleation defects and terminal maturation. Remarkably, FOXO3 ectopic expression increased wild type erythroblast maturation and enucleation suggesting that enhancing FOXO3 activity may improve RBCs production. Altogether these studies uncover FOXO3 as a novel regulator of erythroblast enucleation and terminal maturation suggesting FOXO3 modulation might be therapeutic in disorders with defective erythroid maturation.
Assuntos
Eritrócitos/metabolismo , Eritropoese/genética , Fatores de Transcrição Forkhead/genética , Biologia de Sistemas , Animais , Autofagia/genética , Células da Medula Óssea/metabolismo , Polaridade Celular/genética , Eritroblastos/metabolismo , Eritrócitos/citologia , Citometria de Fluxo , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Homeostase , Humanos , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismoRESUMO
Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. We tested this method in pregnant women, patients with hepatocellular carcinoma, and subjects following bone marrow and liver transplantation. In most subjects, white blood cells were the predominant contributors to the circulating DNA pool. The placental contributions in the plasma of pregnant women correlated with the proportional contributions as revealed by fetal-specific genetic markers. The graft-derived contributions to the plasma in the transplant recipients correlated with those determined using donor-specific genetic markers. Patients with hepatocellular carcinoma showed elevated plasma DNA contributions from the liver, which correlated with measurements made using tumor-associated copy number aberrations. In hepatocellular carcinoma patients and in pregnant women exhibiting copy number aberrations in plasma, comparison of methylation deconvolution results using genomic regions with different copy number status pinpointed the tissue type responsible for the aberrations. In a pregnant woman diagnosed as having follicular lymphoma during pregnancy, methylation deconvolution indicated a grossly elevated contribution from B cells into the plasma DNA pool and localized B cells as the origin of the copy number aberrations observed in plasma. This method may serve as a powerful tool for assessing a wide range of physiological and pathological conditions based on the identification of perturbed proportional contributions of different tissues into plasma.
Assuntos
Carcinoma Hepatocelular/genética , Metilação de DNA , DNA/genética , Neoplasias Hepáticas/genética , Análise de Sequência de DNA/métodos , Transplante de Tecidos , Adulto , Algoritmos , Linfócitos B/metabolismo , Transplante de Medula Óssea , Carcinoma Hepatocelular/sangue , DNA/sangue , DNA/química , Variações do Número de Cópias de DNA/genética , Feminino , Feto/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/sangue , Transplante de Fígado , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Placenta/metabolismo , Gravidez , Linfócitos T/metabolismoRESUMO
An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.
Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Homeostase/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Animais , Humanos , OxirreduçãoRESUMO
The production of all blood cells from hematopoietic stem cells (HSC) is highly sensitive to reactive oxygen species (ROS). Cumulating evidence suggests that mitochondria are critical for HSC fate determination. FOXO are known regulators of anti-oxidant response and key to the maintenance of HSC. Recent works indicate that FOXO3 is implicated in the control of mitochondrial function beyond regulating levels of ROS in HSC. Here we review these findings and discuss implications for homeostatic blood formation and stem cell fate determination.
Assuntos
Linhagem da Célula , Proteína Forkhead Box O3/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Homeostase , Animais , Células Sanguíneas/citologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3(-/-) HSC that are defective in their activity. We show that Foxo3(-/-) HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3(-/-) hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3(-/-) HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells.
Assuntos
Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento/genética , Animais , Proteína Forkhead Box O3 , Homeostase/genética , Homeostase/fisiologia , Camundongos , Mitocôndrias/genética , Estresse Oxidativo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Eukaryotic cells carry two genomes, nuclear (nDNA) and mitochondrial (mtDNA), which are ostensibly decoupled in their replication, segregation and inheritance. It is increasingly appreciated that heteroplasmy, the occurrence of multiple mtDNA haplotypes in a cell, plays an important biological role, but its features are not well understood. Accurately determining the diversity of mtDNA has been difficult, due to the relatively small amount of mtDNA in each cell (<1% of the total DNA), the intercellular variability of mtDNA content and mtDNA pseudogenes (Numts) in nDNA. To understand the nature of heteroplasmy, we developed Mseek, a novel technique to purify and sequence mtDNA. Mseek yields high purity (>90%) mtDNA and its ability to detect rare variants is limited only by sequencing depth, providing unprecedented sensitivity and specificity. Using Mseek, we confirmed the ubiquity of heteroplasmy by analyzing mtDNA from a diverse set of cell lines and human samples. Applying Mseek to colonies derived from single cells, we find heteroplasmy is stably maintained in individual daughter cells over multiple cell divisions. We hypothesized that the stability of heteroplasmy could be facilitated by intercellular exchange of mtDNA. We explicitly demonstrate this exchange by co-culturing cell lines with distinct mtDNA haplotypes. Our results shed new light on the maintenance of heteroplasmy and provide a novel platform to investigate features of heteroplasmy in normal and diseased states.
Assuntos
DNA Mitocondrial/metabolismo , Análise de Sequência de DNA/métodos , Transporte Biológico , Linhagem Celular , Linhagem Celular Tumoral , DNA Mitocondrial/química , DNA Mitocondrial/isolamento & purificação , Variação Genética , Haplótipos , HumanosRESUMO
Anaemia or decreased blood haemoglobin is the most common blood disorder often characterized by reduced red blood cell (RBC) numbers. RBCs are produced from differentiation and commitment of haematopoietic stem cells to the erythroid lineage by a process called erythropoiesis. Coordination of erythropoietin receptor signalling with several erythroid transcription factors including GATA1 is essential for this process. A number of additional players that are critical for RBC production have been identified in recent years. Major technological advances, such as the development of RNA interference, genetically modified animals, including zebrafish, and imaging flow cytometry have led to these discoveries; the emergence of -omics approaches in combination with the optimization of ex vivo erythroid cultures have also produced a more comprehensive understanding of erythropoiesis. Here we summarize studies describing novel regulators of erythropoiesis that modulate erythroid cell production in the context of human erythroid disorders involving hypoxia, iron regulation, immune-related molecules, and the transcription factor FOXO3.
Assuntos
Células Eritroides/patologia , Eritropoese/fisiologia , Homeostase/fisiologia , Animais , Proteína Forkhead Box O3/metabolismo , Humanos , Hipóxia , Doenças do Sistema Imunitário/patologia , Ferro/metabolismoRESUMO
OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. The first large-scale genome-wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk. METHODS: To evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand. RESULTS: Three of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR = 2.04, 95% CI = 1.63-2.56; ptrend = 3.9 × 10(-10)). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19-1.52; ptrend = 2.1 × 10(-6)), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR = 3.05, 95% CI = 1.32-7.05; ptrend = 0.009). CONCLUSIONS: Our study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations.
Assuntos
Predisposição Genética para Doença , Linfoma Difuso de Grandes Células B/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Transporte Vesicular/genética , Adulto , Idoso , Ásia Oriental , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Ineffective erythropoiesis is observed in many erythroid disorders including ß-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3(-/-) erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of ß-thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism-mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis.
Assuntos
Eritroblastos/metabolismo , Eritropoese , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Modelos Animais de Doenças , Eritroblastos/patologia , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/genética , Camundongos , Camundongos Knockout , Serina-Treonina Quinases TOR/genética , Talassemia beta/genética , Talassemia beta/metabolismo , Talassemia beta/patologiaRESUMO
Introduction: Gastrointestinal stromal tumours (GISTs) are an important, though uncommon, cause of obscure gastrointestinal bleeding and may rarely be associated with genodermatoses such as neurofibromatosis type 1 (NF1). NF1-related GISTs have unique phenotypic features compared with sporadic GISTs and may elude diagnosis due to their predilection for the small bowel. Case Presentation: We report a case of a 45-year-old Singaporean woman with café-au-lait macules and cutaneous neurofibromas who presented with occult obscure gastrointestinal bleeding and was eventually discovered to have a bleeding jejunal GIST. This finding, considered together with her cutaneous signs, eventually led to the diagnosis of NF1. Conclusion: Genodermatoses and their gastrointestinal complications are likely under-reported in adult Southeast Asian populations and deserve greater awareness from gastroenterologists practising in this region.
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Leukaemia of various subtypes are driven by distinct chromosomal rearrangement or genetic abnormalities. The leukaemogenic fusion transcripts or genetic mutations serve as molecular markers for minimal residual disease (MRD) monitoring. The current study evaluated the applicability of several droplet digital PCR assays for the detection of these targets at RNA and DNA levels (atypical BCR::ABL1 e19a2, e23a2ins52, e13a2ins74, rare types of CBFB::MYH11 (G and I), PCM1::JAK2, KMT2A::ELL2, PICALM::MLLT10 fusion transcripts and CEBPA frame-shift and insertion/duplication mutations) with high sensitivity. The analytical performances were assessed by the limit of blanks, limit of detection, limit of quantification and linear regression. Our data demonstrated serial MRD monitoring for patients at molecular level could become "digitalized", which was deemed important to guide clinicians in treatment decision for better patient care.
Assuntos
Neoplasias Hematológicas , Leucemia , Humanos , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Reação em Cadeia da Polimerase , Leucemia/diagnóstico , Aberrações Cromossômicas , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Fatores de Elongação da Transcrição/genéticaRESUMO
We postulated that MIR34B/C, a direct transcriptional target of TP53, might be inactivated by promoter hypermethylation in multiple myeloma (MM). MIR34B/C promoter methylation was studied in 8 normal marrow controls, 8 MM cell lines, 95 diagnostic, and 23 relapsed/progressed MM samples by methylation-specific PCR. MIR34B/C was methylated in 6 (75.0%) MM cell lines but not normal controls. 5-Aza-2'-deoxycytidine led to MIR34B/C promoter demethylation and MIR34B reexpression. Moreover, restoration of MIR34B led to reduced cellular proliferation and enhanced apoptosis of myeloma cells. In primary samples, methylation of MIR34B/C occurred in 5.3% at diagnosis and 52.2% at relapse/disease progression (P < .001). In 12 MM patients with paired samples at diagnosis and relapse/progression, MIR34B/C methylation was acquired in 6 at relapse/progression. In conclusion, MIR34B/C is a tumor suppressor in myeloma. Hypermethylation of MIR34B/C is tumor-specific. Frequent MIR34B/C hypermethylation during relapse/progression but not at diagnosis implicated a role of MIR34B/C hypermethylation in myeloma relapse/progression.
Assuntos
Epigênese Genética/fisiologia , Inativação Gênica , MicroRNAs/genética , Mieloma Múltiplo/genética , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Sequência de Bases , Metilação de DNA , Decitabina , Progressão da Doença , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Inativação Gênica/fisiologia , Humanos , Dados de Sequência Molecular , Mieloma Múltiplo/patologia , Cultura Primária de Células , Recidiva , Células Tumorais CultivadasRESUMO
Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.
Assuntos
Doença Celíaca/mortalidade , Doença Celíaca/patologia , Linfoma de Células T Associado a Enteropatia/mortalidade , Linfoma de Células T Associado a Enteropatia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Celíaca/classificação , Estudos de Coortes , Consenso , Linfoma de Células T Associado a Enteropatia/classificação , Feminino , Humanos , Internacionalidade , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Linfócitos T/patologia , Organização Mundial da SaúdeRESUMO
Cirrhotic portal hypertension is the most common cause of new-onset ascites. The clinician, however, should be cognizant of rarer causes of ascites, especially when clinical and laboratory parameters are not in keeping with cirrhosis. We present a case of urinoma as the cause of an initial presentation of ascites.
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Ozone can be medically useful concerning healing wounds and relieving pain in various conditions, such as disc disease. The aspects of human blood ozonation have been reviewed, as well as potential complications that may arise. The mechanisms of ozone therapy are discussed in detail. It is imperative to recognize ozone as a useful proxy in oxidative-stress related diseases, consolidating other medical gases recognized for their therapeutic importance. The utility of hyperbaric oxygen therapy is also discussed. Disc herniation is very common, as more than 3 million cases are treated per year. Herein we review the medical, surgical, and gene-based therapies that ozone therapy can provide regarding disc disease.