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Epigenetic modifications to DNA are crucial for normal cellular and biological functioning. DNA methylation, histone modifications, and chromatin remodeling are the most common epigenetic mechanisms. These changes are heritable but still reversible. The aberrant epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation, play an essential role in developing various human diseases, including cancer. Recent studies show that synthetic and dietary epigenetic inhibitors attenuate the abnormal epigenetic modifications in cancer cells and therefore have strong potential for cancer treatment. In this chapter, we have highlighted various types of epigenetic modifications, their mechanism, and as drug targets for epigenetic therapy.
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Epigênese Genética , Neoplasias , Humanos , Montagem e Desmontagem da Cromatina , Metilação de DNA , Processamento de Proteína Pós-Traducional , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
BACKGROUND: Antimicrobial stewardship programs (ASPs) are an internationally recognized strategy for reducing antimicrobial resistance while maintaining patient safety. ASP activities include the restriction of broad-spectrum antibiotics, the establishment of hospital guidelines based on antibiograms, and the promotion of appropriate antibiotic use. This study aimed to determine whether the implementation of antimicrobial stewardship practices improved the effects of a peri-procedure antibiotic prophylaxis prescribed by urologists for patients with spinal cord injury/disease (SCI/D) undergoing minor urological procedures at a tertiary care hospital. METHODS: This single-group, quasi-experiment study included adult patients with SCI/D who required minor urological procedures (cystoscopy, cytobotox, cystolitholapaxy, and urodynamic study) and who were hospitalized between 2012 and 2020. RESULTS: In total, 233 patients were included in each of the pre- and post-ASP implantation groups. There was a significant reduction in antibiotic use among patients who received a pre-procedure antimicrobial prophylaxis in the post- compared to the pre-implementation group (45.9% vs. 24.46%, p < 0.0001), and there was a highly significant reduction in the post- compared to the pre-implementation group in the number who received a post-procedure prophylaxis (16.7% vs. 1.2%, p < 0.0001). CONCLUSION: ASP implementation is a highly effective strategy for reducing the use of peri-procedure antimicrobial prophylaxes in patients with SCI/D injuries undergoing minor urological procedures.
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Anti-Infecciosos , Gestão de Antimicrobianos , Traumatismos da Medula Espinal , Adulto , Humanos , Antibacterianos/uso terapêutico , Gestão de Antimicrobianos/métodos , Antibioticoprofilaxia/métodos , Anti-Infecciosos/uso terapêutico , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
A dysregulated hypothalamic-pituitary-adrenal (HPA) axis has repeatedly been demonstrated to play a fundamental role in psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) gene, which is also susceptible to epigenetic modulation, is a strong indicator of impaired HPA axis control. In the context of teenage suicide-completers, we have systematically analyzed the 5'UTR of the GR gene to determine the expression levels of all GR exon-1 transcript variants and their epigenetic state. We also measured the expression and the epigenetic state of the FK506-binding protein 51 (FKBP5/FKBP51), an important modulator of GR activity. Furthermore, steady-state DNA methylation levels depend upon the interplay between enzymes that promote DNA methylation and demethylation activities, thus we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45). Focusing on both the prefrontal cortex (PFC) and hippocampus, our results show decreased expression in specific GR exon-1 variants and a strong correlation of DNA methylation changes with gene expression in the PFC. FKBP5 expression is also increased in both areas suggesting a decreased GR sensitivity to cortisol binding. We also identified aberrant expression of DNA methylating and demethylating enzymes in both brain regions. These findings enhance our understanding of the complex transcriptional regulation of GR, providing evidence of epigenetically mediated reprogramming of the GR gene, which could lead to possible epigenetic influences that result in lasting modifications underlying an individual's overall HPA axis response and resilience to stress.
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Metilação de DNA , Receptores de Glucocorticoides , Suicídio Consumado , Proteínas de Ligação a Tacrolimo , Adolescente , Humanos , Éxons , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismoRESUMO
Introduction Diabetes and coronavirus disease 2019 (COVID-19) are interrelated. The presence of hyperglycemia per se during COVID-19 infection regardless of diabetes status has been associated with poor prognosis and increased risk of mortality. Objectives The main aim of the current study was to assess the association between admission hyperglycemia and COVID-19 outcomes. Methods This is a retrospective cohort study including 315 patients, mainly employed in the facility, who presented to the emergency department or were admitted with confirmed COVID-19 infection from April 2020 to August 2021. Results The mean age of the studied cohort was 40.2±12.5 years, where 59.68% were males and 37.7% were symptomatic. Older age, male gender, history of diabetes and hypertension, and elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels were associated with a significantly increased risk of developing cytokine release syndrome (CRS). Admission hyperglycemia was significantly associated with poor outcomes. The time to negativity was 9.30±0.1 days for asymptomatic patients; however, it increased significantly according to clinical presentation, presence of comorbidities, and severe outcomes, in patients with cytokine release syndrome. Conclusions Admission hyperglycemia was associated with an increased risk of progression to critical condition in patients hospitalized with COVID-19 independent of the history of diabetes. Therefore, it should not be overlooked but instead should be detected and appropriately treated to improve outcomes. In addition, post-COVID-19 care should be individualized, where severe cases require almost double the time needed by mild cases to convert to negative.
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Described herein are clinical and cardiac morphologic findings in 12 patients (age 43 to 70 years) (7 men) who underwent orthotopic heart transplantation (OHT) because of severe heart failure (HF) resulting from a single large discrete acute myocardial infarct that healed and was associated with severe narrowing of only one major epicardial coronary artery. Most myocardial infarcts are associated with severe narrowing of >1 major epicardial coronary artery and result in smaller myocardial infarcts. Another unusual feature was the total infarction of the ventricular septum in 3 of the 12 patients.
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Oclusão Coronária/complicações , Vasos Coronários/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Transplante de Coração , Infarto do Miocárdio/diagnóstico , Adulto , Idoso , Doença Crônica , Angiografia Coronária , Oclusão Coronária/diagnóstico , Progressão da Doença , Eletrocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Pericárdio , Índice de Gravidade de Doença , Síndrome , Fatores de TempoRESUMO
Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host's immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κß, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.
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Citocinas/metabolismo , Mieloma Múltiplo/metabolismo , Transdução de Sinais , Animais , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Proliferação de Células , Citocinas/análise , Citocinas/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Evasão Tumoral , Microambiente TumoralRESUMO
Described herein are certain clinical and morphologic findings in 9 patients who at necropsy had hearts weighing >1000 g, a weight approximately 3 times normal. With the exception of 2 patients with hypertrophic cardiomyopathy, the common finding in the remaining 7 patients was obesity. None had valvular heart disease, the previously described major cause of massive cardiomegaly. Thus, obesity needs to be added to the causes of massive cardiomegaly, a cause not previously recognized. Electrocardiograms in 4 patients disclosed high total 12-lead QRS voltage on the electrocardiogram in only one despite the massive cardiomegaly.
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Cardiomegalia/diagnóstico , Miocárdio/patologia , Obesidade/complicações , Adolescente , Adulto , Idoso , Autopsia , Cardiomegalia/etiologia , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Tamanho do Órgão , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: The impact of pylorus preserving procedures (PP) on total pancreatectomy with islet autotransplantation (TPIAT) has not been examined. This study aimed to investigate the clinical impact of the PP on TPIAT. METHODS: The Baylor Simmons Transplant Institute database was queried to identify seventy-three patients who underwent TPIAT from 2006 to 2014. All patients were investigated in postoperative complications, long-term nutritional status, and graft function. RESULTS: Patients with PP did not face worse outcomes in terms of delayed gastric emptying and length of hospital stay. Also, nutritional status and metabolic outcome, such as body weight, serum albumin level, serum vitamin level, HbA1c level, graft survival rate and insulin independent rate, were similar between both groups. CONCLUSIONS: Clinical results including the graft function indicated that patients undergoing TPIAT with PP did not amplify surgical complications such as delayed gastric emptying and showed no significant advantage of nutrition and metabolic outcome.
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Transplante das Ilhotas Pancreáticas , Pancreatectomia , Pancreatite Crônica/cirurgia , Adulto , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Piloro , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Natural products have always been sought as a dependable source for the cure of many fatal diseases including cancer. Resveratrol (RSV), a naturally occurring plant polyphenol, has been of recent research interest and is being investigated for its beneficial biological properties that include antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory activities. These effects are mainly mediated by cell cycle arrest, upregulation of proapoptotic proteins, loss of mitochondrial potential, and generation of reactive oxygen species. Among the beneficial properties of RSV, the anticancer property has been of the prime focus and extensively explored during the last few years. Although reports exist on the chemopreventive role of RSV in many solid tumors, limited information is available on the antiproliferative activity of RSV in human lymphoma cells and experimental models. Potential mechanisms for its antiproliferative effect include induction of cell differentiation, apoptosis, and inhibition of DNA synthesis. In this review, the different kinds of lymphoid malignancies and the main mechanisms of cell death induced by resveratrol are discussed. The challenges are limiting in vivo experimental studies involving resveratrol. An attempt for the translation of this compound into a clinical drug also forms a part of this review.
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Antineoplásicos Fitogênicos/uso terapêutico , Linfoma/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Estilbenos/uso terapêutico , Anticarcinógenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Humanos , Linfoma/patologia , Mieloma Múltiplo/patologia , Resveratrol , Estilbenos/farmacologiaRESUMO
Leptin is a multifunctional adipose-derived cytokine that plays a critical role in bodyweight homeostasis and energy balance. Plasma level of leptin is an indicator of the amount of energy stored in adipose tissues. Recently, leptin and leptin receptor dysregulation have been reported in a variety of malignant cells including colorectal cancers (CRCs). There are growing evidence that leptin may be the link between obesity and CRC carcinogenesis. Leptin influence the growth and proliferation of cancer cells via activation of various growth and survival signaling pathways including JAK/STAT, PI3-kinase/AKT, and/or MAP kinases. In this review, current understanding of leptin and its receptor's roles in the pathogenesis of colonogenic cancer has been described.
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Tecido Adiposo/metabolismo , Neoplasias Colorretais/metabolismo , Leptina/metabolismo , Receptores para Leptina/genética , Tecido Adiposo/patologia , Carcinogênese/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metabolismo Energético , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Leptina/genética , Receptores para Leptina/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: A number of constitutively activated signaling pathways play critical roles in the survival and growth of primary effusion lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis constitutively activated in a number of malignancies, including multiple myeloma, Burkitt's lymphoma and diffuse large cell B-cell lymphoma. However, its role in primary effusion lymphoma has not been fully explored. METHODOLOGY/PRINCIPAL FINDINGS: We used pharmacological inhibition and gene silencing to define the role of NFkB in growth and survival of PEL cells. Inhibition of NFkB activity by Bay11-7085 resulted in decreased expression of p65 in the nuclear compartment as detected by EMSA assays. In addition, Bay11-7085 treatment caused de-phosphorylation of AKT and its downstream targets suggesting a cross-talk between NFkB and the PI3-kinase/AKT pathway. Importantly, treatment of PEL cells with Bay11-7085 led to inhibition of cell viability and induced apoptosis in a dose dependent manner. Similar apoptotic effects were found when p65 was knocked down using specific small interference RNA. Finally, co-treatment of PEL cells with suboptimal doses of Bay11-7085 and LY294002 led to synergistic apoptotic responses in PEL cells. CONCLUSION/SIGNIFICANCE: These data support a strong biological-link between NFkB and the PI3-kinase/AKT pathway in the modulation of anti-apoptotic effects in PEL cells. Synergistic targeting of these pathways using NFKB- and PI3-kinase/AKT-inhibitors may have a therapeutic potential for the treatment of PEL and possibly other malignancies with constitutive activation of these pathways.
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Apoptose , Linfoma de Efusão Primária/enzimologia , Linfoma de Efusão Primária/patologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Proteínas I-kappa B/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , Nitrilas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologiaRESUMO
Leptin is a multifunctional adipose-derived cytokines that play a critical role in bodyweight homeostasis and energy balance. Recently, leptin and leptin receptor dysreulation have been reported in variety of malignant cells including thyroid. Leptin modulates growth and proliferation of cancer cells via activation of various growth and survival signaling pathways including JAK/STAT, PI3-kinase/AKT and/or Map kinases. In this review, current understanding of leptin's role in the pathogenesis of thyroid cancer has been described.
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Leptina/metabolismo , Receptores para Leptina/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Humanos , Transdução de Sinais , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in pathogenesis of diffuse large B cell lymphoma (DLBCL). In an attempt to identify newer therapeutic agents, we investigated the role of Resveratrol (trans-3,4', 5-trihydroxystilbene), a naturally occurring polyphenolic compound on a panel of diffuse large B-cell lymphoma (DLBCL) cells in causing inhibition of cell viability and inducing apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the action of Resveratrol on DLBCL cells and found that Resveratrol inhibited cell viability and induced apoptosis by inhibition of constitutively activated AKT and its downstream targets via generation of reactive oxygen species (ROS). Simultaneously, Resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; and interestingly, co-treatment of DLBCL with sub-toxic doses of TRAIL and Resveratrol synergistically induced apoptosis via utilizing DR5, on the other hand, gene silencing of DR5 abolished this effect. CONCLUSION/SIGNIFICANCE: Altogether, these data suggest that Resveratrol acts as a suppressor of AKT/PKB pathway leading to apoptosis via generation of ROS and at the same time primes DLBCL cells via up-regulation of DR5 to TRAIL-mediated apoptosis. These data raise the possibility that Resveratrol may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway.