Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Am J Pathol ; 194(10): 1951-1966, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39069168

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with high incidence and mortality worldwide. Despite diagnostic and therapeutic advancements, HCC remains poorly responsive to treatment, with a poor prognosis. Understanding the molecular mechanisms driving HCC is crucial for developing effective therapies. Emerging evidence indicates that dysregulated fatty acid metabolism contributes to HCC. Acyl-CoA medium-chain synthetase 5 (ACSM5), involved in fatty acid metabolism, is down-regulated in HCC; however, its role is not well understood. This study was used to analyze ACSM5 expression in HCC patient samples and cell lines. The newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6-ACSM5, were used to investigate the effects and regulatory mechanisms of ACSM5. The results showed that ACSM5 was significantly down-regulated in HCC tumor tissues compared with non-tumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNA methyltransferase 1 (DNMT1) inhibitor effectively increasing ACSM5 expression and reducing promoter region methylation. Overexpression of ACSM5 in Huh7 cells reduced fatty acid accumulation, decreased cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in mouse xenografts. Furthermore, ACSM5 overexpression also decreased STAT3 phosphorylation, subsequently affecting downstream cytokine TGFB and FGF12 mRNA levels. These findings suggest that ACSM5 down-regulation contributes to HCC progression, providing insights into its oncogenic role and highlighting its potential as a biomarker and therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Coenzima A Ligases , Progressão da Doença , Ácidos Graxos , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Ácidos Graxos/metabolismo , Animais , Camundongos , Regulação Neoplásica da Expressão Gênica , Masculino , Camundongos Nus , Linhagem Celular Tumoral , Feminino , Metilação de DNA , Movimento Celular
2.
Hepatology ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39028883

RESUMO

BACKGROUND AND AIMS: Disruption of the epigenome is a hallmark of human disease, including liver cirrhosis and HCC. While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target frequently mutated genes in HCC, there is an unmet need for novel therapeutics to prevent or reverse liver damage leading to hepatic tumorigenesis, which the epigenome may provide. APPROACH AND RESULTS: We performed genome-wide profiling of DNA methylation, copy number, and gene expression from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contributions of these processes to liver disease progression. We identified epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity is associated with increased gene expression heterogeneity. Cirrhotic regions comprise 2 distinct cohorts-one exclusively epigenetic, and the other where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (eg, HNF1A ) and known tumor suppressors (eg, RASSF1A ). These hotspots encompass genes including ACSL1 , ACSL5 , MAT1A , and ELFN1 , which have phenotypic effects in functional screens, supporting their relevance to hepatocarcinogenesis. Moreover, epigenetic heterogeneity hotspots are linked to clinical measures of outcome. CONCLUSIONS: Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.

3.
Clin Infect Dis ; 77(Suppl 7): S581-S587, 2023 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-38118016

RESUMO

Antimicrobial resistance (AMR) is a growing global public health challenge associated with 4.95 million deaths in 2019 and an estimated 10 million deaths per year by 2050 in the absence of coordinated action. A robust AMR surveillance system is therefore required to avert such a scenario. Based on an analysis of country-level AMR data in 8 Capturing Data on Antimicrobial Resistance Patterns and Trends in Use in Regions of Asia (CAPTURA) countries, we present a list of key recommendations to strengthen AMR surveillance. We propose 10 primary considerations under 3 broad categories, including recommendations on (1) laboratory and testing practices, (2) data management and analysis, and (3) data use.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ásia , Saúde Pública , Laboratórios
4.
Clin Infect Dis ; 77(Suppl 7): S507-S518, 2023 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-38118007

RESUMO

Antimicrobial resistance (AMR) is a multifaceted global health problem disproportionately affecting low- and middle-income countries (LMICs). The Capturing data on Antimicrobial resistance Patterns and Trends in Use in Regions of Asia (CAPTURA) project was tasked to expand the volume of AMR and antimicrobial use data in Asia. The CAPTURA project used 2 data-collection streams: facility data and project metadata. Project metadata constituted information collected to map out data sources and assess data quality, while facility data referred to the retrospective data collected from healthcare facilities. A down-selection process, labelled "the funnel approach" by the project, was adopted to use the project metadata in prioritizing and selecting laboratories for retrospective AMR data collection. Moreover, the metadata served as a guide for understanding the AMR data once they were collected. The findings from CAPTURA's metadata add to the current discourse on the limitation of AMR data in LMICs. There is generally a low volume of AMR data generated as there is a lack of microbiology laboratories with sufficient antimicrobial susceptibility testing capacity. Many laboratories in Asia are still capturing data on paper, resulting in scattered or unused data not readily accessible or shareable for analyses. There is also a lack of clinical and epidemiological data captured, impeding interpretation and in-depth understanding of the AMR data. CAPTURA's experience in Asia suggests that there is a wide spectrum of capacity and capability of microbiology laboratories within a country and region. As local AMR surveillance is a crucial instrument to inform context-specific measures to combat AMR, it is important to understand and assess current capacity-building needs while implementing activities to enhance surveillance systems.


Assuntos
Antibacterianos , Países em Desenvolvimento , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Estudos Retrospectivos , Farmacorresistência Bacteriana , Ásia/epidemiologia
5.
Hepatology ; 75(4): 983-996, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34387871

RESUMO

BACKGROUND AND AIMS: Chronic HCV infection is a leading etiologic driver of cirrhosis and ultimately HCC. Of the approximately 71 million individuals chronically infected with HCV, 10%-20% are expected to develop severe liver complications in their lifetime. Epigenetic mechanisms including DNA methylation and histone modifications become profoundly disrupted in disease processes including liver disease. APPROACH AND RESULTS: To understand how HCV infection influences the epigenome and whether these events remain as "scars" following cure of chronic HCV infection, we mapped genome-wide DNA methylation, four key regulatory histone modifications (H3K4me3, H3K4me1, H3K27ac, and H3K27me3), and open chromatin in parental and HCV-infected immortalized hepatocytes and the Huh7.5 HCC cell line, along with DNA methylation and gene-expression analyses following elimination of HCV in these models through treatment with interferon-α (IFN-α) or a direct-acting antiviral (DAA). Our data demonstrate that HCV infection profoundly affects the epigenome (particularly enhancers); HCV shares epigenetic targets with interferon-α targets; and an overwhelming majority of epigenetic changes induced by HCV remain as "scars" on the epigenome following viral cure. Similar findings are observed in primary human patient samples cured of chronic HCV infection. Supplementation of IFN-α/DAA antiviral regimens with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine synergizes in reverting aberrant DNA methylation induced by HCV. Finally, both HCV-infected and cured cells displayed a blunted immune response, demonstrating a functional effect of epigenetic scarring. CONCLUSIONS: Integration of epigenetic and transcriptional data elucidate key gene deregulation events driven by HCV infection and how this may underpin the long-term elevated risk for HCC in patients cured of HCV due to epigenome scarring.


Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Antivirais/farmacologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Epigenoma , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Interferon-alfa/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética
6.
Arterioscler Thromb Vasc Biol ; 41(2): 839-853, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33380174

RESUMO

OBJECTIVE: Electronic cigarette (e-cig) use has recently been implicated in promoting atherosclerosis. In this study, we aimed to investigate the mechanism of e-cig exposure accelerated atherosclerotic lesion development. Approach and Results: Eight-week-old ApoE-/- mice fed normal laboratory diet were exposed to e-cig vapor (ECV) for 2 hours/day, 5 days/week for 16 weeks. We found that ECV exposure significantly induced atherosclerotic lesions as examined by Oil Red O staining and greatly upregulated TLR9 (toll-like receptor 9) expression in classical monocytes and in the atherosclerotic plaques, which the latter was corroborated by enhanced TLR9 expression in human femoral artery atherosclerotic plaques from e-cig smokers. Intriguingly, we found a significant increase of oxidative mitochondria DNA lesion in the plasma of ECV-exposed mice. Administration of TLR9 antagonist before ECV exposure not only alleviated atherosclerosis and the upregulation of TLR9 in plaques but also attenuated the increase of plasma levels of inflammatory cytokines, reduced the plaque accumulation of lipid and macrophages, and decreased the frequency of blood CCR2+ (C-C chemokine receptor type 2) classical monocytes. Surprisingly, we found that cytoplasmic mitochondrial DNA isolated from ECV extract-treated macrophages can enhance TLR9 activation in reporter cells and the induction of inflammatory cytokine could be suppressed by TLR9 inhibitor in macrophages. CONCLUSIONS: E-cig increases level of damaged mitochondrial DNA in circulating blood and induces the expression of TLR9, which elevate the expression of proinflammatory cytokines in monocyte/macrophage and consequently lead to atherosclerosis. Our results raise the possibility that intervention of TLR9 activation is a potential pharmacological target of ECV-related inflammation and cardiovascular diseases.


Assuntos
Aorta/metabolismo , Aterosclerose/etiologia , Dano ao DNA , DNA Mitocondrial/metabolismo , Vapor do Cigarro Eletrônico/efeitos adversos , Inflamação/etiologia , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , DNA Mitocondrial/genética , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Células RAW 264.7 , Transdução de Sinais , Fumantes , Vaping
7.
Appl Microbiol Biotechnol ; 105(10): 4005-4015, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33950278

RESUMO

The coronavirus disease (COVID-19) caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide. Given that this contagious viral outbreak is still unfolding, it is urgent to understand the pathogenesis of SARS-CoV-2 infection and explore effective treatments to protect patients from developing a severe illness related to COVID-19. Recently, IFN-α has been considered a potential therapeutic strategy to treat COVID-19 disease, mainly because the innate immune system rapidly produces IFN-α as the first line of defense to combat viral infections. However, IFN-α can also play a role in immunoregulatory effects, causing pathogenic damage and uncontrolled inflammatory responses. There are 13 human IFN-α subtypes that bind to the same receptor and induce different interferon-stimulated gene (ISG) expression, regulating various antiviral and immunoregulatory effects. The varying degrees of inflammatory regulations may raise concerns about the possible side effects to enlarge the inflammatory responses, exacerbating the severity of infection. Thus, the analysis of various IFN-α subtype induction during SARS-CoV-2 infection is necessary in exploring the mechanism of COVID-19 pathogenesis. This review summarizes the current understanding of IFN-α in the pathogenesis of respiratory virus diseases and IFN-α based clinical intervention used in SARS-CoV-2 infection and other respiratory virus diseases. Besides, new ideas in selecting suitable IFN-α subtypes or combinations as drug candidates for viral infection treatment will also be discussed.Key Points• IFN-α plays an important role in anti-viral and immunoregulatory effects in COVID-19 patients caused by SARS-CoV-2.• The uncontrolled inflammation and disease severity correlated to the diversity of IFN-α subtype induction.• Selecting suitable IFN-α subtypes or combinations as drug candidates will be beneficial for the treatment of patients with COVID-19.


Assuntos
COVID-19 , Antivirais/uso terapêutico , Humanos , Interferon-alfa/uso terapêutico , SARS-CoV-2
8.
Biochem Biophys Res Commun ; 527(1): 317-323, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32446387

RESUMO

This study aimed to identify small molecules that have the potential to treat alpha1-antitrypsin deficiency (AATD) by screening compounds available from a mixture-based scaffold library. 93 scaffold libraries (total diversity of >30 million compounds in mixture format) were screened using a cell model of AATD in order to identify samples that could either reduce intracellular aggregation of Z-form AAT protein, increase extracellular secretion of Z-AAT or both. Mixture libraries containing compounds with in vitro activity, for example library 1295, were screened further to identify individual active compounds. The mixture format of the scaffold library allowed for some preliminary structure-activity relationships to be developed and also enabled the rapid selection of a promising scaffold. Utilizing this scaffold, 1295, a collection of individual "control" compounds contained in the 1295 mixture sample were then screened. A sub-library of individual "control" compounds featuring structural diversity at position R1 (1295.R1), was screened and 7 compounds were found to reduce the intracellular accumulation of Z-AAT without affecting cell viability at a concentration of 25ug/ml (about 50 µM). Screening sub-libraries featuring structural diversity at R2 and R3 (1295.R2 and 1295.R3) identified an additional 15 active compounds. Titration experiments identified 3 compounds from the 1295.R2 library that retained activity at 5ug/ml (approx. 10uM). One compound (1295.263) from 1295.R2 decreased intracellular levels of Z-AAT without affecting cell viability and wild-type AAT levels at the concentration of 5ug/ml. Molecular docking of this compound to the Z-AAT crystal structure identified a potential binding site near the C-terminal domain, an identified polymerization site. Our results indicate that screening large mixture-based compound libraries can be used to identify small molecules that may have the potential to treat AATD and other disease.


Assuntos
Bibliotecas de Moléculas Pequenas/farmacologia , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Deficiência de alfa 1-Antitripsina/patologia
9.
Hepatology ; 69(2): 639-652, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30136421

RESUMO

Disruption of epigenetic mechanisms has been intimately linked to the etiology of human cancer. Understanding how these epigenetic mechanisms (including DNA methylation [5mC], hydroxymethylation [5hmC], and histone post-translational modifications) work in concert to drive cancer initiation and progression remains unknown. Hepatocellular carcinoma (HCC) is increasing in frequency in Western countries but lacks efficacious treatments. The epigenome of HCC remains understudied. To better understand the epigenetic underpinnings of HCC, we performed a genome-wide assessment of 5mC, 5hmC, four histone modifications linked to promoter/enhancer function (H3K4me1, H3K27ac, H3K4me3, and H3K27me3), and transcription across normal, cirrhotic, and HCC liver tissue. Implementation of bioinformatic strategies integrated these epigenetic marks with each other and with transcription to provide a comprehensive epigenetic profile of how and when the liver epigenome is perturbed during progression to HCC. Our data demonstrate significant deregulation of epigenetic regulators combined with disruptions in the epigenome hallmarked by profound loss of 5hmC, locus-specific gains in 5mC and 5hmC, and markedly altered histone modification profiles, particularly remodeling of enhancers. Data integration demonstrates that these marks collaborate to influence transcription (e.g., hyper-5hmC in HCC-gained active enhancers is linked to elevated expression) of genes regulating HCC proliferation. Two such putative epigenetic driver loci identified through our integrative approach, COMT and FMO3, increase apoptosis and decrease cell viability in liver-derived cancer cell lines when ectopically re-expressed. Conclusion: Altogether, integration of multiple epigenetic parameters is a powerful tool for identifying epigenetically regulated drivers of HCC and elucidating how epigenome deregulation contributes to liver disease and HCC.


Assuntos
Carcinoma Hepatocelular/genética , Epigenoma , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Estudos de Casos e Controles , Metilação de DNA , Código das Histonas , Humanos , Fígado/metabolismo
10.
Mol Ther ; 25(10): 2299-2308, 2017 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-28865999

RESUMO

Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate worldwide, with limited treatment options. Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. GPC3-targeting antibody therapy shows limited response in a clinical trial due to the lack of a tumor-specific cytotoxic T lymphocyte (CTL) response. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3+) elicited robust GPC3-specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Treatment with LC/GPC3+ induced durable tumor regression in HCC-bearing C57/B6 mice. Administration of LC/GPC3+ induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), granzyme B, and perforin, and substantially increased the number of infiltrating CD8+ T cells in tumor tissues. Moreover, immune responses elicited by LC/GPC3+ selectively suppressed GPC3+ tumors, but didn't affect the GPC3- tumors in BALB/c mice. Our findings provide the first preclinical evidence that intravenous infusion of the LC/GPC3+ complex can induce a strong anti-HCC effect through regulating systemic and local immune responses. These results indicate that the LC/GPC3+ complex could be developed as precision therapeutics for HCC patients in the future.


Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/prevenção & controle , Glipicanas/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Interferon gama/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo
11.
Am J Pathol ; 186(6): 1537-46, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27102771

RESUMO

Commercially available, highly passaged pancreatic cancer (PC) cell lines are of limited translational value. Attempts to overcome this limitation have primarily consisted of cancer cell isolation and culture directly from human PC specimens. However, these techniques are associated with exceedingly low success rates. Here, we demonstrate a highly reproducible culture of primary PC cell lines (PPCLs) from patient-derived xenografts, which preserve, in part, the intratumoral heterogeneity known to exist in PC. PPCL expansion from patient-derived xenografts was successful in 100% of attempts (5 of 5). Phenotypic analysis was evaluated with flow cytometry, immunofluorescence microscopy, and short tandem repeat profiling. Importantly, tumorigenicity of PPCLs expanded from patient-derived xenografts was assessed by subcutaneous injection into nonobese diabeteic.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice. Morphologically, subcutaneous injection of all PPCLs into mice yielded tumors with similar characteristics to the parent xenograft. PPCLs uniformly expressed class I human leukocyte antigen, epithelial cell adhesion molecule, and cytokeratin-19. Heterogeneity within each PPCL persisted in culture for the frequency of cells expressing the cancer stem cell markers CD44, CD133, and c-Met and the immunologic markers human leukocyte antigen class II and programmed death ligand 1. This work therefore presents a reliable method for the rapid expansion of primary human PC cells and, thereby, provides a platform for translational investigation and, importantly, potential personalized therapeutic approaches.


Assuntos
Técnicas de Cultura de Células , Linhagem Celular Tumoral , Neoplasias Pancreáticas , Idoso , Animais , Feminino , Citometria de Fluxo , Imunofluorescência , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo
12.
Am J Pathol ; 185(5): 1297-303, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25770474

RESUMO

Direct implantation of viable surgical specimens provides a representative preclinical platform in pancreatic adenocarcinoma. Patient-derived xenografts consistently demonstrate retained tumor morphology and genetic stability. However, the evolution of the tumor microenvironment over time remains poorly characterized in these models. This work specifically addresses the recruitment and incorporation of murine stromal elements into expanding patient-derived pancreatic adenocarcinoma xenografts, establishing the integration of murine cells into networks of invading cancer cells. In addition, we provide methods and observations in the establishment and maintenance of a patient-derived pancreatic adenocarcinoma xenograft model. A total of 25 histologically confirmed pancreatic adenocarcinoma specimens were implanted subcutaneously into nonobese diabetic severe combined immunodeficiency mice. Patient demographics, staging, pathological analysis, and outcomes were analyzed. After successful engraftment of tumors, histological and immunofluorescence analyses were performed on explanted tumors. Pancreatic adenocarcinoma specimens were successfully engrafted in 15 (60%) of 25 attempts. Successful engraftment does not appear to correlate with clinicopathologic factors or patient survival. Tumor morphology is conserved through multiple passages, and tumors retain metastatic potential. Interestingly, despite morphological similarity between passages, human stromal elements do not appear to expand with invading cancer cells. Rather, desmoplastic murine stroma dominates the xenograft microenvironment after the initial implantation. Recruitment of stromal elements in this manner to support and maintain tumor growth represents a novel avenue for investigation into tumor-stromal interactions.


Assuntos
Adenocarcinoma/patologia , Modelos Animais de Doenças , Neoplasias Pancreáticas/patologia , Transplante Heterólogo/métodos , Microambiente Tumoral , Animais , Imunofluorescência , Xenoenxertos , Humanos , Camundongos , Camundongos SCID , Neoplasias Pancreáticas
13.
Cancer Immunol Immunother ; 64(12): 1553-63, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26423423

RESUMO

The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-γ (IFNγ) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNγ remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNγ response within and on key cells of the PC microenvironment was evaluated. IFNγ induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNγ also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNγ has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival.


Assuntos
Desoxicitidina/análogos & derivados , Interferons/imunologia , Neoplasias Pancreáticas/fisiopatologia , Microambiente Tumoral/fisiologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Linhagem Celular Tumoral , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos HLA/genética , Humanos , Interferon gama/farmacologia , Neoplasias Pancreáticas/diagnóstico , Receptores CXCR3/genética , Células Tumorais Cultivadas , Gencitabina
14.
Cell Rep ; 43(7): 114451, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38970788

RESUMO

Omicron surged as a variant of concern in late 2021. Several distinct Omicron variants appeared and overtook each other. We combined variant frequencies and infection estimates from a nowcasting model for each US state to estimate variant-specific infections, attack rates, and effective reproduction numbers (Rt). BA.1 rapidly emerged, and we estimate that it infected 47.7% of the US population before it was replaced by BA.2. We estimate that BA.5 infected 35.7% of the US population, persisting in circulation for nearly 6 months. Other variants-BA.2, BA.4, and XBB-together infected 30.7% of the US population. We found a positive correlation between the state-level BA.1 attack rate and social vulnerability and a negative correlation between the BA.1 and BA.2 attack rates. Our findings illustrate the complex interplay between viral evolution, population susceptibility, and social factors during the Omicron emergence in the US.


Assuntos
COVID-19 , SARS-CoV-2 , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , COVID-19/virologia , COVID-19/epidemiologia , Humanos , Estados Unidos/epidemiologia , Genoma Viral , Genômica/métodos
15.
J Surg Case Rep ; 2024(8): rjae481, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39109377

RESUMO

Tessier number 10 cleft is one of the rarest facial clefts. Surgical treatment of this type of cleft is challenging due to the complexity of periorbital and temporal soft tissue deformities. A 23-year-old male patient presented with typical facial deformities of Tessier number 10 cleft. The surgical procedure involved using a free anterolateral thigh flap to reconstruct the eye socket, while the superficial temporal artery pedicle scalp flap was used to reconstruct the eyebrow deformity. The patient had no complications and 16 months after surgery, the patient had good aesthetic results. A hair-bearing scalp flap with a pedicle of the frontal branch of the superficial temporal artery combined with an anterolateral thigh-free flap can effectively resolve most soft tissue deformities of Tessier number 10 cleft and reconstruct the orbital socket in a single surgery. At the same time, it augments the soft tissue of the frontotemporal area and provides good aesthetic results.

16.
Microbiol Resour Announc ; 12(1): e0111322, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36448812

RESUMO

Here, we report a recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage XAM (Omicron BA.1.1/BA.2.9) strain that was collected in Santo Domingo, Dominican Republic. This demonstrates how SARS-CoV-2 variants can vary greatly between regions and thus underlines the great importance of regional genomic surveillance efforts.

17.
Cell Rep Med ; 4(2): 100943, 2023 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-36791724

RESUMO

The chronic infection hypothesis for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence is increasingly gaining credence following the appearance of Omicron. Here, we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately 2-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution results in the emergence and persistence of at least three genetically distinct genotypes, suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Infecção Persistente , Genoma Viral , Genótipo
18.
Plast Reconstr Surg Glob Open ; 11(10): e5347, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37859638

RESUMO

Venomous snakebites can cause severe injury. The loss of tendon and skin of the hand is incredibly challenging for the surgeon. A single-staged reconstruction with the free composite anterolateral thigh flap is an acceptable option for a complex thumb injury. In this case, reconstruction for a 23-year-old patient with a complex cobra-induced thumb injury had failed to cover the defect with a skin graft. There was a limitation in choice, and the patient was treated with the free composite anterolateral thigh (ALT) flap and fascia lata flap in one stage to reconstruct both the extensor tendon and the soft tissue coverage. The flap was well-vascularized, and no complications were reported. A single-stage reconstruction with a composite ALT flap with vascularized fascia was chosen as a suitable alternative. The result is satisfying both aesthetically and functionally. This technique can help shorten treatment time and restore function quickly, allowing patients to return to work in less time. The disadvantages of this technique are flap thickness, which can affect finger movement and aesthetics. The composite ALT flap with vascularized fascia lata shows that it is a reliable procedure for single-staged reconstruction, especially combined with the tendon preparation in the hand.

19.
Sci Rep ; 13(1): 3137, 2023 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-36823427

RESUMO

Following the rising concern on environmental issues caused by conventional fossil-based plastics and depleting crude oil resources, polyhydroxyalkanoates (PHAs) are of great interest by scientists and biodegradable polymer market due to their outstanding properties which include high biodegradability in various conditions and processing flexibility. Many polyhydroxyalkanoate-synthesizing microorganisms, including normal and halophilic bacteria, as well as algae, have been investigated for their performance in polyhydroxyalkanoate production. However, to the best of our knowledge, there is still limited studies on PHAs-producing marine yeast. In the present study, a halophilic yeast strain isolated from Spratly Island in Vietnam were investigated for its potential in polyhydroxyalkanoate biosynthesis by growing the yeast in Zobell marine agar medium (ZMA) containing Nile red dye. The strain was identified by 26S rDNA analysis as Pichia kudriavzevii TSLS24 and registered at Genbank database under code OL757724. The amount of polyhydroxyalkanoates synthesized was quantified by measuring the intracellular materials (predicted as poly(3-hydroxybutyrate) -PHB) by gravimetric method and subsequently confirmed by Fourier transform infrared (FTIR) spectroscopic and nuclear magnetic resonance (NMR) spectroscopic analyses. Under optimal growth conditions of 35 °C and pH 7 with supplementation of glucose and yeast extract at 20 and 10 gL-1, the isolated strain achieved poly(3-hydroxybutyrate) content and concentration of 43.4% and 1.8 gL-1 after 7 days of cultivation. The poly(3-hydroxybutyrate) produced demonstrated excellent biodegradability with degradation rate of 28% after 28 days of incubation in sea water.


Assuntos
Poli-Hidroxialcanoatos , Poli-Hidroxialcanoatos/química , Pichia/metabolismo , Vietnã , Espectroscopia de Ressonância Magnética
20.
Sci Transl Med ; 15(683): eade6023, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36791210

RESUMO

The emergence of the SARS-CoV-2 Omicron sublineages resulted in increased transmission rates and reduced protection from vaccines. To counteract these effects, multiple booster strategies were used in different countries, although data comparing their efficiency in improving protective immunity remain sparse, especially among vulnerable populations, including older adults. The inactivated CoronaVac vaccine was among the most widely distributed vaccine worldwide and was essential in the early control of SARS-CoV-2-related hospitalizations and deaths. However, it is not well understood whether homologous versus heterologous booster doses in those fully vaccinated with CoronaVac induce distinct humoral responses or whether these responses vary across age groups. We analyzed plasma antibody responses from CoronaVac-vaccinated younger or older individuals who received a homologous CoronaVac or heterologous BNT162b2 or ChAdOx1 booster vaccine. All three evaluated boosters resulted in increased virus-specific IgG titers 28 days after the booster dose. However, we found that both IgG titers against SARS-CoV-2 Spike or RBD and neutralization titers against Omicron sublineages were substantially reduced in participants who received homologous CoronaVac compared with the heterologous BNT162b2 or ChAdOx1 booster. This effect was specifically prominent in recipients >50 years of age. In this group, the CoronaVac booster induced low virus-specific IgG titers and failed to elevate neutralization titers against any Omicron sublineage. Our results point to the notable inefficiency of CoronaVac immunization and boosting in mounting protective antiviral humoral immunity, particularly among older adults, during the Omicron wave. These observations also point to benefits of heterologous regimens in high-risk populations fully vaccinated with CoronaVac.


Assuntos
Formação de Anticorpos , COVID-19 , Humanos , Idoso , Vacina BNT162 , SARS-CoV-2 , Imunoglobulina G , Anticorpos Antivirais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA