RESUMO
HucR is a MarR family protein of Deinococcus radiodurans, which binds tightly to the intergenic region of HucR and the uricase gene to inhibit their expression. Urate (or uric acid) antagonizes the repressor function of HucR by binding to HucR to impede its association with the cognate DNA. The previously reported crystal structure of HucR was without the bound urate showing significant structural homology to other MarR structures. In this paper, we report the crystal structure of HucR determined with the urate bound. However, despite the fact that the urate is found at a site well-known to harbor ligands in other MarR family proteins, the overall HucR structure indicates that no significant change in structure takes place with the urate bound. Structure analysis further suggests that the urate interaction in HucR is mediated by histidine/glutamate side chains and ordered water molecules stabilized by various residues. Such interaction is quite unique compared to other known structural interactions between urate and its binding proteins. Furthermore, structural comparison of the apo- and the urate bound forms allows us to hypothesize that the Trp20-mediated water network in the apo-form stabilizes the proper HucR fold for cognate DNA binding, and that urate binding, also via Trp20, and the consequent reorganization of water molecules in the binding pocket, likely disrupts the DNA binding configuration to result in the attenuated DNA binding.
Assuntos
Deinococcus , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , DNA/química , Deinococcus/química , Ligação Proteica , Ácido Úrico/metabolismo , Água/metabolismoRESUMO
The human parasitic head and body lice lay their eggs on either hair or clothing. Attachments of the eggs are possible because the female lice secret a glue substance from the accessory gland along with the egg, which hardens into a nit sheath that secures and protects the egg (The "nit" commonly refers to either the louse egg with an embryo or the empty hatched egg). Proteins called the louse nit sheath protein (LNSP) are suggested to be the major proteins of the nit sheath, but transcriptome profiling of the accessory glands indicated other proteins such as Agp9 and Agp22 are also expressed in the glands. In this study, human body louse LNSP1 (partial), Agp9, and Agp22 are recombinantly produced using the E. coli expression system, and the biophysical properties characterized. Circular dichroism analysis indicated that the secondary structure elements of LNSP1 N-terminal and middle-domains, Agp9, and Agp22 are prominently random coiled with up to 10-30% anti-parallel ß-sheet element present. Size-exclusion chromatography profiles of LNSP1 proteins further suggested that the ß-sheets made of the smaller N-terminal domain stacks onto the ß-sheets of the larger middle-domain.
Assuntos
Infestações por Piolhos , Pediculus , Animais , Escherichia coli/genética , Feminino , Cabelo , Humanos , Infestações por Piolhos/parasitologia , Pediculus/químicaRESUMO
BACKGROUND: Protective mechanical ventilation using low tidal volume has been introduced to surgical patients to reduce the incidence of postoperative pulmonary complications. We investigated the effects of protective ventilation (PV) techniques on anesthesia-induced atelectasis identified via lung ultrasonography in patients undergoing abdominal surgery. METHODS: A total of 42 adult patients who were scheduled for open abdominal surgery with an expected duration > 2 hours were included in the study. Patients were randomized to receive either conventional ventilation (CV; tidal volume of 9-10 mL/kg predicted body weight [PBW] with no positive end-expiratory pressure [PEEP]) or PV (tidal volume of 6-8 mL/kg PBW and 5 cmH2O PEEP) via pressure-controlled ventilation with volume guaranteed. Lung ultrasonography was performed at four predefined time points to assess perioperative atelectasis by dividing each hemithorax into six quadrants based on a modified lung ultrasound (LUS) scoring system. RESULTS: The tidal volume delivered to patients was 9.65 ± 1.65 mL/kg PBW in the CV group and 6.31 ± 0.62 mL/kg PBW in the PV group. Ventilation using low tidal volume led to similar LUS scores in all lung areas and at all time points compared to ventilation using high tidal volume. There was no significant difference between the groups in the number of patients requiring recruitment maneuvers at the end of surgery. CONCLUSION: Ventilation with low tidal volume combined with 5 cmH2O PEEP did not cause further loss of aeration compared to ventilation with high tidal volume. Low tidal volume ventilation can be used in patients without lung injury based on lung assessment by bedside lung ultrasonography. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0003746.
Assuntos
Abdome/cirurgia , Pulmão/diagnóstico por imagem , Atelectasia Pulmonar/terapia , Respiração Artificial , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Respiração com Pressão Positiva , Estudos Prospectivos , Atelectasia Pulmonar/diagnóstico por imagem , Volume de Ventilação Pulmonar/fisiologia , UltrassonografiaRESUMO
BACKGROUND: Bedside sonography of the inferior vena cava has been demonstrated to be a reliable tool for assessing intravascular volume status. Subclavian vein (SCV) assessment was proposed as a reasonable adjunct for measuring the inferior vena cava. OBJECTIVE: We examined whether the preoperative diameter and collapsibility index of the SCV or the infraclavicular axillary vein could predict the incidence of hypotension after induction of general anaesthesia in patients undergoing laparoscopic cholecystectomy. DESIGN: Prospective, observational study. SETTING: Tertiary university hospital. PATIENTS: Adults scheduled for laparoscopic cholecystectomy. INTERVENTION: Sonographic evaluation of the SCV or the axillary vein (SCV-AV) before induction of anaesthesia. MAIN OUTCOME MEASURES: The main outcome was the association between the SCV-AV measurements (diameter an collapsibility index) and intra-operative hypotension (IOH) after induction of anaesthesia. RESULTS: Patients who developed IOH had a higher collapsibility index of the SCV-AV during spontaneous breathing (Pâ=â0.009) and deep inspiration (Pâ=â0.002). After adjusting for confounding variables, the collapsibility index of the SCV-AV during spontaneous breathing was not a significant predictor of a decrease in mean arterial blood pressure (MAP) after inducing anaesthesia (Pâ=â0.127), whereas the collapsibility index of the SCV-AV during deep inspiration was a significant predictor (Pâ<â0.001). CONCLUSION: The collapsibility index of the SCV-AV during deep inspiration was a significant predictor of IOH occurrence and the percentage decrease in MAP after inducing anaesthesia. Further studies in patients with higher collapsibility index are needed to confirm our findings, before the collapsibility index of the SCV-AV can be recommended unequivocally for clinical use. TRIAL REGISTRATION: This trial was registered on 8 September 2017 at the Clinical Trial Registry of Korea (https://cris.nih.go.kr/cris/index.jsp; Identifier: KCT0001078KCT0002457), and the first patient was enrolled on 14 October 2017.
Assuntos
Hipotensão , Veia Subclávia , Adulto , Anestesia Geral/efeitos adversos , Veia Axilar/diagnóstico por imagem , Humanos , Hipotensão/diagnóstico por imagem , Hipotensão/epidemiologia , Hipotensão/etiologia , Estudos Prospectivos , República da Coreia , Veia Subclávia/diagnóstico por imagem , UltrassonografiaRESUMO
The transcription factor C/EBPα is essential for myeloid differentiation and is frequently dysregulated in acute myeloid leukemia. Although studied extensively, the precise regulation of its gene by upstream factors has remained largely elusive. Here, we investigated its transcriptional activation during myeloid differentiation. We identified an evolutionarily conserved octameric sequence, CCCAGCAG, â¼100 bases upstream of the CEBPA transcription start site, and demonstrated through mutational analysis that this sequence is crucial for C/EBPα expression. This sequence is present in the genes encoding C/EBPα in humans, rodents, chickens, and frogs and is also present in the promoters of other C/EBP family members. We identified that ZNF143, the human homolog of the Xenopus transcriptional activator STAF, specifically binds to this 8-bp sequence to activate C/EBPα expression in myeloid cells through a mechanism that is distinct from that observed in liver cells and adipocytes. Altogether, our data suggest that ZNF143 plays an important role in the expression of C/EBPα in myeloid cells.
Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/genética , Células Mieloides/citologia , Regiões Promotoras Genéticas , Transativadores/metabolismo , Ativação Transcricional , Sequência de Bases , Linhagem Celular , Sequência Conservada , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese , Humanos , Células Mieloides/metabolismo , Ligação ProteicaRESUMO
BACKGROUND: Manubriosternal joint (MSJ) disease is a rare cause of anterior chest pain but can be a major sign of systemic arthritic involvement. In patients with ankylosing spondylitis (AS), a type of systemic arthritis, chest pain can be due to MSJ involvement and can be improved by ultrasound-guided corticosteroid injection into the joint. CASE SUMMARY: A 64-year-old man visited our pain clinic complaining of anterior chest pain. There were no abnormal findings on lateral sternum X-ray, but arthritic changes in the MSJ were observed on single-photon emission computed tomography-computed tomography. We performed additional laboratory tests, and he was finally diagnosed with AS. For pain relief, we performed ultrasound-guided intra-articular (IA) corticosteroid injections into the MSJ. After the injections, his pain nearly resolved. CONCLUSION: For patients complaining of anterior chest pain, AS should be considered, and single-photon emission computed tomography-computed tomography can be helpful in diagnosis. In addition, ultrasound-guided IA corticosteroid injections may be effective for pain relief.
RESUMO
Platelet-derived growth factor (PDGF) is a potent mitogenic and migratory factor that regulates the tyrosine phosphorylation of a variety of signalling proteins via intracellular production of H2O2 (refs 1, 2-3). Mammalian 2-Cys peroxiredoxin type II (Prx II; gene symbol Prdx2) is a cellular peroxidase that eliminates endogenous H2O2 produced in response to growth factors such as PDGF and epidermal growth factor; however, its involvement in growth factor signalling is largely unknown. Here we show that Prx II is a negative regulator of PDGF signalling. Prx II deficiency results in increased production of H2O2, enhanced activation of PDGF receptor (PDGFR) and phospholipase Cgamma1, and subsequently increased cell proliferation and migration in response to PDGF. These responses are suppressed by expression of wild-type Prx II, but not an inactive mutant. Notably, Prx II is recruited to PDGFR upon PDGF stimulation, and suppresses protein tyrosine phosphatase inactivation. Prx II also leads to the suppression of PDGFR activation in primary culture and a murine restenosis model, including PDGF-dependent neointimal thickening of vascular smooth muscle cells. These results demonstrate a localized role for endogenous H2O2 in PDGF signalling, and indicate a biological function of Prx II in cardiovascular disease.
Assuntos
Neovascularização Fisiológica/efeitos dos fármacos , Peroxidases/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Aorta/citologia , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Células Cultivadas , Reestenose Coronária/metabolismo , Reestenose Coronária/patologia , Ativação Enzimática , Humanos , Camundongos , Miócitos de Músculo Liso/citologia , Peroxidases/deficiência , Peroxidases/genética , Peroxirredoxinas , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Ligação Proteica , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
Myogenic differentiation is accompanied by alterations in the chromatin states, which permit or restrict the transcriptional machinery and thus impact distinctive gene expression profiles. The mechanisms by which higher-order chromatin remodeling is associated with gene activation and silencing during differentiation is not fully understood. In this study, we provide evidence that the euchromatic lysine methyltransferase GLP regulates heterochromatin organization and myogenic differentiation. Interestingly, GLP represses expression of the methyl-binding protein MeCP2 that induces heterochromatin clustering during differentiation. Consequently, MeCP2 and HP1γ localization at major satellites are altered upon modulation of GLP expression. In GLP knockdown cells, depletion of MeCP2 restored both chromatin organization and myogenic differentiation. These results identify a novel regulatory axis between a histone methylation writer and DNA methylation reader, which is important for heterochromatin organization during differentiation.
Assuntos
Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Desenvolvimento Muscular , Animais , Repetição de Anquirina , Diferenciação Celular , Linhagem Celular , Heterocromatina/ultraestrutura , Histona-Lisina N-Metiltransferase/análise , Proteína 2 de Ligação a Metil-CpG/análise , Camundongos , Domínios ProteicosRESUMO
In this study, we synthesized three conjugated polymer electrolytes (CPEs) with different conjugation lengths to control their dipole moments by varying spacers. P-type CPEs (PFT-D, PFtT-D, and PFbT-D) were generated by the facile oxidation of n-type CPEs (PFT, PFtT, and PFbT) and introduced as the hole-transporting layers (HTLs) of organic solar cells (OSCs) and polymer light-emitting diodes (PLEDs). To identify the effect on electrode work function tunability by changing the molecular conformation and arrangement, we simulated density functional theory calculations of these molecules and performed ultraviolet photoelectron spectroscopy analysis for films of indium tin oxide/CPEs. Additionally, we fabricated OSCs and PLEDs using the CPEs as the HTLs. The stability and performance were enhanced in the optimized devices with PFtT-D CPE HTLs compared to those of PEDOT:PSS HTL-based devices.
RESUMO
H(2)O(2) is a reactive oxygen species that has drawn much interest because of its role as a second messenger in receptor-mediated signaling. Mammalian 2-Cys peroxiredoxins have been shown to eliminate efficiently the H(2)O(2) generated in response to receptor stimulation. 2-Cys peroxiredoxins are members of a novel peroxidase family that catalyze the H(2)O(2) reduction reaction in the presence of thioredoxin, thioredoxin reductase and NADPH. Several lines of evidence suggest that 2-Cys peroxiredoxins have dual roles as regulators of the H(2)O(2) signal and as defenders of oxidative stress. In particular, 2-Cys peroxiredoxin appears to provide selective, specific and localized control of receptor-mediated signal transduction. Thus, the therapeutic potential of 2-Cys peroxiredoxins is clear for diseases, such as cancer and cardiovascular diseases, that involve reactive oxygen species.
Assuntos
Modelos Biológicos , Estresse Oxidativo/fisiologia , Peroxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Peroxidases/genética , Peroxidases/uso terapêutico , Peroxirredoxinas , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Alinhamento de SequênciaRESUMO
In this study, we fabricated organic photovoltaics (OPVs) by introducing the polymer additive HTh6BT into the photoactive layer of a poly(3-hexylthiophene):phenyl-C61-butyric acid methyl ester (P3HT:PCBM) system. The HTh6BT had a relatively low band gap energy of 1.65 eV and a molecular and crystalline structure similar to that of P3HT. In the photoactive layer, the HTh6BT and P3HT can both act as donors. In such parallel-type bulk heterojunctions, each donor can form excitons and generate charges while being separated from the donor/acceptor interface. Changes in the photovoltaic property of the OPV device by the addition of HTh6BT were evaluated, and the optical characteristics of the photoactive layer, as well as the surface morphology, polymer ordering, and crystallinity of the P3HT:PCBM film were analyzed. Compared to a device without HTh6BT, all short-circuit current densities, open-circuit voltages, and fill factors were enhanced, leading to the enhancement of the power conversion efficiency by 36%.
RESUMO
Oxidative stress is a loss of balance between the production of reactive oxygen species during cellular metabolism and the mechanisms that clear these species to maintain cellular redox homeostasis. Increased oxidative stress has been associated with muscular dystrophy, and many studies have proposed mechanisms that bridge these two pathological conditions at the molecular level. In this review, the evidence indicating a causal role of oxidative stress in the pathogenesis of various muscular dystrophies is revisited. In particular, the mediation of cellular redox status in dystrophic muscle by NF-κB pathway, autophagy, telomere shortening, and epigenetic regulation are discussed. Lastly, the current stance of targeting these pathways using antioxidant therapies in preclinical and clinical trials is examined.
Assuntos
Músculo Esquelético/patologia , Atrofia Muscular/terapia , Estresse Oxidativo , Animais , Humanos , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
In this study, we demonstrate that the lysine methyltransferase G9a inhibits sarcomere organization through regulation of the MEF2C-HDAC5 regulatory axis. Sarcomeres are essential for muscle contractile function. Presently, skeletal muscle disease and dysfunction at the sarcomere level has been associated with mutations of sarcomere proteins. This study provides evidence that G9a represses expression of several sarcomere genes and its over-expression disrupts sarcomere integrity of skeletal muscle cells. G9a inhibits MEF2C transcriptional activity that is essential for expression of sarcomere genes. Through protein interaction assays, we demonstrate that G9a interacts with MEF2C and its co-repressor HDAC5. In the presence of G9a, calcium signaling-dependent phosphorylation and export of HDAC5 to the cytoplasm is blocked which likely results in enhanced MEF2C-HDAC5 association. Activation of calcium signaling or expression of constitutively active CaMK rescues G9a-mediated repression of HDAC5 shuttling as well as sarcomere gene expression. Our results demonstrate a novel epigenetic control of sarcomere assembly and identifies new therapeutic avenues to treat skeletal and cardiac myopathies arising from compromised muscle function.
RESUMO
In this study, we fabricated conventional structured organic solar cells (OSCs) by introducing a hole extraction layer (HEL) that consisted of poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) and conjugated polymer electrolyte (CPE) poly[9,9-bis(4'-sulfonatobutyl)fluorene-alt-thiophene] (PFT-D). PFT-D has a -SO3- functional group that acts as a conjugate base against the -SO3H of PSS. In addition, the molecular dipole of PFT-D can screen the Coulombic attraction between PEDOT chains and PSS chains. By blending PEDOT:PSS and PFT-D, the acidity of the HEL solution and changes to the surface morphology and potential of the HEL film as a function of exposure time in air were reduced. As a result, the half-life of the OSC fabricated with blended HEL was five times better at room temperature and 40% humidity without encapsulation as compared to the pristine PEDOT:PSS-based device.
RESUMO
In an attempt to engineer a Yarrowia lipolytica strain to produce glycoproteins lacking the outer-chain mannose residues of N-linked oligosaccharides, we investigated the functions of the OCH1 gene encoding a putative alpha-1,6-mannosyltransferase in Y. lipolytica. The complementation of the Saccharomyces cerevisiae och1 mutation by the expression of YlOCH1 and the lack of in vitro alpha-1,6-mannosyltransferase activity in the Yloch1 null mutant indicated that YlOCH1 is a functional ortholog of S. cerevisiae OCH1. The oligosaccharides assembled on two secretory glycoproteins, the Trichoderma reesei endoglucanase I and the endogenous Y. lipolytica lipase, from the Yloch1 null mutant contained a single predominant species, the core oligosaccharide Man8GlcNAc2, whereas those from the wild-type strain consisted of oligosaccharides with heterogeneous sizes, Man8GlcNAc2 to Man12GlcNAc2. Digestion with alpha-1,2- and alpha-1,6-mannosidase of the oligosaccharides from the wild-type and Yloch1 mutant strains strongly supported the possibility that the Yloch1 mutant strain has a defect in adding the first alpha-1,6-linked mannose to the core oligosaccharide. Taken together, these results indicate that YlOCH1 plays a key role in the outer-chain mannosylation of N-linked oligosaccharides in Y. lipolytica. Therefore, the Yloch1 mutant strain can be used as a host to produce glycoproteins lacking the outer-chain mannoses and further developed for the production of therapeutic glycoproteins containing human-compatible oligosaccharides.
Assuntos
Glicoproteínas/biossíntese , Glicoproteínas/genética , Yarrowia/genética , Yarrowia/metabolismo , Celulase/química , Celulase/genética , Deleção de Genes , Teste de Complementação Genética , Engenharia Genética , Glicoproteínas/química , Lipase/química , Lipase/genética , Manosidases/metabolismo , Manosiltransferases/genética , Manosiltransferases/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Oligossacarídeos/análise , Oligossacarídeos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: Frequent viral breakthroughs limit the usefulness of lamivudine in the treatment of chronic hepatitis B (CHB). The purpose of the present study was to evaluate the effects of precore stop codon mutation (G to A mutation at nucleotide 1896; A(1896)) of hepatitis B virus (HBV) on the occurrence of viral breakthrough following lamivudine therapy. METHODS: Among 260 consecutive CHB patients treated with lamivudine for >12 months, 231 patients whose pretreatment sera were available were tested for A(1896) variant of HBV using direct sequencing. RESULTS: Between patients with A(1896) variant (n = 74) and those without it (n = 157), there was no difference in age, gender, serum alanine aminotransferase (ALT) level, the duration of therapy and prevalence of core promoter mutants. Serum hepatitis B e antigen (HBeAg) positivity and HBV-DNA level were lower (P = 0.00 and P = 0.01) and liver cirrhosis was more commonly associated in patients with A(1896) variant mutant compared with those without it. In univariate analysis, viral breakthrough was more frequent in HBeAg-positive patients (P = 0.03) and in those with high serum HBV-DNA level (P = 0.01) as well as in those without A(1896) variant (P = 0.01). However, in multivariate analysis, the absence of A(1896) variant (P = 0.02) and high serum HBV-DNA level (P = 0.03) were independent factors for viral breakthrough following lamivudine therapy. The cumulative viral breakthrough rates at 1 and 2 years were much lower in patients with A(1896) variant compared with those without it (P = 0.01). CONCLUSION: The stop codon mutation at the precore region of HBV in addition to low serum HBV-DNA level may be associated with low breakthrough rate following lamivudine therapy.
Assuntos
Códon de Terminação/genética , DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Mutação , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Feminino , Seguimentos , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND AND AIM: Viral breakthrough is frequently encountered during long-term lamivudine therapy, mostly associated with YMDD mutants. In this study, we investigated the effects of alpha-interferon (IFN-alpha) combined with lamivudine on the occurrence of viral breakthrough during long-term lamivudine therapy. METHODS: Eighty-three patients with biopsy-proven chronic hepatitis B were randomly allocated to a combination of lamivudine and IFN-alpha (LAM/IFN; n = 41) or lamivudine only (LAM; n = 42), and then followed up for >12 months. We calculated the cumulative rate of undetectable serum HBV-DNA and hepatitis B e antigen (HBeAg) loss, as well as the cumulative occurrence rate of viral breakthrough. We also evaluated the relationship between YMDD mutants and the occurrence of viral breakthrough. RESULTS: There was no difference in cumulative rates of undetectable serum HBV-DNA (100%vs 100% at 24 months, P = 0.13) and cumulative rates of serum HBeAg loss between the LAM/IFN group and the LAM group (49%, 61% and 67%vs 31%, 39% and 42%, respectively, at 12, 24 and 36 months; P = 0.07). The cumulative occurrence rate of viral breakthrough, however, was significantly lower in the LAM/IFN group compared with the LAM group (5%, 20% and 30%vs 10%, 55% and 58%, respectively, at 12, 24 and 36 months; P = 0.006). From the patients with viral breakthrough, YMDD mutants were detected in 82% (18 of 22) of the LAM group in contrast with 56% (five of nine) of the LAM/IFN group in their sera. CONCLUSION: IFN-alpha combined with lamivudine may reduce viral breakthrough during long-term lamivudine therapy, probably by suppressing the appearance of YMDD mutants.
Assuntos
Antivirais/administração & dosagem , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Interferon-alfa/administração & dosagem , Lamivudina/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Hepatite B Crônica/sangue , Humanos , Masculino , Fatores de TempoRESUMO
BACKGROUNDS/AIMS: In the treatment of chronic hepatitis B (CHB) with lamivudine, adequate duration of the therapy remains to be determined. In this prospective study, the authors intended to investigate whether long-term additional administration of lamivudine might enhance the durability of lamivudine-induced HBeAg seroconversion. METHODS: Eighty-five CHB patients who achieved HBeAg seroconversion by lamivudine received additional lamivudine therapy for at least 24 months at a dose of 100 mg per day. Among them, 61 patients whose serum HBeAg and HBV-DNA (solution hybridization assay) had been negative persistently for >24 months discontinued lamivudine therapy and followed-up for >12 months. We calculated the cumulative reappearance rate of serum HBV-DNA and HBeAg and also evaluated the predictive factors for post-treatment virologic relapse. RESULTS: The cumulative reappearance rates of serum HBV-DNA following cessation of lamivudine therapy at 6 months, 1 year and 2 years were 15%, 21%, and 31%, respectively. The cumulative reappearance rates of serum HBeAg at 6 months, 1 year and 2 years were 11%, 13% and 16%, respectively. Old age and presence of precore mutant were two independent predictive factors for viral relapse. CONCLUSION: These results suggested that long-term additional administration of lamivudine might enhance the durability of lamivudine-induced HBeAg seroconversion.
Assuntos
Antígenos E da Hepatite B/análise , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Lamivudina/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Envelhecimento , DNA Viral/sangue , Esquema de Medicação , Feminino , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Prospectivos , Recidiva , Fatores de Risco , Fatores de Tempo , Proteínas do Core Viral/genéticaRESUMO
BACKGROUND/AIMS: Tamoxifen has been tried in patients with hepatocellular carcinoma (HCC), however, its inhibitory mechanism remains unknown. In this study, we evaluated the effects of tamoxifen on HCC cell growth and the expression of transforming growth factor-beta1 (TGF-beta1) which had been known as an important cytokine in growth of HCC. METHODS: Hep 3B cells were cultivated in estrogen free media with 0.1 micro M, 0.5 micro M, 1 micro M, 5 micro M, and 10 micro M of tamoxifen for 6 days. Viable cells were counted daily and the TGF-beta1 concentrations in supernatant were measured by ELISA method. RESULTS: The number of viable HCC cells increased rather significantly after the treatment of tamoxifen of lower concentration (0.1micro M) compared with that of the control (2.59x10(7) vs. 1.97x107; p<0.05). As the concentration of treated tamoxifen was higher, the number of viable HCC cells became gradually less, resulting in the significant decrease of it at the highest concentration (10micro M) compared with that of the control (1.40x10(7) vs. 1.97x10(7); p<0.05). TGF-beta1 concentration in supernatant of tamoxifen-treated samples was significantly decreased compared with those of controls, regardless of the amount of treated tamoxifen. CONCLUSIONS: These results suggest that tamoxifen may suppress TGF-beta1 expression to an extent, although it has different effects on the proliferation of HCC cells, at the various concentrations of this agent in vitro. Such effects of tamoxifen on TGF-beta1 expression may inhibit the growth and progression of HCCs over-expressing TGF-beta1 in vivo.