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1.
Antimicrob Agents Chemother ; 68(4): e0095623, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38446062

RESUMO

Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19 , Pirazóis , Quinolinas , Humanos , SARS-CoV-2/metabolismo , RNA Polimerase Dependente de RNA/metabolismo , Simulação de Acoplamento Molecular , Tratamento Farmacológico da COVID-19 , Antivirais/química
2.
J Formos Med Assoc ; 123(2): 228-237, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37596109

RESUMO

BACKGROUND/PURPOSE: Efforts were made to explore the influence of diagnostic timing for cancer-associated thromboembolic events on survival of ovarian cancer patients. METHODS: We reviewed the medical records of 75 ovarian cancer patients with thromboembolism and evaluated the prognostic factors affecting disease-free survival and overall survival. RESULTS: These 75 patients were classified into two categories by the diagnostic timing of the thromboembolism, during (33 cases) and after (42 cases) initial diagnosis of ovarian cancer groups. The diagnostic timing of thromboembolism was not related to disease-free survival or overall survival of the studied population. Advanced disease stage, clear cell histology, interval debulking surgery, no recurrence/persistence of ovarian cancer, and patients treated with anticoagulant(s) treatment >3 months were associated with the disease-free survival. Advanced disease stage, clear cell histology, body mass index (BMI) ≥24 kg/m2 at the diagnosis of ovarian cancer, and no recurrence/persistence of ovarian cancer influenced the overall survival. In the subgroup analysis, compared to the after initial ovarian cancer diagnosis group, patients with stage I/II disease, BMI <24 kg/m2 at the diagnosis of ovarian cancer, or primary debulking surgery in the during cancer diagnosis group had longer disease-free survival, and overall survival benefit was observed in cases with stage I/II disease, or primary debulking surgery. CONCLUSION: The diagnostic timing of thromboembolism was not related to disease-free or overall survival of ovarian cancer patients, but associated with that of specific patient subgroups.


Assuntos
Neoplasias Ovarianas , Tromboembolia , Humanos , Feminino , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/diagnóstico , Intervalo Livre de Doença , Intervalo Livre de Progressão , Anticoagulantes/uso terapêutico , Tromboembolia/etiologia
3.
J Virol ; 96(7): e0054221, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35319229

RESUMO

While infections by enterovirus A71 (EV-A71) are generally self-limiting, they can occasionally lead to serious neurological complications and death. No licensed therapies against EV-A71 currently exist. Using anti-virus-induced cytopathic effect assays, 3,4-dicaffeoylquinic acid (3,4-DCQA) from Ilex kaushue extracts was found to exert significant anti-EV-A71 activity, with a broad inhibitory spectrum against different EV-A71 genotypes. Time-of-drug-addition assays revealed that 3,4-DCQA affects the initial phase (entry step) of EV-A71 infection by directly targeting viral particles and disrupting viral attachment to host cells. Using resistant virus selection experiments, we found that 3,4-DCQA targets the glutamic acid residue at position 98 (E98) and the proline residue at position 246 (P246) in the 5-fold axis located within the VP1 structural protein. Recombinant viruses harboring the two mutations were resistant to 3,4-DCQA-elicited inhibition of virus attachment and penetration into human rhabdomyosarcoma (RD) cells. Finally, we showed that 3,4-DCQA specifically inhibited the attachment of EV-A71 to the host receptor heparan sulfate (HS), but not to the scavenger receptor class B member 2 (SCARB2) and P-selectin glycoprotein ligand-1 (PSGL1). Molecular docking analysis confirmed that 3,4-DCQA targets the 5-fold axis to form a stable structure with the E98 and P246 residues through noncovalent and van der Waals interactions. The targeting of E98 and P246 by 3,4-DCQA was found to be specific; accordingly, HS binding of viruses carrying the K242A or K244A mutations in the 5-fold axis was successfully inhibited by 3,4-DCQA.The clinical utility of 3,4-DCQA in the prevention or treatment of EV-A71 infections warrants further scrutiny. IMPORTANCE The canyon region and the 5-fold axis of the EV-A71 viral particle located within the VP1 protein mediate the interaction of the virus with host surface receptors. The three most extensively investigated cellular receptors for EV-A71 include SCARB2, PSGL1, and cell surface heparan sulfate. In the current study, a RD cell-based anti-cytopathic effect assay was used to investigate the potential broad spectrum inhibitory activity of 3,4-DCQA against different EV-A71 strains. Mechanistically, we demonstrate that 3,4-DCQA disrupts the interaction between the 5-fold axis of EV-A71 and its heparan sulfate receptor; however, no effect was seen on the SCARB2 or PSGL1 receptors. Taken together, our findings show that this natural product may pave the way to novel anti-EV-A71 therapeutic strategies.


Assuntos
Ácido Clorogênico/análogos & derivados , Enterovirus Humano A , Infecções por Enterovirus , Ilex , Plantas Medicinais , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Ácido Clorogênico/uso terapêutico , Enterovirus Humano A/genética , Infecções por Enterovirus/tratamento farmacológico , Heparitina Sulfato/metabolismo , Humanos , Ilex/química , Simulação de Acoplamento Molecular , Extratos Vegetais/uso terapêutico , Plantas Medicinais/química
4.
Ann Surg Oncol ; 30(11): 6855-6864, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37386310

RESUMO

BACKGROUND: This study compared oncologic outcomes between minimally invasive surgery (MIS) and open surgery for the treatment of endometrial cancer with a high risk of recurrence. METHODS: This study included patients with endometrial cancer who underwent primary surgery at two tertiary centers in Korea and Taiwan. Low-grade advanced-stage endometrial cancer (endometrioid grade 1 or 2) or endometrial cancer with aggressive histology (endometrioid grade 3 or non-endometrioid) at any stage was considered to have a high risk of recurrence. We conducted 1:1 propensity score matching between the MIS and open surgery groups to adjust for the baseline characteristics. RESULTS: Of the total of 582 patients, 284 patients were included in analysis after matching. Compared with open surgery, MIS did not show a difference in disease-free survival [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.67-1.77, P = 0.717] or overall survival (HR 0.67; 95% CI 0.36-1.24, P = 0.198). In the multivariate analysis, non-endometrioid histology, tumor size, tumor cytology, depth of invasion, and lymphovascular space invasion were risk factors for recurrence. There was no association between the surgical approach and either recurrence or mortality in the subgroup analysis according to stage and histology. CONCLUSIONS: MIS did not compromise survival outcomes for patients with endometrial cancer with a high risk of recurrence when compared with open surgery.


Assuntos
Neoplasias do Endométrio , Feminino , Humanos , Estudos Retrospectivos , Taiwan/epidemiologia , Pontuação de Propensão , Neoplasias do Endométrio/patologia , República da Coreia/epidemiologia , Procedimentos Cirúrgicos Minimamente Invasivos , Estadiamento de Neoplasias
5.
Gynecol Oncol ; 167(1): 65-72, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35995599

RESUMO

PURPOSE: The therapeutic effect of para-aortic lymphadenectomy in early-stage high-grade endometrial cancer remains controversial. In this study, we investigated whether combined pelvic and para-aortic lymphadenectomy has a survival benefit compared to pelvic lymphadenectomy alone in patients with pathologically diagnosed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. METHODS: We retrospectively reviewed the medical records of 281 patients with histologically confirmed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers who underwent pelvic lymphadenectomy alone or combined pelvic and para-aortic lymphadenectomy in staging surgery at two tertiary centers in Korea and Taiwan. Prognostic factors to predict outcomes in these cases were also analyzed. RESULTS: Among 281 patients, 144 underwent pelvic lymphadenectomy alone and 137 underwent combined pelvic and para-aortic lymphadenectomy. Within a median follow-up of 45 months, there was no significant difference in recurrence-free survival (RFS) and overall survival (OS) between the two groups. In multivariable analysis, age at diagnosis ≥60 years (HR = 2.20, 95% CI 1.25-3.87, p = 0.006) and positive lymph-vascular space invasion (LVSI) (HR = 2.79, 95% CI 1.60-4.85, p < 0.001) were associated with worse RFS, and only non-endometrioid histology was associated with worse OS (HR = 3.18, 95% CI 1.42-7.12, p = 0.005). In further subgroup analysis, beneficial effects of combined pelvic and para-aortic lymphadenectomy on RFS and OS were not observed. CONCLUSIONS: In this study, combined pelvic and para-aortic lymphadenectomy could not improve survival compared to pelvic lymphadenectomy alone in patients with FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. Therefore, para-aortic lymphadenectomy may be omitted for these cases.


Assuntos
Neoplasias do Endométrio , Neoplasias do Endométrio/patologia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Estadiamento de Neoplasias , Estudos Retrospectivos , Taiwan/epidemiologia
6.
Molecules ; 27(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35889335

RESUMO

The fruit of Tetradium ruticarpum (TR) is commonly used in Chinese herbal medicine and it has known antiproliferative and antitumor activities, which can serve as a good source of functional ingredients. Although some antiproliferative compounds are reported to be present in TR fruit, most studies only focused on a limited range of metabolites. Therefore, in this study, the antiproliferative activity of different extracts of TR fruit was examined, and the potentially antiproliferative compounds were highlighted by applying an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based multi-informative molecular networking strategy. The results showed that among different extracts of TR fruit, the EtOAc fraction F2-3 possessed the most potent antiproliferative activity against HL-60, T24, and LX-2 human cell lines. Through computational tool-aided structure prediction and integrating various data (sample taxonomy, antiproliferative activity, and compound identity) into a molecular network, a total of 11 indole alkaloids and 47 types of quinolone alkaloids were successfully annotated and visualized into three targeted bioactive molecular families. Within these families, up to 25 types of quinolone alkaloids were found that were previously unreported in TR fruit. Four indole alkaloids and five types of quinolone alkaloids were targeted as potentially antiproliferative compounds in the EtOAc fraction F2-3, and three (evodiamine, dehydroevodiamine, and schinifoline) of these targeted alkaloids can serve as marker compounds of F2-3. Evodiamine was verified to be one of the major antiproliferative compounds, and its structural analogues discovered in the molecular network were found to be promising antitumor agents. These results exemplify the application of an LC-MS/MS-based multi-informative molecular networking strategy in the discovery and annotation of bioactive compounds from complex mixtures of potential functional food ingredients.


Assuntos
Alcaloides , Evodia , Quinolonas , Alcaloides/análise , Alcaloides/farmacologia , Cromatografia Líquida , Evodia/química , Frutas/química , Humanos , Alcaloides Indólicos/análise , Alcaloides Indólicos/farmacologia , Extratos Vegetais/química , Quinolonas/análise , Espectrometria de Massas em Tandem
7.
Medicina (Kaunas) ; 58(8)2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-36013593

RESUMO

Background and Objectives: Supplementary motor area (SMA) syndrome is a common post-operation complication in intra-axial brain tumors, such as glioma. Direct damage to parenchyma or scarification of the major vessels during an operation are the main causes. However, it is rarely reported as a postoperative complication in extra-axial tumors. Materials and Methods: We reviewed 11 reported cases of supplementary motor area syndrome after removal of extra-axial meningiomas in the English literature from the PubMed database. We also added our case, which presented as an unusual huge meningioma, to analyze the clinical parameters and outcomes of these 12 reported cases. Results: Recovery time of supplementary motor area syndrome in extra-axial tumors could be within 1-7 weeks, shorter than intra-axial tumors (2-9 weeks). Epilepsy and progressive limb weakness are the most common presentations in 50% of cases. Different degrees of postoperative muscle power deterioration were noted in the first 48 h (from 0-4). Lower limbs (66.6%, 8/12) were slightly predominant compared to upper limbs (58.3%, 7/12). Mutism aphasia was also observed in 41.6% (5/12, including our case), and occurred in tumors which were involved in the dominant side; this recovered faster than limb weakness. Discussion and Conclusions: Our work indicated that SMA syndrome could occur in extra-axial brain tumors presenting as mutism aphasia and limb weakness without any direct brain parenchyma damage. In our analysis, we found that recovery time of postoperative motor function deficit could be within 1-7 weeks. Our study also provides a further insight of SMA syndrome in extra-axial brain tumors.


Assuntos
Neoplasias Encefálicas , Neoplasias Meníngeas , Meningioma , Córtex Motor , Mutismo , Neoplasias Encefálicas/cirurgia , Humanos , Neoplasias Meníngeas/complicações , Neoplasias Meníngeas/cirurgia , Meningioma/complicações , Meningioma/cirurgia , Córtex Motor/patologia , Córtex Motor/cirurgia , Mutismo/etiologia , Síndrome
8.
Br J Neurosurg ; : 1-6, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34159852

RESUMO

Intracranial germinomas mostly occur in teenagers and young adults. The common sites are pineal and suprasellar regions. Males with Klinefelter syndrome, compared with males without chromosomal abnormalities, are known to have a higher incidence of developing pineal or suprasellar germinomas. As for germinoma in the medulla oblongata, this is rare, with only 21 previous cases reported. Due to the rarities, any relationship between people with Klinefelter syndrome and medulla oblongata germinomas remains undetermined. We present a rare case of medulla oblongata germinoma in a 25-year-old man. It is the second case of medulla oblongata germinoma in association with Klinefelter syndrome. We emphasize the importance of karyotyping in every case of germinoma, especially those with intracranial germinomas at atypical locations.

9.
Nanotechnology ; 31(14): 145709, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-31846950

RESUMO

In this work, we have inspected the theoretical resistive switching properties of two ReRAM models based on heterojunction structures of Cu/SiO x nanoparticles (NPs)/Si and Si/SiO x NPs/Si, in which dielectric layers of the silica nanoparticles present dislocations at bicrystal interfaces. To validate the theoretical model, a charge storage device with the structure Cu/SiO x /Si was fabricated and its ReRAM properties were studied. Our examinations on the electrical, thermal and structural aspects of resistive switching uncovered the switching behavior relies upon the material properties and electrical characteristics of the switching layers, as well as the metal electrodes and the interfacial structure of grains within the dielectric materials. We also determined that the application of an external electric field at Grain Boundaries (GB) is crucial to resistive switching behavior. Moreover, we have demonstrated that the switching behavior is influenced by variations in the atomic structure and electronic properties, at the atomic length scale and picosecond timescale. Our findings furnish a useful reference for the future development and optimization of materials used in this technology.

10.
Mol Ther ; 26(2): 404-419, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29248428

RESUMO

Ionizing radiation therapy is a well-established method of eradicating locally advanced tumors. Here, we examined whether local RT enhanced the potency of an antigen-specific DNA vaccine, and we investigated the possible underlying mechanism. Using the HPV16 E6/E7+ syngeneic TC-1 tumor, we evaluated the combination of CTGF/E7 vaccination with local irradiation with regard to synergistic antigen-specific immunity and anti-tumor effects. Tumor-bearing mice treated with local RT (6 Gy twice weekly) and CTGF/E7 DNA vaccination exhibited dramatically increased numbers of E7-specific CD8+ cytotoxic T cell precursors, higher titers of anti-E7 Abs, and significantly reduced tumor size. The combination of local RT and CTGF/E7 vaccination also elicited abscopal effects on non-irradiated local subcutaneous and distant pulmonary metastatic tumors. Local irradiation induced the expression of high-mobility group box 1 protein (HMGB-1) in apoptotic tumor cells and stimulated dendritic cell (DC) maturation, consequently inducing antigen-specific immune responses. Additionally, local irradiation eventually increased the effector-to-suppressor cell ratio in the tumor microenvironment. Overall, local irradiation enhanced the antigen-specific immunity and anti-tumor effects on local and distant metastatic tumors generated by an antigen-specific DNA vaccine. These findings suggest that the combination of irradiation with antigen-specific immunotherapy is a promising new clinical strategy for cancer therapy.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia , Neoplasias/imunologia , Neoplasias/patologia , Microambiente Tumoral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/imunologia , Terapia Combinada , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Imunoterapia/métodos , Camundongos , Neoplasias/genética , Neoplasias/terapia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Microambiente Tumoral/genética , Irradiação Corporal Total , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Am J Physiol Lung Cell Mol Physiol ; 314(4): L654-L669, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351433

RESUMO

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are high-mortality and life-threatening diseases that are associated with neutrophil activation and accumulation within lung tissue. Emerging evidence indicates that neutrophil-platelet aggregates (NPAs) at sites of injury increase acute inflammation and contribute to the development of ALI. Although numerous studies have increased our understanding of the pathophysiology of ALI, there is still a lack of innovative and useful treatments that reduce mortality, emphasizing that there is an urgent need for novel treatment strategies. In this study, a new series of small compounds of ß-nitrostyrene derivatives (BNSDs) were synthesized, and their anti-inflammatory bioactivities on neutrophils and platelets were evaluated. The new small compound C7 modulates neutrophil function by inhibiting superoxide generation and elastase release. Compound C7 elicits protective effects on LPS-induced paw edema and acute lung injury via the inhibition of neutrophil accumulation, proinflammatory mediator release, platelet aggregation, myeloperoxidase activity, and neutrophil extracellular trap (NET) release. NET formation was identified as the bridge for the critical interactions between neutrophils and platelets by confocal microscopy and flow cytometry. This research provides new insights for elucidating the complicated regulation of neutrophils and platelets in ALI and sheds further light on future drug development strategies for ALI/ARDS and acute inflammatory diseases.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Lipopolissacarídeos/toxicidade , Neutrófilos/efeitos dos fármacos , Edema Pulmonar/tratamento farmacológico , Estirenos/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Plaquetas/imunologia , Plaquetas/metabolismo , Plaquetas/patologia , Adesão Celular , Células Cultivadas , Armadilhas Extracelulares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/imunologia , Edema Pulmonar/patologia
14.
J Med Virol ; 87(8): 1404-12, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25940199

RESUMO

We compared multiplex E6 messenger ribonucleic acid (mRNA) tests using real-time quantitative reverse transcriptase polymerase chain reactions (PCR) with human papillomavirus (HPV) DNA subtypes using a MY11/GP6+ PCR-based reverse-blot assay to identify cervical intraepithelial neoplasias of grade 2 or worse (CIN2+). In total, 684 women were studied, of whom 377 (55%) were diagnosed with CIN2+ histologically. The specificity of HPV mRNA to predict histological CIN2+ was higher than that of HPV DNA (81.3% vs. 44.2%). The odds ratios (ORs) to predict histological CIN2+ in women with positive for type 16, 18, 31, and 45 E6 mRNA or by HPV DNA detection were 7.1 (95% confidence interval [CI] 3.9-13.1) and 2.5 (95%CI 1.9-3.5), respectively, compared to those with negative for E6 mRNA or HPV DNA. The OR to predict histological CIN2+ in women with a cytological grade

Assuntos
DNA Viral/análise , Programas de Rastreamento/métodos , Técnicas de Diagnóstico Molecular/métodos , Proteínas Oncogênicas Virais/análise , Infecções por Papillomavirus/complicações , RNA Mensageiro/análise , Displasia do Colo do Útero/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , DNA Viral/genética , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/genética , Valor Preditivo dos Testes , RNA Mensageiro/genética , Medição de Risco , Sensibilidade e Especificidade , Adulto Jovem , Displasia do Colo do Útero/virologia
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(9): 971-4, 2015 Sep.
Artigo em Zh | MEDLINE | ID: mdl-26412181

RESUMO

OBJECTIVE: To summarize the clinical features of sinusoidal obstruction syndrome (SOS) and to improve the understanding of this disease. METHODS: A retrospective study was performed on the clinical data of 12 children with SOS including clinical manifestations, laboratory results, imaging findings, treatment, and prognosis. RESULTS: Of the 12 cases, 8 were secondary to acute lymphoblastic leukemia, and 4 had undergone hematopoietic stem cell transplantation. Manifestations mainly included abdominal distention (4 cases), hepatomegaly with tenderness (9 cases), splenomegaly (6 cases), and weight increase (10 cases). Biochemical tests revealed varying degrees of liver damage in all cases. In the coagulation function test, the activated partial thromboplastin time (APTT) was prolonged in 7 cases. Out of the 7 patients who underwent serum D-dimer test, 4 showed elevated serum level of D-dimer. In routine blood tests, 4 cases showed decreases in both white blood cells and neutrophils. In addition, varying degrees of thrombocytopenia were observed in 9 cases. Eight patients were subjected to color Doppler ultrasound examination, and diffuse hepatomegaly, inhomogeneous liver parenchyma, unclear or thinner hepatic veins, hydrothorax/ascites, or splenomegaly was observed. Sinusoidal dilatation or hepatic cell infiltration was observed in 2 patients who underwent liver biopsy. Treatments were basically symptomatic and supportive therapies, and the prognosis was good in all patients. CONCLUSIONS: SOS should be considered in children who present with hepatomegaly, sudden weight gain, liver dysfunction and coagulation dysfunction after they have received chemotherapy for leukemia and hematopoietic stem cell transplantation.


Assuntos
Hepatopatia Veno-Oclusiva/terapia , Criança , Pré-Escolar , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hepatopatia Veno-Oclusiva/sangue , Humanos , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
16.
BMC Genet ; 15: 67, 2014 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-24919593

RESUMO

BACKGROUND: Aberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Epigenetic inactivation of the protein tyrosine phosphatase receptor-type O gene (PTPRO) has been described in several types of cancer. RESULTS: We screened primary breast cancer tissues for PTPRO promoter hypermethylation and assessed potential associations with pathological features and patient outcome. We also evaluated its potential as a breast cancer biomarker. PTPRO methylation was observed in 53 of 98 (54%) breast cancer tissues but not in adjacent normal tissue. Among matched peripheral blood samples from breast cancer patients, 33 of 98 (34%) exhibited methylated PTPRO in plasma. In contrast, no methylated PTPRO was observed in normal peripheral blood from 30 healthy individuals. PTPRO methylation was positively associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001). Multivariate analysis indicated that aberrant PTPRO methylation could serve as an independent predictor for overall survival hazard ratio (HR): 2.7; 95% CI: 1.1-6.2; P = 0.023), especially for patients with HER2-positive (hazard ratio (HR): 7.5; 95% CI: 1.8-31.3; P = 0.006), but not in ER + and PR + subpopulation. In addition, demethylation induced by 5-azacytidine led to gene reactivation in PTPRO-methylated and -silenced breast cancer cell lines. CONCLUSIONS: Here, we report that tumor PTPRO methylation is a strong prognostic factor in breast cancer. Methylation of PTPRO silences its expression and plays an important role in breast carcinogenesis. The data we present here may provide insight into the development of novel therapies for breast cancer treatment. Additionally, detection of PTPRO methylation in peripheral blood of breast cancer patients may provide a noninvasive means to diagnose and monitor the disease.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/genética , Metilação de DNA , Regiões Promotoras Genéticas , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/sangue , Neoplasias da Mama/diagnóstico , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico
17.
Viruses ; 16(4)2024 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-38675866

RESUMO

Gu-Sui-Bu, the dried rhizome of Davallia mariesii, is a traditional Chinese herbal remedy with a significant history of treating osteoporosis and inflammatory conditions. However, its potential as an anti-influenza agent and its underlying mechanisms of action remain unexplored. To obtain a more potent extract from D. mariesii and gain insights into its mechanism of action against influenza A virus (IAV), we utilized a partitioning process involving organic solvents and water, resulting in the isolation of butanolic subfractions of the D. mariesii extract (DMBE). DMBE exhibited a broad anti-viral spectrum, effectively inhibiting IAV, with an EC50 of 24.32 ± 6.19 µg/mL and a selectivity index of 6.05. We subsequently conducted a series of in vitro assays to evaluate the antiviral effects of DMBE and to uncover its mechanisms of action. DMBE was found to inhibit IAV during the early stages of infection by hindering the attachment of the virus onto and its penetration into host cells. Importantly, DMBE was observed to hinder IAV-mediated cell-cell fusion. It also inhibited neuraminidase activity, plaque size, and the expression levels of phospho-AKT. In summary, this study provides evidence for the effectiveness of D. mariesii as a complementary and alternative herbal remedy against IAV. Specifically, our data highlight DMBE's capabilities in inhibiting viral entry and the release of virions.


Assuntos
Antivirais , Vírus da Influenza A , Extratos Vegetais , Antivirais/farmacologia , Antivirais/química , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Animais , Células Madin Darby de Rim Canino , Cães , Internalização do Vírus/efeitos dos fármacos , Sapindaceae/química , Replicação Viral/efeitos dos fármacos , Ligação Viral/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Neuraminidase/metabolismo , Células A549 , Linhagem Celular
18.
J Gynecol Oncol ; 35(3): e33, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38130137

RESUMO

OBJECTIVE: In early-stage endometrial cancer, aggressive histologic types (grade 3 endometrioid, serous, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types) are associated with an increased risk of distant metastases and worse survival. However, the optimal adjuvant treatment for these patients remains controversial. The present study investigated the outcomes of different adjuvant treatments in patients with 2023 FIGO stage IIC endometrial cancer. METHODS: We retrospectively identified patients with 2023 FIGO stage IIC endometrial cancer who underwent surgery followed by either adjuvant treatment or observation from 2000 to 2020 at two tertiary centers in Korea and Taiwan. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier estimates and Cox proportional-hazards models. We also analyzed recurrence patterns after different adjuvant treatments. RESULTS: A total of 272 patients were identified; 204 received adjuvant treatment postoperatively, whereas 68 only underwent observation. Adjuvant treatment was not associated with improved RFS or OS. Non-endometrioid histologic types (p=0.003) and presence of lymphovascular space invasion (LVSI, p=0.002) were associated with worse RFS, whereas only non-endometrioid histologic types impacted OS (p=0.004). In subgroup analyses, adjuvant treatment improved OS in patients with LVSI (p=0.020) and in patients with both LVSI and grade 3 endometrioid histologic type (p=0.007). We found no difference in locoregional and distant recurrence between patients undergoing adjuvant treatment or observation. CONCLUSION: In this study, the addition of adjuvant treatment was associated with an OS benefit for patients with LVSI, especially those with grade 3 endometrioid tumors.


Assuntos
Neoplasias do Endométrio , Estadiamento de Neoplasias , Humanos , Feminino , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/terapia , Estudos Retrospectivos , Pessoa de Meia-Idade , Taiwan/epidemiologia , Idoso , Quimioterapia Adjuvante , República da Coreia , Centros de Atenção Terciária , Radioterapia Adjuvante , Recidiva Local de Neoplasia/patologia , Adulto , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Intervalo Livre de Doença , Estimativa de Kaplan-Meier , Histerectomia
19.
J Gynecol Oncol ; 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-39028151

RESUMO

OBJECTIVE: In this study, we evaluated the role of prolonged progestin treatment on atypical endometrial hyperplasia (AEH) patients who did not achieve complete regression (CR) after at least 3 months of progestin treatment. Possible prognostic factors predicting disease regression and recurrence were also assessed. METHODS: We retrospectively identified patients who had histologically confirmed persistent disease after at least 3 months of progestin treatment at two tertiary centers in Korea and Taiwan. Clinicopathologic factors and clinical outcomes were obtained from medical records. Logistic regression was used to analyze the relationship between covariates and the probability of CR and relapse. RESULTS: Fifty-two patients were included. Thirty-seven of 52 patients (71.2%) achieved CR after prolonged progestin treatment. Median time from starting progestin treatment to CR was 12.0 months. Daily administration of medroxyprogesterone acetate ≥200 mg or megestrol acetate ≥80 mg was associated with higher probability of regression. Nineteen of 37 patients (51.4%) experienced recurrence, with median time from CR to relapse of 15.0 months. Body mass index ≥27 was associated with higher relapse probability. Twelve of 16 patients with disease progression to endometrial carcinoma underwent surgery. The 12 cases had stage I tumors and lived without disease. CONCLUSION: Extension of progestin treatment course is feasible for AEH patients without an initial response to progestin. Higher daily progestin dosage was associated with higher probability of CR, and obesity was associated with higher risk of relapse. The patients without an initial response to progestins and whose AEH progressed to endometrial carcinoma had good prognoses.

20.
J Adv Res ; 62: 229-243, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38548264

RESUMO

INTRODUCTION: Overwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation. METHODS: Primary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. In vitro and silico analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an in vivo ARDS model in lipopolysaccharide (LPS)-primed mice. RESULTS: We found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS. CONCLUSION: We demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.


Assuntos
Aminopiridinas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inflamação , Lipopolissacarídeos , Neutrófilos , Inibidores da Fosfodiesterase 4 , Purinas , Síndrome do Desconforto Respiratório , Aminopiridinas/farmacologia , Purinas/farmacologia , Animais , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Humanos , Camundongos , Inflamação/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Espécies Reativas de Oxigênio/metabolismo , Masculino , AMP Cíclico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ativação de Neutrófilo/efeitos dos fármacos
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