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1.
J Ophthalmol ; 2021: 9987871, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194822

RESUMO

Backgrounds: Acute invasive fungal rhinosinusitis (AIFRS) is a hazardous infectious disease with rapid progression and high mortality and morbidities. Further orbital involvement is commonly seen. This study aims to analyze risk factors, clinical characteristics, and outcomes between patients with or without orbital involvement. Methods: A retrospective review was performed in a single tertiary medical center over a span of 13 years (2005-2018). A total of 21 patients with diagnosis of AIFRS were enrolled. We reviewed the patients' basic characteristics, comorbidities, clinical presentations, image study findings, culture pathogens, and treatment outcomes and analyzed the differences between orbital-involved and orbital sparing disease. Results: The most common comorbidities in AIFRS were diabetes mellitus (DM) and hematological malignancy. Nine the 21 AIFRS patients had orbital-involved disease. Patients with orbital involvement had a higher prevalence of DM (p < 0.05). Image studies revealed significant infection of the ethmoid sinus, sphenoid sinus, and frontal sinus in the group with orbital complication (p < 0.05). Mucor, Rhizopus, and Aspergillus were cultured in both groups. Five patients in the orbital involvement group expired, with all of them having an initial presentation of conscious disturbance (p < 0.01). Rhino-orbital-cerebral fungal infection was noticed in 3 of the 5 expired patients. Conclusion: In AIFRS patients, DM other than hematological malignancy was the main risk factor for orbital-involved disease. Patients with ethmoid, sphenoid, or frontal sinusitis had a higher possibility of orbital complication. Poor consciousness at initial presentation revealed highest possibility of rhino-orbital-cerebral fungal infection and led to death.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34200176

RESUMO

Prenatal exposure to bisphenol A (BPA) may increase the risk of abnormal birth outcomes, and DNA methylation might mediate these adverse effects. This study aimed to investigate the effects of maternal BPA exposure on maternal and fetal DNA methylation levels and explore whether epigenetic changes are related to the associations between BPA and low birth weight. We collected urine and blood samples originating from 162 mother-infant pairs in a Taiwanese cohort study. We measured DNA methylation using the Illumina Infinium HumanMethylation 450 BeadChip in 34 maternal blood samples with high and low BPA levels based on the 75th percentile level (9.5 µg/g creatinine). Eighty-seven CpGs with the most differentially methylated probes possibly interacting with BPA exposure or birth weight were selected using two multiple regression models. Ingenuity pathway analysis (IPA) was utilized to narrow down 18 candidate CpGs related to disease categories, including developmental disorders, skeletal and muscular disorders, skeletal and muscular system development, metabolic diseases, and lipid metabolism. We then validated these genes by pyrosequencing, and 8 CpGs met the primer design score requirements in 82 cord blood samples. The associations among low birth weight, BPA exposure, and DNA methylation were analyzed. Exposure to BPA was associated with low birth weight. Analysis of the epigenome-wide findings did not show significant associations between BPA and DNA methylation in cord blood of the 8 CpGs. However, the adjusted odds ratio for the dehydrogenase/reductase member 9 (DHRS9) gene, at the 2nd CG site, in the hypermethylated group was significantly associated with low birth weight. These results support a role of BPA, and possibly DHRS9 methylation, in fetal growth. However, additional studies with larger sample sizes are warranted.


Assuntos
Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal , Compostos Benzidrílicos/toxicidade , Peso ao Nascer , Estudos de Coortes , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Exposição Materna/efeitos adversos , Fenóis , Projetos Piloto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Taiwan/epidemiologia
3.
Pharmaceuticals (Basel) ; 14(6)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201235

RESUMO

The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.

4.
Oncogene ; 40(26): 4503-4519, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34117361

RESUMO

Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-ß3 activation. The CAF-cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-ß3 antibody. Human tumors with high TGF-ß3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-ß3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.

5.
Environ Pollut ; 286: 117306, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33991738

RESUMO

We developed and validated a trace analytical method for the simultaneous determination of 10 benzophenone (BP)-type ultraviolet filters (BPs; BP, BP-1, BP-2, BP-3, BP-8, 2-hydroxybenzophenone [2-OHBP], 4-hydroxybenzophenone [4-OHBP], 4-methylbenzophenone [4-MBP], methyl-2-benzoylbenzoate [M2BB], and 4-benzoylbiphenyl [PBZ]) to analyze BPs in 110 commercial fish samples. The quick, easy, cheap, effective, rugged, and safe (QuEChERS) technique coupled with ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was employed. The developed method exhibited satisfactory linearity (R2 > 0.993), favorable precision with intraday and interday relative standard deviation ranges of 1.0%-26.6% and 2.3%-29.3%, respectively, and a limit of detection ranging from 0.001 to 0.1 ng/g. BP and 2-OHBP were detected in 100% of the samples; BP-3, 4-OHBP, PBZ, and 4-MBP were detected in >70% of the samples; M2BB was detected in 33% of the samples, and BP-2 and BP-8 were not detected. Higher mean (minimum-maximum) levels of 2-OHBP and BP were found in fish samples with low lipid content, ranging from 18 (1.1-218.3) to 10 (0.5-45.4) ng/g, and those with high lipid content, ranging from 22 (1.5-76.4) to 9.6 (5.2-18.5) ng/g; low levels of the remaining six BPs were found, ranging from 0.01 to 0.9 ng/g. The mean 2-OHBP levels were 21.3, 14.4, and 30.2 ng/g for fish samples obtained from aquaculture in Taiwan, the wild in Taiwan, and different countries, respectively, with levels up to 218.3 ng/g (field eel) for a sample from Indonesia. BPs may not pose a health risk to Taiwanese adults through the consumption of fish; however, additional studies are needed to examine the risk that these contaminants may pose to ecosystems and human health.


Assuntos
Ecossistema , Espectrometria de Massas em Tandem , Adulto , Animais , Benzofenonas/análise , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos
6.
Technol Cancer Res Treat ; 19: 1533033820983812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33371800

RESUMO

We do not know the clinical and prognostic factors that influence the survival of patients with gastric signet ring cell carcinoma (SRC). Therefore, a retrospective review was undertaken of 219 patients with SRC who had undergone gastrectomy between January 2009 and December 2012 in our hospital. Patient age, sex, TNM stage, vessel carcinoma embolus, perineural invasion, tumor site and operation type, postoperative chemotherapy, and five-year overall survival were recorded and evaluated. In our study, 93 cases (42.5%) were signet ring cell carcinoma only, and 126 cases (57.5%) were signet ring cell carcinoma coexisting with other components (such as adenocarcinoma or mucus adenocarcinoma). Eighty-three patients were female, 136 were male, 46 occurred at the gastroesophageal junction (21.0%), 63 at the fundus/body (28.8%), 80 were antrum/pylorus (36.5%), and 30 were whole stomach (13.7%). The prognosis of gastric antrum/ pylorus cancer was the best (P < 0.05). There were 133 patients (60.7%) with stage III, and the single factor analysis showed that the earlier the stage, the better the prognosis. The overall five-year survival rate was 30.1% in all patients. One-hundred and 41 patients (64.4%) received D2 radical surgery, 64 (29.2%) received D1 radical operation, and 14 (6.4%) received palliative resection, and the patients who received D2 had the best overall survival (P < 0.05). The survival time of the paclitaxel-based regimen in postoperative adjuvant chemotherapy tended to be prolonged. There was no statistical difference in overall survival between the percentage of signet-ring cells and sex. In summary, age, tumor stage, and surgical resection combined with D2 lymphadenectomy were independent prognostic factors for SRC. Adjuvant chemotherapy with a paclitaxel-based regimen may improve the survival of patients with SRC.

7.
J Comput Assist Tomogr ; 44(6): 977-983, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976262

RESUMO

OBJECTIVE: To determine the frequencies of fat-water swaps in iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) water-only images of the postinstrumentation spine and discuss the efficiency of in-phase imaging in improving visibility of the thecal sac. MATERIALS AND METHODS: A total of 276 patients (167 women; mean age, 62.3 years; range, 23-89 years) with metallic devices on the lumbar spine who received complete routine 1.5 T MR imaging, including axial and sagittal images of T1-weighted, T2-weighted, and T2-weighted IDEAL sequences, were included. The exclusion criteria were significant motion artifacts and severe metallic artifacts in any one of the sequences. The images were reviewed by two radiologists to identify fat-water swaps that were divided into 3 groups: extraspinal swaps, intraspinal swaps in sagittal images, and intraspinal swaps in axial images. The qualitative evaluations for the spinal canal in axial images were performed by rating on a five-point scale. Side-by-side comparisons of T2-weighted images and IDEAL in-phase images were also performed. RESULTS: In patient-based data of 276 patients, extraspinal fat-water swaps were noted in 10 patients (3.6%) and intraspinal swaps were noted in 160 patients (58.0%). The intraspinal swaps had a higher incidence in the patients with more levels of metallic devices with screws and the trend was not noted in the extraspinal swaps. A total of 928 axial levels were evaluated in the level-based data of axial images. T1-weighted, T2-weighted, and IDEAL in-phase images had significantly better imaging quality than the IDEAL water-only images (3.9 ± 0.4, 3.9 ± 0.3, 3.8 ± 0.4 vs 3.0 ± 1.3, all P < 0.001). Compared with T2-weighted images, most of the IDEAL in-phase images (reader 1, 90.9%; reader 2, 86.7%) present similar quality. CONCLUSION: Iterative decomposition of water and fat with echo asymmetry and least-squares estimation sequence can provide good fat suppression in most spine MRI with metallic devices but the loss of cerebrospinal fluid signal intensities due to fat-water swaps are noted in more than half of postinstrumentation spine. Routine reconstruction of in-phase images is recommended to improve evaluation of the thecal sac by avoiding pitfall caused by fat-water swaps.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Artefatos , Processamento de Imagem Assistida por Computador/métodos , Fixadores Internos , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Análise dos Mínimos Quadrados , Vértebras Lombares/diagnóstico por imagem , Masculino , Metais , Pessoa de Meia-Idade , Estudos Retrospectivos , Razão Sinal-Ruído , Coluna Vertebral/diagnóstico por imagem , Água , Adulto Jovem
8.
Front Oncol ; 10: 1095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760668

RESUMO

This study aimed to determine the real-world, long-term prognostic impacts, and adverse effects (AEs) of bevacizumab (BEV) in Asian patients with ovarian/tubal/peritoneal cancers. We retrospectively reviewed the medical records of consecutive patients with ovarian/tubal/peritoneal cancer on front-line chemotherapy with or without BEV (Cohort 1) and those who relapsed following chemotherapy and/or BEV (Cohort 2) between 2011 and 2018 in a tertiary medical centre. Patient characteristics, BEV dosages, clinical outcomes, and AEs were analyzed. Hazard ratios for disease progression and death were analyzed using a cox proportional regression model. Benefits of BEV used throughout triweekly, in terms of improved progression-free survival (PFS) and overall survival (OS), were observed at a dosage of 7.5-15 mg/kg among advanced-stage Cohort 1 patients. A progression-free interval of <6 months was the strongest predictor of disease progression and death in advanced-stage patients. BEV throughout and optimal cytoreduction were independent predictors of reduced disease progression. No prognostic advantage was observed between serous and clear cell histologies when BEV was added. Moreover, BEV resulted in improved OS in Cohort 2 patients, especially in the platinum-sensitive subgroup. Most patients had a front-line BEV dosage <10 mg/kg per cycle with <10 treatment cycles. Low rates and grades of BEV-related AEs were observed in both cohorts. BEV used throughout effectively extended PFS and OS in advanced-stage patients with ovarian/tubal/peritoneal cancer. Patients with platinum-sensitive carcinoma, treated with BEV, had a significant improvement in OS and extended PFS. Therefore, BEV can safely be added to chemotherapy for ovarian/tubal/peritoneal cancers.

9.
J Integr Neurosci ; 19(1): 89-99, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259889

RESUMO

Denervated-dependent skeletal muscle atrophy is a disease induced by skeletal muscle associated peripheral neuro-disconnection. Its specific molecular mechanisms remain unknown. The treating for denervated-dependent skeletal muscle atrophy is applied with an herbal complex Buyang Huanwu Tang used in traditional Chinese medicine and subjected to the established denervated-dependent skeletal muscle atrophy in rat models, and the therapeutic effects and associated mechanisms were evaluated in the pathogenesis of denervated-dependent skeletal muscle atrophy. Denervated-dependent skeletal muscle atrophy in rats was established and randomly divided into eight groups, including Normal control, Model, Positive control, Model + Buyang Huanwu Tang, Model + astragalus extracts, Model + Buyang Huanwu Tang-astragalus, Buyang Huanwu Tang + LY294002, and astragalus extract + LY294002 group. Hematoxylin-eosin staining and quantitative RT-PCR (qRT-PCR) assay were used to examine the inflammatory response of muscle tissues. Quantitative RT-PCR and Western blotting assay were utilized to analyze mRNA and protein expression. Immunohistochemistry assay was used to detect molecule expression in anterior cervical muscle tissues. Motor endplate activity was examined using the wholemount acetylcholinesterase staining method. The wet mass ratio of anterior cervical muscle was measured. The results indicated that Buyang Huanwu Tang treatment significantly alleviated inflammatory response, enhanced acetylcholinesterase activity, and motor endplate functions, and promoted wet mass of anterior cervical muscle compared to denervated-dependent skeletal muscle atrophy rat models (P < 0.05). Buyang Huanwu Tang regulated molecules of PI3K/PKB/GSK3ß/FOXO1 signaling pathway. Buyang Huanwu Tang significantly reduced muscle atrophy F-box protein, MuFR-1, Bax and caspase 9 expression, significantly enhanced Bcl-2 expression, and remarkably increased element-binding protein and vascular endothelial growth factor levels, compared to Model group (P < 0.05). Buyang Huanwu Tang suppressed caspase 9 and caspase 3 activity and associated apoptosis. Moreover, PI3K specific blocker, LY294002, significantly inhibited the effects of Buyang Huanwu Tang on the above molecule expression (P < 0.05). In conclusion, Buyang Huanwu Tang improved motor endplate functions of denervated-dependent skeletal muscle atrophy rat model through suppressing mitochondria-mediated apoptosis and activating PI3K/PKB/FOXO1 signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Placa Motora/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/metabolismo , Animais , Masculino , Placa Motora/metabolismo , Placa Motora/patologia , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Ratos Sprague-Dawley
10.
Front Immunol ; 11: 151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32153563

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate important intracellular biological processes. In myasthenia gravis (MG), a disease-specific pattern of elevated circulating miRNAs has been found, and proposed as potential biomarkers. These elevated miRNAs include miR-150-5p, miR-21-5p, and miR-30e-5p in acetylcholine receptor antibody seropositive (AChR+) MG and miR-151a-3p, miR-423-5p, let-7a-5p, and let-7f-5p in muscle-specific tyrosine kinase antibody seropositive (MuSK+) MG. In this study, we examined the regulation of each of these miRNAs using chromatin immunoprecipitation sequencing (ChIP-seq) data from the Encyclopedia of DNA Elements (ENCODE) to gain insight into the transcription factor pathways that drive their expression in MG. Our aim was to look at the transcription factors that regulate miRNAs and then validate some of those in vivo with cell lines that have sufficient expression of these transcription factors This analysis revealed several transcription factor families that regulate MG-specific miRNAs including the Forkhead box or the FOXO proteins (FoxA1, FoxA2, FoxM1, FoxP2), AP-1, interferon regulatory factors (IRF1, IRF3, IRF4), and signal transducer and activator of transcription proteins (Stat1, Stat3, Stat5a). We also found binding sites for nuclear factor of activated T-cells (NFATC1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), early growth response factor (EGR1), and the estrogen receptor 1 (ESR1). AChR+ MG miRNAs showed a stronger overall regulation by the FOXO transcription factors, and of this group, miR-21-5p, let-7a, and let 7f were found to possess ESR1 binding sites. Using a murine macrophage cell line, we found activation of NF-κB -mediated inflammation by LPS induced expression of miR-21-5p, miR-30e-5p, miR-423-5p, let-7a, and let-7f. Pre-treatment of cells with the anti-inflammatory drugs prednisone or deflazacort attenuated induction of inflammation-induced miRNAs. Interestingly, the activation of inflammation induced packaging of the AChR+-specific miRNAs miR-21-5p and miR-30e-5p into exosomes, suggesting a possible mechanism for the elevation of these miRNAs in MG patient serum. In conclusion, our study summarizes the regulatory transcription factors that drive expression of AChR+ and MuSK+ MG-associated miRNAs. Our findings of elevated miR-21-5p and miR-30e-5p expression in immune cells upon inflammatory stimulation and the suppressive effect of corticosteroids strengthens the putative role of these miRNAs in the MG autoimmune response.


Assuntos
MicroRNA Circulante/genética , MicroRNA Circulante/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/metabolismo , Miastenia Gravis/metabolismo , Receptores de Estrogênio/metabolismo , Fatores de Transcrição STAT/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos/imunologia , Estudos de Coortes , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células RAW 264.7 , RNA Mensageiro/genética , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Transdução de Sinais/genética , Linfócitos T/metabolismo
11.
Front Pharmacol ; 11: 206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194423

RESUMO

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the KRAS mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.

12.
PhytoKeys ; 131: 69-81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565025

RESUMO

A new species of Bolbitis, B. lianhuachihensis sp. nov., was found in central Taiwan. It most resembles B. virens var. compacta and B. hainanensis. A phylogenetic tree of Taiwanese and other Asian species of Bolbitis species supports the recognition of the new species. Morphologically, the combination of anastomosing venation and fewer sterile pinnae are critical characters to discriminate B. lianhuachihensis from other Taiwanese Bolbitis species. Bolbitis lianhuachihensis can be further distinguished from B. virens var. compacta and B. hainanensis by having lanceolate sterile pinnae and absent or fewer free veinlets in small areoles of sterile pinnae. The morphological descriptions, illustration, ecology and distribution of the new species are presented. A key to all Taiwanese Bolbitis is also provided.

13.
Front Oncol ; 9: 437, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179244

RESUMO

Background: Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related deaths worldwide. Preclinical studies found that copper-lowering agents could re-sensitize platinum-resistant cancer cells by enhancing the human copper transporter 1 (hCtr1)-mediated uptake of platinum. In the clinic, re-sensitization of platinum-resistance in relapsed EOC has been discovered by the application of trientine plus platinum (NCT01178112). However, no pharmacokinetic data of trientine has been reported in cancer patients. Purpose: Our study aimed to explore the safety and activity of trientine combined with carboplatin and pegylated liposomal doxorubicin (PLD) in patients with EOC, tubal, and peritoneal cancer who experienced disease progression during platinum-based chemotherapy or showed relapse <12 months after completing first-line chemotherapy. Also, we aimed to demonstrate pharmacokinetic parameters and to discover potential biomarkers in our EOC patients. Methods: In this dose escalation study, 18 Asian patients in six dosing cohorts received fixed doses of carboplatin (AUC 4) and PLD (LipoDox®, TTY Biopharm Co. Ltd., Taipei, Taiwan) (40 mg/m2, day 1 per 4-week cycle), and escalated daily trientine doses (range: 300-1800 mg; initiated 7 days before the 1st combination cycle) according to a 3 + 3 design. Results: No dose-limiting toxicity or treatment-related death was observed. Four patients (22.2%) developed grade 3 drug-related adverse events (AEs), whereas no grade 4 AEs were encountered. Anemia and grade 2 dizziness were the most common hematological toxicity and neurotoxicity, respectively. In a pharmacokinetics comparison with healthy volunteers in the literature, our patients achieved greater absorption after oral trientinem, and more rapid elimination of triethylenetetramine dihydrochloride at high doses. The clinical benefit rate was 33.3 and 50.0% in the platinum-resistant and the partially platinum-sensitive group, respectively. A high baseline serum iron level and low serum copper level might help differentiate subgroups of patients with different clinical responses. Nevertheless, no associations of the clinical response with the levels of serum hCtr1, ceruloplasmin, or copper were observed. Conclusion: Combination therapy with carboplatin, trientine, and PLD was well-tolerated and safe. Our results encourage the development of a future phase II trial. Clinical trial registration: ClinicalTrials.gov # NCT03480750.

14.
Am J Transl Res ; 11(5): 3056-3068, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31217875

RESUMO

Denervated-dependent skeletal muscle atrophy (DSMA) is considered to be the neuro-disconnection of skeletal muscle. This study aimed to investigate the protective effects of Buyang Huanwu Tang (BYHWT) on the DSMA and clarify associated molecular and genetic mechanisms. DSMA rat models were established according to the previously published study and divided into Model group and BYHWT group. Meanwhile, normal rats were assigned as Normal control (NC) group. Hematoxylin and eosin (HE) staining was used to examine inflammatory responses. Motor endplate activity was evaluated with wholemount acetylcholinesterase (AChE) staining. Mass-spectrometry analysis was conducted to compare differentially expressed proteins. RNAs were prepared and applied to gene functional analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to analyze biological functions. The results indicated that BYHWT remarkably alleviated inflammatory responses and significantly improved motor endplate function, compared to that in DSMA Model rats (P<0.05). In BYHWT group, there were 393 differentially up-regulated and 576 differentially down-regulated molecules compared to that in Model group. Comparing to Model group, the cellular response to interferon-gamma, integral component of plasma membrane and voltage-gated potassium channel activity genes in BYHWT group were the most biological process (BP), cellular component (CC) and molecular function (MF) differential genes, respectively. Fructose/mannose metabolism and glycerolipid metabolism KEGG signaling pathways illustrated the most significant enrichment of differentially expressed genes. In conclusion, BYHWT alleviated the inflammations and improved the motor endplate function of DSMA rats by activating cellular response to interferon-gamma, integral component of plasma membrane and voltage-gated potassium channel activity genes and associated signaling pathways.

15.
Int J Hyg Environ Health ; 222(6): 955-964, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31248753

RESUMO

Parabens are a group of esters of parahydroxybenzoic acid and are utilized as antimicrobial preservatives in the majority of personal care products (PCPs). Epidemiological studies regarding the adverse effects of parabens on fetuses are still limited. The aim of this study was to determine the association between maternal paraben exposure and birth outcomes. One hundred and ninety-nine pregnant women were enrolled, and maternal urine was collected in the third trimester. The urine concentrations of four parabens (methyl (MP), ethyl (EP), propyl (PP), and butyl (BP)) were determined by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Generalized additive model-penalized regression splines and a multivariable regression model were employed to determine the association between paraben exposure levels and birth outcomes. A causal mediation analysis was conducted to determine the mediation effect of oxidative stress on birth outcomes. The geometric means of urinary MP, EP, PP, and BP were 51.79, 1.26, 4.21, and 1.25 µg/g cre., respectively. In the penalized regression splines, sex-specific associations between maternal MP levels and birth outcomes were observed; a downward curvature was observed between the MP level and birth weight, length, head circumference, and thoracic circumference among female newborns. Pregnant women in the group with MP levels above the third quartile had neonates with significantly lower body weight (ß = -215.98 g, p value = 0.02) compared to those in the group with MP levels lower than the third quartile. No significant mediation of oxidative stress was observed between maternal MP exposure and female birth weight. The estimated proportion mediated ranged from -6% to 15%. The negative association between maternal paraben exposure and female birth outcomes in relation to child development should be carefully considered.


Assuntos
Anti-Infecciosos/urina , Tamanho Corporal , Poluentes Ambientais/urina , Exposição Materna , Parabenos/análise , Adulto , Monitoramento Biológico , Feminino , Humanos , Masculino , Troca Materno-Fetal , Estresse Oxidativo , Gravidez , Caracteres Sexuais , Taiwan
16.
Chemosphere ; 226: 290-297, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30933738

RESUMO

This study determined whether maternal bisphenol A (BPA) exposure influences birth outcomes through oxidative stress and estimated the daily intake of BPA through breast milk for infants. One hundred and eighty-six pregnant women without pregnancy complications were enrolled and maternal urine was collected in the third trimester. Postnatal breast milk was collected in the first and third months after delivery. Concentrations of BPA were determined through ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Generalized additive model-penalized regression splines and a multivariable regression model were employed to determine the effects of BPA exposure and oxidative stress levels on birth outcomes. A causal mediation analysis was conducted to clarify the mediation effects of oxidative stress due to maternal BPA exposure on birth outcomes. The daily intake of BPA in breast milk was calculated using probabilistic risk assessment methods. The geometric means (geometric standard deviation) of BPA levels for maternal urine and first- and third-month breast milk were 2.19 (2.88) µg/g creatinine., 1.35 (3.53) ng/g, and 3.17 (2.97) ng/g, respectively. No significant mediation existed among maternal BPA exposure, oxidative stress level, and neonatal head circumference. Three percent of 1-monthold babies and 1% of 3-month-old babies exceeded the BPA tolerable daily intake of 4 µg/kg-bw/day proposed by the European Food Safety Authority. This study revealed the BPA exposure profile for pregnant women and infants in northern Taiwan. The marginally significant correlation between maternal BPA exposure and neonatal head circumference should be considered.


Assuntos
Compostos Benzidrílicos/análise , Exposição Materna/efeitos adversos , Leite Humano/química , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Pesos e Medidas Corporais , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Feminino , Humanos , Lactente , Saúde do Lactente , Recém-Nascido , Espectrometria de Massas , Gravidez , Análise de Regressão , Medição de Risco , Taiwan
17.
Cell Death Dis ; 10(4): 322, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975980

RESUMO

We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels, as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66-sensitized chemoresistant cells to cisplatin and paclitaxel treatment, and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPß), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin. This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance, and supports the application of SC66 as a therapy for ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Cisplatino/farmacologia , Colágeno Tipo XI/metabolismo , Cicloexanonas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Piridinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Linhagem Celular Tumoral , Colágeno Tipo XI/genética , Cicloexanonas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Paclitaxel/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/uso terapêutico , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
BMC Ophthalmol ; 19(1): 268, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888553

RESUMO

BACKGROUND: Previous case reports have demonstrated the occurrence of ischemic optic neuropathy (ION) following intravitreal injections of antivascular endothelial growth factor (anti-VEGF). However, no previous studies have investigated the impact of injection numbers on the risk of ION. The aim of our study was to investigate whether repeated intravitreal injections of anti-VEGF would increase the risk of subsequent ION in patients with neovascular age-related macular degeneration (AMD). METHODS: A population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted from 2007 to 2013. Neovascular AMD patients receiving intravitreal injections of anti-VEGF during the study period were enrolled in the study cohort. Enrollees were divided into three groups according to the categorized levels of injection number (first level: < 10 times, second level: 10-15 times, and third level: > 15 times). Kaplan-Meier curves were generated to compare the cumulative hazard of subsequent ION among the three groups. Cox regression analyses were used to estimate crude and adjusted hazard ratios (HRs) for ION development with respect to the different levels of injection numbers. The confounders included for adjustment were age, sex, and comorbidities (diabetes, hypertension, hyperlipidemia, ischemic heart disease, and glaucoma). RESULTS: In total, the study cohort included 77,210 patients. Of these, 26,520, 38,010, and 12,680 were in the first-, second-, and third-level groups, respectively. The Kaplan-Meier method revealed that the cumulative hazards of ION were significantly higher in those who had a higher injection number. After adjusting for confounders, the adjusted HRs for ION in the second- and third-level groups were 1.91 (95% confidence interval [CI], 1.32-2.76) and 2.20 (95% CI, 1.42-3.43), respectively, compared with those in the first-level group. CONCLUSIONS: Among patients with neovascular AMD, those who receive a higher number of anti-VEGF injections have a significantly higher risk of developing ION compared with individuals who receive a lower number of injections.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Neovascularização de Coroide/tratamento farmacológico , Neuropatia Óptica Isquêmica/induzido quimicamente , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Neovascularização de Coroide/diagnóstico , Bases de Dados Factuais , Feminino , Angiofluoresceinografia , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Neuropatia Óptica Isquêmica/diagnóstico , Retratamento , Estudos Retrospectivos , Fatores de Risco , Taiwan , Tomografia de Coerência Óptica , Degeneração Macular Exsudativa/diagnóstico
19.
Opt Express ; 26(18): 23397-23410, 2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30184841

RESUMO

Enabling laser white-lighting at a correlated color temperature (CCT) of 6500K with the use of only red/green/blue (RGB) tri-color laser diodes (LDs) is demonstrated, which can further perform wavelength division multiplexing (WDM) communication with a high-spectral-usage 16 QAM-OFDM data stream at 11.2 Gbps over 0.5 m. The sampling rate of encoded data is optimized to avoid the aliasing effect and to effectively amplify the signal with high on/off extinction and modulation depth. Proper oversampling can decrease the peak-to-average power ratio (PAPR) of the OFDM data and filter out unwanted noise. There are also six different diffusers used to diverge the white-light mixed by the RGB LD beam. By analyzing the color-casting transmittance, surface roughness, CCT uniformity, divergent angle of the diffuser, and the data transmission capacity, the frosted glass (FG2.8) diffuser with high transmittance diverges the white light with the divergent angle of ± 20° and supports the highest data rate of 14 Gbps over 0.5 m. To fit the day-light CCT, the blue LD power at an optimized bias current is further attenuated with a 0.6-optical density filter for reducing CCT from 100000K to 6500K; however, such an adjustment also degrades the SNR ratio to sacrifice the achievable data rate of the blue LD. The polycarbonate (PC1.5) diffuser with proper surface roughness diverged white-light exhibits the best CCT uniformity and a divergent angle of ± 30° but supports a data rate of only 6.4 Gbps over 0.5 m. The poly (methyl methacrylate) PMMA1.5 diffuser scatters the white light with the largest angle of ± 40°; however, the data rate also decreases to 4.8 Gbps over 0.5 m.

20.
Environ Res ; 167: 567-574, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30165327

RESUMO

Nonylphenol (NP) and/or bisphenol A (BPA) may have reproductive effects. Although the mechanisms of action remain unclear, steroid hormones biosynthesis, hypothalamus pituitary adrenal axis activity, oxidative stress, and crosstalk interaction of NP and BPA mixture and its pathways may play a contributory role. This cross-sectional study examined whether the interactive effects of NP/BPA and oxidative stress biomarkers played a role in reproductive indices (penis length and anogenital distance (AGD)) in 244 mother-fetus pairs. Four biomarkers of oxidative stress, (8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2Gua), 8-iso-prostaglandin F2α (8-isoPF2α), and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)) were simultaneously analyzed using the high-performance liquid chromatography-electrospray ionization tandem mass spectrometry method. No significant associations were found between reproductive indices and NP/BPA or oxidative stress biomarkers. Maternal exposure to a mixture of NP and BPA may enhance 8-OHdG. Interactive effects were found in the high 8-isoPF2α group, and prenatal NP exposure was inversely associated with penis length (ß = -3.68 mm; p = 0.01). Similar results were noted among boys who were born to mothers in the high 8-isoPF2α group, in which BPA was inversely associated with penis length (ß = -4.43 mm; p = 0.005). Our findings suggest important implications for prenatal exposure to oxidative stress, as evidenced by the 8-isoPF2α level. Thus, NP and BPA may interact to shape fetal reproductive tract development, particularly in boys. The interactive effects of NP/BPA, oxidative stress, and reproductive indices should be considered.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Genitália Masculina/anatomia & histologia , Estresse Oxidativo , Fenóis/efeitos adversos , Estudos Transversais , Feminino , Feto/anatomia & histologia , Humanos , Masculino , Gravidez
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