ABSTRACT
BACKGROUND: BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms. METHODS: CRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts. RESULTS: We elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings. CONCLUSIONS: Our findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.
Subject(s)
Drug Resistance, Neoplasm , Eukaryotic Translation Initiation Factor 5A , Melanoma , Mutation , Peptide Initiation Factors , Polyamines , Proto-Oncogene Proteins B-raf , RNA-Binding Proteins , Vemurafenib , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/metabolism , Melanoma/pathology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Drug Resistance, Neoplasm/genetics , Animals , Polyamines/metabolism , Mice , Peptide Initiation Factors/metabolism , Peptide Initiation Factors/genetics , Cell Line, Tumor , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Vemurafenib/pharmacology , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-myc/genetics , Xenograft Model Antitumor Assays , CRISPR-Cas Systems , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Lysine/analogs & derivativesABSTRACT
Herein, a novel extracellular matrix (ECM) hydrogel is proposed fabricated solely from decellularized, human fibroblast-derived matrix (FDM) toward advanced wound healing. This FDM-gel is physically very stable and viscoelastic, while preserving the natural ECM diversity and various bioactive factors. Subcutaneously transplanted FDM-gel provided a permissive environment for innate immune cells infiltration. Compared to collagen hydrogel, excellent wound healing indications of FDM-gel treated in the full-thickness wounds are noticed, particularly hair follicle formation via highly upregulated ß-catenin. Sequential analysis of the regenerated wound tissues disclosed that FDM-gel significantly alleviated pro-inflammatory cytokine and promoted M2-like macrophages, along with significantly elevated vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) level. A mechanistic study demonstrated that macrophages-FDM interactions through cell surface integrins α5ß1 and α1ß1 resulted in significant production of VEGF and bFGF, increased Akt phosphorylation, and upregulated matrix metalloproteinase-9 activity. Interestingly, blocking such interactions using specific inhibitors (ATN161 for α5ß1 and obtustatin for α1ß1) negatively affected those pro-healing growth factors secretion. Macrophages depletion animal model significantly attenuated the healing effect of FDM-gel. This study demonstrates that the FDM-gel is an excellent immunomodulatory material that is permissive for host cells infiltration, resorbable with time, and interactive with macrophages, where it thus enables regenerative matrix remodeling toward a complete wound healing.
Subject(s)
Extracellular Matrix , Fibroblasts , Hydrogels , Macrophages , Wound Healing , Humans , Macrophages/metabolism , Macrophages/drug effects , Macrophages/immunology , Wound Healing/drug effects , Animals , Fibroblasts/metabolism , Fibroblasts/drug effects , Extracellular Matrix/metabolism , Mice , Disease Models, Animal , MaleABSTRACT
MicroRNAs (miRNAs) are small, non-coding RNAs crucial for gene regulation and implicated in various human diseases. Their potential as clinical prognostic and diagnostic biomarkers in biological fluids necessitates reliable detection methods. In this study, a combination of streptavidin-coupled magnetic beads and capillary electrophoresis with laser-induced fluorescence (CE-LIF) was used to extract and analyze plasma miRNAs. Specifically, miRNAs hybridized with a biotinylated fluorescent DNA probe were isolated from plasma using magnetic beads. These hybridized miRNAs were then directly injected into the CE-LIF system for analysis, eliminating the need for additional processing steps. Both the hybridization and bead-to-probe binding were executed concurrently, regulated by temperature and time. Through the optimization of magnetic bead extraction and CE-LIF conditions, we developed a highly sensitive assay for miR-21 quantification in plasma. The assay displayed remarkable linearity (R2 = 0.9975) within a 0.1-5 pM range and exhibited favorable precision (0.22-1.26 %) and accuracy (98.31-111.19 %). Importantly, we successfully detected endogenous miR-21 in plasma samples from both a lung cancer patient and healthy adults, revealing a 1.7-fold overexpression of miR-21 in lung cancer plasma relative to normal samples. Our findings suggest that this developed system offers a simple and sensitive approach for detecting endogenous miRNAs in plasma, showing its potential utility in disease diagnostics. To our knowledge, this is the first study to utilize CE-LIF for plasma miRNA detection.
ABSTRACT
Light-emitting diodes (LEDs) are regarded as an effective artificial light source for producing sprouts, microgreens, and baby leaves. Thus, this study aimed to investigate the influence of different LED lights (white, red, and blue) on the biosynthesis of secondary metabolites (glucosinolates, carotenoids, and phenolics) and the biological effects on kale microgreens. Microgreens irradiated with white LEDs showed higher levels of carotenoids, including lutein, 13-cis-ß-carotene, α-carotene, ß-carotene, and 9-cis-ß-carotene, than those irradiated with red or blue LEDs. These findings were consistent with higher expression levels of carotenoid biosynthetic genes (BoPDS and BoZDS) in white-irradiated kale microgreens. Similarly, microgreens irradiated with white and blue LEDs showed slightly higher levels of glucosinolates, including glucoiberin, progoitrin, sinigrin, and glucobrassicanapin, than those irradiated with red LEDs. These results agree with the high expression levels of BoMYB28-2, BoMYB28-3, and BoMYB29 in white- and blue-irradiated kale microgreens. In contrast, kale microgreens irradiated with blue LEDs contained higher levels of phenolic compounds (gallic acid, catechin, ferulic acid, sinapic acid, and quercetin). According to the total phenolic content (TPC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition assays, the extracts of kale microgreens irradiated with blue LEDs had slightly higher antioxidant activities, and the DPPH inhibition percentage had a positive correlation with TPC in the microgreens. Furthermore, the extracts of kale microgreens irradiated with blue LEDs exhibited stronger antibacterial properties against normal pathogens and multidrug-resistant pathogens than those irradiated with white and red LEDs. These results indicate that white-LED lights are suitable for carotenoid production, whereas blue-LED lights are efficient in increasing the accumulation of phenolics and their biological activities in kale microgreens.
ABSTRACT
The structural control of metal-organic frameworks (MOFs) is essential for the development of superlative MOFs because the structural features of MOFs and their components play a critical role in determining their properties, and ultimately, their applications. The best components to endow the desired properties for MOFs are available via the appropriate choice from many existing chemicals or synthesizing new ones. However, to date, considerably less information exists regarding fine-tuning the MOF structures. Herein, a strategy for tuning MOF structures by merging two MOF structures into a single MOF, is demonstrated. Depending on the incorporated amounts and relative contributions of the two coexisting organic linkers, benzene-1,4-dicarboxylate (BDC2- ) and naphthalene-1,4-dicarboxylate (NDC2- ), which have conflicting spatial-arrangement preferences within an MOF structure, MOFs are rationally designed to have a Kagomé or rhombic lattice. In particular, MOFs with rhombic lattices are constructed to have specific lattice angles by compromising the optimal structural arrangements between the two mixed linkers. The relative contributions of the two linkers during MOF construction determine the final MOF structures, and the competitive influence between BDC2- and NDC2- is effectively regulated to produce specific MOF structures with controlled lattices.
ABSTRACT
The hairy root (HR) culture system is an excellent alternative strategy to the whole plant system for producing valuable compounds. However, selection of suitable Agrobacterium strain for the successful induction of HR is an essential step for enhanced production of beneficial secondary metabolites. In this study, we examined the transformation efficiency of various A. rhizogenes strains (ATCC 13333, ATCC 15834, A4, R1000, R1200, and R1601) for transgenic HRs induction in Ocimum basilicum. Among the tested strains, the R1601 was found to be one of the most promising strain for mass production of HR in terms of transformation efficiency (94%) and the number and length of HR (8.4 ± 0.52 and 1.68 ± 0.14 cm). The HR induced by the same strain exhibited highest levels of rosmarinic acid level (62.05 ± 4.94 µg/g DW) and total phenolic content (62.3 ± 4.95 µg/g DW). A total of 55 metabolites were identified using high-performance liquid chromatography (HPLC) and gas chromatography-time-of-flight mass spectrometry (GC-TOFMS). The PCA and PLS-DA plot of the identified metabolites showed that HR induced by A4 and ATCC 15834 displayed variation in primary and secondary metabolite contents. Analysis of the metabolic pathway identified a total of 56 pathways, among which 35 were found to be impacted. A heat map and hierarchical clustering analysis indicated that HR induced by different Agrobacterium strains exhibited differential metabolites profiles. In conclusion, Agrobacterium strains R1601 is one of the best and most promising strains for inducing mass HR production and enhanced levels of secondary metabolites in O. basilicum.
ABSTRACT
Heracleum moellendorffii Hance is a non-woody forest plant widely used in China, Korea, and Japan because of its various therapeutic properties. However, the genetic details of the carotenoid pathway (CP), xanthophyll pathway (XP), and apocarotenoid pathway (AP) genes have not been studied. Thus, the CP, XP, and AP genes of H. moellendorffii were detected and analyzed. A total of fifteen genes were identified, of which eight, four, and three belonged to CP, XP, and AP, respectively. All identified genes possessed full open reading frames. Phylogenetic characterization of the identified gene sequences showed the highest similarity with other higher plants. Multiple alignments and 3D dimensional structures showed several diverse conserved motifs, such as the carotene-binding motif, dinucleotide-binding motif, and aspartate or glutamate residues. The results of real-time PCR showed that the CP, XP, and AP genes were highly expressed in leaves, followed by the stems and roots. In total, eight different individual carotenoids were identified using HPLC analysis. The highest individual and total carotenoid content were achieved in the leaves, followed by the stems and roots. This study will provide more information on the gene structure of the CP, XP, and AP genes, which may help to increase the accumulation of carotenoids in H. moellendorffii through genetic engineering. These results could be helpful for further molecular and functional studies of CP, XP, and AP genes.
Subject(s)
Heracleum , Biosynthetic Pathways/genetics , Carotenoids/metabolism , Gene Expression Regulation, Plant , Lutein , Phylogeny , Xanthophylls/metabolismABSTRACT
Chelidonium majus L. is a perennial herbaceous plant that has various medicinal properties. However, the genomic information about its carotenoid biosynthesis pathway (CBP), xanthophyll biosynthesis pathway (XBP), and apocarotenoid biosynthesis pathway (ABP) genes were limited. Thus, the CBP, XBP, and ABP genes of C. majus were identified and analyzed. Among the 15 carotenoid pathway genes identified, 11 full and 4 partial open reading frames were determined. Phylogenetic analysis of these gene sequences showed higher similarity with higher plants. Through 3D structural analysis and multiple alignments, several distinct conserved motifs were identified, including dinucleotide binding motif, carotene binding motif, and aspartate or glutamate residues. Quantitative RT-PCR showed that CBP, XBP, and ABP genes were expressed in a tissue-specific manner; the highest expression levels were achieved in flowers, followed by those in leaves, roots, and stems. The HPLC analysis of the different organs showed the presence of eight different carotenoids. The highest total carotenoid content was found in leaves, followed by that in flowers, stems, and roots. This study provides information on the molecular mechanisms involved in CBP, XBP, and ABP genes, which might help optimize the carotenoid production in C. majus. The results could also be a basis of further studies on the molecular genetics and functional analysis of CBP, XBP, and ABP genes.
ABSTRACT
BACKGROUND: Although quantitative real-time PCR (qRT-PCR) is a common and sensitive method for miRNAs analysis, it is necessary to optimize conditions and minimize qRT-PCR inhibitors to achieve reliable results. The aim of this study was to minimize interference by contaminants in qRT-PCR, maximize product yields for miRNA analyses, and optimize PCR conditions for the reliable screening of miRNAs in plasma. METHODS: The annealing temperature was first optimized by assessing amplification efficiencies. The effects of extraction conditions on levels of inhibitors that interfere with PCR were evaluated. The tested extraction conditions were the volume of the upper layer taken, number of chloroform extractions, and the inclusion of ethanol washing, a process that reduces PCR interference during RNA extraction using TRIzol. RESULTS: An acceptable amplification efficiency of RT-qPCR was achieved by the optimization of the annealing temperature of the tested miRNAs and by the collection a supernatant volume corresponding to about 50% of the volume of TRIzol with triple chloroform extraction. These optimal extraction and PCR conditions were successfully applied to plasma miRNA screening to detect biomarker candidates for the diagnosis of acute myocardial infarction. CONCLUSION: This is the first study to optimize extraction and qRT-PCR conditions, while improving miRNA yields and minimizing the loss of extracted miRNA by evaluations of the amplification efficiency.
Subject(s)
Heart Diseases/blood , Heart Diseases/diagnosis , MicroRNAs/genetics , Real-Time Polymerase Chain Reaction/methods , Biomarkers/blood , Biomarkers/metabolism , Heart Diseases/genetics , Humans , MicroRNAs/blood , MicroRNAs/isolation & purificationABSTRACT
A sensitive and specific capillary electrophoresis with laser-induced fluorescence (CE-LIF) and a simple extraction process was developed to simultaneously detect G3139 and its metabolites as a model of antisense oligonucleotides (ASOs). This method has shown excellent linearity within the tested concentration range for G3139 and its metabolites, with a detection limit of 3.0 pM and a recovery of >84.2%. Based on our developed plasma extraction method, we have evaluated the pharmacokinetics and metabolites from rat plasma after intravenous administration of G3139 at 0.76 mg/kg. The results showed that G3139 and its metabolites were successfully simultaneously detected and analyzed through a single run using CE-LIF with baseline separation until the 30-h test sampling time point. The half-life of G3139 and its metabolites was observed at 31 and 68 h, respectively. This study may provide an effective analytical method for the pharmacokinetic and metabolite evaluation required to develop ASOs to treat a variety of diseases.
Subject(s)
Oligonucleotides, Antisense , Thionucleotides , Animals , Electrophoresis, Capillary , Lasers , Oligonucleotides, Antisense/genetics , RatsABSTRACT
AIMS: The purpose of this study was to investigate the health-related quality of life (HRQOL) of patients with cardiovascular disease and its relationship to hospital readmission. METHODS: The cross-sectional study used data from 1037 adults aged ⩾19 years diagnosed with myocardial infarction or angina pectoris. Raw data were obtained from the fourth to sixth Korea National Health and Nutrition Examination Survey (2007-2014). RESULTS: Readmission was found to be associated with age, living status, education level, unemployment, individual income level, stroke, osteoarthritis, diabetes, depression, low stress level, walking days per week, and activity limitations due to cardiovascular disease. CONCLUSION: In summary, readmission was related to HRQOL among patients with myocardial infarction. Interventions that consider efforts to reduce readmission through improved diagnosis and development of systematic management of cardiovascular disease symptoms are required.
Subject(s)
Cardiovascular Diseases , Quality of Life , Adult , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/therapy , Cross-Sectional Studies , Humans , Nutrition Surveys , Patient Readmission , Republic of Korea/epidemiologyABSTRACT
Current research suggests therapy-induced senescence (TIS) of cancer cells characterized by distinct morphological and biochemical phenotypic changes represent a novel functional target that may enhance the effectiveness of cancer therapy. In order to identify novel small-molecule inducers of cellular senescence and determine the potential to be used for the treatment of melanoma, a new method of high-throughput screening (HTS) and high-contents screening (HCS) based on the detection of morphological changes was designed. This image-based and whole cell-based technology was applied to screen and select a novel class of antiproliferative agents on cancer cells, 4H-chromeno[2,3-d]pyrimidin-4-one derivatives, which induced senescence-like phenotypic changes in human melanoma A375â¯cells without serious cytotoxicity against normal cells. To evaluate structure-activity relationship (SAR) study of 4H-chromeno[2,3-d]pyrimidin-4-one scaffold starting from hit 3, a focused library containing diversely modified analogues was constructed and which led to the identification of 38, a novel compound to have remarkable anti-melanoma activity in vitro with good metabolic stability.
Subject(s)
Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Cell Proliferation/drug effects , Cellular Senescence/drug effects , Melanoma/drug therapy , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemistry , Benzopyrans/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Male , Melanoma/pathology , Mice, Inbred BALB C , Pyrimidines/chemistryABSTRACT
MicroRNAs (miRNAs) are involved in the pathogenesis of many human diseases, and various miRNAs have been reported and developed as therapeutic candidates for treating various diseases. Various miRNA and carrier modification systems have been investigated for effective systemic miRNA delivery to cells, organs, and tissues of interest. Consequently, effective and reliable analytical methods of miRNAs are required for evaluating the pharmacokinetics and biodistribution of miRNAs as therapeutic candidates. The capillary electrophoresis with laser-induced fluorescence (CE-LIF) method has been recently reported as a promising and relatively rapidly developing tool with the potential to provide highly sensitive and specific analysis of biological molecules including miRNAs. Here, the CE-LIF method was used for application in the pharmacokinetic and distribution studies of miRNA-497 as a model miRNA for a lung target; miRNA-497 hybridized with 6-FAM-labeled DNA probes were separated using CE-LIF and detected within 6 min without any interference. This method showed a wide calibration range of 1.0-50 nM and 0.1-50 nM for plasma and the four organs, liver, spleen, lung, and kidney, respectively, with acceptable precision and accuracy. Using CE-LIF, the miRNA-497 level was evaluated in rat plasma and organs after intravenously administering 1 mg ml-1 of a miRNA-497 mimic. Hence, miRNA-497 displayed a relatively short half-life of 1.76 h and was delivered to the lungs but mainly accumulated in the liver and spleen. This study evaluated the pharmacokinetics and biodistribution of the miRNA-497 mimic using CE-LIF for the first time and suggested the need for further studies to extend the half-life and conduct lung-targeted delivery of miRNA-497.
ABSTRACT
Diabetic foot ulcers represent one of the major and rising health issues, as the number of diabetic patients is increasing. MicroRNAs (miRNAs) are among various bioactive molecules under investigation for diabetic wound healing. The prolonged pro-inflammatory phase in diabetic wounds partly attributes to its non-healing nature. Therefore, we hypothesized that miRNA-497, known for its regulation of inï¬ammatory responses, would enhance diabetic wound healing. We screened miRNA candidates, including miRNA-497 in the wounded skin of streptozotocin-induced type 1 diabetic mice. The therapeutic potential of miRNA-497 mimic was studied by intradermal injection around the wound in diabetic mice. In addition, the effects of miRNA-497 on pro-inflammatory cytokines were analyzed in the wound lesion of diabetic mice, and in human dermal fibroblasts cells exposed to high glucose and lipopolysaccharide.We found a significant reduction of miRNA-497 expression in the dermal wounds of the diabetic mice relative to normal mice. Intradermal injection of miRNA-497 around the full-thickness dermal wounds in diabetic mice accelerated wound closure effectively compared to the control miRNA. miRNA-497 treatment in vivo and in vitro decreased representative pro-inflammatory cytokines such as IL-1ß, IL-6, and TNF-α. Such anti-inflammatory effects of miRNA-497 shed light on its role in accelerating diabetic wound healing. In conclusion, miRNA-497, with its down-regulation activity for pro-inflammatory cytokines, is proposed as a potential therapeutic agent for diabetic wound healing.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Diabetes Mellitus, Experimental/drug therapy , MicroRNAs/pharmacology , Wound Healing/drug effects , Animals , Cells, Cultured , Cytokines/genetics , Diabetes Mellitus, Experimental/physiopathology , Humans , Male , Mice , Mice, Inbred C57BL , MicroRNAs/analysis , MicroRNAs/physiology , Streptozocin , Wound Healing/physiologyABSTRACT
BACKGROUND: Health-related quality of life management for patients with coronary artery disease should be considered in the context of sleep and oral health, as both associated with heart health. AIM: To identify differences in health-related quality of life by sleep duration and subjective oral health among these patients and to examine factors influencing health-related quality of life. METHODS: A descriptive cross-sectional design using secondary data from the 2013 Korea Community Health Survey. Data were collected from August 16, 2013, to October 31, 2013, with 6454 adults with coronary artery disease aged 19 or older. RESULTS: We observed a significant difference in health-related quality of life by sleep duration, subjective oral health, and chewing discomfort. A hierarchical regression analysis identified factors affecting health-related quality of life: no smoking and no economic activity had negative effects, and highest level of education, having a spouse, no hypertension, no dyslipidemia, no arthritis, good subjective oral health, and no chewing discomfort had positive effects. CONCLUSION: Good subjective oral health and no chewing discomfort significantly predicted health-related quality of life among study patients. To improve health-related quality of life of these patients, promotion and education regarding regular dental clinic visits is needed to ensure early interventions.
Subject(s)
Asian People , Coronary Artery Disease/complications , Coronary Artery Disease/ethnology , Oral Health/ethnology , Quality of Life , Sleep , Adult , Aged , Coronary Artery Disease/psychology , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Republic of Korea , Smoking , Surveys and QuestionnairesABSTRACT
OBJECTIVES: The purpose of this cross-sectional study was to compare health-related quality of life (QOL) and mental health between older women with and without urinary incontinence. METHOD: This study is a secondary data analysis using raw data from 1874 women aged 65 years or older who participated in the Korea National Health and Nutrition Examination Survey (KNHANES) IV (2008-2009), a nationally representative sample. RESULTS: In the pain/discomfort dimension of the EuroQol-5, 25.4% of the participants experienced urinary incontinence and 14.7% did not (p = .001). In the anxiety/depression dimension, urinary incontinence was present in 8.3% of the participants and absent in 3.6% (p = 0.012). In addition, the results of an ANCOVA showed that scores in both the EuroQol visual analogue scale and the EQ-5D index were significantly lower in participants with urinary incontinence relative to those without. The risk of stress and depression in older women with urinary incontinence was approximately 2 and 1.5 times higher, respectively, than that of participants without urinary incontinence. CONCLUSION: Health-related QOL in older women with urinary incontinence was relatively low, while levels of stress and depression were high. Therefore, in order to improve QOL and mental health in older women, the understanding and management of urinary incontinence interventions is required.
Subject(s)
Mental Health , Quality of Life , Urinary Incontinence/psychology , Aged , Aged, 80 and over , Anxiety/psychology , Case-Control Studies , Cross-Sectional Studies , Depression/psychology , Female , Health Status , Humans , Male , Psychiatric Status Rating Scales , Republic of Korea/epidemiology , Surveys and Questionnaires , Urinary Incontinence/epidemiology , Urinary Incontinence/physiopathologyABSTRACT
The improvement of the quality of life (QOL) of children with disabilities has been considered important. Therefore, the Special Needs Education Assessment Tool (SNEAT) was developed based on the concept of QOL to objectively evaluate the educational outcome of children with disabilities. SNEAT consists of 11 items in three domains: physical functioning, mental health, and social functioning. This study aimed to verify the reliability and construct validity of SNEAT using 93 children collected from the classes on independent activities of daily living for children with disabilities in Okinawa Prefecture between October and November 2014. Survey data were collected in a longitudinal prospective cohort study. The reliability of SNEAT was verified via the internal consistency method and the test-pretest method; both the coefficient of Cronbach's α and the intra-class correlation coefficient were over 0.7. The validity of SNEAT was also verified via one-way repeated-measures ANOVA and the latent growth curve model. The scores of all the items and domains and the total scores obtained from one-way repeated-measures ANOVA were the same as the predicted scores. SNEAT is valid based on its goodness-of-fit values obtained using the latent growth curve model, where the values of comparative fit index (0.983) and root mean square error of approximation (0.062) were within the goodness-of-fit range. These results indicate that SNEAT has high reliability and construct validity and may contribute to improve QOL of children with disabilities in the classes on independent activities of daily living for children with disabilities.
Subject(s)
Disabled Children/education , Education, Special , Educational Measurement , Child , Female , Humans , Male , Reproducibility of ResultsABSTRACT
New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.
Subject(s)
Adenosine Triphosphate/biosynthesis , Electron Transport Complex III/antagonists & inhibitors , Extensively Drug-Resistant Tuberculosis/drug therapy , Imidazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Piperidines/pharmacology , Pyridines/pharmacology , Animals , Cell Proliferation/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Electron Transport Complex III/genetics , Imidazoles/pharmacokinetics , Mice , Mice, Inbred BALB C , Piperidines/pharmacokinetics , Pyridines/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: Authors aimed to determine the targeting ability of vascular endothelial growth factor receptor 2 (VEGFR2)-conjugated quantum dots (QDs) in vitro, and apply it for a xenograft prostate cancer mouse model. MATERIALS AND METHODS: Conjugation reaction of QDs was performed by using the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and sulfo-(N-hydroxysulfosuccinimide) (Sulfo-NHS). The human umbilical vein cord endothelial cells (HUVECs) were incubated with QDs, conjugated with antiVGFR2, to see a specific binding in vitro. Fluorescent cell images were taken by a confocal microscope. The human prostate cancer cells (PC3) were injected to five nude mice on hind limbs to make the xenograft tumor model. QD-antiVEGFR2 antibody complex was injected into the tumor model and fluorescence measurements were performed at 1, 4, 9, 12, 15, and 24 hours after the injection. RESULTS: The specific interaction between HUVECs and QD-antiVEGFR2 antibody was clearly shown in vitro. The in vivo fluorescence image disclosed that there was an increased signal of tumor, 12 hours after the injection of QDs. CONCLUSION: By showing endothelial cells binding with QDs-antiVEGFR2 antibodyand an experimental application of the antibody for VEGFR2 imaging in the prostate cancer xenograft mouse model, we suggests that the antibody-conjugated QDs can be a potential imaging tool for angiogenesis of the cancer.
Subject(s)
Neovascularization, Pathologic/pathology , Prostatic Neoplasms/pathology , Quantum Dots , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Carbodiimides/pharmacology , Cell Line, Tumor , Disease Models, Animal , Electrophoresis, Agar Gel , Fluorescence , In Vitro Techniques , Male , Mice , Mice, Nude , Microscopy, Confocal , Succinimides/pharmacology , Transplantation, HeterologousABSTRACT
BACKGROUND: This study proposed a desirable direction for the future development of the Korean Journal of Family Medicine (KJFM) by comparing with the overseas SCI journals, Family Medicine (FM) and The Journal of Family Practice (JFP) based on the statistical viewpoints. METHODS: All of the original articles published in KJFM from January 1981 to June 2011, FM from January 1998 to June 2011, and JFP from January 1978 to June 2011, were reviewed and compared in terms of content, data size, research design, and statistical method. RESULTS: Of 3,226 total original articles, KJFM published 1,549, FM 322, and JFP 1,355, respectively. Both JFP and KJFM mainly focused on biomedical topics (67.2% and 61.7%), while FM focused on education (55.9%). Most of the studies in three journals used the data size of between 100 to 300 cases. The most frequently used research design was cross-sectional, FM 66.8%, JFP 58.4%, and KJFM 72.4%, respectively. The statistical methods in KJFM were gradually diversified. CONCLUSION: The quality of the original articles in KJFM has been improved over the years, but still has conducted based on the relatively weak research designs. Under the circumstances that the higher ranked SCI journals demand the prospective design and large size of data, and most researchers in Korea could not use the large scaled prospective data, we need to collaborate to accumulate the small sized data sets and try to make a registry. More refined statistical method such as a propensity score matching analysis for retrospective data could be an alternative.