ABSTRACT
OBJECTIVES: Non-immune hydrops fetalis (NIHF) is the pathological accumulation of fluids in fetal compartments, without maternal isoimmunization. Fetal interventions (e.g. shunting, fetal paracentesis, fetal thoracocentesis, fetal pleurodesis) are used to alleviate fluid accumulations, but the outcome is uncertain because the underlying causes of NIHF vary. We aimed to explore the etiology and long-term outcome of NIHF after fetal intervention. METHODS: This was a retrospective review of fetuses with NIHF, defined by the presence of fetal ascites, pleural or pericardial effusion, skin edema or cystic hygroma, or a combination of these features, who underwent intervention at our institution during the period 2012-2021. Clinical surveillance, genetic analysis and viral infection screening were used to define the etiology. Chart reviews and telephone interviews were conducted to assess the long-term outcomes. RESULTS: In total, 55 fetuses were enrolled and 46 cases had final follow-up data after delivery. Etiology was identified in 33 cases, including four for which the underlying causes were not identified initially using small-gene-panel tests but which were later diagnosed with monogenic disorders by whole-exome sequencing (WES). Twenty-three cases with follow-up survived, having a follow-up period of 2-11 years at the time of writing, of which 17 were healthy. All 11 cases initially presenting as congenital chylothorax survived with favorable outcome. CONCLUSIONS: The etiologies of NIHF are heterogeneous, and the long-term (spanning 2-11 years) outcome of fetal intervention varies, according to the underlying etiology, with cases caused by congenital chylothorax having the best prognosis. Genome-wide tests, such as WES, may be helpful in determining the underlying condition in cases caused by a genetic disorder, and this may affect fetal therapy approaches in the future. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Chylothorax , Pleural Effusion , Pregnancy , Female , Humans , Hydrops Fetalis/etiology , Hydrops Fetalis/genetics , Ascites/diagnostic imaging , Ascites/etiology , Retrospective Studies , Chylothorax/complications , Pleural Effusion/etiology , Pleural Effusion/complicationsSubject(s)
Cleft Lip , Cleft Palate , Pregnancy , Female , Humans , Cleft Palate/diagnostic imaging , Deglutition , Ultrasonography , Prenatal CareABSTRACT
OBJECTIVE: Rehabilitation of disabled children with autism has become a challenge for current rehabilitation centres. This study conducted psychological investigations on disabled children and analysed the symptoms and characteristics of autism in these children to develop more reasonable rehabilitation treatment plans that would help the children receive psychological counselling and effective rehabilitation. SUBJECTS AND METHODS: This study investigated 107 disabled children from the Disabled Rehabilitation Research Centre of the South China Minority Autonomous Region. Using the PEP-3 scale as a research tool, a questionnaire was developed to investigate and collect data on the mental health of disabled children. The survey was conducted from 2017 to 2021, and 107 children's mental health data were collected in the form of questionnaires based on PEP-3 evaluation indicators. After cleaning the data, the questionnaire data were screened and processed. Descriptive statistical and correlation analysis tools were used for model analysis to understand the overall data distribution and the potential relationships among various data variables. RESULTS: The results of correlation analysis showed that cognition, language expression, language understanding, emotion, and social interaction in the subtest of developmental behaviour were the main indicators of the degree of autism in children. These indicators had a strong and significant correlation with the comprehensive score. Moreover, these indicators had a significant correlation with the individual self-care and adaptive behaviours reported by the children's caregivers. Small muscles, big muscles, and imitation (vision and movement) indicators had a significant correlation with problematic behaviours and physical fitness, and language and cognitive indicators also had a strong correlation with emotion and social interaction. CONCLUSIONS: Emphasis should be placed on the improvement of the language and cognitive abilities of disabled children with autism, and corresponding rehabilitation plans, and training can be formulated according to children with different degrees of illness to get a better rehabilitation outcome. Further, identification of key indicators of autism will be of help in aiding the development of rehabilitation treatment for disabled children with autism and formulation of long-term rehabilitation plans.
Subject(s)
Autistic Disorder , Disabled Children , Adaptation, Psychological , Caregivers , Child , Humans , Surveys and QuestionnairesABSTRACT
Essentials Uncertainty remains about antiplatelets for vascular access patency in hemodialysis patients. 95 971 people under hemodialysis were followed in a claims database in Taiwan. Aspirin reduced vascular access failure rate and did not increase major bleeding rate. Clopidogrel, Aggrenox, and warfarin might increase major bleeding rate. SUMMARY: Background Dialysis adequacy is a major determinant of survival for patients with end-stage renal disease. Good vascular access is essential to achieve adequate dialysis. Objectives This study evaluated the impacts of different drugs on the vascular access failure rate of an arteriovenous fistula or an arteriovenous graft and the rate of major bleeding in hemodialysis patients. Patients and methods We studied patients with end-stage renal disease registered in the Taiwan National Health Insurance program from 1 January 1997 to 31 December 2012. A total of 95 971 patients were enrolled in our study. Vascular access dysfunction was defined as the need for thrombectomy or percutaneous angioplasty. Major bleeding was defined as emergency department visits or hospitalization with a primary diagnosis of gastrointestinal bleeding or intracerebral hemorrhage. The adjusted odds ratios between person-quarters with or without antiplatelet or oral anticoagulant use were calculated using a generalized estimating equation. Results The odds ratio of vascular access failure was 0.21 (0.11-0.39) for aspirin, 0.76 (0.74-0.79) for clopidogrel, 0.67 (0.59-0.77) for dipyridamole, 0.67 (0.53-0.86) for Aggrenox and 0.96 (0.90-1.03) for warfarin. The highest odds ratio for intracerebral hemorrhage was 5.33 (1.25-22.72) in younger patients using Aggrenox. The highest odds ratio for gastrointestinal bleeding was 1.34 (1.10-1.64) for clopidogrel. Conclusion Antiplatelet agents, but not warfarin, might reduce the vascular access thrombosis rate. The gastrointestinal bleeding rate was increased in the group using clopidogrel. Aggrenox should be used with caution in young individuals because it might increase the rate of intracerebral hemorrhage.
Subject(s)
Anticoagulants/therapeutic use , Arteriovenous Shunt, Surgical/adverse effects , Blood Vessel Prosthesis Implantation/adverse effects , Graft Occlusion, Vascular/prevention & control , Kidney Failure, Chronic/therapy , Platelet Aggregation Inhibitors/therapeutic use , Renal Dialysis , Thrombosis/prevention & control , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Aspirin/therapeutic use , Aspirin, Dipyridamole Drug Combination/therapeutic use , Clopidogrel/therapeutic use , Databases, Factual , Female , Gastrointestinal Hemorrhage/chemically induced , Graft Occlusion, Vascular/diagnosis , Graft Occlusion, Vascular/etiology , Humans , Intracranial Hemorrhages/chemically induced , Kidney Failure, Chronic/diagnosis , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Protective Factors , Retrospective Studies , Risk Assessment , Risk Factors , Taiwan , Thrombosis/diagnosis , Thrombosis/etiology , Treatment Failure , Warfarin/therapeutic use , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Fabry disease is an X-linked disease, and enzyme-based screening methods are not suitable for female patients. METHODS: In total, 1000 young stroke patients (18-55 years, 661 with ischaemic stroke and 339 with hypertensive intracerebral hemorrhage) were recruited. The Sequenom iPLEX assay was used to detect 26 Fabry related mutation genes. The frequency of Fabry disease in young stroke was reviewed and compared between Asian and non-Asian countries. RESULTS: Two male patients with ischaemic stroke were found to have a genetic mutation of IVS4+919G>A. There was no α-galactosidase A (GLA) gene mutation in female patients. The frequency in Asian stroke patients was 0.62% (male vs. female 0.63% vs. 0.58%) with 0.72% for ischaemic stroke and none for hemorrhagic stroke, compared to 0.88% (0.77% vs. 1.08%) with 0.83% for ischaemic stroke and 1.40% for hemorrhagic stroke reported in western countries. CONCLUSION: IVS4+919G>A is the GLA mutation in Taiwanese young ischaemic stroke patients. Fabry disease is more frequent among non-Asian patients compared to Asian patients.
Subject(s)
Brain Ischemia/genetics , Fabry Disease/diagnosis , Fabry Disease/genetics , Genetic Testing , Stroke/genetics , Adolescent , Adult , Age Factors , Brain Ischemia/epidemiology , Fabry Disease/epidemiology , Female , Humans , Male , Middle Aged , Stroke/epidemiology , Taiwan/epidemiology , Young AdultABSTRACT
Q fever (QF) is a worldwide zoonosis associated with outbreaks. Only a few nationwide studies regarding the surveillance and epidemiology of human QF have been reported. Although QF is endemic in Taiwan, a nationwide database investigation of the epidemiology and characteristics of QF and its associations with scrub typhus (ST), murine typhus (MT) and leptospirosis (LS) has never been reported. We analysed nationwide databases of suspected QF, ST, MT and LS cases from October 2007 to December 2014 obtained from the Centers for Disease Control, Taiwan. A total of 468 (4.2%) QF cases were identified among 11 109 suspected QF cases. QF cases were mainly distributed in the southern and Kaohsiung-Pingtung regions but rarely in the eastern region. Compared to non-QF cases, QF cases had significantly higher percentages of males (88.7 versus 66.2%) and high-risk occupations (farming, animal husbandry or veterinary medicine) (16.2 versus 10.5%). But the percentages of specific animal contact, including cattle (0.6 versus 0.8%) and goats (0.9 versus 1.0%), were low in both. The majority of suspected QF cases (89.4%) were simultaneously suspected with ST, MT or LS, and the combinations of suspected diseases differed between regions. The number of suspected QF cases from the eastern region decreased since 2009, which was not observed in other regions. A total of 1420 (12.8%) cases had confirmed diseases, including QF (453, 4.1%), QF+ST (7, 0.06%), QF+MT (4, 0.04%), QF+LS (4, 0.04%), MT (186, 1.7%), ST (545, 4.9%), ST+LS (11, 0.1%) and LS (210, 1.9%). Compared to cases of unknown disease, QF cases had larger percentages of high-risk occupations (16.2 versus 9.6%) but similar histories of animal contact (29.8 versus 25.1%). QF is an endemic disease in southern Taiwan. It is difficult to differentiate QF from ST, MT or LS only by high-risk occupations and history of animal contact, and co-infection of QF with these diseases should be considered.
Subject(s)
Coinfection/epidemiology , Leptospirosis/complications , Q Fever/complications , Scrub Typhus/complications , Taiwan/epidemiology , Typhus, Endemic Flea-Borne/complications , Adult , Aged , Animals , Coinfection/microbiology , Databases, Factual , Female , Humans , Leptospirosis/epidemiology , Male , Middle Aged , Scrub Typhus/epidemiology , Typhus, Endemic Flea-Borne/epidemiology , ZoonosesABSTRACT
The new allele B*39:01:15 differs from B*39:01:01 by a point mutation at position 315 (G>T) of exon 2.
Subject(s)
Alleles , Arthritis, Rheumatoid/genetics , HLA-B39 Antigen/genetics , Point Mutation , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Base Sequence , Codon , Exons , HLA-B39 Antigen/immunology , Histocompatibility Testing , Humans , Molecular Sequence Data , Sequence Alignment , Sequence Analysis, DNA , TaiwanABSTRACT
Tigecycline (TGC)-resistant extensively drug-resistant Acinetobacter baumannii (XDRAB) is an increasing threat in regard to nosocomial infections. The resistance-nodulation-cell division (RND) efflux pump has played an important role in TGC resistance. In this study, total 81 TGC-resistant XDRAB isolates were analyzed for their responses to the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP). We found that NMP could reduce by 4-fold or greater than 4-fold the minimum inhibitory concentration (MIC) of TGC in 45 isolates (55.6 %). After typing with pulsed-field gel electrophoresis (PFGE), group A appeared to be the major cluster with good synergistic response to NMP. Transcripts of the AdeABC efflux pump gene were consistently more correlated with TGC resistance than transcripts of the AdeFGJ or AdeIJK efflux pump genes in these isolates. Of the 81 isolates, the amino acid sequences of AdeR and AdeS were further classified and combined into 31 different codes. Although the dissemination of TGC-resistant XDRAB isolates was genetically diverse in our hospital, their responses to NMP conversion were still strain-dependent. We found that AdeRS combination codes were better than PFGE typing in separating groups of isolates with different sensitivity to NMP conversion.
Subject(s)
Acinetobacter Infections/microbiology , Acinetobacter baumannii/drug effects , Bacterial Proteins/genetics , Membrane Transport Proteins/genetics , Minocycline/analogs & derivatives , Acinetobacter baumannii/genetics , Acinetobacter baumannii/isolation & purification , Acinetobacter baumannii/metabolism , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Drug Resistance, Multiple, Bacterial , Electrophoresis, Gel, Pulsed-Field , Humans , Membrane Transport Proteins/metabolism , Microbial Sensitivity Tests , Minocycline/pharmacology , TigecyclineABSTRACT
BACKGROUND AND PURPOSE: Our aim was to investigate the influence of admission dehydration on the discharge outcome in acute ischaemic and hemorrhagic stroke. METHODS: Between January 2009 and December 2011, 4311 ischaemic and 1371 hemorrhagic stroke patients from the stroke registry of Chang Gung healthcare system were analyzed. The eligible patients were identified according to inclusion/exclusion criteria. In total, 2570 acute ischaemic and 573 acute hemorrhagic stroke patients were finally recruited. According to the blood urea nitrogen (BUN) to creatinine (Cr) ratio (BUN/Cr), these patients were divided into dehydrated (BUN/Cr ≥ 15) and non-dehydrated (BUN/Cr < 15) groups. Demographics, admission costs and discharge outcomes including modified Rankin scale (mRS) and Barthel index (BI) were examined. Data were analyzed using multivariate analysis of two-stage least squares including logistic and linear regression. RESULTS: Acute ischaemic stroke with admission dehydration had higher infection rates (P = 0.006), worse discharge BI (62.8 ± 37.4 vs. 73.4 ± 32.4, P < 0.001, adjusted P < 0.001), worse mRS (2.7 ± 1.6 vs. 2.3 ± 1.5, P < 0.001, adjusted P = 0.009) and higher admission costs (2470.8 ± 3160.8 vs. 1901.2 ± 2046.8 US dollars, P < 0.001, adjusted P = 0.013) than those without dehydration. However, acute hemorrhagic stroke with or without admission dehydration showd no difference in admission costs (P = 0.618) and discharge outcomes (BI, P = 0.058; mRS, P = 0.058). CONCLUSION: Admission dehydration is associated with worse discharge outcomes and higher admission costs in acute ischaemic stroke but not in hemorrhagic stroke.
Subject(s)
Brain Ischemia/complications , Dehydration , Hospitalization/economics , Patient Admission/economics , Stroke/etiology , Aged , Aged, 80 and over , Costs and Cost Analysis , Female , Humans , Male , Middle Aged , Patient Discharge , Predictive Value of Tests , Registries , Retrospective Studies , Severity of Illness Index , Statistics, Nonparametric , Treatment OutcomeABSTRACT
Drug addiction behavior that is established and maintained by psychostimulants has been shown to be associated with the expression of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine (DA) system. Cocaine has been used for most prior studies testing this effect of psychostimulants and therefore relatively little is known about its counterpart amphetamine (AMP). To fill this gap, the present study was designed to test whether BDNF mRNA expression levels in the DA terminal regions were changed specifically by d-AMP-induced conditioned place preference (CPP) followed by drug-primed reinstatement. The dose of d-AMP, 1mg/kg, was confirmed to significantly induce CPP. Using this dose, a group of rats was initially subjected to d-AMP CPP, which was followed by entry into an extinction protocol with an additional 3-day withdrawal before a drug-primed reinstatement test was carried out. Following extinction of d-AMP CPP, a lower dose of d-AMP, namely 0.75mg/kg, was able to significantly reinstate CPP. The BDNF mRNA levels in the selected brain areas were determined by real-time polymerase chain reaction (PCR) after the CPP and reinstatement. The BDNF mRNA level in the medial prefrontal cortex (mPFC) was significantly increased after the reinstatement, but not the CPP test. And, none of the other four assessed brain areas showed any change in BDNF mRNA level after d-AMP CPP or reinstatement. These findings support the notion that BDNF is involved in drug-seeking behavior and indicate that d-AMP reinstatement after extinction may be linked to an increase in BDNF mRNA expression in the mPFC.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Conditioning, Psychological/drug effects , Dextroamphetamine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Animals , Brain-Derived Neurotrophic Factor/genetics , Extinction, Psychological/drug effects , Male , RNA, Messenger/metabolism , Rats , Rats, WistarABSTRACT
BACKGROUND: Functional outcome and the risk factors for stroke survivors have explored in previous study. However, a comprehensive understanding of the patterns and critical risk factors of functional recovery is limited. AIM: To explore the trajectory groups and determinants of functional recovery for ischemic stroke patients during 1 year after stroke. DESIGN: Longitudinal study. SETTING: Inpatient. POPULATION: First-time stroke patients. METHOD: A total of 367 first-time ischemic stroke patients from the Stroke Registry in the Chang Gung Hospital (SRICH) database were analyzed in this study. Study variables comprised demographic and disease characteristics, laboratory data, and functional outcome. The Latent Class Growth Analysis (LCGA) was used to identify various trajectory clusters and multinomial logistic regression was used to identify the predictors of functional recovery. RESULT: Five trajectory clusters of functional recovery were identified using the Barthel Index. Among five clusters of functional recovery, nearly 18% of first-ever ischemic stroke patients maintained functional dependence, whereas 82% of stroke patients demonstrated functional recovery; and the significant recovery time totaled three months after the stroke. Determinants for various trajectory clusters of functional recovery were body mass index and serum albumin level, especially a higher serum albumin concentration predicted a more favorable functional recovery. CONCLUSION: Our findings suggest that diverse functional recovery clusters persisted and serum albumin concentration at admission was a critical assessment factor. CLINICAL REHABILITATION: Such information could be useful for identifying the different rehabilitation needs of varying trajectory groups and for effectively improving functional ability among the ischemic stroke population.
Subject(s)
Albumins/analysis , Recovery of Function , Stroke Rehabilitation , Age Factors , Aged , Analysis of Variance , Biomarkers/blood , Chi-Square Distribution , Comorbidity , Female , Humans , Length of Stay , Logistic Models , Longitudinal Studies , Male , Middle Aged , TaiwanABSTRACT
Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-â£miRNA-520h-â£PP2A/C-â£Akt â NF-κB â FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , MicroRNAs/genetics , Stilbenes/pharmacology , Animals , Cell Line , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Disease Progression , Down-Regulation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/genetics , Female , HEK293 Cells , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, SCID , MicroRNAs/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Protein Phosphatase 2/genetics , Protein Phosphatase 2/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Resveratrol , Xenograft Model Antitumor AssaysABSTRACT
Hashimoto disease (HD) is an autoimmune thyroid disease resulting from complex interactions between genetic and environmental factors. The human leukocyte antigen (HLA) gene has been established to be involved in the susceptibility to HD. We aim to investigate the associations between HLA-B alleles and Han Chinese children with HD by both case-control and family-based studies. A total of 108 unrelated children with HD, 380 unrelated healthy controls, 58 trios of affected patients and their parents, and 75 trios of unaffected siblings and their parents were recruited. HLA-B genotyping was performed by polymerase chain reaction and detected with a sequence-specific oligonucleotide probes system. We found that B*46:01 allele (OR = 2.31, 95% CI 1.60-3.34, P(c) = 9.99 × 10(-5)) and carrier (OR = 3.28, 95% CI 2.10-5.11, P(c) = 1.35 × 10(-6)) were associated with HD risk. Transmission/disequilibrium test further confirmed an overtransmission of the B*46:01 (OR 2.55, 95% CI 1.36-6.10, P = 6.5 × 10(-3)). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-B*46:01 confers susceptibility to HD in Han Chinese children. Further studies with larger children cohort are required to confirm the role of B*46:01 in the development of HD.
Subject(s)
Asian People , Genetic Predisposition to Disease , HLA-B Antigens/genetics , Hashimoto Disease/genetics , Polymorphism, Genetic , Adolescent , Adult , Alleles , Case-Control Studies , Child , Child, Preschool , Family , Female , Gene Frequency , HLA-B Antigens/immunology , Haplotypes , Hashimoto Disease/immunology , Histocompatibility Testing , Humans , Linkage Disequilibrium , Male , Middle Aged , SiblingsABSTRACT
Graves disease (GD) is an autoimmune thyroid disease with a female preponderance and a wide range of ages at onset, and human leukocyte antigen (HLA) gene plays a primary role in the susceptibility to GD. We aim to investigate the associations between HLA-DRB1 alleles and Taiwanese children with GD by both case-control and family-based studies. A total of 241 unrelated children with GD, 539 healthy controls, 115 trios of affected patients and their parents, and 121 trios of unaffected siblings and their parents were recruited. HLA-DRB1 genotyping was performed by polymerase chain reaction and sequence-based typing assays. We found that DRB1*09:01 (OR=2.60, 95% CI 2.02-3.35, Pc=6.55×10(-13)) was associated with GD risk, while DRB1*12:02 (OR=0.32, 95% CI 0.20-0.53, Pc=4.55×10(-5)) was protective against GD. Transmission/disequilibrium test further confirmed an overtransmission of the DRB1*09:01 (OR 3.37, 95% CI 2.13-6.22, Pc=1.0×10(-5)) and an undertransmission of the DRB1*12:02 (OR 0.21, 95% CI 0.05-0.42, Pc=1.7×10(-3)). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-DRB1*09:01 confers susceptibility to GD and DRB1*12:02 exerts protection against GD development in Taiwanese children.
Subject(s)
Genetic Predisposition to Disease , Graves Disease/genetics , Graves Disease/immunology , HLA-DRB1 Chains/genetics , Adolescent , Alleles , Amino Acids/genetics , Case-Control Studies , Child , Child, Preschool , Family , Female , Gene Frequency/genetics , Humans , Linkage Disequilibrium/genetics , Male , Siblings , Taiwan/ethnology , Young AdultABSTRACT
BACKGROUND: Activating mutations of Fms-like tyrosine kinase 3 (FLT3) constitute a major driver in the pathogenesis of acute myeloid leukaemia (AML). Hence, pharmacological inhibitors of FLT3 are of therapeutic interest for AML. METHODS: The effects of inhibition of FLT3 activity by a novel potent FLT3 inhibitor, BPR1J-097, were investigated using in vitro and in vivo assays. RESULTS: The 50% inhibitory concentration (IC(50)) of BPR1J-097 required to inhibit FLT3 kinase activity ranged from 1 to 10 nM, and the 50% growth inhibition concentrations (GC(50)s) were 21±7 and 46±14 nM for MOLM-13 and MV4-11 cells, respectively. BPR1J-097 inhibited FLT3/signal transducer and activator of transcription 5 phosphorylation and triggered apoptosis in FLT3-driven AML cells. BPR1J-097 also showed favourable pharmacokinetic property and pronounced dose-dependent tumour growth inhibition and regression in FLT3-driven AML murine xenograft models. CONCLUSION: These results indicate that BPR1J-097 is a novel small molecule FLT-3 inhibitor with promising in vivo anti-tumour activities and suggest that BPR1J-097 may be further developed in preclinical and clinical studies as therapeutics in AML treatments.
Subject(s)
Benzamides/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Benzamides/chemistry , Benzamides/pharmacology , Cell Proliferation/drug effects , HEK293 Cells/drug effects , Humans , Indazoles/pharmacology , Inhibitory Concentration 50 , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Male , Mice , Mice, Nude , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
BACKGROUND: Accumulating evidence indicates that oestrogens have significant direct effects on normal prostate development and carcinogenesis. The majority of the biological activities of oestrogens are mediated through the oestrogen receptor (ER), which functions as a hormone-inducible transcription factor to regulate target gene expression by binding to oestrogen response elements (EREs) in the regulatory regions of target genes. Sequence variants in EREs might affect the ER-ERE interaction and subsequent physiological activities. Therefore, we tested whether common single-nucleotide polymorphisms (SNPs) inside EREs are related to the clinical outcomes of androgen-deprivation therapy (ADT) in men with prostate cancer. METHODS: We systematically evaluated 49 ERE SNPs predicted using a genome-wide database in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed using Kaplan-Meier analysis and a Cox regression model. RESULTS: Based on multiple hypothesis testing, BNC2 rs16934641 was found to be associated with disease progression; in addition, TACC2 rs3763763 was associated with PCSM, and ALPK1 rs2051778 and TACC2 rs3763763 were associated with ACM. These SNPs remained significant in multivariate analyses that included known clinicopathological predictors. Moreover, a combined genotype effect on ACM was observed when ALPK1 rs2051778 and TACC2 rs3763763 were analysed in combination. Patients with a greater number of unfavourable genotypes had a shorter time to ACM during ADT (P for trend <0.001). CONCLUSION: The incorporation of ERE SNPs into models with known predictors might improve outcome prediction in patients with prostate cancer receiving ADT.
Subject(s)
Androgen Antagonists/therapeutic use , Androgens/genetics , Estrogens/genetics , Prostate/metabolism , Prostatic Neoplasms , Receptors, Estrogen/genetics , Aged , Antineoplastic Agents, Hormonal/therapeutic use , Databases, Genetic , Disease Progression , Gene Expression Regulation , Genome-Wide Association Study , Humans , Kaplan-Meier Estimate , Male , Polymorphism, Single Nucleotide , Proportional Hazards Models , Prostate/pathology , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/etiology , Prostatic Neoplasms/metabolism , Transcription Factors/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
BACKGROUND: Activated androgen receptor binds to androgen-responsive elements (AREs) in genome to regulate target gene transcription and, consequently, mediates physiological or tumorigenic processes of the prostate. Our aim was to determine whether genetic variants in AREs are associated with clinical outcomes after androgen-deprivation therapy (ADT) in prostate cancer patients. PATIENTS AND METHODS: We systematically investigated 55 common single-nucleotide polymorphisms (SNPs) in the genome-wide insilico-predicted AREs in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed by Kaplan-Meier analysis and Cox regression model. RESULTS: In univariate analysis, two, five, and four SNPs were associated with disease progression, PCSM, and ACM, respectively. After adjusting for known prognostic factors, ARRDC3 rs2939244, FLT1 rs9508016, and SKAP1 rs6504145 remained as significant predictors for PCSM and FBXO32 rs7830622 and FLT1 rs9508016 remained as significant predictors for ACM in multivariate analysis. Moreover, strong combined genotype effects on PCSM and ACM were also observed (P(trend) < 0.001). CONCLUSION: Our results suggest that SNPs in AREs influence prostate cancer survival and may further advance our understanding of the disease progression.
Subject(s)
Arrestins/genetics , Phosphoproteins/genetics , Polymorphism, Single Nucleotide , Prostatic Neoplasms/genetics , Receptors, Androgen/genetics , Vascular Endothelial Growth Factor Receptor-1/genetics , Aged , Androgen Antagonists/therapeutic use , Genotype , Humans , Kaplan-Meier Estimate , Male , Neoplasm Staging , Prognosis , Proportional Hazards Models , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Response Elements/geneticsABSTRACT
AIMS: Viral pathogens in environmental media are generally highly diffuse, yet small quantities of pathogens may pose a health risk. This study evaluates the ability of TransPlex™ whole transcriptome amplification (WTA) to amplify small quantities of RNA viruses from complex environmental matrices containing background nucleic acids. METHODS AND RESULTS: DNA extracts from mock drinking water samples containing mixed microbial populations were spiked with small quantities of echovirus type 13 (EV) RNA. Samples were amplified using a Transplex™ WTA kit, and EV-specific quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify target pathogens before and after application of WTA. Samples amplified by WTA demonstrated a decreased limit of detection. The log-linear relationship between serial dilutions was maintained following amplification by WTA. CONCLUSIONS: WTA is able to increase the quantity of target organism RNA in mixed populations, while maintaining log linearity of amplification across different target concentrations. SIGNIFICANCE AND IMPACT OF THE STUDY: WTA may serve as an effective preamplification step to increase the levels of RNA prior to detection by other molecular methods such as PCR, microarrays and sequencing.
Subject(s)
Enterovirus B, Human/isolation & purification , RNA, Viral/analysis , Water Microbiology , Enterovirus B, Human/genetics , Gene Expression Profiling/methods , Polymerase Chain Reaction , RNA, Viral/genetics , Water SupplyABSTRACT
AIMS/HYPOTHESIS: The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8(+) T cells. METHODS: We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8(+) T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice). RESULTS: TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes. CONCLUSIONS/INTERPRETATION: TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.