Molecular simulation screening and sensory evaluation unearth a novel kokumi compound with bitter-masking effect: N-lauroyl-L-tryptophan.

N-lauroyl-L-tryptophan (LT), which has the strongest potential flavor-presenting activity, was skillfully screened from numerous N-Lau-AAs docked to different taste receptors by molecular simulation techniques. Subsequently, LT was synthesized employing food-grade commercial enzymes and structurally characterized, the optimized yields of LT could reach 69.08%, 76.16%, and 50.40%, respectively. Sensory and E-tongue evaluations showed that LT at 1 mg/L significantly benefited the performance of different taste sensations and exhibited different bitter taste masking effects: L-Ile (68.42%), L-Trp (68.18%), D-salicylic acid (48.48%) and quinine (35.00%). The molecular docking results illustrated that LT had a high affinity for various taste receptors, dominated by hydrogen bonding and hydrophobic interactions. This work provided a rare systematic elucidation of the potential and mechanism of enzymatically synthesized LT in enhancing taste properties. It provides novel insights into the directions and strategies for the excavation and innovation of flavor enhancers and food flavors.

Research misconduct knowledge and associated factors among nurses in China: A national cross-sectional survey.

AIM: To measure the knowledge level of research misconduct and explore its associated factors among nurses. BACKGROUND: Engagement in research misconduct by nurses may transfer to professional misconduct in the clinical setting, thereby jeopardizing the quality of patient care. We still know little about the research misconduct situation among nurses. Previous attempts also hardly reflected participants' real knowledge level of research misconduct. METHODS: We applied multistage sampling (province, hospital, and participants) in this cross-sectional survey, and recruited 4112 nurses from 200 tertiary hospitals in 25 provinces. RESULTS: The average knowledge score of the participants was 15.99 ± 5.79. Associated factors of scientific misconduct knowledge score included career situation, educational level, fertility status, research activities index, and perceived consequences for research misconduct. CONCLUSION: It is urgent and necessary to design continuing research integrity training for nurses. Hospital managers and policy-makers should pay more attention to key trainees, including newcomers, nurses from less developed groups and institutions, and those from clinical departments. Training designers should also consider how to help nurses with offspring balance their family and work, and should not neglect the training for nurses with extensive research experience. In addition to conveying knowledge and information, the training can integrate cognitive education of research misconduct to improve the effect.

Knowledge, attitude and behaviour to evidence-based practice among psychiatric nurses: A cross-sectional survey.

Objective: To identify the status of knowledge, attitude, and behaviour toward evidence-based practice (EBP) among Chinese psychiatric nurses, and to examine the influencing factors of EBP behaviour. Methods: We utilised a cross-sectional design. A total of 923 psychiatric nurses from 168 hospitals in 27 provinces in the mainland of China participated in our survey. The EBP questionnaire, the barriers to research utilisation scale and the facilitators to research utilisation scale were used for data collection via WeChat group from July 2018 to April 2019. Multiple regression analysis was used to analyse the influencing factors of psychiatric nurses' evidence-based practice behaviour. Results: The score of Chinese psychiatric nurses' EBP attitude, behaviour and knowledge were 4.81 ± 1.34, 4.11 ± 1.36 and 3.53 ± 1.29, respectively. Multiple regression analysis showed that nurses' EBP behaviour was mainly determined by knowledge and attitude, which together explained 61.8% of the variance. The two top barriers were the dimensions of presentation and research. Facilitators include managerial support, employing nurses with research skills as models and providing advanced education on evidence-based nursing. Conclusion: Psychiatric nurses have positive attitudes toward EBP, but their level of knowledge and behaviour is insufficient. Heavy workload, insufficient time, and a lack of knowledge and skills is the main barrier. Managerial support, employing nurses with research skills as models and providing advanced education are the main facilitators.

Development and Psychometrics Test of Home Environment Assessment Checklist for Community-Dwelling Older Adults with Dementia.

BACKGROUND: Home environment is a core domain in the care of community-dwelling older adults with dementia, but there is no suitable instrument to measure it in China. OBJECTIVE: To develop and psychometrically test the home environment assessment checklist for community-dwelling older adults with dementia. METHODS: A three-step process was performed to develop and test this instrument: 1) based on the evidence-based theory, the checklist was summarized as the main points of evidence from living environment settings among older adults with dementia, 2) the draft tool was assigned to an iterative process of evaluation by a panel of examiners consisting of experts from treatment, nursing and caring, people with dementia and their caregivers, 3) inter-rater reliability and internal consistency were calculated with a sample of 348 caregivers of the older adults with dementia. RESULTS: The HEAC consisted of 71 items in domains addressing safety, stability and familiarity, visual cues, and sensory stimulation. Psychometric evaluation showed that this tool demonstrated sound reliability and validity. Content validity was 0.969 which was established by a panel of experts (n = 10). Inter-rater reliability of two researchers was 0.978, and 0.848 for researchers and caregivers. Test-retest reliability was excellent (ICC = 0.757-0.877) in community-dwelling older adults with dementia 2 week apart. CONCLUSION: The HEAC is a new tool to help collect the reliable information on the barriers and facilitators of home environment for community-dwelling older adults with dementia and to precipitate the home modification process to improve the quality of care for people with dementia and their caregivers in daily life.

The Effectiveness of Non-Pharmacological Interventions on Apathy in Patients With Dementia: A Systematic Review of Systematic Reviews.

BACKGROUND: Apathy is one of the behavioral and psychological symptoms of dementia (BPSD), which is the most frequent and can accelerate the progress of dementia. AIMS: To systematically review the evidence of effectiveness of non-pharmacological interventions on apathy in patients with dementia. METHODS: Databases including the Cochrane Library, Joanna Briggs Institute (JBI) Library, PubMed, EMBASE, CINAHL, PsycINFO, Psychology and Behavioral Sciences Collection, CNKI, and Wan Fang Data were searched for systematic reviews of the effectiveness of non-pharmacological interventions on apathy in patients with dementia. AMSTAR 2 was applied to assess the methodological quality of reviews. RESULTS: Nine systematic reviews were included. The average level of overall confidence for included systematic reviews was low. Among all the non-pharmacological interventions involved in this review, the effectiveness of multisensory stimulation, music therapy, cognitive stimulation, and pet therapy was relatively robust. The effects of reminiscence therapy, therapeutic conversation, progressive muscle relaxation, art therapy, exercise therapy, occupational therapy, dementia special care units, nursing staff education, and comprehensive interventions need to be validated further. Meanwhile, the current evidence failed to support the effects of psychomotor therapy and validation therapy on apathy. LINKING EVIDENCE TO ACTION: Non-pharmacological interventions for apathy in patients with dementia are acceptable. In spite of requirements for adequate and high-quality original studies and quantitative systematic reviews to validate the efficacy of non-pharmacological interventions, multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are deemed the most helpful according to evidences available.

Overview of systematic reviews: Effectiveness of non-pharmacological interventions for eating difficulties in people with dementia.

AIM: To evaluate the effectiveness of non-pharmacological interventions for eating difficulties in people with dementia (PWD). BACKGROUND: Eat difficulties are common problems in PWD. Prolonged eating difficulties may lead to inadequate/excessive food and drink intake and other adverse outcomes. DESIGN: Overview of systematic reviews. DATA SOURCES: Cochrane Library, JBI Library, PubMed, Embase, CINAHL, PsycINFO, and Psychology and Behavioral Sciences Collection, CNKI, WANFANG, from inception up until 23 September 2019. REVIEW METHODS: This overview was conducted in accordance with methodological recommendations of Cochrane. Two researchers independently selected studies based on inclusion criteria, extracted data, assessed eligible studies using AMSTAR 2 and GRADE system, and summarized the conclusions. RESULTS: Eighteen systematic reviews were included. Some evidence showed that environmental modifications, education/training, and Oral nutrition supplements (ONS) were beneficial to improving eating difficulties. But the current evidence failed to support the effectiveness of other interventions. CONCLUSION: The overall confidence of systematic reviews is relatively low. High-quality studies are needed to further validate the effectiveness of non-pharmacological interventions for eating difficulties in PWD. IMPACT: This overview provides evidence on the effectiveness of non-pharmacological interventions for eating difficulties in PWD. It will guide caregivers to choose more effective interventions to cope with eating difficulties and reduce the risk of adverse outcomes.

Long Noncoding RNA DANCR Suppressed Lipopolysaccharide-Induced Septic Acute Kidney Injury by Regulating miR-214 in HK-2 Cells.

BACKGROUND Acute kidney injury (AKI) is one of the most important causes of death in sepsis patients. Here, we first measured the level of DANCR (differentiation antagonizing nonprotein coding RNA) expression in AKI, and the potential mechanism was further elucidated. MATERIAL AND METHODS We used qRT-PCR to examine the level of DANCR in patient blood serum samples and in HK-2 cells. In addition, DANCR overexpression was established using lentiviral transfection in HK-2 cells. Subsequently, Cell Counting Kit-8 (CCK-8) assay and flow cytometry were applied to evaluate the role of DANCR in HK-2 cells treated with lipopolysaccharide (LPS). Enzyme linked immunosorbent assay (ELISA), western blot and recovery experiments were performed to elucidate the further mechanism. RESULTS We found that DANCR was decreased in the serum of AKI patients and HK-2 cells treated with LPS. Additionally, DANCR promoted cell viability and suppressed cell apoptosis and cytokine production in LPS-treated HK-2 cells. Bioinformatics analysis showed that DANCR served as a sponge for miR-214. Furthermore, DANCR inhibited the expression of Krüppel-like factor 6 (KLF6). CONCLUSIONS Our study suggests that AKI development could be alleviated by sponging miR-214 and regulating KLF6 expression, which provides a novel potential mechanism involved in the diagnosis and treatment of sepsis-induced AKI patients.

Azithromycin Promotes the Osteogenic Differentiation of Human Periodontal Ligament Stem Cells after Stimulation with TNF-α.

BACKGROUND AND OBJECTIVE: This study investigated the effects and underlying mechanisms of azithromycin (AZM) treatment on the osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) after their stimulation with TNF-α in vitro. Methods. PDLSCs were isolated from periodontal ligaments from extracted teeth, and MTS assay was used to evaluate whether AZM and TNF-α had toxic effects on PDLSCs viability and proliferation. After stimulating PDLSCs with TNF-α and AZM, we analyzed alkaline phosphatase staining, alkaline phosphatase activity, and alizarin red staining to detect osteogenic differentiation. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to detect the mRNA expression of osteogenic-related genes, including RUNX2, OCN, and BSP. Western blotting was used to measure the NF-κB signaling pathway proteins p65, phosphorylated p65, IκB-α, phosphorylated IκB-α, and ß-catenin as well as the apoptosis-related proteins caspase-8 and caspase-3. Annexin V assay was used to detect PDLSCs apoptosis. RESULTS: TNF-α stimulation of PDLSCs decreased alkaline phosphatase and alizarin red staining, alkaline phosphatase activity, and mRNA expression of RUNX2, OCN, and BSP in osteogenic-conditioned medium. AZM enhanced the osteogenic differentiation of PDLSCs that were stimulated with TNF-α. Western blot analysis showed that ß-catenin, phosphorated p65, and phosphorylated IκB-α protein expression decreased in PDLSCs treated with AZM. In addition, pretreatment of PDLSCs with AZM (10 µg/ml, 20 µg/ml) prevented TNF-α-induced apoptosis by decreasing caspase-8 and caspase-3 expression. CONCLUSIONS: Our results showed that AZM promotes PDLSCs osteogenic differentiation in an inflammatory microenvironment by inhibiting the WNT and NF-κB signaling pathways and by suppressing TNF-α-induced apoptosis. This suggests that AZM has potential as a clinical therapeutic for periodontitis.

d-/l-Isothymidine incorporation in the core sequence of aptamer BC15 enhanced its binding affinity to the hnRNP A1 protein.

The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was reported to participate in the development of a variety of tumors. BC15 is a DNA aptamer targeting hnRNP A1. Firstly, through sequence truncation, we identified 31-mer sequence BC15-31 as the core sequence of BC15 with a strong binding affinity and high selectivity to the hnRNP A1 protein. Isothymidine (isoT) modification was then applied for the structural optimization of BC15-31, systematic modification and biological evaluation were carried out. Incorporation of isoT in the 1,3 sites at the 5'-end of BC15-31 can significantly enhance the protein affinity. Chemical modifications close to the 3'-end can greatly improve the stability of the aptamer. Furthermore, BC15-31 modified with isoT at both the 5'-end and 3'-end displayed an additive effect with enhanced bioactivity and stability at the same time. Our study strategy on BC15 provides a useful guideline for chemical modification and optimization of the aptamer for further clinical application.

Absence of fear renewal and functional connections between prefrontal cortex and hippocampus in infant mice.

Impairment in fear extinction is widely viewed as a major contributor to, or even an underlying mechanism of, the pathogenesis of anxiety disorders and PTSD. Children with traumatic experience have a higher risk for developing anxiety disorders and PTSD in the adult. Little is known about the nature of fear memory extinction and its underlying mechanism during this period. Here we showed that while renewal of fear memory is context-specific in adult mice, it is absent in infant mice (P17). Using local injection of GABAa receptor antagonist picrotoxin, we found that there is no functional connectivity between infralimbic prefrontal cortex and hippocampus in P17 mice, while prefrontal cortex projection to amygdala is functioning. Hence, the lack of fear renewal is likely caused by the lack of connections between hippocampus and prefrontal cortex which are known to be involved in the regulation of extinction memory.

[Effect of Chinese herb chicory extract on expression of renal transporter Glut9 in rats with hyperuricemia].

Sixty SD male rats were randomly divided into normal group, model group, benzbromarone group(20 mg•kg⁻¹â€¢d⁻¹), chicory extract high dose, middle dose and low dose groups (5, 7.5, 10 g•kg⁻¹â€¢d⁻¹). The rats in normal group were given with water, and the rats in other groups were given with 10% fructose solution to establish hyperuricemia models. All the rats were sacrificed on the 42th day. Then their serum uric acid(SUA), serum creatinine(CRE), urea nitrogen(BUN) and urinary uric acid(UUA) levels were detected to calculate the clearance rate of uric acid in kidney(CUA). Meanwhile, the protein and gene expression levels of renal glucose transporter family member 9(Glut9) were detected by immunohistochemical and Real-time quantitative reverse transcription-polymerase chain reaction(RT-qPCR) methods. The effects of Chinese herb chicory extract on expression of renal Glut9 and decreasing uric acid were explored in this study, and the results showed that chicory extract could reduce SUA level in rats with hyperuricemia, increase renal CUA, decrease the protein expression of renal Glut9, inhibit uric acid re-absorption in kidney, and thus promote renal uric acid excretion.

Chemical modification improves the stability of the DNA aptamer GBI-10 and its affinity towards tenascin-C.

Aptamers are useful tools in molecular imaging due to their numerous attractive properties, such as excellent affinity and selectivity to diverse types of target molecules and biocompatibility. We carried out structure-activity relationship studies with the tenascin-C (TN-C) binding aptamer GBI-10, which is a promising candidate in tumor imaging. To increase the tumor targeting ability and nuclease resistance under physiological conditions, systematic modifications of GBI-10 with single and multiple 2'-deoxyinosine (2'-dI) or d-/l-isonucleoside (d-/l-isoNA) were performed. Results indicated that sector 3 of the proposed secondary structure is the most important region for specific binding with TN-C. By correlating the affinity of eighty-four GBI-10 derivatives with their predicted secondary structure by Zuker Mfold, we first validated the preferred secondary structure at 37 °C. We found that d-/l-isoNA modified GBI-10 derivatives exhibited improved affinity to the target as well as plasma stability. Affinity measurement and confocal imaging analysis highlighted one potent compound: 4AL/26TL/32TL, which possessed a significantly increased targeting ability to tumor cells. These results revealed the types of modified nucleotides, and the position and number of substituents in GBI-10 that were critical to the TN-C binding ability. Stabilized TN-C-binding DNA aptamers were prepared and they could be further developed for tumor imaging. Our strategy to introduce 2'-dI and d-/l-isoNA modifications after the selection process is likely to be generally applicable to improve the in vivo stability of aptamers without compromising their binding ability.

Preliminary application of laparoscopic technique in treatment of upper urinary calculi / 中国内镜杂志

Objective To evaluate the reasonable individual program for upper urinary tract calculi in minimally invasive treatment. Methods From January 2013 to June 2016, 147 patients (sides) with upper urinary calculi who had some characteristics received laparoscopic nehprectomy or corresponding surgical treatment. The number of cases of postoperative stagnation, the average hospitalization time and the average cost of treatment were compared with those of 147 patients (lateral) who underwent PCNL and URSL with the similarity, shape and load of stones before June 2016, respectively. Results The removal rate of stage I was 100.00％ (147/147) in laparoscopic group, which was significantly higher than that in PCNL and URSL group (91.84％, 135/147), the difference was statistically significant (P = 0.001); Laparoscopic group postoperative blood transfusion (0/147) and interventional hemostasis (0/147) were significantly lower in 6 cases (6/147) and 4 cases (4/147) in PCNL and URSL groups,the differences were statistically significant (P = 0.013, P = 0.044). There was no postoperative severe infection in laparoscopic group (0/147), which has no significant difference (P = 0.156) in postoperative severe infection between PCNL and URSL group (2/147). There were 9 cases of 134 cases of postoperative (9/134) fever at ≥ 38℃ in laparoscopic group, which was significantly lower than that in PCNL and URSL group (28/147), the difference was statistically significant (P = 0.002); Laparoscopic group of postoperative urinary tract stenosis in 3 cases (3/114), which was significantly lower than that of PCNL and URSL group (9/101), the difference was statistically significant (P = 0.045). The average length of stay in laparoscopic group was (10.12 ± 0.29) d, which was significantly lower (P = 0.011) than that in PCNL and URSL group (13.97 ± 0.38) days. The average cost of treatment in laparoscopic group (12541.84 ± 181.54) yuan was significantly lower than that in PCNL and URSL group (18124.65 ± 302.32) yuan, the difference was statistically significant (P = 0.018). Conclusion In some cases, when the upper urinary tract calcuci are suitable for 'cut out', the use of laparoscopic treatment is more secure; when there is a need for surgical treatment of complications, can be treated simultaneously. Laparoscopic technique is one of the important methods of minimally invasive treatment for upper urinary calculi.

[Acute hypotensive episodes prediction based on non-linear chaotic analysis].

In intensive care units (ICU) , the occurrence of acute hypotensive episodes (AHE) is the key problem for the clinical research and it is meaningful for clinical care if we can use appropriate computational technologies to predict the AHE. In this study, based on the records of patients in ICU from the MIMIC II clinical data, the chaos signal analysis method was applied to the time series of mean artery pressure, and then the patient's Lyapunov exponent curve was drawn ultimately. The research showed that a curve mutation appeared before AHE symptoms took place. This is powerful and clear basis for AHE determination. It is also expected that this study may offer a reference to research of AHE theory and clinical application.

Supramolecular assemblies of novel aminonucleoside phospholipids and their bonding to nucleic acids.

A novel class of aminonucleoside phospholipids has been developed. These molecules could spontaneously assemble into supramolecular structures including multilamellar organization, hydrogels, superhelical strands, and vesicles. Their ability to bind to DNA by hydrogen bonding and π-π stacking interactions was investigated by many means.

[Chicory extract's influence on gut bacteria of abdominal obesity rat].

OBJECTIVE: To investigate the efficacy mechanisme of chicory extract interventing abdominal obesity rat from the aspect of gut bacteria. METHOD: Male SD rats were randomly divided into five groups, namely the normal group, model group, large and small dose group of chicory and the fenofibrate group. Normal group was given deionized water, the other group was given fructose water and give the medical treatment of chicory and fenofibrate. Assay triglycerides, total cholesterol, LDL and HDL by biochemical methods and measure body weight and abdominal circumference and microscopicly observe the count changes of gut bacteria through real-time PCR method. RESULT: Compared with normal group, the triglyceride level and abdominal circumference were significantly higher (P < 0.05), weight and high-density lipoprotein increased but no significant changes and E. coli, lactobacillus increased significantly. Compared with model group, chicory extract large and small dose group and the fenofibrate group can significantly reduce triglyceride levels (P < 0.05), reduce the number of E. coli and Lactobacillus and increase the number of bifidobacteria. The fenofibrate group can significantly reduce total cholesterol and high-density lipoprotein levels. CONCLUSION: The chicory's treatment effect on abdominal obesity is significant. The efficacy mechanisme intervention abdominal obesity may be related to the reduction of the number of lactic acid bacteria and E. coli and the increase of bifidobacteria.

Stability and bioactivity of thrombin binding aptamers modified with D-/L-isothymidine in the loop regions.

Thrombin binding aptamer (TBA) is a 15-mer single-strand DNA that was identified by SELEX screening technology. It adopts a chair-type antiparallel G-quadruplex and can specifically interact with thrombin, thus inhibiting blood coagulation. Isonucleoside (isoNA) is a type of nucleoside isomer in which the base is shifted to 2'-positions of the glycosyl group, endowed with the ability to modulate local conformation of nucleotides, and L-isoNA could alter the conformation more due to the inversion of glycosyl configuration. Incorporation of L-isothymidine (L-isoT) at T3, T9, T12 positions and D-isoT at the T7 position in TBA's loop regions promoted the formation of G-quadruplex, resulting in enhanced affinity with thrombin and an increased anticoagulant effect. Computer simulation indicated that TBA-12L showed the strongest binding with thrombin, which was consistent with experimental results. The bioactivity of double isoNA incorporated TBA with D-IsoT at T7 and L-IsoT at T12 was comparable to that of TBA-12L, suggesting that the T12 of TBA was very important in interaction with thrombin. Our study also suggested that TBA might interact with two thrombin molecules through the TT loops (T3T4, T12T13) and TGT loop, but the second bonding did not show additional biological effects.

The N-terminal CEBPA mutant in acute myeloid leukemia impairs CXCR4 expression.

CXC chemokine receptor 4 (CXCR4) is an essential regulator for homing and maintenance of hematopoietic stem cells within the bone marrow niches. Analysis of clinical implications of bone marrow CXCR4 expression in patients with acute myeloid leukemia showed not only higher CXCR4 expression was an independent poor prognostic factor, irrespective of age, white blood cell counts, cytogenetics, and mutation status of NPM1/FLT3-ITD and CEBPA, but also showed CXCR4 expression was inversely associated with mutations of CEBPA, a gene encoding transcription factor C/EBPα. Patients with wild-type CEBPA had significantly higher CXCR4 expression than those with mutated CEBPA. We hypothesized that CEBPA might influence the expression of CXCR4. To test this hypothesis, we first examined endogenous CXCR4 expression in 293T and K562 cells over-expressing wild-type C/EBPα p42 and demonstrated that CXCR4 levels were increased in these cells, whilst the expression of the N-terminal mutant, C/EBPα p30, diminished CXCR4 transcription. We further showed p42 was bound to the CXCR4 promoter by the chromatin immunoprecipitation assays. Induction of p42 in the inducible K562-C/EBPα cell lines increased the chemotactic migration. Moreover, decreased expression of C/EBPα by RNA interference decreased levels of CXCR4 protein expression in U937 cells, thereby abrogating CXCR4-mediated chemotaxis. Our results provide, for the first time, evidence that C/EBPα indeed regulates the activation of CXCR4, which is critical for the homing and engraftment of acute myeloid leukemia cells, while p30 mutant impairs CXCR4 expression.

Nucleolin-targeting liposomes guided by aptamer AS1411 for the delivery of siRNA for the treatment of malignant melanomas.

BRAF gene mutation is found in more than 60% of malignant melanomas, which are difficult to treat. In this study, a new tumor-targeting liposome was developed to deliver anti-BRAF siRNA (siBraf) for the treatment of melanomas. Nucleolin is overexpressed on the surface of cancer cells. AS1411, an aptamer showing specific binding to nucleolin, was conjugated to PEGylated cationic liposome as the targeting probe ASLP (AS1411-PEG-liposome). The ASLP/siRNA complex was formed through electrostatic interaction between ASLP and siRNA. The binding of AS1411 to the surface of PEGylated liposomes was confirmed by gel electrophoresis and capillary electrophoresis. Real-time PCR and Western blot analysis showed that ASLP/siBraf exhibited strong silencing activity of BRAF gene. The much higher accumulation of the siRNA in tumor cells comparing with normal cells indicated that ASLP displayed excellent tumor-targeting capability. Notably, ASLP/siBraf showed significant silencing activity in A375 tumor xenograft mice and inhibited the melanoma growth. These results suggested that the new nucleolin-targeted siRNA delivery system by AS1411 may have the potential for the treatment of melanoma.

Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression.

We aimed to analyze clinical impacts of the U2AF1 mutation on patients with myelodysplastic syndrome (MDS) and its stability during disease progression. We checked mutation status of the U2AF1 by direct sequencing in 478 de novo MDS patients and correlated with the clinical characteristics and outcomes. We also sequentially analyzed the U2AF1 mutation in 421 samples from 142 patients to determine its stability during the disease courses. Thirty-six patients (7.5%) were found to have U2AF1 mutations, which occurred more frequently in younger patients (P = 0.033). U2AF1 mutation was an independent poor-risk factor for overall survival (OS) in all patients (P = 0.030) and younger patients (P = 0.041). U2AF1 mutation could also predict shorter time-to-leukemia transformation (TTL) in younger patients (P = 0.020). In addition, U2AF1 mutation was associated with shorter TTL in lower-risk MDS patients. Sequential analyses showed all original U2AF1 mutations in U2AF1-mutated patients were retained during follow-ups unless complete remission was achieved, whereas none of the U2AF1-wild patients acquired a novel mutation during disease evolution. U2AF1 mutation is more prevalent in younger MDS patients and associated with inferior outcomes although it is stable during the clinical course. The mutation may be used as a biomarker for risk stratification.