A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its ...stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated +8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2(-)/FLT3-ITD(+) genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.
Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk ...cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.
Resistance mutations A2058G and A2059G, within the 23S rRNA gene of Treponema pallidum, have been reported to cause treatment failures in patients receiving azithromycin for syphilis. Genotyping of ...T. pallidum strains sequentially isolated from patients with recurrent syphilis is rarely performed. From September 2009 to August 2013, we collected 658 clinical specimens from 375 patients who presented with syphilis for genotyping to examine the number of 60-bp repeats in the acidic repeat protein (arp) gene, T. pallidum repeat (tpr) polymorphism, and tp0548 gene, and to detect A2058G and A2059G point mutations by restriction fragment length polymorphism. Treponemal DNA was identified in 45.2% (n = 298) of the specimens that were collected from 216 (57.6%) patients; 268 (40.7%) specimens tested positive for the 23S rRNA gene, and were examined for macrolide resistance. Two isolates (0.7%) harboured the A2058G mutation, and no A2059G mutation was identified. A total of 14 strains of T. pallidum were identified, with 14f/f (57.5%) and 14b/c (10.0%) being the two predominant strains. Forty patients who presented with recurrent episodes of syphilis had T. pallidum DNA identified from the initial and subsequent episodes, with five cases showing strain discrepancies. One patient had two strains identified from different clinical specimens collected in the same episode. Our findings show that 14f/f is the most common T. pallidum strain in Taiwan, where the prevalence of T. pallidum strains that show A2058G or A2059G mutation remains low. Different genotypes of T. pallidum can be identified in patients with recurrent episodes of syphilis.
The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this ...study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.
Summary
Background
Data are limited regarding the effectiveness and safety of generic velpatasvir plus sofosbuvir (VEL/SOF) for hepatitis C virus (HCV) in patients with or without human ...immunodeficiency virus (HIV) coinfection.
Aim
To evaluate the effectiveness and safety of generic VEL/SOF‐based therapy for HCV infection in patients with or without HIV coinfection in Taiwan.
Methods
Sixty‐nine HIV/HCV‐coinfected and 159 HCV‐monoinfected patients receiving 12 weeks of generic VEL/SOF with or without ribavirin (RBV) for HCV were prospectively enrolled. The anti‐viral responses and the adverse events (AEs) were compared between the two groups. The characteristics potentially related to sustained virological response 12 weeks off therapy (SVR12) were analysed.
Results
The SVR12 was achieved in 67 HIV/HCV‐coinfected patients (97.1%; 95% CI: 90.0%‐99.2%) and in 156 HCV‐monoinfected patients (98.1%; 95% CI: 94.6%‐99.4%) receiving VEL/SOF‐based therapy, respectively. The SVR12 rates were comparable between HIV/HCV‐coinfected and HCV‐monoinfected patients, regardless of pre‐specified baseline characteristics. One hundred twenty‐two (53.5%) and seven (3.1%) patients had baseline resistance‐associated substitutions (RASs) in HCV NS5A and NS5B regions, but the SVR12 rates were not affected by the presence or absence of RASs. One (1.4%) and five (3.1%) patients in the HIV/HCV‐coinfected and HCV‐monoinfected groups had serious AEs. No patient died or discontinued treatment due to AEs. The eGFR remained stable throughout the course of treatment in HIV/HCV‐coinfected patients receiving anti‐retroviral therapy containing tenofovir disoproxil fumarate (TDF).
Conclusions
Generic VEL/SOF‐based therapy is well‐tolerated and provides comparably high SVR12 rates for HCV infection in patients with and without HIV coinfection.
This study investigated seasonal variations in the mass concentration and chemical composition of ambient aerosols observed at three stations (coastal, mountainous, and downtown sites) in northern ...Taiwan from March 2009 to February 2012. The results show that the major aerosol components include ammonium, sulfate, nitrate, sea salt, dust, organic carbon, and elemental carbon, whereas the mass fraction of each species depends on the sampling location and season. A significant correlation (r = 0.7–0.8) was observed in aerosol concentrations measured at the respective stations, indicating that aerosol concentrations were dominated by regional‐scale factors. Ammonium, sulfate, and nitrate consistently reached respective peak values in the spring in conjunction with dust particle levels. This shows that the transport of dust and particulate air pollutants from the Asian continent has affected the atmospheric environment in this area. Distinct seasonality was observed for sea salt and secondary organic carbon (SOC): sea salt levels peaked in the autumn, whereas SOC levels peaked in the summer, implying that their sources were regulated by independent seasonal factors. Correlation between sea salt concentration and surface wind speed was derived from coastal measurements and showed a high value for the wind speed sensitivity parameter of around 0.37 for our location. In addition, it was revealed that the SOC concentration in aerosols was positively correlated with oxidant photolysis index (Ox × UVB), suggesting that the SOC seasonality was dominated by hydroxyl radical production.
Key Points
Inorganic particulate pollutants and dust consistently peaked in the spring due to Asian outflow effects
Ambient concentrations of sea salt particles were exponentially correlated with surface wind speeds
The production of secondary organic aerosols was dominated by the photolysis of total oxidants
Summary
Sarcopenia was reported to be significantly associated with osteoporosis. In this study, we reported for the first time that sarcopenia was an independent risk predictor of osteoporotic ...vertebral compression refractures (OVCRFs). Other risk factors of OVCRFs are low bone mass density T-scores, female sex, and advanced age.
Introduction
The purpose of this study was to investigate the association between osteoporotic vertebral compression refractures (OVCRFs) and sarcopenia, and to identify other risk factors of OVCRFs.
Methods
We evaluated 237 patients with osteoporotic vertebral compression fracture who underwent percutaneous kyphoplasty (PKP) in our hospital from August 2016 to December 2017. To diagnose sarcopenia, a cross-sectional computed tomography (CT) image at the inferior aspect of the third lumbar vertebra (L3) was selected for estimating muscle mass. Grip strength was used to assess muscle strength. Possible risk factors, such as age, sex, body mass index (BMI), bone mineral density (BMD), location of the treated vertebra, anterior-posterior ratio (AP ratio) of the fractured vertebra, cement leakage, and vacuum clefts, were assessed. The multivariable analysis was used to determine the risk factors of OVCRFs.
Results
During the follow-up period, OVCRFs occurred in 64 (27.0%) patients. Sarcopenia was present in 48 patients (20.3%), including 21 OVCRFs and 27 non-OVCRFs patients. Sarcopenia was significantly correlated with advanced age, lower BMI, lower BMD, and hypoalbuminemia. Compared with non-sarcopenic patients, sarcopenic patients had higher OVCRFs risk. In univariate analysis, sarcopenia (
p
= 0.003), female (
p
= 0.024), advanced age (≥ 75 years;
p
< 0.001), lower BMD (
p
< 0.001), lower BMI (
p
= 0.01), TL junction (vertebral levels at the thoracolumbar junction) (
p
= 0.01), cardiopulmonary comorbidity (
p
= 0.042), and hypoalbuminemia (
p
= 0.003) were associated with OVCRFs. Multivariable analysis revealed that sarcopenia (OR 2.271; 95% CI 1.069–4.824,
p
= 0.033), lower BMD (OR 1.968; 95% CI 1.350–2.868,
p
< 0.001), advanced age (≥ 75 years; OR 2.431; 95% CI 1.246–4.744,
p
= 0.009), and female sex (OR 4.666; 95% CI 1.400–15.552,
p
= 0.012) were independent risk predictors of OVCRFs.
Conclusions
Sarcopenia is an independent risk predictor of osteoporotic vertebral compression refractures. Other factors affecting OVCRFs are low BMD T-scores, female sex, and advanced age.
Hyperuricemia (HUA) is associated with the prevalence of metabolic syndrome (MetS) and cardiovascular risks in various populations. HUA is also able to induce cardiomyocyte hypertrophy in mouse ...models. However, the dose-response effects of serum uric acid (SUA) on the prevalence of MetS and electrocardiographic left ventricular hypertrophy (LVH) are unclear.
We retrospectively collected data from 18,932 individuals who underwent an annual health examination between 1/1/2016 and 12/31/2016. We excluded those with systemic diseases or missing questionnaires. The primary study endpoints were the prevalence of MetS and LVH, which were defined by the criteria for the Taiwanese population and the “SPRINT” trial. The cohort consisted of 17,913 individuals with a mean age of 31.2 years (SD 7.4) and a mean body mass index of 24.6 kg/m2 (SD 3.6); 87.1% of the individuals were men. The prevalence rates of HUA, MetS, and LVH were 29.5%, 9.4%, and 0.32%, respectively, in the overall study population. The HUA group was predominantly male and had significantly poorer lifestyle choices and greater laboratory cardiometabolic biomarker values than did the normouricemic group. However, the frequencies of physical activity were comparable between the two groups. After adjusting for confounders, SUA was associated with MetS (OR:1.473, 95% CI:1.408–1.540, P < 0.001) and LVH (OR:1.301, 95% CI:1.064–1.591, P = 0.01).
We demonstrated that the dose-response effects of SUA are associated with the prevalence of MetS and electrocardiographic LVH in healthy individuals from Taiwan. Based on this evidence, future studies should investigate urate-lowering therapy and cardiovascular benefits in individuals with HUA (ClinicalTrials.gov number NCT03473951).
•Serum uric acid (SUA) was associated with the prevalence of metabolic syndrome and LVH.•The association is independent of life style choice and physical activity.•The association did not change with adjustment for kidney function.•Future studies might evaluate urate-lowering effects on the improvement of metabolic syndrome and LVH.
Conspectus The chalcogenolato silver and copper superatoms are currently a topic of cutting edge research besides the extensively studied Au n (SR) m clusters. Crystal structure analysis is an ...indispensable tool to gain deep insights into the anatomy of these sub-nanometer clusters. The metal framework and spatial arrangement of the chalcogenolates around the metal core assist in unravelling the structure–property relationships and fundamental mechanisms involved in their fabrication. In this Account, we discuss our contribution toward the development of dichalcogenolato Ag and Cu cluster chemistry covering their fabrication and precise molecular structures. Briefly introducing the significance of the single crystal structures of the atomically precise clusters, the novel dichalcogenolated two-electron superatomic copper and its alloy systems are presented first. The Cu13{S2CNR}6{CCR′}4+ is so far the first unique copper cluster having Cu13 centered cuboctahedra, which is a miniature of bulk fcc structure. The galvanic exchange of the central Cu with Ag or Au results in a similar anatomy of formed bimetallic Au/Ag@Cu12(S2CN n Bu2)6(CCPh)4CuCl2 species. This is unique in the sense that other contemporary M13 cores in group 11 superatomic chemistry are compact icosahedra. The central doping of Ag or Au significantly affects the physiochemical properties of the bimetallic Cu-rich clusters. It is manifested in the dramatic quantum yield enhancement of the doped species Au@Cu12(S2CN n Bu2)6(CCPh)4+ with a value of 0.59 at 77 K in 2-MeTHF. In the second part, the novel eight-electron dithiophosphate- and diselenophosphate-protected silver systems are presented. A completely different type of architecture was revealed for the first time from the successful structural determination of Ag21{S2P(O i Pr)2}12+, Ag20{S2P(O i Pr)2}12 and Au@Ag19{S2P(OPr)2}12. They exhibit a nonhollow M13 (Ag or AuAg12) icosahedron, capped by 8 and 7 Ag atoms in the former and latter two species, respectively. The overall metal core units are protected by 12 dithiophosphate ligands and the metal–ligand interface structure was found to be quite different from that of Au n (SR) m . Notably, the Ag20{S2P(O i Pr)}12 cluster provides the first structural evidence of a silver superatom with a chiral metallic core. This chirality arises through the simple removal of one of capping Ag+ cations of Ag21{S2P(O i Pr)2}12+ present on its C 3 axis. Further, the effects of the ligand exchange on the structures of Ag20{Se2P(O i Pr)2}12, Ag21{Se2P(OEt)2}12+, and AuAg20{Se2P(OEt)2}12+ are studied extensively. The structure of the former species is similar to its dithiophosphate counterpart (C 3 symmetry). The latter two (T symmetry) differ in the arrangement of 8 capping Ag atoms, as they form a cube engraving the Ag13 (AuAg12) icosahedron. The blue shifts in absorption spectra and photoluminescence further indicate the strong influence of the central Au atom in the doped clusters. Finally, the first paradigm of unusual heteroatom doping induced size–structure transformations is discussed by presenting the case of formation of Au3Ag18{Se2P(O i Pr)2}12+ upon Au doping into Ag20{Se2P(O i Pr)2}120. Finally, before concluding this Account, we discuss the possibility of many unique structural isomers with different physical properties for the aforementioned Ag superatoms which need to be explored extensively in the future.
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