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.
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.
The optical design and performance of the recently opened 13A biological small‐angle X‐ray scattering (SAXS) beamline at the 3.0 GeV Taiwan Photon Source of the National Synchrotron Radiation ...Research Center are reported. The beamline is designed for studies of biological structures and kinetics in a wide range of length and time scales, from angstrom to micrometre and from microsecond to minutes. A 4 m IU24 undulator of the beamline provides high‐flux X‐rays in the energy range 4.0–23.0 keV. MoB4C double‐multilayer and Si(111) double‐crystal monochromators (DMM/DCM) are combined on the same rotating platform for a smooth rotation transition from a high‐flux beam of ∼4 × 1014 photons s−1 to a high‐energy‐resolution beam of ΔE/E ≃ 1.5 × 10−4; both modes share a constant beam exit. With a set of Kirkpatrick–Baez (KB) mirrors, the X‐ray beam is focused to the farthest SAXS detector position, 52 m from the source. A downstream four‐bounce crystal collimator, comprising two sets of Si(311) double crystals arranged in a dispersive configuration, optionally collimate the DCM (vertically diffracted) beam in the horizontal direction for ultra‐SAXS with a minimum scattering vector q down to 0.0004 Å−1, which allows resolving ordered d‐spacing up to 1 µm. A microbeam, of 10–50 µm beam size, is tailored by a combined set of high‐heat‐load slits followed by micrometre‐precision slits situated at the front‐end 15.5 m position. The second set of KB mirrors then focus the beam to the 40 m sample position, with a demagnification ratio of ∼1.5. A detecting system comprising two in‐vacuum X‐ray pixel detectors is installed to perform synchronized small‐ and wide‐angle X‐ray scattering data collections. The observed beamline performance proves the feasibility of having compound features of high flux, microbeam and ultra‐SAXS in one beamline.
The optical design and performance of the BioSAXS beamline at the Taiwan Photon Source are reported
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.
The metabolic syndrome may cause disease progression in patients with chronic hepatitis B (CHB). However, the interactions between hepatitis B virus (HBV) infection and metabolic factors remain ...unknown. We investigated the association of HBV infection with metabolic profiles in HBV‐infected and noninfected subjects. In addition, the impacts of serum HBV DNA level on metabolic profiles were studied. Initially, a case–control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 322 patients with chronic HBV infection, and the control group consisted of 870 matched subjects without HBV infection. Fasting blood glucose, lipid profiles and adiponectin levels were compared. The results were then confirmed in a second retrospective cohort study in 122 CHB patients with serum HBV DNA levels and HOMA‐IR index values. In the case–control analysis, the HBV group had significantly higher serum adiponectin, but lower triglyceride (TG) and high‐density lipoprotein cholesterol (HDL) levels than the control group. These relationships already existed in subjects younger than 45 years of age and were modified by serum alanine aminotransferase (ALT) levels. In the retrospective cohort, serum HBV DNA levels were negatively proportional to TG levels, but not to other metabolic parameters. Moreover, this relationship was significant only in subjects with higher ALT levels. Compared with healthy adults, patients with chronic HBV infection have significantly higher serum adiponectin, but lower TG and HDL levels. These relationships are modified by ALT levels and already exist in middle‐age patients with chronic HBV infection, implying HBV may interact with host metabolism.
Cytokine storm syndrome (CSS) is a critical clinical condition induced by a cascade of cytokine activation, characterized by overwhelming systemic inflammation, hyperferritinaemia, haemodynamic ...instability and multiple organ failure (MOF). At the end of 2019, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) emerged in Wuhan, China, and rapidly developed into a global pandemic. More and more evidence shows that there is a dramatic increase of inflammatory cytokines in patients with COVID‐19, suggesting the existence of cytokine storm in some critical illness patients. Here, we summarize the pathogenesis, clinical manifestation of CSS, and highlight the current understanding about the recognition and potential therapeutic options of CSS in COVID‐19.
Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to ...selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration IC50 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.
Background and purpose
Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between ...infectious burden (IB) and Alzheimer's disease (AD) was examined.
Methods
Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV‐1), Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori were measured by enzyme‐linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens.
Results
Seropositivities toward zero−two, three and four−five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini‐Mental State Examination scores were negatively correlated with IB in all cases. Serum beta‐amyloid protein (Aβ) levels (i.e. Aβ40, Aβ42 and total Aβ) and inflammatory cytokines (i.e. interferon‐γ, tumor necrosis factor α, interleukin‐1β and interleukin‐6) in individuals exposed to four−five infectious pathogens were significantly higher than those exposed to zero−two or three pathogens.
Conclusions
IB consisting of CMV, HSV‐1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.
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Face-centered-cubic (fcc) type high entropy alloys (HEAs) exhibit outstanding ductility even at the liquid nitrogen temperature, but they are relatively weak in strength which is far from the ...requirements for practical structural applications. One of the general concepts employed previously in alloy design is the suppression of ‘brittle’ intermetallic compound formation which usually leads to a serious embrittlement. Surprisingly, we reveal in this study that the precipitation of hard σ and μ intermetallic compounds tremendously strengthened the CoCrFeNiMo0.3 HEA but without causing a serious embrittlement. It exhibits a tensile strength as high as 1.2 GPa and a good ductility of ∼19%. A careful study of the deformation behavior reveals that the fcc matrix exhibits an extremely high work hardening exponent of 0.75, which suppresses the propagation of microcracks originated at these brittle particles. Our work presents a very successful demonstration of using complex hard intermetallic particles to manipulate the properties of fcc-type HEA systems. Furthermore, lattice distortion has been carefully measured in powder-metallurgy materials by line broadening from X-ray diffraction (XRD). It is interesting to discover that lattice planes are highly distorted in HEAs and this distortion also contributes to solid solution hardening.
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