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.
Purpose
In patients with chemotherapy, there is no consensus on the timing of ileostomy closure. Ileostomy reversal could improve the quality of life and minimise the long-term adverse events of ...delayed closure. In this study, we evaluated the impact of chemotherapy on ileostomy closure and searched for the predictive factors for complications.
Methods
We retrospectively analysed 212 patients with rectal cancer who underwent ileostomy closure surgery during and without chemotherapy and were consecutively enrolled between 2010 and 2016. As a result of the heterogeneity of the two groups, propensity score matching (PSM) was performed with a 1:1 PSM cohort.
Results
A total of 162 patients were included in the analysis. The overall stoma closure-related complications (12.4% vs. 11.1%,
p
= 1.00) and major complications (2.5% vs. 6.2%,
p
= 0.44) were not significantly different between the two groups. Multivariate analysis demonstrated that chronic kidney disease and bevacizumab use are risk factors for major complications.
Conclusion
Patients with oral or intravenous chemotherapy can safely have ileostomy closure with an adequate time delay from chemotherapy. When patients use bevacizumab, major complications related to ileostomy closure should still be cautioned.
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
Recent developments in the instrumentation and data analysis of synchrotron small‐angle X‐ray scattering (SAXS) on biomolecules in solution have made biological SAXS (BioSAXS) a mature and popular ...tool in structural biology. This article reports on an advanced endstation developed at beamline 13A of the 3.0 GeV Taiwan Photon Source for biological small‐ and wide‐angle X‐ray scattering (SAXS–WAXS or SWAXS). The endstation features an in‐vacuum SWAXS detection system comprising two mobile area detectors (Eiger X 9M/1M) and an online size‐exclusion chromatography system incorporating several optical probes including a UV–Vis absorption spectrometer and refractometer. The instrumentation and automation allow simultaneous SAXS–WAXS data collection and data reduction for high‐throughput biomolecular conformation and composition determinations. The performance of the endstation is illustrated with the SWAXS data collected for several model proteins in solution, covering a scattering vector magnitude q across three orders of magnitude. The crystal‐model fittings to the data in the q range ∼0.005–2.0 Å−1 indicate high similarity of the solution structures of the proteins to their crystalline forms, except for some subtle hydration‐dependent local details. These results open up new horizons of SWAXS in studying correlated local and global structures of biomolecules in solution.
A new endstation for biological small‐ and wide‐angle X‐ray scattering is detailed, which provides development opportunities for studying correlated local and global structures of biomolecules in solution.
The narrow-line Seyfert 1 galaxy IRAS 13224−3809 has been observed with XMM-Newton for 500 ks. The source is rapidly variable on time-scales down to a few 100 s. The spectrum shows strong broad Fe − ...K
and L emission features which are interpreted as arising from reflection from the inner parts of an accretion disc around a rapidly spinning black hole. Assuming a power law emissivity for the reflected flux and that the innermost radius corresponds to the innermost stable circular orbit, the black hole spin is measured to be 0.989 with a statistical precision better than 1 per cent. Systematic uncertainties are discussed. A soft X-ray lag of 100 s confirms this scenario. The bulk of the power-law continuum source is located at a radius of 2-3 gravitational radii.
We report on the deepest X-ray observation of the narrow-line Seyfert 1 galaxy Mrk 335 in the low-flux state obtained with Suzaku. The data are compared to a 2006 high-flux Suzaku observation when ...the source was ∼10 times brighter. Describing the two flux levels self-consistently with partial covering models would require extreme circumstances, as the source would be subject to negligible absorption during the bright state and 95 per cent covering with near Compton-thick material when dim. Blurred reflection from an accretion disc around a nearly maximum spinning black hole (a > 0.91, with preference for a spin parameter as high as ∼0.995) appears more likely and is consistent with the long-term and rapid variability. Measurements of the emissivity profile and spectral modelling indicate the high-flux Suzaku observation of Mrk 335 is consistent with continuum-dominated, jet-like emission (i.e. beamed away from the disc). It can be argued that the ejecta must be confined to within ∼ 25r
g if it does not escape the system. During the low-flux state, the corona becomes compact and only extends to about 5r
g from the black hole, and the spectrum becomes reflection dominated. The low-frequency lags measured at both epochs are comparable indicating that the accretion mechanism is not changing between the two flux levels. Various techniques to study the spectral variability (e.g. principal component analysis, fractional variability, difference spectra, and hardness ratio analysis) indicate that the low-state variability is dominated by changes in the power-law flux and photon index, but that changes in the ionization state of the reflector are also required. Most notably, the ionization parameter becomes inversely correlated with the reflected flux after a long-duration flare-like event during the observation.
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.
Background
Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of ...cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV‐6, HHV‐7, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined.
Methods
A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum‐specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples.
Results
Among the various cADRs, HHV‐6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)‐1β, IL‐2, IL‐6, interferon‐γ, tumor necrosis factor‐α, were significantly lower in DRESS patients with HHV‐6 reactivation when compared to those without HHV‐6 reactivation. In addition, these mediators were significantly lower before and during HHV‐6 reactivation, compared to cytokine levels after HHV‐6 reactivation in the same patient.
Conclusion
HHV‐6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV‐6 reactivation.
Lung cancer is the leading cause of cancer death worldwide, with metastasis underlying majority of related deaths. Angiomotin (AMOT), a scaffold protein, has been shown to interact with oncogenic ...Yes-associated protein/transcriptional co-activator with a PDZ-binding motif (YAP/TAZ) proteins, suggesting a potential role in tumor progression. However, the functional role of AMOT in lung cancer remains unknown. This study aimed to identify the patho-physiological characteristics of AMOT in lung cancer progression. Results revealed that AMOT expression was significantly decreased in clinical lung cancer specimens. Knockdown of AMOT in a low metastatic CL1-0 lung cancer cell line initiated cancer proliferation, migration, invasion and epithelial-mesenchymal transition. The trigger of cancer progression caused by AMOT loss was transduced by decreased cytoplasmic sequestration and increased nuclear translocation of oncogenic co-activators YAP/TAZ, leading to increased expression of the growth factor, Cyr61. Tumor promotion by AMOT knockdown was reversed when YAP/TAZ or Cyr61 was absent. Further, AMOT knockdown increased the growth and spread of Lewis lung carcinoma in vivo. These findings suggest that AMOT is a crucial suppressor of lung cancer metastasis and highlight its critical role as a tumor suppressor and its potential as a prognostic biomarker and therapeutic target for lung cancer.
PDF
