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.
The emergence of SARS-CoV-2 variants of concern with progressively increased transmissibility between humans is a threat to global public health. The Omicron variant of SARS-CoV-2 also evades ...immunity from natural infection or vaccines
, but it is unclear whether its exceptional transmissibility is due to immune evasion or intrinsic virological properties. Here we compared the replication competence and cellular tropism of the wild-type virus and the D614G, Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529) variants in ex vivo explant cultures of human bronchi and lungs. We also evaluated the dependence on TMPRSS2 and cathepsins for infection. We show that Omicron replicates faster than all other SARS-CoV-2 variants studied in the bronchi but less efficiently in the lung parenchyma. All variants of concern have similar cellular tropism compared to the wild type. Omicron is more dependent on cathepsins than the other variants of concern tested, suggesting that the Omicron variant enters cells through a different route compared with the other variants. The lower replication competence of Omicron in the human lungs may explain the reduced severity of Omicron that is now being reported in epidemiological studies, although determinants of severity are multifactorial. These findings provide important biological correlates to previous epidemiological observations.
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.
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.
BackgroundThe secondary cell wall is a defining feature of xylem cells and allows them to resist both gravitational forces and the tension forces associated with the transpirational pull on their ...internal columns of water. Secondary walls also constitute the majority of plant biomass. Formation of secondary walls requires co-ordinated transcriptional regulation of the genes involved in the biosynthesis of cellulose, hemicellulose and lignin. This co-ordinated control appears to involve a multifaceted and multilayered transcriptional regulatory programme.ScopeTranscription factor MYB46 (At5g12870) has been shown to function as a master regulator in secondary wall formation in Arabidopsis thaliana. Recent studies show that MYB46 not only regulates the transcription factors but also the biosynthesis genes for all of the three major components (i.e. cellulose, hemicellulose and lignin) of secondary walls. This review considers our current understanding of the MYB46-mediated transcriptional regulatory network, including upstream regulators, downstream targets and negative regulators of MYB46.Conclusions and OutlookMYB46 is a unique transcription factor in that it directly regulates the biosynthesis genes for all of the three major components of the secondary wall as well as the transcription factors in the biosynthesis pathway. As such, MYB46 may offer a useful means for pathway-specific manipulation of secondary wall biosynthesis. However, realization of this potential requires additional information on the ‘MYB46-mediated transcriptional regulatory programme’, such as downstream direct targets, upstream regulators and interacting partners of MYB46.
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.
Sonographic measurement of mesenteric fat predicts presence of fatty liver and can impact on manifestation of hyperandrogenism through its effects on SHBG.
Objective:
Visceral fat is believed to be ...important in the pathogenesis of metabolic syndrome and fatty liver. In this study, we examined the relationship between mesenteric fat thickness and other sonographic indices of adiposity and the presence of fatty liver among subjects with polycystic ovary syndrome (PCOS).
Subjects and Methods:
A total of 117 Chinese subjects with PCOS were evaluated (mean age, 28.6 ± 6.5 yr; mean body mass index, 24.3 ± 5.3 kg/m2). Anthropometric measurements and metabolic risk profile, including a standard oral glucose tolerance test, were assessed in all subjects. All subjects underwent an ultrasound examination for measurement of thickness of mesenteric, preperitoneal, and sc fat as well as evaluation for fatty liver.
Results:
Forty-six (39.3%) of the subjects had fatty liver. PCOS subjects with fatty liver had higher body mass index, waist circumference, waist-hip ratio, and systolic blood pressure; a more unfavorable lipid profile with higher triglyceride; lower high-density lipoprotein cholesterol; higher fasting glucose and insulin; higher 2-h glucose during oral glucose tolerance test; lower SHBG; and higher alanine aminotransferase. Subjects with fatty liver had increased thickness of preperitoneal, mesenteric, and sc fat, as well as increased carotid intima-media thickness. Abdominal fat thickness showed moderate correlation to alanine aminotransferase as well as fasting insulin. On multivariate logistic regression, fasting insulin and mesenteric fat thickness were identified as independent predictors of fatty liver among subjects with PCOS.
Conclusion:
Fatty liver is present in a significant proportion of Chinese patients with PCOS. Sonographic measurement of mesenteric fat is an independent determinant of fatty liver among subjects with PCOS and identifies subjects at increased cardiovascular risk.
Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) ...with clinical outcomes in type 2 diabetes in public and private healthcare settings.
The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years 95% CI 132.35-140.18), the non-JADE group had higher (145.32 95% CI 138.68-152.20; P = 0.020) while the JADE-P group had lower event rates (70.94 95% CI 67.12-74.91; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias.
ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Background. Klebsiella pneumoniae, a Gram‐negative bacillus usually forming glistening mucoid colonies with viscid consistency on the culture plate, is a common pathogen causing various clinical ...infection patterns. However, little is known about the clinical implications of this mucoid character.
Objective. The purposes of this study, therefore, were to investigate the frequency of hypermucoviscosity (HV) in bacteraemic isolates of K. pneumoniae, and determine the significance of any association between HV and various clinical manifestations.
Design. Retrospective observational study.
Patients. Patients diagnosed with K. pneumoniae bacteraemia at a community‐based university hospital between June 1999 and June 2001 were enrolled in this analysis.
Measurements. Clinical data concerning comorbid diseases and infection patterns was collected. K. pneumoniae bacteraemic isolates were examined for the presence of HV using a modified string test. The clinical impact of HV and risk factors for the invasive syndrome were assessed using statistical analysis. Polymerase chain reaction (PCR) was performed to detect magA, a gene related to HV phenotype.
Results. Overall, 200 (64.9%) of the 308 cases of K. pneumoniae bacteraemia were community‐acquired infections. Compared with hospital‐acquired K. pneumoniae bacteraemia (HA‐KpB), community‐acquired K. pneumoniae bacteraemia (CA‐KpB) was more likely to be monomicrobial in nature (83.5% vs. 64.8%; P < 0.001) and caused by HV strains (41.5% vs. 14.8%; P < 0.001). The prevalence rate of magA among HV phenotypical K. pneumoniae strains was 24.1%. Patients infected with HV‐positive strains were more likely to have the distinctive invasive syndrome (i.e. liver abscess, meningitis, pleural empyaema or endophthalmitis) than those infected with HV‐negative variants (37.3% vs. 6.8%; P < 0.001). Multivariate logistic regression analysis, adjusted for age, showed that HV phenotype in K. pneumoniae strains (OR 8.86; 95% CI, 3.70–21.25; P < 0.001) was positively associated with the development of the invasive syndrome in CA‐KpB cases.
Conclusions. The HV phenotype of K. pneumoniae bacteraemic isolates was associated with the development of a distinctive invasive syndrome. Identification of the HV phenotype should prompt clinicians to initiate aggressive investigations for invasive diseases.
Edge localized modes (ELMs) in high-confinement mode plasmas were completely suppressed in KSTAR by applying n=1 nonaxisymmetric magnetic perturbations. Initially, the ELMs were intensified with a ...reduction of frequency, but completely suppressed later. The electron density had an initial 10% decrease followed by a gradual increase as ELMs were suppressed. Interesting phenomena such as a saturated evolution of edge T(e) and broadband changes of magnetic fluctuations were observed, suggesting the change of edge transport by the applied magnetic perturbations.
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