Chromothripsis in myeloid malignancies.

Chromothripsis refers to massive genomic rearrangements developed during a catastrophic event. In total acute myeloid leukemia (AML), the incidence of chromothripsis ranges from 0 to 6.6%, in cases of complex karyotype AML, the incidence of chromothripsis ranges from 27.3 to 100%, whereas in cases of AML with TP53 mutations, the incidence ranges from 11.1 to 90%. For other types of malignancies, the incidence of chromothripsis also varies, from 0 to 10.5% in myelodysplastic syndrome to up to 61.5% in cases of myelodysplastic syndrome with TP53 mutations.Chromothripsis is typically associated with complex karyotypes and TP53 mutations, and monosomal karyotypes are associated with the condition. ERG amplifications are frequently noted in cases of chromothripsis, whereas MYC amplifications are not. Moreover, FLT3 and NPM1 mutations are negatively associated with chromothripsis. Chromothripsis typically occurs in older patients with AML with low leukocyte counts and bone marrow blast counts. Rare cases of patients with chromothripsis who received intensive induction chemotherapy revealed low response rates and poor overall prognosis. Signal pathways in chromothripsis typically involve copy number gain and upregulation of oncogene gene sets that promote cancer growth and a concomitant copy number loss and downregulation of gene sets associated with tumor suppression functions.Patients with chromothripsis showed a trend of lower complete remission rate and worse overall survival in myeloid malignancy. Large-scale studies are required to further elucidate the causes and treatments of the condition.

Impact assessment of spatial-temporal distribution of riverine dust on air quality using remote sensing data and numerical modeling.

Soil erosion is a severe problem in Taiwan due to the steep terrain, fragile geology, and extreme climatic events resulting from global warming. Due to the rapidly changing hydrological conditions affecting the locations and the amount of transported sand and fine particles, timely impact evaluation and riverine dust control are difficult, particularly when resources are limited. To comprehend the impact of desertification in estuarine areas on the variation of air pollutant concentrations, this study utilized remote sensing technology coupled with an air pollutant dispersion model to determine the unit contribution of potential pollution sources and quantify the effect of riverine dust on air quality. The images of the downstream area of the Beinan River basin captured by Formosat-2 in May 2006 were used to analyze land use and land cover (LULC) composition. Subsequently, the diffusion model ISCST-3 based on Gaussian distribution was utilized to simulate the transport of PM across the study area. Finally, a mixed-integer programming model was developed to optimize resource allocation for dust control. Results reveal that sand deposition in specific river sections significantly influences regional air quality, owing to the unique local topography and wind field conditions. The present optimal plan model for regional air quality control further showed that after implementing engineering measures including water cover, revegetation, armouring cover, and revegetation, total PM concentrations would be reduced by 51%. The contribution equivalent calculation, using the air pollution diffusion model, was effectively integrated into the optimization model to formulate a plan for reducing riverine dust with limited resources based on air quality requirements.

Thrombospondin-1 associated with carotid intima-media thickness among individuals with hypertension.

In vivo and in vitro studies have demonstrated that thrombospondin-1 (TSP-1) is involved in atherosclerotic pathogenesis. However, the role of TSP-1 in clinical atherosclerosis remains unknown. This cross-sectional study investigated the relationship between TSP-1 and carotid intima-media thickness (IMT) and examined whether it interacts with conventional cardiovascular risk factors. A total of 587 participants were enrolled from February 2018 to December 2021. TSP-1 was dichotomized based on median value. Carotid IMT was measured bilaterally in each segment, and the average value was taken as the overall IMT variable. Analysis of covariance models were used to ascertain the main and interaction effects of cardiovascular risk factors and circulating TSP-1 levels on carotid IMT. Those with high TSP-1 (n = 294) had significantly higher carotid IMT than did those with low TSP-1 (n = 293; 0.74 ± 0.12 vs 0.72 ± 0.11 mm; p = 0.011). After the combined effects of TSP-1 and vascular risk factors on carotid IMT were evaluated, an interaction effect on IMT was observed between TSP-1 and hypertension (adjusted F = 8.760; p = 0.003). Stratification analysis revealed that individuals with hypertension and high TSP-1 had significantly higher IMT than did those with low TSP-1 (adjusted p = 0.007). However, this difference was not observed in normotensive individuals (adjusted p = 0.636). In conclusion, this is the first study to provide clinical data supporting the correlation between TSP-1 and atherosclerosis. TSP-1 may be a crucial marker of increased susceptibility to atherosclerosis in individuals with hypertension.

Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.

Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPAbZIP-inf) is classified within the favorable-risk group by the 2022 European LeukemiaNet (ELN-2022). However, heterogeneous clinical outcomes are still observed in these patients. In this study, we aimed to investigate the mutation profiles and transcriptomic patterns associated with poor outcomes in patients with CEBPAbZIP-inf. One hundred and thirteen CEBPAbZIP-inf patients were identified in a cohort of 887 AML patients homogeneously treated with intensive chemotherapy. Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf. RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS). CEBPAbZIP-inf patients with a shorter EFS had higher expression of IFN-stimulated genes (IRF2, IRF5, OAS2, and IFI35). Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival, and the results were independently validated in the TARGET AML cohort. In conclusion, concurrent WT1 or DNMT3A mutations and a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPAbZIP-inf, and upfront allogeneic transplantation may be indicated for better long-term disease control.

Cerebral Semaphorin3D is a novel risk factor for age-associated cognitive impairment.

BACKGROUND: We previously reported that miR-195 exerts neuroprotection by inhibiting Sema3A and cerebral miR-195 levels decreased with age, both of which urged us to explore the role of miR-195 and miR-195-regulated Sema3 family members in age-associated dementia. METHODS: miR-195a KO mice were used to assess the effect of miR-195 on aging and cognitive functions. Sema3D was predicted as a miR-195 target by TargetScan and then verified by luciferase reporter assay, while effects of Sema3D and miR-195 on neural senescence were assessed by beta-galactosidase and dendritic spine density. Cerebral Sema3D was over-expressed by lentivirus and suppressed by si-RNA, and effects of over-expression of Sema3D and knockdown of miR-195 on cognitive functions were assessed by Morris Water Maze, Y-maze, and open field test. The effect of Sema3D on lifespan was assessed in Drosophila. Sema3D inhibitor was developed using homology modeling and virtual screening. One-way and two-way repeated measures ANOVA were applied to assess longitudinal data on mouse cognitive tests. RESULTS: Cognitive impairment and reduced density of dendritic spine were observed in miR-195a knockout mice. Sema3D was identified to be a direct target of miR-195 and a possible contributor to age-associated neurodegeneration as Sema3D levels showed age-dependent increase in rodent brains. Injection of Sema3D-expressing lentivirus caused significant memory deficits while silencing hippocampal Sema3D improved cognition. Repeated injections of Sema3D-expressing lentivirus to elevate cerebral Sema3D for 10 weeks revealed a time-dependent decline of working memory. More importantly, analysis of the data on the Gene Expression Omnibus database showed that Sema3D levels were significantly higher in dementia patients than normal controls (p < 0.001). Over-expression of homolog Sema3D gene in the nervous system of Drosophila reduced locomotor activity and lifespan by 25%. Mechanistically, Sema3D might reduce stemness and number of neural stem cells and potentially disrupt neuronal autophagy. Rapamycin restored density of dendritic spines in the hippocampus from mice injected with Sema3D lentivirus. Our novel small molecule increased viability of Sema3D-treated neurons and might improve autophagy efficiency, which suggested Sema3D could be a potential drug target. Video Abstract CONCLUSION: Our results highlight the importance of Sema3D in age-associated dementia. Sema3D could be a novel drug target for dementia treatment.

miR-328-3p Affects Axial Length Via Multiple Routes and Anti-miR-328-3p Possesses a Potential to Control Myopia Progression.

Purpose: We previously reported miR-328-3p as a novel risk factor for myopia through a genetic association study of the PAX6 gene. In the present study, we first explored the effects of miR-328-3p on other myopia-related genes, and then tested whether anti-miR-328-3p may be used for myopia control. Methods: The luciferase report assay and transient transfection were used to confirm miR-328-3p target genes. The chromatin immunoprecipitation (ChIP) assay was used to investigate retinoic acid receptor on the miR-328-3p promoter. Mice and pigmented rabbits were induced to have myopia by the form deprivation method, and then anti-miR-328-3p oligonucleotide was topically instilled to the myopic eyes. The axial length was measured to assess the therapeutic effect of anti-miR-328-3p. A toxicity study using much higher doses was conducted to assess the safety and ocular irritation of anti-miR-328-3p. Results: The report assay and transfection of miR-328-3p mimic confirmed that miR-328-3p dose-dependently decreased both mRNA and protein expression of fibromodulin (FMOD) and collagen1A1 (COL1A1). We subsequently showed that FMOD promoted TGF-ß1 expression, and overexpression of FMOD increased the phosphorylation levels of p38-MAPK and JNK. The ChIP study showed that retinoic acid binds to miR-328-3p promoter and up-regulates miR-328-3p expression. In myopic animal studies, anti-miR-328-3p was as effective as 1% atropine and had a dose-dependent effect on suppressing axial elongation. In the toxicity study, anti-miR-328-3p did not cause any unwanted effects in the eyes or other organs. Conclusions: Micro (mi)R-328-3p affects myopia development via multiple routes. anti-miR-328-3p possesses a potential as a novel therapy for myopia control.

Hyperspectral sensing of heavy metals in soil by integrating AI and UAV technology.

Given the limitation of conventional soil pollution monitoring through mapping which is a costly, time-consuming work, the study aims to establish an image recognition model to identify the source of pollution automatically. The study choses a contaminated land and then use a non-destructive instrument that can quickly and effectively measure the content of heavy metals. A two concentration prediction models of Ni, Cu, Zn, Cr, Pb, As, Cd, and Hg using hyperspectral imaging were developed, Decision Tree and Back Propagation Neural Network, in combination of particle swarm optimization employed for optimization algorithm. As a result, random forest is more accurate than the forecast result of back propagation neural network. This study has established an excellent Cu and Cr model, which can accurately capture the pollution source. In addition, through aerial photographs, we also found that there were also high pollution reactions on the banks of the river. The developed model is beneficial for high pollution areas which can be quickly found, thereby following investigation and remediation work can be carried out with less time and cost consuming comparing with the conventional soil monitoring.

Cabozantinib promotes erythroid differentiation in K562 erythroleukemia cells through global changes in gene expression and JNK activation.

Cabozantinib is a potent tyrosine kinase inhibitor with multiple targets including MET, VEGFR2, RET, KIT, and FLT3. Cabozantinib is widely used for the treatment of medullary thyroid cancer and renal cell carcinoma. We recently suggested cabozantinib as a potential therapeutic alternative for acute myeloid leukemia (AML) patients with FLT3-internal tandem duplication (FLT3-ITD). Here, we report that cabozantinib can promote differentiation in erythroid leukemia cells. We found that K562 erythroid leukemia cells treated with 1 µM cabozantinib for 72 h underwent erythroid lineage differentiation. Transcriptomic analysis revealed that various pathways associated with heme biosynthesis, hemoglobin production, and GATA1 targets were upregulated, whereas cell survival pathways were downregulated. Further examination revealed that cabozantinib-induced erythroid differentiation is at least in part regulated by JNK activation and phosphorylation. Levels of phosphorylated BCR-ABL, AKT, STAT5, ERK, and p38 also decreased following cabozantinib treatment. Therefore, we indicate that cabozantinib has dual functions. First, it induces K562 cell differentiation toward the erythroid lineage by upregulating heme biosynthesis, globin synthesis, and erythroid-associated reactions. Second, cabozantinib inhibits K562 cell proliferation by inhibiting the phosphorylation of BCR-ABL and the downstream MAPK, PI3K-AKT, and JAK-STAT signaling pathways.

Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission.

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR < 0.5), clinical features, as well as genomic and transcriptomic profiles remain unclear, and evidence supporting allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains controversial. This study aimed to elucidate the genomic features, prognosis, and transplantation outcome of FLT3-ITDIow in AML patients with intermediate-risk cytogenetics. FLT3-ITDlow was associated with a negative enrichment of the leukemic stem cell signature, a marked enrichment of the RAS pathway, and with higher frequencies of RAS pathway mutations, different from those with FLT3-ITDhigh. Concurrent CEBPA double mutations were favorable prognostic factors, whereas MLL-PTD, and mutations in splicing factors were unfavorable prognostic factors in FLT3-ITDlow patients. Patients with FLT3-ITDlow had a shorter overall survival (OS) and event-free survival (EFS) than those with FLT3wt. Allo-HSCT in CR1 was associated with a significantly longer OS and EFS compared with postremission chemotherapy in patients with FLT3-ITDlow. In conclusion, FLT3-ITDlow is associated with different mutational and transcriptomic profiles compared with FLT3-ITDhigh. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITDlow, who markedly benefit from allo-HSCT in CR1.

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis.

Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10-6] and to endoplasmic reticulum stress [p-value = 8.67 × 10-7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10-8], and responses to a redox state [p-value = 5.80 × 10-5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10-8] and an ATP metabolic process [p-value = 3.95 × 10-4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.

Emerging impacts of ionic liquids on eco-environmental safety and human health.

Owing to their unique physicochemical properties, ionic liquids (ILs) have been rapidly applied in diverse areas, such as organic synthesis, electrochemistry, analytical chemistry, functional materials, pharmaceutics, and biomedicine. The increase in the production and application of ILs has resulted in their release into aquatic and terrestrial environments. Because of their low vapor pressure, ILs cause very little pollution in the atmosphere compared to organic solvents. However, ILs are highly persistent in aquatic and terrestrial environments due to their stability, and therefore, potentially threaten the safety of eco-environments and human health. Specifically, the environmental translocation and retention of ILs, or their accumulation in organisms, are all related to their physiochemical properties, such as hydrophobicity. Based on results of ecotoxicity, cytotoxicity, and toxicity in mammalian models, the mechanisms involved in IL-induced toxicity include damage of cell membranes and induction of oxidative stress. Recently, artificial intelligence and machine learning techniques have been used in mining and modeling toxicity data to make meaningful predictions. Major future challenges are also discussed. This review will accelerate our understanding of the safety issues of ILs and serve as a guideline for the design of the next generation of ILs.

Using an unmanned aerial system to monitor and assess irrigation water channels susceptible to sediment deposition.

The irrigation channel of the Qishan River is among the most crucial agricultural water resource facilities in Qishan District, Kaohsiung City, Taiwan. The channel was blocked by debris due to flood events caused by Typhoon Morakot in 2009. This study analyzed images captured by an unmanned aerial system to identify channel areas susceptible to sediment deposition and propose measures for reducing the effects of natural hazards on irrigation water resources. The analysis results revealed that the channel was located downstream of the Qishan River; however, debris flows, riverbank landslides, and natural dam breaches deposited sediment in the downstream section, preventing the flow of water. Furthermore, the sediment and driftwood blocked the channel. The channel was also blocked due to a hyperconcentrated flow. Sediment deposition areas and volumes were estimated. On the basis of these results, we suggest that the damaged riverbed groundsills and river tributary banks be restored to inhibit erosion. In addition, subsurface water collection and transfer structures should be constructed to maintain the flow of water during the dry season. The study findings are expected to increase the efficiency of agricultural irrigation water management and prevent natural hazards from affecting water resources.

Lymphadenopathy Associated With Neutralizing Anti-interferon-gamma Autoantibodies Could Have Monoclonal T-cell Proliferation Indistinguishable From Malignant Lymphoma and Treatable by Antibiotics: A Clinicopathologic Study.

Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management.

Structural Engineering and Optimization of Zwitterionic Salts for Expeditious Discovery of Thermoresponsive Materials.

This work reported the discovery of N-triflimide (NTf)-based zwitter-ionic liquids (ZILs) that exhibit UCST-type phase transitions in water, and their further structural optimization in fine-tuning polarity to ultimately afford newfangled thermosensitive materials carrying attractive and biocompatible Tc values that clearly demonstrated the true value of the tunability of ZIL structure. This research established that with non-aromatic, acyclic ZILs as small-molecule thermoresponsive materials, their mixing and de-mixing with water triggered by temperatures are entirely reversible.

Impact assessment of river dust on regional air quality through integrated remote sensing and air quality modeling.

Sand and dust storms in arid and semiarid regions deteriorate regional air quality and threaten public health security. To quantify the negative effects of river dust on regional air quality, this study selected the estuary areas located in central Taiwan as a case study and proposed an integrated framework to measure the fugitive emission of dust from riverbeds with the aid of satellite remote sensing and wind tunnel test, together with the concentrations of particulate matter with a diameter of <10 µm (PM10) around the river system by using The Air Pollution Model. Additionally, the effects of 25 types of meteorological conditions on the health risk due to exposure to dust were evaluated near the estuary areas. The results reveal landscape changes in the downstream areas of Da'an and Dajia rivers, with an increase of 370,820 m2 and 1,554,850 m2 of bare land areas in the dry season compared with the wet season in Da'an and Dajia rivers, respectively. On the basis of the maximum emission of river dust, PM10 concentration increases considerably during both wet and dry seasons near the two rivers. Among 25 different types of weather conditions, frontal surface transit, outer-region circulation from tropical depression system, weak northeast monsoons, and anticyclonic outflow have considerable influence on PM10 diffusion. In particular, weak northeast monsoons cause the highest health risk in the areas between Da'an and Dajia rivers, which is the densely populated Taichung City. Future studies should attempt to elucidate the environmental impact of dust in different weather conditions and understand the spatial risks to human health due to PM10 concentration. Facing the increasing threat of climate and landscape changes, governments are strongly encouraged to begin multimedia assessments in environmental management and propose a long-term and systematic framework in resources planning.

Combinatorial discovery of thermoresponsive cycloammonium ionic liquids.

This work demonstrated, for the first time, the combinatorial discovery and rational identification of small-molecule cycloammonium-based thermoresponsive ionic liquids that exhibit LCST phase transition and carry attractive Tc values in water.

miR-195 reduces age-related blood-brain barrier leakage caused by thrombospondin-1-mediated selective autophagy.

Blood-brain barrier (BBB) disruption contributes to neurodegenerative diseases. Loss of tight junction (TJ) proteins in cerebral endothelial cells (ECs) is a leading cause of BBB breakdown. We recently reported that miR-195 provides vasoprotection, which urges us to explore the role of miR-195 in BBB integrity. Here, we found cerebral miR-195 levels decreased with age, and BBB leakage was significantly increased in miR-195 knockout mice. Furthermore, exosomes from miR-195-enriched astrocytes increased endothelial TJ proteins and improved BBB integrity. To decipher how miR-195 promoted BBB integrity, we first demonstrated that TJ proteins were metabolized via autophagic-lysosomal pathway and the autophagic adaptor p62 was necessary to promote TJ protein degradation in cerebral ECs. Next, proteomic analysis of exosomes revealed miR-195-suppressed thrombospondin-1 (TSP1) as a major contributor to BBB disruption. Moreover, TSP1 was demonstrated to activate selective autophagy of TJ proteins by increasing the formation of claudin-5-p62 and ZO1-p62 complexes in cerebral ECs while TSP1 impaired general autophagy. Delivering TSP1 antibody into the circulation showed dose-dependent reduction of BBB leakage by 20%-40% in 25-month-old mice. Intravenous or intracerebroventricular injection of miR-195 rescued TSP1-induced BBB leakage. Dementia patients with BBB damage had higher levels of serum TSP1 compared to those without BBB damage (p = 0.0015), while the normal subjects had the lowest TSP1 (p < 0.0001). Taken together, the study implies that TSP1-regulated selective autophagy facilitates the degradation of TJ proteins and weakens BBB integrity. An adequate level of miR-195 can suppress the autophagy-lysosome pathway via a reduction of TSP1, which may be important for maintaining BBB function.

Clinical characteristics and treatment outcomes of pulmonary invasive fungal infection among adult patients with hematological malignancy in a medical centre in Taiwan, 2008-2013.

BACKGROUND/PURPOSE: This study was aimed to investigate clinical characteristics and treatment outcomes of pulmonary invasive fungal infection (IFI) among patients with hematological malignancy. METHODS: All patients with hematological malignancy who were treated at a medical centre from 2008 to 2013 were evaluated. Pulmonary IFI was classified according to the European Organization for Research and Treatment of Cancer 2008 consensus. RESULTS: During the study period, 236 (11.3%) of 2083 patients with hematological malignancy were diagnosed as pulmonary IFI, including 41 (17.4%) proven, 75 (31.8%) probable, and 120 (50.8%) possible cases. Among the 116 patients of proven and probable cases of pulmonary IFI, aspergillosis alone (n = 90, 77.6%) was predominant, followed by cryptococcosis alone (n = 9, 7.8%), and mucormycosis (n = 4, 3.4%). The overall incidence of patients with pulmonary IFI was 5.9 per 100 patient-years. The highest incidence (per 100 patient-year) was found in patients with acute myeloid leukaemia (13.7) followed by acute lymphoblastic leukaemia (11.3), and myelodysplastic syndrome/severe aplastic anaemia (6.7). Fourteen (5.9%) of the 236 patients with pulmonary IFI died within 12 weeks after diagnosis of pulmonary IFI. Univariate analysis revealed that elderly age (>65 years) (P = 0.034), lack of response to anti-fungal treatment (P < 0.001), and admission to the intensive care unit (ICU) (P < 0.001) were predictors of poor prognosis. However, only admission to the ICU was an independent predictor of poor prognosis for 12-week mortality (P = 0.022) based on multivariate analysis. CONCLUSION: Patients with acute leukaemia and myelodysplastic syndrome/severe aplastic anaemia were at high risk of pulmonary IFI.

Chronic disseminated candidiasis manifesting as hepatosplenic abscesses among patients with hematological malignancies.

BACKGROUND: The outcomes of deep-seated abscesses attributed to chronic disseminated candidiasis (CDC) in patients with hematological malignancies have rarely been reported in recent years. METHODS: We retrospectively reviewed and analyzed the data of patients with hematological malignancies who received a diagnosis of CDC at a medical center in Taiwan between 2008 and 2013. RESULTS: Sixty-one patients (32 men and 29 women) were diagnosed with CDC. The median age was 51 years (range: 18-83). The overall incidence of CDC was 1.53 per 100 patient-years in patients with hematological malignancies between 2008 and 2013. The highest incidence of CDC was 4.3 per 100 patient-years for acute lymphoblastic leukemia, followed by 3.6 for acute myeloid leukemia. We detected 3 (4.9%) proven, 13 (21.3%) probable, and 45 (73.8%) possible cases of CDC. A total of 13 patients had positive blood cultures for Candida species: C. tropicalis (8), C. albicans (2), C. glabrata (2), and C. famata (1). The median duration of antifungal treatment was 96 days (range: 7-796 days). Serial imaging studies revealed that the resolution rate of CDC was 30.0% at 3 months and 54.3% at 6 months. Five patients (8.2%) had residual lesions that persisted beyond one year. A multivariate analysis of the 90-day outcome revealed that shock was the only independent prognostic factor of 90-day survival in patients with CDC. CONCLUSION: The incidence of CDC did not decrease between 2008 and 2013. Patients with acute leukemia had a higher risk of CDC than those with other hematological malignancies. Imaging studies conducted at 6 months after diagnosis revealed that only half of the patients showed complete resolution. CDC requires prolonged treatment, and serial imaging at 6 months interval is suggested. Shock is the only independent prognostic factor of 90-day survival in patients with CDC.

Long non-coding RNA HOXB-AS3 promotes myeloid cell proliferation and its higher expression is an adverse prognostic marker in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS. METHODS: shRNAs were used to downregulate HOXB-AS3 in the cell lines and the effect was evaluated by quantitative polymerase chain reaction. The proliferation of the cell lines was illustrated by proliferation and BrdU flow assays. Further, we retrospectively analyzed the HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis, and evaluated its clinical importance. RESULTS: Downregulation of HOXB-AS3 suppressed cell proliferation. Mechanistically, HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P <  0.0001; median relapse-free survival, 12.9 months versus not reached, P = 0.0070). In MDS, patients with higher HOXB-AS3 expression also had adverse prognosis compared with those with lower HOXB-AS3 expression (median OS, 14.6 months versus 42.4 months, P = 0.0018). The prognostic significance of HOXB-AS3 expression was validated in the TCGA AML cohort and another MDS cohort from our institute. The subgroup analyses in MDS patients showed that higher HOXB-AS3 expressions could predict poor prognosis only in lower-risk (median OS, 29.2 months versus 77.3 months, P = 0.0194), but not higher-risk group. CONCLUSIONS: This study uncovers a promoting role of HOXB-AS3 in myeloid malignancies and identifies the prognostic value of HOXB-AS3 expression in AML and MDS patients, particularly in the lower-risk group.