- Anti-streptavidin IgG antibody interference in anti-cyclic citrullinated peptide (CCP) IgG antibody assays is a rare but important cause of false-positive anti-CCP results. [Journal Article]
- CCClin Chem Lab Med 2018 Feb 21
- CONCLUSIONS: Anti-streptavidin IgG antibodies rarely cause false-positive results in some anti-CCP assays. However, despite being an infrequent assay problem, it could possibly lead to diagnostic confusion or even an incorrect diagnosis of rheumatoid arthritis.
- Sliding friction and contact angle hysteresis of droplets on microhole-structured surfaces. [Journal Article]
- EPEur Phys J E Soft Matter 2018 Feb 20; 41(2):25
- Microstructured surfaces with continuous solid topography have many potential applications in biology and industry. To understand the liquid transport property of microstructured surfaces with contin...
Microstructured surfaces with continuous solid topography have many potential applications in biology and industry. To understand the liquid transport property of microstructured surfaces with continuous solid topography, we studied the sliding behavior of a droplet on microhole-structured surfaces. We found that the sliding friction of the droplet increased with increasing solid area fraction due to enlarged apparent contact area and enhanced contact angle hysteresis. By introducing a correction factor to the modified Cassie-Baxter relation, we proposed an improved theoretical model to better predict the apparent receding contact angle. Our experimental data also revealed that the geometric topology of surface microstructures could affect the sliding friction with microhole-decorated surfaces, exhibiting a larger resistance than that for micropillar-decorated surfaces. Assisted by optical microscopy, we attributed this topology effect to the continuity and the true total length of the three-phase contact line at the receding edge during the sliding. Our study provides new insights into the liquid sliding behavior on microstructured surfaces with different topologies, which may help better design functional surfaces with special liquid transport properties.
- A multicenter, retrospective analysis of elderly patients with acute myeloid leukemia who were treated with decitabine. [Journal Article]
- OOncotarget 2018 Jan 19; 9(5):6607-6614
- Decitabine is widely accepted as the treatment options for elderly acute myeloid leukemia (AML) patients. However, the efficacy has yet been assessed in Asian population. We retrospectively analyzed ...
Decitabine is widely accepted as the treatment options for elderly acute myeloid leukemia (AML) patients. However, the efficacy has yet been assessed in Asian population. We retrospectively analyzed the outcomes of 80 Korean elderly AML patients who were treated with decitabine. The median age was 74 years (range, 64 to 86 years) and 6 (7.5%), 48 (60.0%), and 25 (31.3%) patients were categorized to favorable, intermediate, and poor risk group, respectively. The median OS was 10.2 months (95% CI 5.0-15.4). Given that decitabine treatment demonstrated improved clinical outcomes, it could be considered as one of the first-line treatment for Korean elderly AML patients.
- SNP-array lesions in core binding factor acute myeloid leukemia. [Journal Article]
- OOncotarget 2018 Jan 19; 9(5):6478-6489
- Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the d...
Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis.ZBTB7Amutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p.FOXP1focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carriedFOXP1truncating mutations. Finally,CCDC26disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia.
- Rapid development of myeloproliferative neoplasm in mice withPtpn11 D61Y mutation and haploinsufficient forDnmt3a. [Journal Article]
- OOncotarget 2018 Jan 19; 9(5):6055-6061
- PTPN11gain-of-function mutation is the most common mutation found in patients with juvenile myelomonocytic leukemia and DNMT3A loss occurs in over 20% of acute myeloid leukemia pa...
PTPN11gain-of-function mutation is the most common mutation found in patients with juvenile myelomonocytic leukemia and DNMT3A loss occurs in over 20% of acute myeloid leukemia patients. We studied the combined effect of bothPtpn11gain-of-function mutation (D61Y) andDnmt3ahaploinsufficiency on mouse hematopoiesis, the presence of which has been described in both juvenile myelomonocytic leukemia and acute myeloid leukemia patients. Double mutant mice rapidly become moribund relative to any of the other genotypes, which is associated with enlargement of the spleen and an increase in white blood cell counts. An increase in the mature myeloid cell compartment as reflected by the presence of Gr1+Mac1+cells was also observed in double mutant mice relative to any other group. Consistent with these observations, a significant increase in the absolute number of granulocyte macrophage progenitors (GMPs) was seen in double mutant mice. A decrease in the lymphoid compartment including both T and B cells was noted in the double mutant mice. Another significant difference was the presence of extramedullary erythropoiesis with increased erythroid progenitors in the spleens ofDnmt3a +/ -;D61Ymice relative to other groups. Taken together, our results suggest that the combined haploinsufficiency ofDnmt3aand presence of an activatedShp2changes the composition of multiple hematopoietic lineages in mice relative to the individual heterozygosity of these genes.
- Consecutive epigenetically-active agent combinations act inID1-RUNX3-TET2andHOXApathways forFlt3ITD+veAML. [Journal Article]
- OOncotarget 2018 Jan 19; 9(5):5703-5715
- Co-occurrence ofFlt3ITDandTET2mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, includingRUNX3,and by hyperexpression ofID1,encoding Wnt agonist. These aff...
Co-occurrence ofFlt3ITDandTET2mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, includingRUNX3,and by hyperexpression ofID1,encoding Wnt agonist. These affectHOXAover-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, includingFlt3ITD+ve,described with a signature of repressed tumor suppressor genes, involving Wnt antagonistRUNX3, occurring along withID1andHOXAover-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linkingRUNX3/Wnt antagonist de-repression (80%) andID1downregulation (85%), to a response, also preceded by profoundHOXA9repression. Response occurred in context of concurrentTET2mutation/hypomorphy andFlt3ITD+vemutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response inFlt3ITD+vecases exhibiting such Wnt pathway dysregulation.
- Endogenous volatile organic compounds in acute myeloid leukemia: Origins and potential clinical applications. [Journal Article]
- JBJ Breath Res 2018 Feb 21
- Not unlike many cancer types, acute myeloid leukemia (AML) exhibits many metabolic changes and reprogramming, causing changes in lipid metabolism. Some of the distinct molecular abnormalities associa...
Not unlike many cancer types, acute myeloid leukemia (AML) exhibits many metabolic changes and reprogramming, causing changes in lipid metabolism. Some of the distinct molecular abnormalities associated with AML also modify the metabolic changes. Both processes result in changes in the production of endogenous volatile organic compounds (VOCs). The increasing availability of highly sensitive methods for detecting trace chemicals provides the opportunity to investigate the role of patient-specific VOC finger-prints as biomarkers for detecting early relapse or minimal residual disease (MRD) in AML. Since VOC production is reliant on metabolic activities, when combined with currently available methods, VOC analysis may identify within a group of patients with flow cytometric or molecular evidence of residual disease those most at risk for disease relapse.
- Glutaminolysis is a metabolic dependency in FLT3ITDacute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition. [Journal Article]
- BloodBlood 2018 Feb 20
- FLT3 internal tandem duplication (FLT3ITD) are common mutations in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) h...
FLT3 internal tandem duplication (FLT3ITD) are common mutations in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITDAML patients remains poor and demands the identification of novel, specific and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide CRISPR/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITDAML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations, and validate the role of GLS as a clinically actionable therapeutic target in both primary AML andin vivomodels. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI, and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITDand other TK activating mutation driven leukemias.
- Disruption of Wnt/β-catenin exerts anti-leukemia activity and synergizes with FLT3 inhibition in FLT3-mutant acute myeloid leukemia. [Journal Article]
- CCClin Cancer Res 2018 Feb 20
- Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear local...
Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKIs) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the anti-leukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML.
New Search Next
- Phase Ib Study of Glasdegib, A Hedgehog Pathway Inhibitor, in Combination With Standard Chemotherapy in Patients With AML or High-Risk MDS. [Journal Article]
- CCClin Cancer Res 2018 Feb 20
- CONCLUSIONS: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS.