Unlocking the potential of anti-CD33 therapy in adult and childhood acute myeloid leukaemia

Acute Myeloid Leukaemia (AML) develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a heterogeneous disease clinically, morphologically, and genetically, and biological differences between adult and childhood AML have been identified. AML comprises 15-20% of all children less than fifteen years diagnosed with acute leukaemia. Relapse occurs in up to 40% of children with AML and is the commonest cause of death.1,2 Relapse arises from leukaemic stem cells (LSCs) that persist after conventional chemotherapy. The treatment of AML is challenging and new strategies to target LSCs are required. The cell surface marker CD33 has been identified as a therapeutic target, and novel anti-CD33 immunotherapies are promising new agents in the treatment of AML. This review will summarise recent developments emphasising the genetic differences in adult and childhood AML, while highlighting the rationale for CD33 as a target for therapy, in all age groups

Concordance of copy number abnormality detection using SNP arrays and Multiplex Ligation-dependent Probe Amplification (MLPA) in acute lymphoblastic leukaemia

In acute lymphoblastic leukaemia, MLPA has been used in research studies to identify clinically relevant copy number abnormality (CNA) profiles. However, in diagnostic settings other techniques are often employed. We assess whether equivalent CNA profiles are called using SNP arrays, ensuring platform independence. We demonstrate concordance between SNP6.0 and MLPA CNA calling on 143 leukaemia samples from two UK trials; comparing 1,287 calls within eight genes and a region. The techniques are 99% concordant using manually augmented calling, and 98% concordant using an automated pipeline. We classify these discordant calls and examine reasons for discordance. In nine cases the circular binary segmentation (CBS) algorithm failed to detect focal abnormalities or those flanking gaps in IKZF1 probe coverage. Eight cases were discordant due to probe design differences, with focal abnormalities detectable using one technique not observable by the other. Risk classification using manually augmented array calling resulted in four out of 143 patients being assigned to a different CNA risk group and eight patients using the automated pipeline. We conclude that MLPA defined CNA profiles can be accurately mirrored by SNP6.0 or similar array platforms. Automated calling using the CBS algorithm proved successful, except for IKZF1 which should be manually inspected

Effects of Muscular Fatigue on Endurance Athletes During a Backyard Ultra Race: A Pilot Study

Neuromuscular fatigue is a complex phenomenon that occurs during long-duration exercise. A backyard ultra-race requires participants to intermittently run laps (\u3c1hour) for distances that ultimately surpass ultramarathon mileage. Quantifying physiological fatigue during ultramarathon races is difficult due to duration, pace, and terrain; however, vertical jump via force plate analysis is an effective field-based method to quantify neuromuscular fatigue, and may be used to further predict individual race longevity. PURPOSE: The purpose of this study is to measure muscular fatigue utilizing force plate analysis during a back-yard ultra-marathon. METHODS: Twelve participants were recruited from sign-up participation in a local backyard ultramarathon race. Each participant performed maximal effort countermovement jumps on the force plate. Participants were instructed to place hands on hips and perform a maximal effort jump two times with two to three seconds rest between. Jumps were collected at baseline and immediately following completion of each 4.167-mile race loop. Participants completed the race course loops until volitional fatigue or until they could no longer maintain a loop in 60 minutes (failure). Participants who completed a total of four laps were included in the analysis for vertical jump height (VJ) and braking rate of force development (BRFD). A repeated-measures analysis of variance (ANOVA) was performed to determine differences in fatigue from baseline to each subsequent lap. Furthermore, data was separated by sex in order to identify any sex-related differences in fatigue. Alpha level was set at 0.05. RESULTS: Eight female (age= 27.6±14.15y; height=161±7cm; weight= 63.22±9.73kg) and four male (age=36.25±10.2y; height= 174.63±5.64cm; weight= 71.21±5.6kg) volunteer runners were included in this analysis. ANOVA (sex x time) revealed no statistically significant interactions for BRFD and VJ. There were no significant main effects observed in BRFD; however, there was a time main effect for VJ (p\u3c0.05). Across the entire sample population, statistical significance was observed in VJ between the second and fourth time point (p\u3c0.05). Though there were no interactions between sex, female VJ between the second and fourth timepoint reached statistical significance (p\u3c0.05). CONCLUSION: VJ measured via force plate analysis may be a viable option to quantify rates of muscular fatigue during an ultramarathon race. Other extracted variables such as BRFD may not be reliable tools due to the lack of skill in participants. Although current literature provides evidence of sex related differences in fatigue rates, there were no significant findings for sex. Limitations include the sample size and possible variability in training status for some novice runners. Further exploration into the sport of ultra-running is warranted to determine if sex-related differences in fatigue within this population

Lattice QCD matrix elements for the B0s − B¯0s width difference beyond leading order

Predicting the B0s −B¯0s width difference Δ Γ s relies on the heavy quark expansion and on hadronic matrix elements of Δ B = 2 operators. We present the first lattice QCD results for matrix elements of the dimension-7 operators R 2 , 3 and linear combinations ˜ R 2 , 3 using nonrelativistic QCD for the bottom quark and a highly improved staggered quark (HISQ) action for the strange quark. Computations use MILC ensembles of gauge field configuations with 2 + 1 + 1 flavors of sea quarks with the HISQ discretization, including lattices with physically light up/down quark masses. We discuss features unique to calculating matrix elements of these operators and analyze uncertainties from series truncation, discretization, and quark mass dependence. Finally we report the first Standard Model determination of Δ Γ s using lattice QCD results for all hadronic matrix elements through O ( 1 / m b ) . The main result of our calculations yields the 1 / m b contribution Δ Γ 1 / m b = − 0.022 ( 10 ) p s − 1 . Adding this to the leading order contribution, the Standard Model prediction is Δ Γ s = 0.092 ( 14 ) p s − 1

Heterogeneity Mapping of Protein Expression in Tumors using Quantitative Immunofluorescence

Morphologic heterogeneity within an individual tumor is well-recognized by histopathologists in surgical practice. While this often takes the form of areas of distinct differentiation into recognized histological subtypes, or different pathological grade, often there are more subtle differences in phenotype which defy accurate classification (Figure 1). Ultimately, since morphology is dictated by the underlying molecular phenotype, areas with visible differences are likely to be accompanied by differences in the expression of proteins which orchestrate cellular function and behavior, and therefore, appearance. The significance of visible and invisible (molecular) heterogeneity for prognosis is unknown, but recent evidence suggests that, at least at the genetic level, heterogeneity exists in the primary tumor1,2, and some of these sub-clones give rise to metastatic (and therefore lethal) disease

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

Burkitt's lymphoma

Burkitt's lymphoma is a highly aggressive B-cell non-Hodgkin lymphoma and is the fastest growing human tumour. The disease is associated with Epstein-Barr virus and was one of the first tumours shown to have a chromosomal translocation that activates an oncogene (c-MYC). Burkitt's lymphoma is the most common childhood cancer in areas where malaria is holoendemic. The incidence is very high in immunosuppressed patients in non-endemic areas, especially when associated with HIV infection. Outcome with intensive chemotherapy has improved and is now excellent in children, but the prognosis is poor in elderly adults. The success of intensive treatment relies on good supportive care. The therapy offered in oncology units in low-income countries is not as aggressive as in centres in high-income countries and outcomes are less successful. Adjuvant monoclonal antibody therapy with rituximab shows promise for improved outcomes and reduced toxic effects in the future

Comparison of Bioimpedance Analysis and Dual Energy X-Ray Absorptiometry in Division III Football Athletes

Body composition is an integral component of physiology and pathology, as well as an indication of how the musculoskeletal system changes over time in response to training and/or nutritional modifications. Two common methods of estimating body composition include bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA). There is a debate regarding the agreement between these two methods, and it is thought that the population being tested may influence the similarity of estimates obtained by these technologies. Limited data comparing these two methodologies in athletic populations are available. PURPOSE: The purpose of this study was to take examine the agreement between BIA and DXA for estimates of body mass (BM) and body fat percentage (BF%). METHODS: Forty-three division III football players (mean ± SD; age: 19.9 ± 1.7 y; height: 179.7 ± 7.4 cm; BM: 100.3 ± 21.9 kg; DXA BF%: 21.8 ± 7.1%) reported to the Human Performance Lab after abstaining from exercise for the previous 24 hours and fasting from food/beverages (except water) for 12 hours. After an initial height assessment, BM and BF% were assessed using both BIA (Inbody 770) and DXA (Hologic Horizon W). BIA was performed in the standing position using an 8-point electrode arrangement. The electrode panels were placed at the hands and feet. DXA was performed with the participants in a supine position and hips internally rotated. Differences in BM and BF% from DXA and BIA were compared using paired-samples t-tests, Bland-Altman analysis, and validity metrics. RESULTS: BM detected by DXA was significantly lower than BM obtained from the BIA scale (DXA: 98.2 ± 20.8 kg, BIA: 100.3 ± 21.9 kg; p \u3c 0.001). Additionally, Bland-Altman analysis indicated significantly greater underestimation of BM by DXA in individuals with higher BM values (slope: 0.053; p \u3c 0.001). BF% did not significantly differ between DXA and BIA (DXA: 21.8 ± 7.1%, BIA: 21.8 ± 8.4%; p = 0.86). However, Bland-Altman analysis indicated significant proportional bias, with underestimations of BF% by BIA in leaner individuals but overestimations of BF% in those with higher BF% (slope: 0.176; p = 0.005). The total error and 95% limits of agreement for BF% were 3.2% and ± 6.4%, respectively. CONCLUSION: This study demonstrates that although DXA and BIA exhibit good group-level agreement for BF%, several inconsistencies between these methodologies are present. Estimates of BM differed between technologies. Additionally, proportional bias for BF% was observed indicating different levels of agreement between DXA and BIA depending on the body fat of the individuals being tested. Based on these findings, caution should be employed when interpreting data from DXA and BIA assessments in athletic populations

Genome sequencing data for wild and cultivated bananas, plantains and abacá

We performed shotgun genome sequencing on a total of 19 different Musa genotypes including representatives of wild banana species Musa acuminata and M. balibisiana, allopolyploid bananas and plantains, Fe'i banana, pink banana (also known as hairy banana) and abacá (also known as hemp banana). We aligned sequence reads against a previously sequenced reference genome and assessed ploidy and, in the case of allopolyploids, the contributions of the A and B genomes; this provides important quality-assurance data about the taxonomic identities of the sequenced plant material. These data will be useful for phylogenetics, crop improvement, studies of the complex story of intergenomic recombination in AAB and ABB allotriploid bananas and plantains and can be integrated into resources such as the Banana Genome Hub