Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML.

Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.

Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/.

Retinitis pigmentosa (RP) is a heterogeneous disease and the main cause of vision loss within the group of inherited retinal diseases (IRDs). IRDs are a group of rare disorders caused by mutations in one or more of over 280 genes which ultimately result in blindness. Modifier genes play a key role in modulating disease phenotypes, and mutations in them can affect disease outcomes, rate of progression, and severity. Our previous studies have demonstrated that the nuclear hormone receptor 2 family e, member 3 (Nr2e3) gene reduced disease progression and loss of photoreceptor cell layers in RhoP23H-/- mice. This follow up, pharmacology study evaluates a longitudinal NR2E3 dose response in the clinically relevant heterozygous RhoP23H mouse. Reduced retinal degeneration and improved retinal morphology was observed 6 months following treatment evaluating three different NR2E3 doses. Histological and immunohistochemical analysis revealed regions of photoreceptor rescue in the treated retinas of RhoP23H+/- mice. Functional assessment by electroretinogram (ERG) showed attenuated photoreceptor degeneration with all doses. This study demonstrates the effectiveness of different doses of NR2E3 at reducing retinal degeneration and informs dose selection for clinical trials of RhoP23H-associated RP.

SPINK2 Protein Expression Is an Independent Adverse Prognostic Marker in AML and Is Potentially Implicated in the Regulation of Ferroptosis and Immune Response.

There is an urgent need for the identification as well as clinicopathological and functional characterization of potent prognostic biomarkers and therapeutic targets in acute myeloid leukemia (AML). Using immunohistochemistry and next-generation sequencing, we investigated the protein expression as well as clinicopathological and prognostic associations of serine protease inhibitor Kazal type 2 (SPINK2) in AML and examined its potential biological functions. High SPINK2 protein expression was an independent adverse biomarker for survival and an indicator of elevated therapy resistance and relapse risk. SPINK2 expression was associated with AML with an NPM1 mutation and an intermediate risk by cytogenetics and European LeukemiaNet (ELN) 2022 criteria. Furthermore, SPINK2 expression could refine the ELN2022prognostic stratification. Functionally, an RNA sequencing analysis uncovered a potential link of SPINK2 with ferroptosis and immune response. SPINK2 regulated the expression of certain P53 targets and ferroptosis-related genes, including SLC7A11 and STEAP3, and affected cystine uptake, intracellular iron levels and sensitivity to erastin, a specific ferroptosis inducer. Furthermore, SPINK2 inhibition consistently increased the expression of ALCAM, an immune response enhancer and promoter of T-cell activity. Additionally, we identified a potential small-molecule inhibitor of SPINK2, which requires further characterization. In summary, high SPINK2 protein expression was a potent adverse prognostic marker in AML and might represent a druggable target.

Directed Evolution of an Iron(II)- and α-Ketoglutarate-Dependent Dioxygenase for Site-Selective Azidation of Unactivated Aliphatic C-H Bonds.

FeII - and α-ketoglutarate-dependent halogenases and oxygenases can catalyze site-selective functionalization of C-H bonds via a variety of C-X bond forming reactions, but achieving high chemoselectivity for functionalization using non-native functional groups remains rare. The current study shows that directed evolution can be used to engineer variants of the dioxygenase SadX that address this challenge. Site-selective azidation of succinylated amino acids and a succinylated amine was achieved as a result of mutations throughout the SadX structure. The installed azide group was reduced to a primary amine, and the succinyl group required for azidation was enzymatically cleaved to provide the corresponding amine. These results provide a promising starting point for evolving additional SadX variants with activity on structurally distinct substrates and for enabling enzymatic C-H functionalization with other non-native functional groups.

Non-Native Anionic Ligand Binding and Reactivity in Engineered Variants of the Fe(II)- and α-Ketoglutarate-Dependent Oxygenase, SadA.

Mononuclear non-heme Fe(II)- and α-ketoglutarate-dependent oxygenases (FeDOs) catalyze a site-selective C-H hydroxylation. Variants of these enzymes in which a conserved Asp/Glu residue in the Fe(II)-binding facial triad is replaced by Ala/Gly can, in some cases, bind various anionic ligands and catalyze non-native chlorination and bromination reactions. In this study, we explore the binding of different anions to an FeDO facial triad variant, SadX, and the effects of that binding on HO• vs X• rebound. We establish not only that chloride and bromide enable non-native halogenation reactions but also that all anions investigated, including azide, cyanate, formate, and fluoride, significantly accelerate and influence the site selectivity of SadX hydroxylation catalysis. Azide and cyanate also lead to the formation of products resulting from N3•, NCO•, and OCN• rebound. While fluoride rebound is not observed, the rate acceleration provided by this ligand leads us to calculate barriers for HO• and F• rebound from a putative Fe(III)(OH)(F) intermediate. These calculations suggest that the lack of fluorination is due to the relative barriers of the HO• and F• rebound transition states rather than an inaccessible barrier for F• rebound. Together, these results improve our understanding of the FeDO facial triad variant tolerance of different anionic ligands, their ability to promote rebound involving these ligands, and inherent rebound preferences relative to HO• that will aid efforts to develop non-native catalysis using these enzymes.

Sensitivity Training for Mothers With Premature Infants: A Randomized Controlled Trial.

OBJECTIVE: This single-blind parallel design randomized controlled trial evaluated the feasibility and effectiveness of a modified version of the Mother-Infant Transaction Program (MITP) in enhancing Chinese mothers' sensitivity towards their premature infants' physiological and social cues. METHODS: Sixty mothers of hospitalized premature infants (mean gestational age = 32.1 weeks; SD = 2.8) were randomly assigned to either the MITP group or the treatment-as-usual control group. The intervention group (n = 30) received four sessions of parental sensitivity training adapted from the MITP, delivered by clinical psychologists before the infants were discharged. The control group (n = 30) received standard care provided by the hospitals. Each dyad was assessed at baseline (Time 1), immediately after intervention (Time 2), and when the infants were at the gestation-corrected ages of 3, 6, 9, and 12 months (Times 3-6). Maternal sensitivity, mother-infant interaction quality, parenting stress, postpartum depression, and mother's perception of infant's temperament were measured at Times 1-4, whereas infants' weight gain and developmental performance were assessed at Times 3-6. RESULTS: The MITP group showed significantly higher maternal sensitivity and better mother-infant interaction quality after completing the training. They also reported less parenting stress and postnatal depression than the control group at Time 2 and subsequent follow-ups. The intervention significantly predicted better weight gain and developmental outcomes in infants across Times 3-6, mediated by maternal wellbeing and interaction quality. CONCLUSION: Our results demonstrated the feasibility and effectiveness of this adapted sensitivity training among Chinese mothers with premature infants. [ClinicalTrials.gov NCT04383340].

A Scoping Review of Professional Identity Formation in Undergraduate Medical Education.

BACKGROUND: Professional identity formation (PIF) in medical students is a multifactorial phenomenon, shaped by ways that clinical and non-clinical experiences, expectations and environmental factors merge with individual values, beliefs and obligations. The relationship between students' evolving professional identity and self-identity or personhood remains ill-defined, making it challenging for medical schools to support PIF systematically and strategically. Primarily, to capture prevailing literature on PIF in medical school education, and secondarily, to ascertain how PIF influences on medical students may be viewed through the lens of the ring theory of personhood (RToP) and to identify ways that medical schools support PIF. METHODS: A systematic scoping review was conducted using the systematic evidence-based approach. Articles published between 1 January 2000 and 1 July 2020 related to PIF in medical students were searched using PubMed, Embase, PsycINFO, ERIC and Scopus. Articles of all study designs (quantitative and qualitative), published or translated into English, were included. Concurrent thematic and directed content analyses were used to evaluate the data. RESULTS: A total of 10443 abstracts were identified, 272 full-text articles evaluated, and 76 articles included. Thematic and directed content analyses revealed similar themes and categories as follows: characteristics of PIF in relation to professionalism, role of socialization in PIF, PIF enablers and barriers, and medical school approaches to supporting PIF. DISCUSSION: PIF involves iterative construction, deconstruction and inculcation of professional beliefs, values and behaviours into a pre-existent identity. Through the lens of RToP, factors were elucidated that promote or hinder students' identity development on individual, relational or societal levels. If inadequately or inappropriately supported, enabling factors become barriers to PIF. Medical schools employ an all-encompassing approach to support PIF, illuminating the need for distinct and deliberate longitudinal monitoring and mentoring to foster students' balanced integration of personal and professional identities over time.

t(1;22)(p13;q13) Acute Megakaryoblastic Leukemia Complicated by Hepatic Fibrosis: Antifibrosis Therapy?

BACKGROUND: There is no established effective treatment for patients with t(1;22)(p13;q13) acute megakaryoblastic leukemia (AMKL) and hepatic fibrosis. OBSERVATION: Here we report the outcomes of 2 t(1;22)(p13;q13) AMKL patients with hepatic fibrosis. One patient died from liver failure despite the control of leukemia. The other patient was successfully treated with reduced-intensity chemotherapy and antifibrosis therapy with tretinoin and α-tocopheryl acetate, the hepatic fibrosis resolved and leukemia was in remission for 3 years. CONCLUSIONS: Reduced-intensity chemotherapy plus antifibrosis therapy with tretinoin and α-tocopheryl acetate could be a treatment option for these patients with t(1;22)(p13;q13) AMKL and hepatic fibrosis.

The impact of the COVID-19 pandemic on physical and mental health in the two largest economies in the world: a comparison between the United States and China.

The broad impact of the COVID-19 on self-reported daily behaviors and health in Chinese and US samples remains unknown. This study aimed to compare physical and mental health between people from the United States (U.S.) and China, and to correlate mental health parameters with variables relating to physical symptoms, knowledge about COVID-19, and precautionary health behaviors. To minimize risk of exposure, respondents were electronically invited by existing study respondents or by data sourcing software and surveys were completed via online survey platforms. Information was collected on demographics, physical symptoms, contact history, knowledge about COVID-19, psychologic parameters (i.e. IES-R; DASS-21), and health behaviors. The study included a total of 1445 respondents (584 U.S.; 861 China). Overall, Americans reported more physical symptoms, contact history, and perceived likelihood of contracting COVID-19. Americans reported more stress and depressive symptoms, while Chinese reported higher acute-traumatic stress symptoms. Differences were identified regarding face mask use and desires for COVID-19 related health information, with differential mental health implications. Physical symptoms that were possibly COVID-19 related were associated with adverse mental health. Overall, American and Chinese participants reported different mental and physical health parameters, health behaviors, precautionary measures, and knowledge of COVID-19; different risk and protective factors were also identified.

Development of a novel mobile application, HBB Prompt, with human factors and user-centred design for Helping Babies Breathe skills retention in Uganda.

BACKGROUND: Helping Babies Breathe (HBB) is a life-saving program that has helped reduce neonatal morbidity and mortality, but knowledge and skills retention after training remains a significant challenge for sustainability of impact. User-centred design (UCD) can be used to develop solutions to target knowledge and skills maintenance. METHODS: We applied a process of UCD beginning with understanding the facilitators of, and barriers to, learning and retaining HBB knowledge and skills. HBB Master Trainers and frontline HBB providers participated in a series of focus group discussions (FGDs) to uncover the processes of skills acquisition and maintenance to develop a mobile application called "HBB Prompt". Themes derived from each FGD were identified and implications for development of the HBB Prompt app were explored, including feasibility of incorporating strategies into the format of an app. Data analysis took place after each iteration in Phase 1 to incorporate feedback and improve subsequent versions of HBB Prompt. RESULTS: Six HBB trainers and seven frontline HBB providers participated in a series of FGDs in Phase 1 of this study. Common themes included lack of motivation to practise, improving confidence in ventilation skills, ability to achieve the Golden Minute, fear of forgetting knowledge or skills, importance of feedback, and peer-to-peer learning. Themes identified that were not feasible to address pertained to health system challenges. Feedback about HBB Prompt was generally positive. Based on initial and iterative feedback, HBB Prompt was created with four primary functions: Training Mode, Simulation Mode, Quizzes, and Dashboard/Scoreboard. CONCLUSIONS: Developing HBB Prompt with UCD to help improve knowledge and skills retention was feasible and revealed key concepts, including drivers for successes and challenges faced for learning and maintaining HBB skills. HBB Prompt will be piloted in Phase 2 of this study, where knowledge and skills retention after HBB training will be compared between an intervention group with HBB Prompt and a control group without the app. Trial registration Clinicaltrials.gov (NCT03577054). Retrospectively registered July 5, 2018, https://clinicaltrials.gov/ct2/show/study/NCT03577054 .

An Evaluation for the Causes of Reduced Hb A2 and the Molecular Characterization of HBD Variants in Hong Kong.

Prenatal screening of ß-thalassemia (ß-thal) carriers is based on the hallmark phenotype of microcytosis and raised Hb A2. The unanticipated birth of ß-thal major (ß-TM) offspring to ß-thal carriers who were misdiagnosed during prenatal screening have been reported. A subset of these resulted from the masked phenotype due to the coinheritance of HBD variants. In a broader sense, the causes of reduced Hb A2 in thalassemia screening, the prevalence and spectrum of HBD variants in Hong Kong remain to be characterized. Over a 13-month period, a total of 2982 samples were referred for thalassemia screening. Surplus samples with reduced Hb A2 levels (2.0%) were evaluated. HBD variations were assessed by direct sequencing. Sixty-six samples were tested. Hb H disease, HBD variants, α-thalassemia (α-thal) trait and iron deficiency were detected in 40 (60.6%), 12 (18.2%), eight (12.1%) and seven (10.6%) samples, respectively. Seven samples carried more than one of the mentioned conditions. The cause remained elusive in seven samples. Thirteen HBD variants were detected and two were recurrent, including HBD: c.-127T>C [-77 (T>C)] and HBD: c.314G>A (Hb Chori-Burnaby). A novel nonsense variant HBD: c.262C>T [codon 87 (C>T)] was detected in cis with HBD: c.-127T>C. Overall, the prevalence of HBD variants was 0.4%. This study advanced our understanding of the causes of reduced Hb A2 in clinical practice and identified hereditary disorders of α- and δ-globin genes as the prevailing causes. It established the landscape of HBD variations in our locality and highlighted the pitfall of phenotypic screening of ß-thal carriers.

T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire.

Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ∼2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ∼50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment.

The impact of death and dying on the personhood of medical students: a systematic scoping review.

BACKGROUND: The re-introduction of medical students into healthcare systems struggling with the COVID-19 pandemic raises concerns as to whether they will be supported when confronted with death and dying patients in resource-limited settings and with reduced support from senior clinicians. Better understanding of how medical students respond to death and dying will inform educationalists and clinicians on how to best support them. METHODS: We adopt Krishna's Systematic Evidence Based Approach to carry out a Systematic Scoping Review (SSR in SEBA) on the impact of death and dying on medical students. This structured search process and concurrent use of thematic and directed content analysis of data from six databases (Split Approach) enhances the transparency and reproducibility of this review. RESULTS: Seven thousand six hundred nineteen were identified, 149 articles reviewed and 52 articles included. The Split Approach revealed similar themes and categories that correspond to the Innate, Individual, Relational and Societal domains in the Ring Theory of Personhood. CONCLUSION: Facing death and dying amongst their patients affect how medical students envisage their personhood. This underlines the need for timely, holistic and longitudinal support systems to ensure that problems faced are addressed early. To do so, there must be effective training and a structured support mechanism.

Evolutionary transformation of rod photoreceptors in the all-cone retina of a diurnal garter snake.

Vertebrate retinas are generally composed of rod (dim-light) and cone (bright-light) photoreceptors with distinct morphologies that evolved as adaptations to nocturnal/crepuscular and diurnal light environments. Over 70 years ago, the "transmutation" theory was proposed to explain some of the rare exceptions in which a photoreceptor type is missing, suggesting that photoreceptors could evolutionarily transition between cell types. Although studies have shown support for this theory in nocturnal geckos, the origins of all-cone retinas, such as those found in diurnal colubrid snakes, remain a mystery. Here we investigate the evolutionary fate of the rods in a diurnal garter snake and test two competing hypotheses: (i) that the rods, and their corresponding molecular machinery, were lost or (ii) that the rods were evolutionarily modified to resemble, and function, as cones. Using multiple approaches, we find evidence for a functional and unusually blue-shifted rhodopsin that is expressed in small single "cones." Moreover, these cones express rod transducin and have rod ultrastructural features, providing strong support for the hypothesis that they are not true cones, as previously thought, but rather are modified rods. Several intriguing features of garter snake rhodopsin are suggestive of a more cone-like function. We propose that these cone-like rods may have evolved to regain spectral sensitivity and chromatic discrimination as a result of ancestral losses of middle-wavelength cone opsins in early snake evolution. This study illustrates how sensory evolution can be shaped not only by environmental constraints but also by historical contingency in forming new cell types with convergent functionality.

Process and findings informing the development of a provincial emergency medicine network.

We describe the process undertaken to inform the development of the recently launched British Columbia (BC) Emergency Medicine Network (EM Network). Five methods were undertaken: (1) a scoping literature review, (2) a survey of BC emergency practitioners and EM residents, (3) key informant interviews, (4) focus groups in sites across BC, and (5) establishment of a brand identity. There were 208 survey respondents: 84% reported consulting Internet resources once or more per emergency department shift; however, 26% reported feeling neutral, somewhat unsatisfied, or very unsatisfied with searching for information on the Internet to support their practice. Enthusiasm was expressed for envisioned EM Network resources, and the key informant interviews and focus group results helped identify and refine key desired components of the EM Network. In describing this, we provide guidance and lessons learned for health leaders and others who aspire to establish similar clinical networks, whether in EM or other medical disciplines.

RUNX1 upregulation via disruption of long-range transcriptional control by a novel t(5;21)(q13;q22) translocation in acute myeloid leukemia.

RUNX1 encodes a Runt-related transcription factor that is critical for hematopoiesis. In this study, through a combinatorial molecular approach, we characterized a novel t(5;21)(q13;q22) translocation involving RUNX1 that was acquired during the progression of myelodysplastic syndrome to acute myeloid leukemia (AML) in a pediatric patient. We found that this translocation did not generate RUNX1 fusion but aberrantly upregulated RUNX1. This upregulation was attributed to the disruption of long-range chromatin interactions between the RUNX1 P2 promoter and a silencer in the first intron of the gene. Characterization of the silencer revealed a role of SNAG repressors and their corepressor LSD1/KDM1A in mediating the effect. Our findings suggest that chromosomal rearrangements may activate RUNX1 by perturbing its transcriptional control to contribute to AML pathogenesis, in keeping with an emerging oncogenic role of RUNX1 in leukemia.

DNA of Erythroid Origin Is Present in Human Plasma and Informs the Types of Anemia.

BACKGROUND: There is much interest in the tissue of origin of circulating DNA in plasma. Data generated using DNA methylation markers have suggested that hematopoietic cells of white cell lineages are important contributors to the circulating DNA pool. However, it is not known whether cells of the erythroid lineage would also release DNA into the plasma. METHODS: Using high-resolution methylation profiles of erythroblasts and other tissue types, 3 genomic loci were found to be hypomethylated in erythroblasts but hypermethylated in other cell types. We developed digital PCR assays for measuring erythroid DNA using the differentially methylated region for each locus. RESULTS: Based on the methylation marker in the ferrochelatase gene, erythroid DNA represented a median of 30.1% of the plasma DNA of healthy subjects. In subjects with anemia of different etiologies, quantitative analysis of circulating erythroid DNA could reflect the erythropoietic activity in the bone marrow. For patients with reduced erythropoietic activity, as exemplified by aplastic anemia, the percentage of circulating erythroid DNA was decreased. For patients with increased but ineffective erythropoiesis, as exemplified by ß-thalassemia major, the percentage was increased. In addition, the plasma concentration of erythroid DNA was found to correlate with treatment response in aplastic anemia and iron deficiency anemia. Plasma DNA analysis using digital PCR assays targeting the other 2 differentially methylated regions showed similar findings. CONCLUSIONS: Erythroid DNA is a hitherto unrecognized major component of the circulating DNA pool and is a noninvasive biomarker for differential diagnosis and monitoring of anemia.

First Report of Hb Kent [ß37(C3)Trp→Cys (TGG>TGC) HBB: c.114G>C] in a Chinese Family.

We report a novel HBB: c.114G>C mutation in a Chinese family. This mutation resulted in a ß37(C3)Trp→Cys amino acid substitution and was synonymous with Hb Kent, a hemoglobin (Hb) variant that was reported exclusively in patients of European descent. Though Hb Kent has a normal oxygen affinity and molecular stability, it has a characteristic dual variant appearance on cellulose acetate electrophoresis (CAE) and high performance liquid chromatography (HPLC) caused by the posttranslational modification of cysteine. We also report the phenotypic expression of this variant when coinherited with the Southeast Asian (- -SEA) double α-globin gene deletion.

Helicase-like transcription factor is a RUNX1 target whose downregulation promotes genomic instability and correlates with complex cytogenetic features in acute myeloid leukemia.

Helicase-like transcription factor is a SWI/SNF chromatin remodeling factor involved in various biological processes. However, little is known about its role in hematopoiesis. In this study, we measured helicase-like transcription factor mRNA expression in the bone marrow of 204 adult patients with de novo acute myeloid leukemia. Patients were dichotomized into low and high expression groups at the median level for clinicopathological correlations. Helicase-like transcription factor levels were dramatically reduced in the low expression patient group compared to those in the normal controls (n=40) (P<0.0001). Low helicase-like transcription factor expression correlated positively with French-American-British M4/M5 subtypes (P<0.0001) and complex cytogenetic abnormalities (P=0.02 for ≥3 abnormalities;P=0.004 for ≥5 abnormalities) but negatively with CEBPA double mutations (P=0.012). Also, low expression correlated with poorer overall (P=0.005) and event-free (P=0.006) survival in the intermediate-risk cytogenetic subgroup. Consistent with the more aggressive disease associated with low expression, helicase-like transcription factor knockdown in leukemic cells promoted proliferation and chromosomal instability that was accompanied by downregulation of mitotic regulators and impaired DNA damage response. The significance of helicase-like transcription factor in genome maintenance was further indicated by its markedly elevated expression in normal human CD34(+)hematopoietic stem cells. We further demonstrated that helicase-like transcription factor was a RUNX1 target and transcriptionally repressed by RUNX1-ETO and site-specific DNA methylation through a duplicated RUNX1 binding site in its promoter. Taken together, our findings provide new mechanistic insights on genomic instability linked to helicase-like transcription factor deregulation, and strongly suggest a tumor suppressor function of the SWI/SNF protein in acute myeloid leukemia.

Agreement between bioelectrical impedance and dual energy X-ray absorptiometry in assessing fat, lean and bone mass changes in adults after a lifestyle intervention.

We aimed to assess the agreement of a commercially available bioelectrical impedance analysis (BIA) device in measuring changes in fat, lean and bone mass over a 10-week lifestyle intervention, with dual energy X-ray absorptiometry (DXA) as reference. A sample of 136 volunteers (18-66 years) underwent a physical activity intervention to enhance lean mass and reduce fat mass. BIA (Tanita BC545) and DXA (Hologic Explorer) measures of whole-body composition were taken at baseline and at the end of the intervention. After an average of 74 ± 18 days intervention, DXA showed significant changes in 2 of 3 outcome variables: reduced fat mass of 0.802 ± 1.092 kg (P < 0.001), increased lean mass of 0.477 ± 0.966 kg (P < 0.001); minor non-significant increase of 0.007 ± 0.041 kg of bone mass (P = 0.052). The respective changes in BIA measures were a significant reduction of 0.486 ± 1.539 kg fat (P < 0.001), but non-significant increases of 0.084 ± 1.201 kg lean mass (P = 0.425), and 0.014 ± 0.091 kg bone (P = 0.074). Significant, but moderately weak, correlations were seen in absolute mass changes between DXA and BIA: 0.511 (fat), 0.362 (lean) and 0.172 (bone). Compared to DXA, BIA demonstrated mediocre agreement to changes in fat mass, but poor agreement to lean mass changes. BIA significantly underestimated the magnitude of changes in fat and lean mass compared to DXA.