Search

Mountainous watersheds are characterized by variability in functional traits, including vegetation, topography, geology, and geomorphology, which determine nitrogen (N) retention, and release. Coal Creek and East River are two contrasting catchments within the Upper Colorado River Basin that differ markedly in total nitrate (NO3−) export. The East River has a diverse vegetation cover, and sinuous floodplains, and is underlain by N‐rich marine shale. At 0.21 ± 0.14 kg ha−1 yr−1, the East River exports ∼3.5 times more NO3− relative to the conifer‐dominated Coal Creek (0.06 ± 0.02 kg ha−1 yr−1). While this can partly be explained by the larger size of the East River, the distinct watershed traits of these two catchments imply different mechanisms controlling the aggregate N‐export signal. A causality analysis shows physical and biogenic processes were critical in determining NO3− export from the East River catchment. Stable isotope ratios of NO3− (δ15NNO3 and δ18ONO3) show the East River catchment is a strong hotspot for biogeochemical processing of NO3− at the hillslope soil‐saprolite. By contrast, the conifer‐dominated Coal Creek retained nearly all atmospherically deposited NO3−, and its export was controlled by catchment hydrological traits (i.e., snowmelt periods and water table depth). The conservative N‐cycle within Coal Creek is likely due to the abundance of conifer trees, and smaller riparian regions, retaining more NO3− overall and reduced processing prior to export. This study highlights the value of integrating isotope systematics to link watershed functional traits to mechanisms of watershed element retention and release. Plain Language Summary: The role different functional traits play in the retention and release of nitrogen remains uncertain. Here we describe how two neighboring catchments in the Upper Colorado River Basin, characterized by contrasting vegetation, geology, and geomorphology, cycle and export nitrogen. The East River catchment, which is underlain by nitrogen‐rich shale, and has a diverse vegetation cover, releases over three times as much nitrate (NO3−) than the conifer‐dominated Coal Creek, which is underlain by granitic rock. However, a suite of analyses show that the distinct watershed traits of these two catchments lead to diverse pathways of nitrogen cycling. Biogenic processes, critical to determining NO3− export in East River, impart strong biogeochemical processing prior to export. By contrast, Coal Creek retains almost all of the atmospherically deposited NO3−, likely due to uptake by conifers, and a small riparian region. This study highlights the use of nitrate isotope systematics to parse different mechanisms leading to NO3− export. Key Points: Comparing and contrasting neighboring catchments identifies watershed traits regulating the cycling, retention and release of nitrogenConifer forest‐dominated catchments show a conservative nitrogen cycling, retaining ∼97% of atmospherically dominated nitrateBy contrast, meadow‐dominated catchments underlain Mancos shale are biogeochemical hotspots for N‐cycling, and export higher nitrate loads [ABSTRACT FROM AUTHOR]

Global climate change impacts species and ecosystems in potentially harmful ways. For migratory bird species, earlier spring warm‐up could lead to a mismatch between nesting activities and food availability. CO2 provides a useful proxy for temperature and an environmental indicator of climate change when temperature data are not available for an entire time series.Our objectives were to (a) examine nesting phenology over time; (b) determine how nesting phenology relates to changes in atmospheric CO2 concentration; and (c) demonstrate the usefulness of historical museum collections combined with modern observations for trend analyses.We assessed changes in nesting dates of 72 bird species in the Upper Midwest of the United States by comparing contemporary lay dates with those obtained from archived, historical museum nest records over a 143‐year period (1872–2015).Species‐specific changes in lay date per one unit change in the CO2 residual ranged from −0.75 (95% CI: −1.57 to −0.10) to 0.45 (95% CI: −0.29 to 1.43). Overall, lay dates advanced ~10 days over the 143‐year period. Resident, short‐distance migrants and long‐distance migrants lay dates advanced by ~15, 18 and 16 days on average respectively. Twenty‐four species (33.3%) significantly advanced, one (1.4%) significantly delayed and we failed to detect an advance or delay in lay date for 47 species (65.3%). Overall mean advance in first lay date (for the species that have significantly advanced laying date) was 25.1 days (min: 10.7, max: 49.9).Our study highlights the scientific importance of both data gathering and archiving through time to understand phenological change. The detailed archived information reported by egg collectors provide the early data of our study. As with studies of egg‐shell thinning and pesticide exposure, our use of these data illustrates another scientific utility of egg collections that these pioneer naturalists never imagined. As museums archive historical data, these locations are also ideal candidates to store contemporary field data as it is collected. Together, such information will provide the ability to track, understand and perhaps predict responses to human‐driven environmental change. [ABSTRACT FROM AUTHOR]

Objective: We estimated the prevalence of diagnosed eating disorders, overall and by select demographics, among commercially insured individuals identified as transgender in a national claims database. Methods: From the 2018 IBM® MarketScan® Commercial Database, there were 10,415 people identifiable as transgender based on International Classification of Disease (ICD‐10) codes and procedure codes, specific to gender‐affirming care, from inpatient and outpatient claims. Eating disorders were identified from ICD‐10 codes and included anorexia nervosa, bulimia nervosa, binge eating disorder, eating disorder not otherwise specified, avoidant restrictive feeding and intake disorder, and other specified feeding and eating disorders. We estimated the prevalence of specific eating disorders diagnoses by selecting patient characteristics. Results: Of individuals receiving some form of gender‐affirming care, 2.43% (95% confidence interval: 2.14%–2.74%) were diagnosed with an eating disorder: 0.84% anorexia nervosa, 0.36% bulimia nervosa, 0.36% binge eating disorder, 0.15% avoidant restrictive feeding and intake disorder, 0.41% other specified feeding and eating disorders, and 1.37% with an unspecified eating disorder. Among transgender‐identifiable patients aged 12–15 years, 5.60% had an eating disorder diagnosis, whereas 0.52% had an eating disorder diagnosis in patients aged 45–64 years. Discussion: In patients identifiable as transgender, with receipt of gender‐affirming care, the prevalence of diagnosed eating disorders was low compared to extant self‐reported data for eating disorder diagnosis in transgender individuals. Among this population, eating disorders were highest in adolescents and young adults. Clinically verified prevalence estimates for eating disorder diagnosis in transgender people with a history of gender‐affirming care warrant further investigation. Public Significance: The present study aims to provide clinically validated, contemporary prevalence estimates for diagnosed eating disorders among a medically affirmed population of transgender adults and children in the United States. We report low prevalence of having any eating disorder relative to prevalence estimates reported in prior literature without clinical validation. These findings may be explained by access to affirming care and medical care generally. [ABSTRACT FROM AUTHOR]

Background: Because of concerns about sexual minorities' poor cancer survivorship, this study compared cancer survivors' health outcomes in relation to multiple intersecting social positions, namely gender, sexual orientation, and race/ethnicity. Methods: This secondary data analysis used 2014‐2019 Behavior Risk Factor Surveillance Survey data. The survey respondents consisted of 40,482 heterosexual and sexual minority men and 69,302 heterosexual and sexual minority women who identified as White, Black, or Hispanic. Logistic regression models compared White, Black, and Hispanic male and female cancer survivors' health status, depression, and health‐related quality of life by sexual orientation. Models were adjusted for sociodemographic characteristics and access to care. Results: Mental health findings showed consistency, with sexual minority male and female cancer survivors having 2 to 3 times greater odds of depression and/or poor mental health among White, Black, and Hispanic survivors. Among White women, sexual minorities reported greater odds of fair or poor health, poor physical health, and poor activity days, whereas White sexual minority men showed similar odds in comparison with their heterosexual counterparts. Among Black and Hispanic sexual minority men and women, differences in the odds of fair or poor health, poor physical health, and poor activity days in comparison with their heterosexual counterparts were mostly explained by sociodemographic and access‐to‐care factors. Conclusions: Physical and mental health outcomes vary in relation to sexual orientation and race/ethnicity among both female and male cancer survivors. Clinicians, researchers, and health care administrators must better understand and address the unique needs of cancer survivors in relation to multiple axes of social inequality to advance cancer equity. For patient‐centered care, it is important to have detailed information on the experiences of survivors with multiple intersecting social positions and their diverse needs. Sexual minority cancer survivors who are White, Black, or Hispanic are in urgent need of attention to improve their mental health and reduce their depression. [ABSTRACT FROM AUTHOR]

Objectives: To develop a reliable and valid measure of social connectedness among nursing home residents with Alzheimer's disease and related dementias (ADRD) using items available in the Minimum Dataset 3.0 (MDS).Methods: We conducted a retrospective scale development study using the 2016 MDS with two populations of nursing home residents with ADRD: (1) new admissions (not post-acute care) (n = 146,694); (2) residents with comprehensive annual assessments (n = 294,704). Twenty-nine items were included for consideration. Psychometric evaluation included content validity, item analysis, internal consistency reliability, criterion-related validity, and exploratory factor analysis. Analyses were stratified by self- or staff-assessed pain.Results: The resulting five item Social Connectedness Index (SCI) has good content (Fleiss Kappa = 0.67), criterion-related and construct validity and adequate internal consistency reliability (Kuder Richardson-20: 0.63-0.74) in persons with ADRD. As anticipated, younger residents, men, and those with severe cognitive impairment, anxiety, and depression were more likely to be categorized in the low social connectedness group.Conclusion: The SCI is a promising measure for estimating the amount of social connectedness present for nursing home residents with ADRD. Further work needs to be done to evaluate the usefulness of the SCI for evaluating health and well-being among this population over time. [ABSTRACT FROM AUTHOR]

As part of an educational exercise designed to introduce school students to the technique of single‐crystal X‐ray diffraction and enhance their understanding of primary and secondary bonding, a group of nine secondary school students was given the opportunity to prepare new compounds and to solve and refine data collected on the crystalline materials they had prepared. Their investigation of the alkali metal salts of 4‐hydroxybenzoic acid (H2hba) yielded nine new compounds and their structures are described in this article. Whilst the salts might be expected to have similar atomic arrangements, there are significant differences in their structures. Although H2hba is a relatively simple organic molecule, it displays remarkable coordinative flexibility, forming ionic solids containing the uncharged molecule, the monoanion Hhba− or the dianion hba2−. A common feature of the structures is their layered arrangement: alternating hydrophilic layers made up of closely packed metal–oxygen polyhedra separated by the hydrophobic component of the hydroxybenzoate linking units. Close packing of these units seems to be a dominant influence in determining the overall structure. The hydroxybenzoate units are usually both parallel and antiparallel with their immediate neighbours, with packing that can be edge‐to‐face, face‐to‐face or a mixture of the two. Hydrogen bonding plays a key role in the structure of most compounds and a short strong hydrogen bond (SSHB) is observed in two of the networks. The compounds of 4‐hydroxybenzoic acid, C7H6O3, described here are: poly[di‐μ‐aqua‐μ‐4‐oxidobenzoato‐dilithium], [Li2(C7H4O3)(H2O)2]n, 1, poly[triaqua‐μ‐4‐oxidobenzoato‐dilithium], [Li2(C7H4O3)(H2O)3]n, 2, poly[μ‐4‐hydroxybenzoato‐lithium], [Li(C7H5O3)]n, 3, catena‐poly[4‐hydroxybenzoate [[diaquasodium]‐di‐μ‐aqua]], {[Na(H2O)4](C7H5O3)}n, 4, poly[di‐μ‐aqua‐aqua‐μ‐4‐hydroxybenzoato‐potassium], [K(C7H5O3)(H2O)3]n, 5, poly[μ‐aqua‐μ‐4‐hydroxybenzoato‐potassium], [K(C7H5O3)(H2O)]n, 6, poly[aqua‐μ‐4‐hydroxybenzoato‐rubidium], [Rb(C7H5O3)(H2O)]n, 7, poly[aqua‐μ‐4‐hydroxybenzoato‐caesium], [Cs(C7H5O3)(H2O)]n, 8, poly[[μ‐aqua‐aqua(μ‐4‐hydroxybenzoato)(4‐hydroxybenzoic acid)sodium] monohydrate], {[Na(C7H5O3)(C7H6O3)(H2O)2]·H2O}n, 9, poly[[(μ‐4‐hydroxybenzoato)(μ‐4‐hydroxybenzoic acid)rubidium] monohydrate], {[K(C7H5O3)(C7H6O3)]·H2O}n, 10, and poly[[(μ‐4‐hydroxybenzoato)(μ‐4‐hydroxybenzoic acid)rubidium] monohydrate], {[Rb(C7H5O3)(C7H6O3)]·H2O}n, 11. [ABSTRACT FROM AUTHOR]

The balance between avoiding severe acute respiratory syndrome coronavirus‐2 contagion and reducing wider clinical risk is unclear for gestational diabetes mellitus (GDM) testing. Recent recommendations promote diagnostic approaches that limit collection but increase undiagnosed GDM, which potentially increases adverse pregnancy outcome risks. The most sensitive approach to detecting GDM at 24–28 weeks beyond the two‐hour oral glucose tolerance test (OGTT) is a one‐hour OGTT (88% sensitivity). Less sensitive approaches use fasting glucose alone (≥5.1 mmol/L: misses 44–54% GDM) or asking ~20% of women for a second visit (fasting glucose 4.7–5.0 mmol/L (62–72% sensitive)). Choices should emphasise local and patient decision‐making. [ABSTRACT FROM AUTHOR]

This paper examines the efficiency of the legal gambling market for major league baseball. Weak-form tests of market efficiency within and across odds lines are performed. Surprisingly, the consistently observed favorite-longshot bias in racetrack betting is shown to exist in reverse for baseball bettors. However, these and other deviations from efficiency are shown to be insufficient to allow for profitable betting strategies when commissions are considered. [ABSTRACT FROM AUTHOR]

Generalist parasites exploit multiple host species at the population level, but the individual parasite's strategy may be either itself a generalist or a specialist pattern of host species use. Here, we studied the relationship between host availability and host use in the individual parasitism patterns of the Shiny Cowbird Molothrus bonariensis, a generalist avian obligate brood parasite that parasitizes an extreme range of hosts. Using five microsatellite markers and an 1120-bp fragment of the mt DNA control region, we reconstructed full-sibling groups from 359 cowbird eggs and chicks found in nests of the two most frequent hosts in our study area, the Chalk-browed Mockingbird Mimus saturninus and the House Wren Troglodytes aedon. We were able to infer the laying behavior of 17 different females a posteriori and found that they were mostly faithful to a particular laying area and host species along the entire reproductive season and did not avoid using previously parasitized nests (multiple parasitism) even when other nests were available for parasitism. Moreover, we found females using the same host nest more than once (repeated parasitism), which had not been previously reported for this species. We also found few females parasitizing more than one host species. The use of an alternative host was not related to the main hosts' nest availability. Overall, female shiny cowbirds use a spatially structured and host species specific approach for parasitism, but they do so nonexclusively, resulting in both detectable levels of multiple parasitism and generalism at the level of individual parasites. [ABSTRACT FROM AUTHOR]

Sports and racetrack betting markets have been investigated by researchers for more than 50 years. Many authors have argued that the observed biases and inefficiencies in these markets are a consequence of bettors incorrectly assessing the objective probabilities that favorites or underdogs will win. This article is the first examination of the National Football League season wins total over/under betting market where the designations of favorite and longshot do not apply. The market is found to be highly inefficient, providing several opportunities for profitable wagering. We believe these inefficiencies are a consequence of the representativeness heuristic. Most significantly, there is evidence that bettors, when considering teams with strong records in the previous season, overreact to historical performance and fail to recognize the statistical phenomenon of regression to the mean. [ABSTRACT FROM AUTHOR]

Introduction Perioperative anxiety is a common and undesirable outcome in pediatric surgical patients. The use of interactive tools to minimize perioperative anxiety is vastly understudied. The main objective of the current investigation was to compare the effects of a tablet-based interactive distraction ( TBID) tool to oral midazolam on perioperative anxiety. We hypothesized that the TBID tool was not inferior to midazolam to reduce perioperative anxiety. Methods 108 children, ages 1-11 years, presenting for outpatient surgical procedures were prospectively randomized to oral midazolam (0.5 mg·kg−1; 20 mg max) or TBID. The primary outcome was the change in anxiety level from baseline to parental separation and anesthetic induction. Other data collected included emergence delirium, parental satisfaction, time-to- PACU discharge, and posthospitalization behavior. Results The mean difference (95% CI) in the increase of anxiety at parental separation between the TBID and the midazolam group was −9 (−2.6 to −16.4), P = 0.006, demonstrating superiority to midazolam group (one-sided P = 0.003). For children 2-11 years, the mean difference (95% CI) in anxiety at induction was significant between the TBID and midazolam groups, −14.0 (−6.1 to −22.0), P < 0.001. The median ( IQR) time-to- PACU discharge was 111 (75-197) min in the midazolam group and 87 (55-137) min in the TBID group, P = 0.03. Decreased emergence delirium and increased parental satisfaction were also observed in the TBID group. Conclusions A TBID tool reduces perioperative anxiety, emergence delirium, and time-to-discharge and increases parental satisfaction when compared to midazolam in pediatric patients undergoing ambulatory surgery. [ABSTRACT FROM AUTHOR]

This paper builds on prior research by analysing the impact of cultural factors on both price clustering and price resistance in China's stock markets. The results support the presence of cultural factors impacting on price clustering with the digit 8 showing a higher propensity for clustering and the digits 4 and 7 showing a lower propensity in the A-share market, where stock is denominated in renminbi and traded by mainland Chinese. These results are further supported by an analysis of the B-share market, where cultural factors have no (or less) impact on the price of Chinese stocks traded by foreign investors in US dollars (or in Hong Kong dollars). A range of measures for price resistance show the digits 0 and 5 to be significant resistance points in the A-share market. Although digit 8 cannot be considered as a resistance point, its resistance level is highest among the remaining numbers. In conclusion, cultural factors help to explain not only price clustering in the Chinese stock markets but price resistance levels as well, albeit at a weak level. [ABSTRACT FROM AUTHOR]

Although it is well established that brown-headed cowbirds Molothrus ater are host generalists, the parasitism strategies of individual females are not well documented. Here we use microsatellite genotyping to characterize host use by individual female cowbirds. Of 205 offspring sampled at a site in northeastern Illinois during one breeding season, we identified or inferred 33 mothers of 141 offspring, with up to 13 (mean 4.72) offspring assigned to individual females. Most (83%) females were host generalists and parasitized up to five host species, indicating that community-wide patterns of parasitism do not result from different individuals specializing on different host species. However, some females (17%) parasitized a single species, suggesting that alternative host-use strategies may exist within a single population. For host generalist females, individuals often parasitized host species that differed in body mass, nest-site placement, and quality, indicating that female cowbirds exhibit extremely flexible host ranges. However, female cowbirds consistently discriminated among potential hosts, for example, by completely avoiding some common, but unsuitable species. [ABSTRACT FROM AUTHOR]

Deals with the importance of in-hospital statin therapy for the management of patients with acute coronary syndromes. Evidence for early state of statin therapy; Risks of discontinuing statin therapy; Implications for in-hospital start of lipid-lowering therapy; Challenges for evidence-based pharmacy practice.

Racetrack and sports betting markets have been researched extensively with respect to the question of market efficiency. In contrast to the consistently observed favourite–longshot bias found in racetrack betting markets, it has been shown that gamblers in the market for Major League Baseball games reveal the opposite behaviour. This paper updates the previous study with ten years of additional data for the 1990–99 seasons. The strength of the reverse favourite–longshot bias is virtually identical to the original paper. The result suggests that, contrary to most reported inefficiencies in gambling markets, this bias appears to be permanent. [ABSTRACT FROM AUTHOR]

Investigates the market efficiency and profitable wagering of the sports betting market, the National Hockey League (NHL) for the years 1990-1996. different degrees of inefficiency; Structure of the NHL betting market; Several tests of market efficiency; Profitable wagering strategies; Favorite-longshot bias in NHL; Comparison of results to other betting markets.

This article examines the existence of a super premium in the yield on speculative-grade (SG) securities. The premium is presumably caused by a market imperfection imposed on the corporate bond market by regulations that prohibit particular institutions from the purchase of lower-grade securities. Results suggest that the bond market is partially segmented by regulations which use ratings as a line of demarcation. Specifically, the evidence in the study indicates that the dichotomy of investment grade and speculative grade securities defined by federal and state regulations has an effect on the relative yields of the two classes of corporate bonds. The yields on SG securities contain a super premium over and above that necessary to compensate the investor for the additional default risk associated with SG bonds. Based on the results in the study, it would seem logical that investors who are not restricted by regulations may invest in a diversified portfolio of SG bonds with the highest credit quality. While such investments would have a small amount of additional default risk over the lowest securities, investors can earn a premium that is more than enough to compensate for the additional default risk, at least for the period under study.

In adult acute myeloid leukaemia (AML), immunophenotypic differences enable discrimination of leukaemic stem cells (LSCs) from healthy haematopoietic stem cells (HSCs). However, immunophenotypic stem cell characteristics are less explored in paediatric AML. Employing a 15-colour flow cytometry assay, we analysed the expression of eight aberrant surface markers together with BCL-2 on CD34 + CD38 - bone marrow stem cells from 38 paediatric AML patients and seven non-leukaemic, age-matched controls. Furthermore, clonality was investigated by genetic analyses of sorted immunophenotypically abnormal stem cells from six patients. A total of 50 aberrant marker positive (non-HSC-like) subsets with 41 different immunophenotypic profiles were detected. CD123, CLEC12A, and IL1RAP were the most frequently expressed markers. IL1RAP, CD93, and CD25 expression were not restricted to stem cells harbouring leukaemia-associated mutations. Differential BCL-2 expression was found among defined cytogenetic subgroups. Interestingly, only immunophenotypically abnormal non-HSC-like subsets demonstrated BCL-2 overexpression. Collectively, we observed pronounced immunophenotypic heterogeneity within the stem cell compartment of paediatric AML patients. Additionally, certain aberrant markers used in adults seemed to be ineligible for detection of leukaemia-representing stem cells in paediatric patients implying that inference from adult studies must be done with caution., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

The SRSF2 mutations are frequently found in acute myeloid leukemia (AML) and mostly affect the P95 residue. Mutations in this splicing factor mediate abnormal splicing associated with exon skipping events, including EZH2 as a crucial target. While SRSF2 mutations are enriched in secondary AML and associated with worse outcomes following chemotherapy consolidation, very little is known about the associated biological and clinical implications in AML patients consolidated with allogeneic hematopoietic stemcell transplantation (HSCT). Here we retrospectively analyzed 263 adult AML patients who received an allogeneic HSCT regarding the biological and clinical implications of the SRSF2 mutation status at diagnosis and in morphologic remission at HSCT. We found 12.5% of the patients to be SRSF2 mutated at diagnosis. Mutated patients had increased EZH2 missplicing events with P95H likely driving this pathobiology most effectively. However, the amount of EZH2 missplicing events, as a functional surrogate marker did not associate with relevant biological or clinical characteristics. We observed a persistence of mutations in remission before HSCT in the majority (93%) of SRSF2 mutated AML patients. Importantly, the variant allele frequency (VAF) levels of SRSF2 mutations in remission at HSCT did not correlate with outcomes following HSCT consolidation, limiting the applicability of SRSF2 mutations as a marker for residual AML disease. Following allogeneic HSCT SRSF2 mutated AML patients experienced a 2-year overall survival of 77%, indicating that SRSF2 mutated AML patients may benefit from HSCT consolidation., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The concept of leukaemic stem cells (LSCs) was experimentally suggested 25 years ago through seminal data from John Dick's group, who showed that a small fraction of cells from acute myeloid leukaemia (AML) patients were able to be adoptively transferred into immunodeficient mice. The initial estimation of the frequency was 1:250 000 leukaemic cells, clearly indicating the difficulties ahead in translating knowledge on LSCs to the clinical setting. However, the field has steadily grown in interest, expanse and importance, concomitantly with the realisation of the molecular background for AML culminating in the sequencing of hundreds of AML genomes. The literature is now ripe with contributions describing how different molecular aberrations are more or less specific for LSCs, as well as reports showing selectivity in targeting LSCs in comparison to normal haematopoietic stem and progenitor cells. However, we argue here that these important data have not yet been fully realised within the clinical setting. In this clinically focused review, we outline the difficulties in identifying and defining LSCs at the individual patient level, with special emphasis on intraclonal heterogeneity. In addition, we suggest areas of future focus in order to realise the concept as real-time benefit for AML patients., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Targeted therapy directed against rare disease-propagating leukaemic stem cells (LSCs) is a promising prospect for improving the outcome of acute myeloid leukaemia (AML) patients. Thus, distinguishing LSCs from normal haematopoietic stem and progenitor cells (HSPCs) is essential. The CLEC12A receptor has been proposed as a specific marker of LSCs, and consequently as an appealing treatment target. To explore the role of CLEC12A in further detail, we investigated whether a sorting strategy based on the activity of aldehyde dehydrogenase and CLEC12A expression could separate residual normal HSPCs from LSCs in bone marrow from 5 AML patients. We demonstrate that this distinction was possible in 2/5 cases, however with evidence of pre-leukaemic mutations in the CLEC12A- stem cells in one case. In contrast, cytogenetic and/or molecular aberrations were detected in both the CLEC12A+/- cell subsets in 3/5 AML cases studied. Furthermore, targeted next generation sequencing (NGS) of the sorted cell subsets revealed a pronounced clonal heterogeneity in the CLEC12A- cells suggestive of the leukaemia often originating in this immature cell subset. In conclusion, we provide proof-of-concept that precision diagnostics employing targeted cytogenetic/NGS-based analyses on highly purified cell subsets could be a powerful tool for selecting patients eligible for LSC-directed therapy., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

The C-type lectin domain family 12, member A (CLEC12A) receptor has emerged as a leukaemia-associated and cancer stem cell marker in myeloid malignancies. However, a detailed delineation of its expression in normal haematopoiesis is lacking. Here, we have characterized the expression pattern of CLEC12A on the earliest stem- and myeloid progenitor subsets in normal bone marrow. We demonstrate distinct CLEC12A expression in the classically defined myeloid progenitors, where on average 39.1% (95% CI [32.5;45.7]) of the common myeloid progenitors (CMPs) expressed CLEC12A, while for granulocyte-macrophage progenitors and megakaryocyte-erythroid progenitors (MEPs), the average percentages were 81.0% (95% CI [76.0;85.9]) and 11.9% (95% CI [9.3;14.6]), respectively. In line with the reduced CLEC12A expression on MEPs, functional assessment of purified CLEC12A +/- CMPs and MEPs in the colony-forming unit assay demonstrated CLEC12A + subsets to favour non-erythroid colony growth. In conclusion, we provide evidence that the earliest CLEC12A + cell in the haematopoietic tree is the classically defined CMP. Furthermore, we show that CLEC12A-expressing CMPs and MEPs are functionally different than their negative counterparts. Importantly, these data can help determine which cells will be spared during CLEC12A-targeted therapy, and we propose CLEC12A to be included in future studies of myeloid cancer stem cell biology., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

In acute myeloid leukemia (AML), leukemia-initiating cells exist within the CD34+/CD38- cell compartment. They are assumed to be more resistant to chemotherapy, enriched in minimal residual disease cell populations, and responsible for relapse. Here we evaluated clinical and biological associations and the prognostic impact of a high diagnostic CD34+/CD38- cell burden in 169 AML patients receiving an allogeneic stem cell transplantation in complete remission. Here, the therapeutic approach is mainly based on immunological graft-versus-leukemia effects. Percentage of bone marrow CD34+/CD38- cell burden at diagnosis was measured using flow cytometry and was highly variable (median 0.5%, range 0%-89% of all mononuclear cells). A high CD34+/CD38- cell burden at diagnosis associated with worse genetic risk and secondary AML. Patients with a high CD34+/CD38- cell burden had shorter relapse-free and overall survival which may be mediated by residual leukemia-initiating cells in the CD34+/CD38- cell population, escaping the graft-versus-leukemia effect after allogeneic transplantation. Evaluating the CD34+/CD38- cell burden at diagnosis may help to identify patients at high risk of relapse after allogeneic transplantation. Further studies to understand leukemia-initiating cell biology and develop targeting therapies to improve outcomes of AML patients are needed., (© 2017 Wiley Periodicals, Inc.)