One football season of sub-concussive head blows has been shown to be associated with subclinical white matter (WM) changes on diffusion tensor imaging (DTI). Prior research analyses of helmet-based ...impact metrics using mean and peak linear and rotational acceleration showed relatively weak correlations to these WM changes; however, these analyses failed to account for the emerging concept that neuronal vulnerability to successive hits is inversely related to the time between hits (TBH). To develop a novel method for quantifying the cumulative effects of sub-concussive head blows during a single season of collegiate football by weighting helmet-based impact measures for time between helmet impacts. We further aim to compare correlations to changes in DTI after one season of collegiate football using weighted cumulative helmet-based impact measures to correlations using non-weighted cumulative helmet-based impact measures and non-cumulative measures. We performed a secondary analysis of DTI and helmet impact data collected on ten Division III collegiate football players during the 2011 season. All subjects underwent diffusion MR imaging before the start of the football season and within 1 week of the end of the football season. Helmet impacts were recorded at each practice and game using helmet-mounted accelerometers, which computed five helmet-based impact measures for each hit: linear acceleration (LA), rotational acceleration (RA), Gadd Severity Index (GSI), Head Injury Criterion (HIC
15
), and Head Impact Technology severity profile (HITsp). All helmet-based impact measures were analyzed using five methods of summary: peak and mean (non-cumulative measures), season sum-totals (cumulative unweighted measures), and season sum-totals weighted for time between hits (TBH), the interval of time from hit to post-season DTI assessment (TUA), and both TBH and TUA combined. Summarized helmet-based impact measures were correlated to statistically significant changes in fractional anisotropy (FA) using bivariate and multivariable correlation analyses. The resulting
R
2
values were averaged in each of the five summary method groups and compared using one-way ANOVA followed by Tukey post hoc tests for multiple comparisons. Total head hits for the season ranged from 431 to 1850. None of the athletes suffered a clinically evident concussion during the study period. The mean
R
2
value for the correlations using cumulative helmet-based impact measures weighted for both TUA and TBH combined (0.51 ± 0.03) was significantly greater than the mean
R
2
value for correlations using non-cumulative HIMs (vs. 0.19 ± 0.04,
p
< 0.0001), unweighted cumulative helmet-based impact measures (vs. 0.27 + 0.03,
p
< 0.0001), and cumulative helmet-based impact measures weighted for TBH alone (vs. 0.34 ± 0.02,
p
< 0.001).
R
2
values for weighted cumulative helmet-based impact measures ranged from 0.32 to 0.77, with 60% of correlations being statistically significant. Cumulative GSI weighted for TBH and TUA explained 77% of the variance in the percent of white matter voxels with statistically significant (PWMVSS) increase in FA from pre-season to post-season, while both cumulative GSI and cumulative HIC
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weighted for TUA accounted for 75% of the variance in PWMVSS decrease in FA. A novel method for weighting cumulative helmet-based impact measures summed over the course of a football season resulted in a marked improvement in the correlation to brain WM changes observed after a single football season of sub-concussive head blows. Our results lend support to the emerging concept that sub-concussive head blows can result in sub-clinical brain injury, and this may be influenced by the time between hits. If confirmed in an independent data set, our novel method for quantifying the cumulative effects of sub-concussive head blows could be used to develop threshold-based countermeasures to prevent the accumulation of WM changes with multiple seasons of play.
Malignant stem cells have long been considered a key therapeutic target in leukemia. Therapeutic strategies designed to target the fundamental biology of leukemia stem cells while sparing normal ...hematopoietic cells may provide better outcomes for leukemia patients. One process in leukemia stem cell biology that has intriguing therapeutic potential is energy metabolism. In this article we discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients. In addition, we highlight the similarities and differences in energy metabolism between leukemia stem cells and malignant stem cells from solid tumors.
Cancer stem cells have unique metabolic biology that can in some instances be exploited for therapeutic intervention. This review summarizes the progress and challenges inherent to this field, including metabolic flexibility, inter and intra-patient heterogeneity, and commonalities and differences in energy metabolism between leukemia and solid tumors.
In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, ...steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death. In contrast, LSCs obtained from relapsed AML patients are not reliant on amino acid metabolism due to their ability to compensate through increased fatty acid metabolism. These findings indicate that clinically relevant eradication of LSCs can be achieved with drugs that target LSC metabolic vulnerabilities.
•Leukemia stem cells (LSCs) rely on amino acids for survival•LSCs use amino acids to fuel oxidative phosphorylation (OXPHOS)•Venetoclax with azacitidine inhibits OXPHOS in LSCs from leukemia patients•Venetoclax with azacitidine targets OXPHOS by inhibiting amino acid metabolism
By interrogating metabolic properties of human acute myeloid leukemia, Jones et al. reveal increased amino acid metabolism in leukemia stem cells (LSCs), which rely on amino acids for oxidative phosphorylation and survival. Venetoclax with azacitidine induces LSC toxicity by decreasing amino acid uptake.
Surfing is a popular recreational and competitive sport in the United States and worldwide. Previous studies indicate surfers are frequently injured, but most studies are survey based, and little is ...known about surfing injuries that present to emergency departments (EDs).
This study examines the epidemiology of surfing injuries presenting to US EDs.
A retrospective analysis was performed using data from the National Electronic Injury Surveillance System database from the US Consumer Product Safety Commission from 2002 to 2013.
A total of 2072 cases were analyzed, corresponding to a national estimate of 131 494 total injuries over the 12-year period (95% confidence interval, 34 515-228 473). The median age of included cases was 27 years (interquartile range, 19-37). Lower extremity injuries were most common (25.9%), followed by the face (23.1%) and head and neck (22.7%). Lacerations were the most common injury type (40.7%), followed by sprains and strains (14.4%), contusions (12.9%), and fractures (11.9%); 95.7% of cases were treated and released. Patients older than 60 years, those injured to the trunk, and those suffering fractures or internal organ injuries were admitted at a statistically significant increased frequency (P<.05).
Surfing injuries are common but rarely serious. The injuries most commonly affect the lower extremity, head, neck, and face and are most frequently lacerations. Age older than 60 years, injuries to the trunk, and internal organ injuries were associated with a statistically significant increased frequency of hospital admission.
To study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug ...resistance. We validated
,
, and
as genes whose inactivation results in venetoclax resistance in AML cell lines. Resistance to venetoclax resulted from an inability to execute apoptosis driven by BAX loss, decreased expression of BCL2, and/or reliance on alternative BCL2 family members such as BCL2L1. The resistance was accompanied by changes in mitochondrial homeostasis and cellular metabolism. Evaluation of
knockout cells for sensitivities to a panel of small-molecule inhibitors revealed a gain of sensitivity to TRK inhibitors. We relate these observations to patient drug responses and gene expression in the Beat AML dataset. Our results implicate
, the apoptotic network, and mitochondrial functionality as drivers of venetoclax response in AML and suggest strategies to overcome resistance. SIGNIFICANCE: AML is challenging to treat due to its heterogeneity, and single-agent therapies have universally failed, prompting a need for innovative drug combinations. We used a genetic approach to identify genes whose inactivation contributes to drug resistance as a means of forming preferred drug combinations to improve AML treatment.
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Hydroxocobalamin is used for cyanide toxicity after smoke inhalation, but diagnosis is challenging. Retrospective studies have associated hydroxocobalamin with acute kidney injury (AKI). This is a ...retrospective analysis of patients receiving hydroxocobalamin for suspected cyanide toxicity. The primary outcome was the proportion of patients meeting predefined appropriate use criteria defined as ≥1 of the following: serum lactate ≥8 mmol/L, systolic blood pressure (SBP) <90 mmHg, new-onset seizure, cardiac arrest, or respiratory arrest. Secondary outcomes included incidence of AKI, pneumonia, resolution of initial neurologic symptoms, and in-hospital mortality. Forty-six patients were included; 35 (76%) met the primary outcome. All met appropriate use criteria due to respiratory arrest, 15 (43%) for lactate, 14 (40%) for SBP, 12 (34%) for cardiac arrest. AKI, pneumonia, and resolution of neurologic symptoms occurred in 30%, 21%, and 49% of patients, respectively. In-hospital mortality was higher in patients meeting criteria, 49% vs. 9% (95% CI 0.16, 0.64). When appropriate use criteria were modified to exclude respiratory arrest in a post-hoc analysis, differences were maintained, suggesting respiratory arrest alone is not a critical component to determine hydroxocobalamin administration. Predefined appropriate use criteria identify severely ill smoke inhalation victims and provides hydroxocobalamin treatment guidance.
•Clinical use criteria may identify appropriate candidates for hydroxocobalamin treatment.•Criteria applied: hypotension, cardiac or respiratory arrest, seizure, or elevated lactate.•Respiratory arrest alone may not be an indicator for hydroxocobalamin treatment.•Time to treatment should be optimized at institutions using hydroxocobalamin.•Emerging associations of hydroxocobalamin with kidney injury require further study.
We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we ...demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP, and leading to LSC death. Given the role of cysteine in driving LSC energy production, we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme, we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism, and that targeting this axis may represent a useful therapeutic strategy.
•LSCs rely on cysteine for survival.•Cysteine metabolism is required for ETC II activity in LSCs.
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Here, we demonstrate how IDEAcology aids in preparing for and implementing a structured expert elicitation using the IDEA protocol, an iterative quantitative expert elicitation framework.
Expert ...judgement is used to inform decision‐making on environmental assessment and management when imminent decisions are required, and quantitative data are absent or uninformative. Structured elicitation protocols can help improve the final judgements derived from experts, but they can also be administratively heavy and time‐consuming, requiring manual collation of experts' estimates and rationales, construction and dissemination of summary plots for discussion and collating final estimates post‐discussion. These challenges highlight the need for a centralised portal that enables synchronous access by all contributors, real‐time structured facilitation of discussion, whether in person or online, and streamlined data management.
To meet this need, we developed the IDEAcology interface (www.ideacology.com) to support data collation, summary, interactions and ultimately the deployment of structured expert elicitation using the IDEA protocol. The IDEAcology interface is designed to be a central portal for scientists and practitioners to easily implement structured expert elicitation projects, while also facilitating data management by providing a reliable and efficient way for elicitation managers to design and run an elicitation, and for experts to input, visualise and cross‐examine estimates.
The key advantages that IDEAcology provides include an easy‐to‐use interface with synchronous access to a single platform, reducing logistic difficulties, facilitating transparent discussion, improving the accuracy of estimates, enabling fast and efficient reporting by providing analysis‐ready data outputs and lastly, flexibility in the types of elicitation questions that can be accommodated in the interface.
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