SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis.

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients.

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.

Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F1-ATPase inhibitor ATP5IF1. In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

Are we asking the right questions to people with Achilles tendinopathy? The best questions to distinguish mild versus severe disability to improve your clinical management.

OBJECTIVE: Determine the capacity of individual items on the Tendinopathy Severity Assessment - Achilles (TENDINS-A), Foot and Ankle Outcome Score (FAOS), and Victorian Institute of Sports Assessment - Achilles (VISA-A) to differentiate patients with mild and severe tendon-related disability in order to provide clinicians the best questions when they are consulting patients with Achilles tendinopathy. DESIGN: Cross-sectional. PARTICIPANTS: Seventy participants with Achilles tendinopathy (61.4% mid-portion only, 31.4% insertional only, 7.2% both). OUTCOME MEASURES: The discrimination index was determined for each TENDINS-A, FAOS, and VISA-A item to determine if items could discriminate between mild and severe disability. A Guttman analysis for polytomous items was conducted. RESULTS: All 62 tems from the TENDINS-A, FAOS, and VISA-A were ranked with the best items relating to pain with physical tendon loading, time for pain to settle following aggravating activities and time for the tendon to 'warm-up' following inactivity. CONCLUSIONS: Pain with loading the Achilles tendon, time for pain to settle following aggravating activity, as well as time taken for the tendon symptoms to subside after prolonged sitting or sleeping are the best questions indicative of the severity of disability in patients with Achilles tendinopathy. These questions can assist clinicians with assessing baseline severity and monitoring treatment response.

An Academic-Community Partnership to Address Gun Violence in the Roseland Neighborhood of Chicago.

BACKGROUND AND OBJECTIVES: Gun violence is the leading cause of death for youth. This study examined an academic-community partnership to address gun violence through a strength-based approach called Asset-Based Community Development. METHODS: We used a case study design. Participants were Black youth who encounter frequent gun violence (average age = 16.7 years; 72% male). Our partnership involved survey development/completion and semistructured discussions. We also interviewed community stakeholders to collect data on local assets. We interpreted data through a communitywide forum to guide social action to address gun violence. RESULTS: The majority of youth (76%) witnessed neighborhood violence in the last year. The top youth concerns related to gun violence included poverty, guns, and gangs. Community stakeholders saw local people and local organizations as primary community assets. A community forum to interpret these data led to social action in the form of an environmental strategy-cleaning up an unused commercial building for the development of a youth tech center. The majority of youth participants (89.5%) agreed or strongly agreed that they had a voice in the research process. CONCLUSION: Participatory research that takes an asset-based approach can enable relevant inquiry that engages youth and guides social action to address gun violence.

Where is Your Pain? Achilles Tendinopathy Pain Location on Loading Is Different to Palpation, Imaging and Recall Location.

OBJECTIVE: To describe and compare pain maps reported during Achilles tendon loading exercises with recall pain location, in people with pain on palpation in their Achilles tendon and tendon pathology on imaging. DESIGN: Cross-sectional analysis of baseline RCT. METHOD: Participants were recruited from a larger Achilles tendinopathy clinical trial. Inclusion criteria were at least 2-month self-reported history of Achilles tendinopathy, midtendon palpation pain, and pathology on ultrasound tissue characterization. Participants were asked to identify their Achilles tendon pain location on a pain map with 8 prespecified locations while at rest prior to loading (recall pain), and subsequently during tendon loading exercises (loading pain). Participants could select multiple locations or select "other" if the locations did not represent their pain. RESULTS: Ninety-three participants were included (93% of participants from a clinical trial). The locations of pain on loading were diverse; all 8 pain locations (and an "other" option) were represented within this sample. Twenty-five percent of participants did not report pain with loading (n = 23 of 93). Of the 70 participants with loading pain, recall pain location differed to loading pain location in 40% (n = 28 of 70) of the participants. CONCLUSION: Palpation pain location, recall pain location, or location of pathology on imaging were not valid proxies for load-related pain in the Achilles tendon. How different pain locations respond to treatment is unknown. Some pathologies (eg, plantaris) have clear pain locations (eg, medial tendon), and assessing pain location may assist differential diagnosis. J Orthop Sports Phys Ther 2024;54(1):1-9. Epub 7 December 2023. doi:10.2519/jospt.2023.12131.

Warming-up for the Latest on Diagnosing and Managing Tendinopathy.

SYNOPSIS: JOSPT is starting 2024 on a high, with a tendinopathy-focused edition that showcases more of the high-quality tendinopathy research you know and love in systematic reviews, original research articles, a consensus paper, and editorials. As any athlete knows, a good warm-up is crucial to performing well at the main event. Here, we help you warm up and prime your brain to take on all the content of this tendinopathy-focused issue of the Journal. J Orthop Sports Phys Ther 2024;54(1):1-2. Epub 5 December 2023. doi:10.2519/jospt.2023.12440.

The Tendinopathy Game Changers: Five Papers From the Last 5 Years That Might Change How You Manage Tendons.

SYNOPSIS: The clinical and scientific understanding of tendinopathy has substantially advanced since the Fifth International Scientific Tendinopathy Symposium in 2019. This editorial aims to highlight some of the fantastic tendinopathy research from the past 5 years. We have selected what we consider the "best paper" for each year from 2019 to 2023, which might change how you treat tendons. Selecting only 5 papers was not easy. Did your favorite papers make the cut? Or do you think we missed some key studies? We encourage you to tell us what you think using the social media hashtag #JOSPTtendon. J Orthop Sports Phys Ther 2024;54(1):1-3. Epub 16 November 2023. doi:10.2519/jospt.2023.12372.

Shifting the Energy Toward Los Angeles: Comparing the Energetic Contribution and Pacing Approach Between 2000- and 1500-m Maximal Ergometer Rowing.

PURPOSE: To compare the energetic contribution and pacing in 2000- and 1500-m maximal rowing-ergometer performances. METHODS: On separate visits (>48 h apart, random order), 18 trained junior (16.7 [0.4] y) male rowers completed 3 trials: a 7 × 4-minute graded exercise test, a 2000-m time trial (TT2000), and a 1500-m TT (TT1500). Respiratory gases were continuously measured throughout each trial. The submaximal power-to-oxygen-consumption relationship from the graded exercise test was used to determine the accumulated oxygen deficit for each TT. Differences in mean power output (MPO), relative anaerobic contribution, percentage of peak oxygen uptake, pacing index, maximum heart rate, rating of perceived exertion, and blood lactate concentration were assessed using linear mixed modeling. RESULTS: Compared to TT2000 (324 [24] W), MPO was 5.2% (3.3%) higher in TT1500 (341 [29 W]; P < .001, ηp2=.70). There was a 4.9% (3.3%) increase (P < .001, ηp2=.71) in anaerobic contribution from 17.3% (3.3%) (TT2000) to 22.2% (4.3%) (TT1500). Compared to TT1500, maximum heart rate, rating of perceived exertion, and blood lactate concentration were all greater (P < .05) in TT2000. The pacing index was not different between trials. Percentage increase in MPO from TT2000 to TT1500 was negatively associated with pacing variance in TT1500 (R2 = .269, P = .027). CONCLUSIONS: Maximal ergometer performance over 1500 m requires a significantly greater anaerobic contribution compared with 2000 m. Junior male athletes adopt a consistent pacing strategy across both distances. However, those who experienced greater percentage increases in MPO over the shorter test adopted a more even pacing strategy. To prepare for 1500-m performance, greater emphasis should be placed on developing capacity for work in the severe domain and completing race simulations with a more even pacing strategy.

Does lower-limb osteoarthritis alter motor cortex descending drive and voluntary activation? A systematic review and meta-analysis.

Purpose: The aim of the study was to quantify motor cortex descending drive and voluntary activation (VA) in people with lower-limb OA compared to controls. Methods: A systematic review and meta-analysis according to the PRISMA guidelines was carried out. Seven databases were searched until 30 December 2022. Studies assessing VA or responses to transcranial magnetic stimulation (TMS; i.e. motor evoked potential, intracortical facilitation, motor threshold, short-interval intracortical inhibition, and silent period) were included. Study quality was assessed using Joanna Briggs Institute criteria and evidence certainty using GRADE. The meta-analysis was performed using RevMan inverse variance, mixed-effect models. Results: Eighteen studies were included, all deemed low-quality. Quadriceps VA was impaired with knee OA compared to healthy controls (standardised mean difference (SMD) = 0.84, 95% CI = -1.12-0.56, low certainty). VA of the more symptomatic limb was impaired (SMD = 0.42, 95% CI = -0.75-0.09, moderate certainty) compared to the other limb in people with hip/knee OA. As only two studies assessed responses to TMS, very low-certainty evidence demonstrated no significant difference between knee OA and healthy controls for motor evoked potential, intracortical facilitation, resting motor threshold or short-interval intracortical inhibition. Conclusions: Low-certainty evidence suggests people with knee OA have substantial impairments in VA of their quadriceps muscle when compared to healthy controls. With moderate certainty we conclude that people with hip and knee OA had larger impairments in VA of the quadriceps in their more painful limb compared to their non-affected/other limb.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Epidemiology of musculoskeletal injury in military recruits: a systematic review and meta-analysis.

BACKGROUND: Injuries are a common occurrence in military recruit training, however due to differences in the capture of training exposure, injury incidence rates are rarely reported. Our aim was to determine the musculoskeletal injury epidemiology of military recruits, including a standardised injury incidence rate. METHODS: Epidemiological systematic review following the PRISMA 2020 guidelines. Five online databases were searched from database inception to 5th May 2021. Prospective and retrospective studies that reported data on musculoskeletal injuries sustained by military recruits after the year 2000 were included. We reported on the frequency, prevalence and injury incidence rate. Incidence rate per 1000 training days (Exact 95% CI) was calculated using meta-analysis to allow comparisons between studies. Observed heterogeneity (e.g., training duration) precluded pooling of results across countries. The Joanna Briggs Institute Quality Assessment Checklist for Prevalence Studies assessed study quality. RESULTS: This review identified 41 studies comprising 451,782 recruits. Most studies (n = 26; 63%) reported the number of injured recruits, and the majority of studies (n = 27; 66%) reported the number of injuries to recruits. The prevalence of recruits with medical attention injuries or time-loss injuries was 22.8% and 31.4%, respectively. Meta-analysis revealed the injury incidence rate for recruits with a medical attention injury may be as high as 19.52 injuries per 1000 training days; and time-loss injury may be as high as 3.97 injuries per 1000 training days. Longer recruit training programs were associated with a reduced injury incidence rate (p = 0.003). The overall certainty of the evidence was low per a modified GRADE approach. CONCLUSION: This systematic review with meta-analysis highlights a high musculoskeletal injury prevalence and injury incidence rate within military recruits undergoing basic training with minimal improvement observed over the past 20 years. Longer training program, which may decrease the degree of overload experienced by recruit, may reduce injury incidence rates. Unfortunately, reporting standards and reporting consistency remain a barrier to generalisability. TRIAL REGISTRATION: PROSPERO (Registration number: CRD42021251080).

Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across cancer types.

Targeting mitochondrial oxidative phosphorylation (OXPHOS) to treat cancer has been hampered due to serious side-effects potentially arising from the inability to discriminate between non-cancerous and cancerous mitochondria. Herein, comprehensive mitochondrial phenotyping was leveraged to define both the composition and function of OXPHOS across various murine cancers and compared to both matched normal tissues and other organs. When compared to both matched normal tissues, as well as high OXPHOS reliant organs like heart, intrinsic expression of the OXPHOS complexes, as well as OXPHOS flux were discovered to be consistently lower across distinct cancer types. Assuming intrinsic OXPHOS expression/function predicts OXPHOS reliance in vivo, these data suggest that pharmacologic blockade of mitochondrial OXPHOS likely compromises bioenergetic homeostasis in healthy oxidative organs prior to impacting tumor mitochondrial flux in a clinically meaningful way. Although these data caution against the use of indiscriminate mitochondrial inhibitors for cancer treatment, considerable heterogeneity was observed across cancer types with respect to both mitochondrial proteome composition and substrate-specific flux, highlighting the possibility for targeting discrete mitochondrial proteins or pathways unique to a given cancer type.

Ultrafast internal conversion and photochromism in gas-phase salicylideneaniline.

Salicylideneaniline (SA) is an archetypal system for excited-state intramolecular proton transfer (ESIPT) in non-planar systems. Multiple channels for relaxation involving both the keto and enol forms have been proposed after excitation to S1 with near-UV light. Here, we present transient absorption measurements of hot gas-phase SA, jet-cooled SA, and SA in Ar clusters using cavity-enhanced transient absorption spectroscopy (CE-TAS). Assignment of the spectra is aided by simulated TAS spectra, computed by applying time-dependent complete active space configuration interaction (TD-CASCI) to structures drawn from nonadiabatic molecular dynamics simulations. We find prompt ESIPT in all conditions followed by the rapid generation of the trans keto metastable photochrome state and fluorescent keto state in parallel. Increasing the internal energy increases the photochrome yield and decreases the fluorescent yield and fluorescent state lifetime observed in TAS. In Ar clusters, internal conversion of SA is severely hindered, but the photochrome yield is unchanged. Taken together, these results are consistent with the photochrome being produced via the vibrationally excited keto population after ESIPT.

Quantifying Fear Avoidance Behaviors in People With Concussion: A COSMIN-Informed Systematic Review.

OBJECTIVE: The validity of existing fear avoidance behavior patient-reported outcome measures (PROMs) for concussion is unknown. This study aims to (1) identify PROMs that assess fear avoidance behavior in individuals with concussion and (2) assess the measurement properties of these PROMs. DESIGN: A systematic review of outcome measurement instruments using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. LITERATURE SEARCH: We performed a systematic search of 7 databases. STUDY SELECTION CRITERIA: Studies were included if they assessed fear avoidance behavior (eg, kinesiophobia or cogniphobia) in participants with concussion, occurring in all settings (eg, sport, falls, assaults). DATA SYNTHESIS: Methodological quality of the PROMs was assessed using the COSMIN checklist, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. RESULTS: We identified 40 studies assessing fear avoidance. Four studies (n = 875 participants, representing 3 PROMs) were eligible for COSMIN assessment. Content validity for all PROMs was insufficient due to extreme risk of bias. The Fear Avoidance Short Form Scale demonstrated the greatest validity: moderate-certainty evidence for sufficient structural validity and internal consistency, and low-certainty evidence for measurement invariance. CONCLUSION: Current PROMs for measuring fear avoidance behaviors in people with concussion have insufficient content validity and should be used with caution in research and clinical practice. J Orthop Sports Phys Ther 2023;53(9):540-565. Epub: 10 August 2023. doi:10.2519/jospt.2023.11685.

TENDINopathy Severity Assessment - Achilles (TENDINS-A): Development and Content Validity Assessment of a New Patient-Reported Outcome Measure for Achilles Tendinopathy.

OBJECTIVE: To develop a new patient-reported outcome measure (PROM) assessing TENDINopathy Severity of the Achilles (TENDINS-Achilles) and evaluate its content validity. DESIGN: Mixed-methods, modified Delphi. METHODS: We performed 1 round of semistructured one-on-one interview responses with professionals and patients, for initial item generation. This was followed by 1 round of survey responses for professionals and a final round of semistructured one-on-one interviews with patients. The work culminated in a PROM to quantify Achilles tendinopathy severity under the core health domain of disability. Participants identified 3 subdomains contributing to the severity of disability of Achilles tendinopathy: pain, symptoms, and functional capacity. RESULTS: All 8 patient participants invited to participate were enrolled. Forty professional participants (50% women, six different continents) were invited to participate and 30 were enrolled (75% response rate). Therefore, a total of 30 professionals and 8 patients were included within this study. Following 3 rounds of qualitative or quantitative feedback, this study has established the content validity of TENDINS-A (good relevance, comprehensibility, and comprehensiveness) as a new PROM to assess the severity of Achilles tendinopathy, which assesses aspects of pain, symptoms, and functional capacity. CONCLUSION: TENDINS-A has established content validity and is appropriate for use with clinical and research populations. We recommend users interpret TENDINS-A results cautiously, until further testing evaluates the most appropriate scoring scale, reliability, construct validity, criterion validity, and responsiveness of TENDINS-A. Until these psychometric properties are established, we suggest using TENDINS-A alongside existing tools. J Orthop Sports Phys Ther 2023;53(11):1-16. Epub: 24 August 2023. doi:10.2519/jospt.2023.11964.

Understanding the role of magnesium stearate in lowering punch sticking propensity of drugs during compression.

The sticking of active pharmaceutical ingredient (API) to the surfaces of compaction tooling, frequently referred to as punch sticking, causes costly downtime or product failures in commercial tablet manufacturing. Magnesium stearate (MgSt) is a common tablet lubricant known to ameliorate the sticking problem, even though there exist exceptions. The mechanism by which MgSt lowers punch sticking propensity (PSP) by covering API surface is sensible but not yet experimentally proven. This work was aimed at elucidating the link between PSP and surface area coverage (SAC) of tablets by MgSt, in relation to some key formulation properties and process parameters, namely MgSt concentration, API loading, API particle size, and mixing conditions. The study was conducted using two model APIs with known high PSPs, tafamidis (TAF) and ertugliflozin-pyroglutamic acid (ERT). Results showed that PSP decreases exponentially with increasing SAC by MgSt. The composition of material stuck to punch face was also explored to better understand the onset of punch sticking and the impact of possible MgSt-effected punch conditioning event.

Can we really say getting stronger makes your tendon feel better? No current evidence of a relationship between change in Achilles tendinopathy pain or disability and changes in Triceps Surae structure or function when completing rehabilitation: A systematic review.

OBJECTIVES: Determine if improvements in pain and disability in patients with mid-portion Achilles tendinopathy relate to changes in muscle structure and function whilst completing exercise rehabilitation. DESIGN: A systematic review exploring the relationship between changes in pain/disability and muscle structure/function over time, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. METHODS: Six online databases and the grey literature were searched from database inception to 16th December 2022 whereas clinical trial registries were searched from database inception to 11th February 2020. We included clinical studies where participants received exercise rehabilitation (±placebo interventions) for mid-portion Achilles tendinopathy if pain/disability and Triceps Surae structure/function were measured. We calculated Cohen's d (95 % confidence intervals) for changes in muscle structure/function over time for individual studies. Data were not pooled due to heterogeneity. Study quality was assessed using a modified Newcastle-Ottawa Scale. RESULTS: Seventeen studies were included for synthesis. No studies reported the relationship between muscle structure/function and pain/disability changes. Twelve studies reported muscle structure/function outcome measures at baseline and at least one follow-up time-point. Three studies reported improvements in force output after treatment; eight studies demonstrated no change in structure or function; one study did not provide a variation measure, precluding within group change over time calculation. All studies were low quality. CONCLUSIONS: No studies explored the relationship between changes in tendon pain and disability and changes in muscle structure and function. It is unclear whether current exercise-based rehabilitation protocols for mid-portion Achilles tendinopathy improve muscle structure or function. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (registration number: CRD42020149970).

Simultaneous Inhibition of Ceramide Hydrolysis and Glycosylation Synergizes to Corrupt Mitochondrial Respiration and Signal Caspase Driven Cell Death in Drug-Resistant Acute Myeloid Leukemia.

Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and glycosylation has been shown to be an element in chemotherapy-resistant AML, a problem considering the crucial role ceramide plays in eliciting apoptosis. Herein we employed agents that block ceramide clearance to determine if such a "reset" would be of therapeutic benefit. SACLAC was utilized to limit ceramide hydrolysis, and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) was used to block the glycosylation route. The SACLAC D-threo-PDMP inhibitor combination was synergistically cytotoxic in drug-resistant, P-glycoprotein-expressing (P-gp) AML but not in wt, P-gp-poor cells. Interestingly, P-gp antagonists that can limit ceramide glycosylation via depression of glucosylceramide transit also synergized with SACLAC, suggesting a paradoxical role for P-gp in the implementation of cell death. Mechanistically, cell death was accompanied by a complete drop in ceramide glycosylation, concomitant, striking increases in all molecular species of ceramide, diminished sphingosine 1-phosphate levels, resounding declines in mitochondrial respiratory kinetics, altered Akt, pGSK-3ß, and Mcl-1 expression, and caspase activation. Although ceramide was generated in wt cells upon inhibitor exposure, mitochondrial respiration was not corrupted, suggestive of mitochondrial vulnerability in the drug-resistant phenotype, a potential therapeutic avenue. The inhibitor regimen showed efficacy in an in vivo model and in primary AML cells from patients. These results support the implementation of SL enzyme targeting to limit ceramide clearance as a therapeutic strategy in chemotherapy-resistant AML, inclusive of a novel indication for the use of P-gp antagonists.

"I lied a little bit." A qualitative study exploring the perspectives of elite Australian athletes on self-reported data.

OBJECTIVES: Explore the perceptions and experiences of elite Australian athletes' engagement with reporting data in surveillance systems. DESIGN: Qualitative Descriptive. SETTING: Semi-structured interviews conducted using Zoom. PARTICIPANTS: We recruited 13 elite Australian athletes competing at a national or international level for semi-structured interviews. MAIN OUTCOME MEASURES: Audio recordings were transcribed using DeScript, checked for errors and imported into QSR NVIVO. Thematic analysis using QSR NVIVO was used to determine key themes from transcripts. RESULTS: Thematic analysis uncovered four key themes: 'the paradox of reporting', 'data for data's sake', 'eyes on reporting' and 'athlete friendly reporting'. CONCLUSION: Athletes perceived reporting as a burden and the athlete management system presented numerous technological difficulties which led to athletes to backfill data entries and compromise data accuracy. Athletes had little knowledge on how their data was used and managed and often received minimal feedback from staff accessing the data. Athletes were unaware of who has access to their data, which is of concern as sensitive information may be collected and athletes may be underage. As a result, many athletes chose to report dishonest data to avoid their performance being questioned.