Is developmental plasticity triggered by DNA methylation changes in the invasive cane toad (Rhinella marina)?

Many organisms can adjust their development according to environmental conditions, including the presence of conspecifics. Although this developmental plasticity is common in amphibians, its underlying molecular mechanisms remain largely unknown. Exposure during development to either 'cannibal cues' from older conspecifics, or 'alarm cues' from injured conspecifics, causes reduced growth and survival in cane toad (Rhinella marina) tadpoles. Epigenetic modifications, such as changes in DNA methylation patterns, are a plausible mechanism underlying these developmental plastic responses. Here we tested this hypothesis, and asked whether cannibal cues and alarm cues trigger the same DNA methylation changes in developing cane toads. We found that exposure to both cannibal cues and alarm cues was associated with local changes in DNA methylation patterns. These DNA methylation changes affected genes putatively involved in developmental processes, but in different genomic regions for different conspecific-derived cues. Genetic background explains most of the epigenetic variation among individuals. Overall, the molecular mechanisms triggered by exposure to cannibal cues seem to differ from those triggered by alarm cues. Studies linking epigenetic modifications to transcriptional activity are needed to clarify the proximate mechanisms that regulate developmental plasticity in cane toads.

Safety planning intervention and follow-up: A telehealth service model for suicidal individuals in emergency department settings: Study design and protocol.

BACKGROUND: The Safety Planning Intervention with follow-up services (SPI+) is a promising suicide prevention intervention, yet many Emergency Departments (EDs) lack the resources for adequate implementation. Comprehensive strategies addressing structural and organizational barriers are needed to optimize SPI+ implementation and scale-up. This protocol describes a test of one strategy in which ED staff connect at-risk patients to expert clinicians from a Suicide Prevention Consultation Center (SPCC) via telehealth. METHOD: This stepped wedge, cluster-randomized trial compares the effectiveness, implementation, cost, and cost offsets of SPI+ delivered by SPCC clinicians versus ED-based clinicians (enhanced usual care; EUC). Eight EDs will start with EUC and cross over to the SPCC phase. Blocks of two EDs will be randomly assigned to start dates 3 months apart. Approximately 13,320 adults discharged following a suicide-related ED visit will be included; EUC and SPCC samples will comprise patients from before and after SPCC crossover, respectively. Effectiveness data sources are electronic health records, administrative claims, and the National Death Index. Primary effectiveness outcomes are presence of suicidal behavior and number/type of mental healthcare visits and secondary outcomes include number/type of suicide-related acute services 6-months post-discharge. We will use the same data sources to assess cost offsets to gauge SPCC scalability and sustainability. We will examine preliminary implementation outcomes (reach, adoption, fidelity, acceptability, and feasibility) through patient, clinician, and health-system leader interviews and surveys. CONCLUSION: If the SPCC demonstrates clinical effectiveness and health system cost reduction, it may be a scalable model for evidence-based suicide prevention in the ED.

The International Olympic Committee framework on fairness, inclusion and nondiscrimination on the basis of gender identity and sex variations does not protect fairness for female athletes.

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's "no presumption of advantage" principle disregards this reality. Studies show that transgender women (male-born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of "meaningful competition" is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case-by-case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision-making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports.

Evaluating the Prevalence of Four Recommended Practices for Suicide Prevention Following Hospital Discharge.

BACKGROUND: The Joint Commission's National Patient Safety Goal (NPSG) for suicide prevention (NPSG.15.01.01) requires that accredited hospitals maintain policies/procedures for follow-up care at discharge for patients identified as at risk for suicide. The proportion of hospitals meeting these requirements through use of recommended discharge practices is unknown. METHODS: This cross-sectional observational study explored the prevalence of suicide prevention activities among Joint Commission-accredited hospitals. A questionnaire was sent to 1,148 accredited hospitals. The authors calculated the percentage of hospitals reporting implementation of four recommended discharge practices for suicide prevention. RESULTS: Of 1,148 hospitals, 346 (30.1%) responded. The majority (n = 212 [61.3%]) of hospitals had implemented formal safety planning, but few of those (n = 41 [19.3%]) included all key components of safety planning. Approximately a third of hospitals provided a warm handoff to outpatient care (n = 128 [37.0%)] or made follow-up contact with patients (n = 105 [30.3%]), and approximately a quarter (n = 97 [28.0%]) developed a plan for lethal means safety. Very few (n = 14 [4.0%]) hospitals met full criteria for implementing recommended suicide prevention activities at time of discharge. CONCLUSION: The study revealed a significant gap in implementation of recommended practices related to prevention of suicide postdischarge. Additional research is needed to identify factors contributing to this implementation gap.

Bridging the Gap: Local Field Potentials Offer a Peek Into the Brain of a Person With Parkinson Disease.

Clinically available deep brain recordings in patients with Parkinson disease (PD) offer insights into disease mechanisms and create a pathway for personalized treatment strategies. This case illustrates the transformative potential of recordings of neuronal firing in the form of local field potentials (LFPs) by detailing a patient's clinical trajectory for 6 months after deep brain stimulation (DBS) surgery to treat their PD symptoms. LFPs, obtained easily in clinic with a tablet interface to measure and track brain rhythms across the disease course, enriched the patient's clinical picture. Specifically, strong beta peaks were captured at initial programming, and, as the beta peaks diminished over the course of optimizing settings, symptoms improved. These signals may also reveal insights into the neural dynamics of PD such as hypersynchrony in basal ganglia circuitry. Furthermore, the ability to record chronically may unlock new understanding of neuronal dysfunction in PD, possibly enabling future adaptive DBS. In conclusion, identification, tracking, and modulation of LFPs correlated with subjective and objective clinical improvement in the case presented. The use of neurophysiologic signals in the future may lead to therapeutic innovations for our patients with PD.

mTBI evaluation, management, and referral to allied healthcare: practices of first-line healthcare professionals.

PRIMARY OBJECTIVE: To gain an understanding of current evaluation practices, post-injury recommendations, and referrals to allied healthcare professions (AHP) by first-line healthcare professionals (FHPs) providing care for people with mild traumatic brain injury (mTBI). RESEARCH DESIGN: Survey study. METHODS AND PROCEDURES: Physicians, physician assistants, nurse practitioners, nurses, and athletic trainers (n = 126) completed an online survey, including Likert scale and free response question relating to mTBI evaluation, management, and referral practices. MAIN OUTCOMES AND RESULTS: FHPs surveyed reported being confident in their ability to evaluate patients with suspected mTBI, relying most heavily on patient-reported symptoms and physical signs as methods of evaluation. Most FHPs reported making recommendations to compensate for the symptoms experienced following mTBI diagnosis. In contrast, FHPs expressed challenges in the evaluation and management of symptoms associated with mTBI along with limited knowledge of and referrals to AHPs. CONCLUSIONS: Overall, FHPs feel confident in the diagnosis of mTBI but experience assessment and management challenges. AHPs are underutilized on mTBI management teams calling for a need for multidisciplinary collaboration on research, education, and rehabilitation efforts to optimally care for people experiencing mTBI symptoms.

A biological invasion modifies the dynamics of a host-parasite arms race.

By imposing novel selection pressures on both participants, biological invasions can modify evolutionary 'arms races' between hosts and parasites. A spatially replicated cross-infection experiment reveals strong spatial divergence in the ability of lungworms (Rhabdias pseudosphaerocephala) to infect invasive cane toads (Rhinella marina) in Australia. In areas colonized for longer than 20 years, toads are more resistant to infection by local strains of parasites than by allopatric strains. The situation reverses at the invasion front, where super-infective parasites have evolved. Invasion-induced shifts in genetic diversity and selective pressures may explain why hosts gain advantage over parasites in long-colonized areas, whereas parasites gain advantage at the invasion front.

The Well-Being of Older Offenders on Release in the Community.

In Canada and internationally the number of older offenders on parole and living in the community is increasing rapidly. Older offenders in the community are a vulnerable population at high risk for lack of well-being. Semi-structured interviews were conducted with N = 64 offenders aged 50 years and older on conditional release from custody in Canada, including long-term, recidivist, and first-time older offenders. Compared to their non-offender counterparts, older offenders in the community experience many of the same problems of aging and well-being, but are at greater risk for mental health problems, traumatic injuries, and for recidivists, substance abuse. Most long-term and first-time older offenders find themselves living at or below the poverty line. One third of older offenders experience social isolation from community and family due to their criminal history and incarceration. For those with Indigenous ancestry, Indigenous communities, and cultural organizations play a significant role in supporting older offenders.

ERK hyperactivation serves as a unified mechanism of escape in intrinsic and acquired CDK4/6 inhibitor resistance in acral lentiginous melanoma.

Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in >60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression serve as a mechanism of intrinsic early/adaptive CDK4i/6i resistance. ALM cells that have acquired CDK4i/6i resistance following chronic treatment exposure also exhibit hyperactivation of the MAPK pathway. MEK and/or ERK inhibition increases CDK4i/6i efficacy against therapy naïve and CDK4i/6i-resistant AM cells in xenograft and patient-derived xenograft (PDX) models and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach for patients with metastatic ALM to improve outcomes.

Advancing Suicide Intervention Strategies for Teens (ASSIST): study protocol for a multisite randomised controlled trial.

INTRODUCTION: Brief interventions that reduce suicide risk following youth's experience with acute care due to suicidality are needed. METHODS AND ANALYSIS: The study will use a three-arm randomised controlled trial designed to test the effectiveness of the Safety Planning Intervention with structured follow-up (SPI+) and the Collaborative Assessment and Management of Suicidality (CAMS) compared with enhanced usual care. The primary outcomes measure will be suicidal events, defined as death by suicide, attempted suicide, preparatory acts toward imminent suicidal behaviour or suicidal ideation resulting in a change in emergency evaluation or inpatient admission. Secondary measures will be the number of suicide attempts and severity of suicidal ideation. The experimental interventions, SPI+ and CAMS, consist of up to eight sessions over approximately 8 weeks that are designed to manage (SPI+) or treat (CAMS) patient-identified 'drivers' of suicidal thoughts and behaviours. Mechanisms and moderators of change will be evaluated to understand treatment impacts. ETHICS AND DISSEMINATION: This study has been approved by the Seattle Children's Institutional Review Board and is monitored by external agencies including the University of Washington Institute for Translational Health Sciences, and a National Institute of Mental Health (NIMH)-appointed Data Safety and Monitoring Board. Trial results will help establish evidence towards safe and effective treatment strategies for youth transitioning from acute to outpatient care due to a suicidal crisis. The data will be shared with the NIMH Data Archives and disseminated through publications and conferences. TRIAL REGISTRATION NUMBER: NCT05078970.

The adaptive significance of large size at birth in marine snakes.

Evolutionary shifts from one habitat type to another can clarify selective forces that affect life-history attributes. Four lineages of snakes (acrochordids and three clades within the Elapidae) have invaded marine habitats, and all have larger offspring than do terrestrial snakes. Predation by fishes on small neonates offers a plausible selective mechanism for that shift, because ascending to breathe at the ocean surface exposes a marine snake to midwater predation whereas juvenile snakes in terrestrial habitats can remain hidden. Consistent with this hypothesis, snake-shaped models moving through a coral-reef habitat in New Caledonia attracted high rates of attack by predatory fishes, and small models (the size of neonatal terrestrial snakes) were attacked more frequently than were large models (the size of neonatal sea snakes). Vulnerability to predatory fishes may have imposed strong selection for increased offspring size in marine snakes.

Managed care updates of subscriber jail release to prompt community suicide prevention: clinical trial protocol.

BACKGROUND: Recent jail detention is a marker for trait and state suicide risk in community-based populations. However, healthcare providers are typically unaware that their client was in jail and few post-release suicide prevention efforts exist. This protocol paper describes an effectiveness-implementation trial evaluating community suicide prevention practices triggered by advances in informatics that alert CareSource, a large managed care organization (MCO), when a subscriber is released from jail. METHODS: This randomized controlled trial investigates two evidence-based suicide prevention practices triggered by CareSource's jail detention/release notifications, in a partial factorial design. The first phase randomizes ~ 43,000 CareSource subscribers who pass through any Ohio jail to receive Caring Contact letters sent by CareSource or to Usual Care after jail release. The second phase (running simultaneously) involves a subset of ~ 6,000 of the 43,000 subscribers passing through jail who have been seen in one of 12 contracted behavioral health agencies in the 6 months prior to incarceration in a stepped-wedge design. Agencies will receive: (a) notifications of the client's jail detention/release, (b) instructions for re-engaging these clients, and (c) training in suicide risk assessment and the Safety Planning Intervention for use at re-engagement. We will track suicide-related and service linkage outcomes 6 months following jail release using claims data. CONCLUSIONS: This design allows us to rigorously test two intervention main effects and their interaction. It also provides valuable information on the effects of system-level change and the scalability of interventions using big data from a MCO to flag jail release and suicide risk. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (NCT05579600). Registered 27 June, 2023.

An exposure-based implementation strategy to decrease clinician anxiety about implementing suicide prevention evidence-based practices: protocol for development and pilot testing (Project CALMER).

BACKGROUND: Clinicians often report that their own anxiety and low self-efficacy inhibit their use of evidence-based suicide prevention practices, including gold-standard screening and brief interventions. Exposure therapy to reduce clinician maladaptive anxiety and bolster self-efficacy use is a compelling but untested approach to improving the implementation of suicide prevention evidence-based practices (EBPs). This project brings together an interdisciplinary team to leverage decades of research on behavior change from exposure theory to design and pilot test an exposure-based implementation strategy (EBIS) to target clinician anxiety to improve suicide prevention EBP implementation. METHODS: We will develop, iteratively refine, and pilot test an EBIS paired with implementation as usual (IAU; didactic training and consultation) in preparation for a larger study of the effect of this strategy on reducing clinician anxiety, improving self-efficacy, and increasing use of the Columbia Suicide Severity Rating Scale and the Safety Planning Intervention in outpatient mental health settings. Aim 1 of this study is to use participatory design methods to develop and refine the EBIS in collaboration with a stakeholder advisory board. Aim 2 is to iteratively refine the EBIS with up to 15 clinicians in a pilot field test using rapid cycle prototyping. Aim 3 is to test the refined EBIS in a pilot implementation trial. Forty community mental health clinicians will be randomized 1:1 to receive either IAU or IAU + EBIS for 12 weeks. Our primary outcomes are EBIS acceptability and feasibility, measured through questionnaires, interviews, and recruitment and retention statistics. Secondary outcomes are the engagement of target implementation mechanisms (clinician anxiety and self-efficacy related to implementation) and preliminary effectiveness of EBIS on implementation outcomes (adoption and fidelity) assessed via mixed methods (questionnaires, chart-stimulated recall, observer-coded role plays, and interviews). DISCUSSION: Outcomes from this study will yield insight into the feasibility and utility of directly targeting clinician anxiety and self-efficacy as mechanistic processes informing the implementation of suicide prevention EBPs. Results will inform a fully powered hybrid effectiveness-implementation trial to test EBIS' effect on implementation and patient outcomes. TRIAL REGISTRATION: Clinical Trials Registration Number: NCT05172609 . Registered on 12/29/2021.

Managed Care Updates of Subscriber Jail Release to Prompt Community Suicide Prevention: Clinical Trial Protocol.

Background: Recent jail detention is a marker for trait and state suicide risk in community-based populations. However, healthcare providers are typically unaware that their client was in jail and few post-release suicide prevention efforts exist. This protocol paper describes an effectiveness-implementation trial evaluating community suicide prevention practices triggered by advances in informatics that alert CareSource, a large managed care organization (MCO), when a subscriber is released from jail. Methods: This randomized controlled trial investigates two evidence-based suicide prevention practices triggered by CareSource's jail detention/release notifications, in a partial factorial design. The first phase randomizes ~43,000 CareSource subscribers who pass through any Ohio jail to receive Caring Contact letters sent by CareSource or to Usual Care after jail release. The second phase (running simultaneously) involves a subset of ~6,000 of the 43,000 subscribers passing through jail who have been seen in one of 12 contracted behavioral health agencies in the 6 months prior to incarceration in a stepped-wedge design. Agencies will receive: (a) notifications of the client's jail detention/release, (b) instructions for re-engaging these clients, and (c) training in suicide risk assessment and the Safety Planning Intervention for use at re-engagement. We will track suicide-related and service linkage outcomes 6 months following jail release using claims data. Conclusions: This design allows us to rigorously test two intervention main effects and their interaction. It also provides valuable information on the effects of system-level change and the scalability of interventions using big data from a MCO to flag jail release and suicide risk. Trial Registration: The trial is registered at clinicaltrials.gov (NCT05579600). Registered 27 June, 2023, https://beta.clinicaltrials.gov/study/NCT05579600?cond=Suicide&term=Managed%20Care&rank=1.

A Suicide Prevention Intervention for Emerging Adult Sexual and Gender Minority Groups: Protocol for a Pilot Hybrid Effectiveness Randomized Controlled Trial.

BACKGROUND: Suicide attempts and suicide death disproportionately affect sexual and gender minority emerging adults (age 18-24 years). However, suicide prevention strategies tailored for emerging adult sexual and gender minority (EA-SGM) groups are not widely available. The Safety Planning Intervention (SPI) has strong evidence for reducing the risk for suicide in the general population, but it is unclear how best to support EA-SGM groups in their use of a safety plan. Our intervention (Supporting Transitions to Adulthood and Reducing Suicide [STARS]) builds on content from an existing life skills mobile app for adolescent men who have sex with men (iREACH) and seeks to target core risk factors for suicide among EA-SGM groups, namely, positive affect, discrimination, and social disconnection. The mobile app is delivered to participants randomized to STARS alongside 6 peer mentoring sessions to support the use of the safety plan and other life skills from the app to ultimately reduce suicide risk. OBJECTIVE: We will pilot-test the combination of peer mentoring alongside an app-based intervention (STARS) designed to reduce suicidal ideation and behaviors. STARS will include suicide prevention content and will target positive affect, discrimination, and social support. After an in-person SPI with a clinician, STARS users can access content and activities to increase their intention to use SPI and overcome obstacles to its use. EA-SGM groups will be randomized to receive either SPI alone or STARS and will be assessed for 6 months. METHODS: Guided by the RE-AIM (reach, efficacy, adoption, implementation, and maintenance) framework, we will recruit and enroll a racially and ethnically diverse sample of 60 EA-SGM individuals reporting past-month suicidal ideation. Using a type-1 effectiveness-implementation hybrid design, participants will be randomized to receive SPI (control arm) or to receive SPI alongside STARS (intervention arm). We will follow the participants for 6 months, with evaluations at 2, 4, and 6 months. Preliminary effectiveness outcomes (suicidal ideation and behavior) and hypothesized mechanisms of change (positive affect, coping with discrimination, and social support) will serve as our primary outcomes. Secondary outcomes include key implementation indicators, including participants' willingness and adoption of SPI and STARS and staff's experiences with delivering the program. RESULTS: Study activities began in September 2021 and are ongoing. The study was approved by the institutional review board of the University of Pennsylvania (protocol number 849500). Study recruitment began on October 14, 2022. CONCLUSIONS: This project will be among the first tailored, mobile-based interventions for EA-SGM groups at risk for suicide. This project is responsive to the documented gaps for this population: approaches that address chosen family, focus on a life-course perspective, web approaches, and focus on health equity and provision of additional services relevant to sexual and gender minority youth. TRIAL REGISTRATION: ClinicalTrials.gov NCT05018143; https://classic.clinicaltrials.gov/ct2/show/NCT05018143. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48177.

Implementation of a Community-Based Mind-Body (Tae-Bo) Physical Activity Programme on Health-Related Physical Fitness in Rural Black Overweight and Obese Women with Manifest Risk Factors for Multimorbidity.

Non-communicable diseases (NCDs) are the leading cause of death globally, particularly impacting low- and middle-income countries and rural dwellers. Therefore, this programme aimed to investigate if a community-based mind-body PA programme implemented in a low-resource setting could improve health-related physical fitness outcomes. Black overweight or obese adult women (25 ± 4.7 years) with a body mass index (BMI) > 25 kg·m-2 recruited from a rural settlement in South Africa with manifest risk factors for multimorbidity were assigned to a 10-week waiting-to-treat non-exercising control group (n = 65) or a community-based mind-body programme (n = 60) consisting of 45-60 min, thrice-weekly Tae-Bo. The intervention resulted in significant (p ≤ 0.05) improvements in body weight (p = 0.043), BMI (p = 0.037), and waist (p = 0.031) and hip circumferences (p = 0.040). Flexibility was found to be significantly increased at mid- and post-programme (p = 0.033 and p = 0.025, respectively) as was static balance (mid: p = 0.022; post: p = 0.019), hand grip strength (mid: p = 0.034; post: p = 0.029), sit-up performance (mid: p = 0.021; post: p = 0.018), and cardiorespiratory endurance (mid: p = 0.017; post: p = 0.011). No significant change was found in sum of skinfolds following the programme (p = 0.057). Such a community-based mind-body programme presents an opportunity to level health inequalities and positively improve health-related physical fitness in low-resource communities irrespective of the underlying barriers to participation.

Do changes in body mass alter white blood cell profiles and immune function in Australian cane toads (Rhinella marina)?

Variation in food resources can result in dramatic fluctuations in the body condition of animals dependent on those resources. Decreases in body mass can disrupt patterns of energy allocation and impose stress, thereby altering immune function. In this study, we investigated links between changes in body mass of captive cane toads (Rhinella marina), their circulating white blood cell populations, and their performance in immune assays. Captive toads that lost weight over a three-month period had increased levels of monocytes and heterophils and reduced levels of eosinophils. Basophil and lymphocyte levels were unrelated to changes in mass. Because individuals that lost mass had higher heterophil levels but stable lymphocyte levels, the ratio of these cell types was also higher, partially consistent with a stress response. Phagocytic ability of whole blood was higher in toads that lost mass, owing to increased circulating levels of phagocytic cells. Other measures of immune performance were unrelated to mass change. These results highlight the challenges faced by invasive species as they expand their range into novel environments which may impose substantial seasonal changes in food availability that were not present in the native range. Individuals facing energy restrictions may shift their immune function towards more economical and general avenues of combating pathogens. This article is part of the theme issue 'Amphibian immunity: stress, disease and ecoimmunology'.

ERK Hyperactivation Serves as a Unified Mechanism of Escape in Intrinsic and Acquired CDK4/6 Inhibitor Resistance in Acral Lentiginous Melanoma.

Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in > 60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression are a unified mechanism of both intrinsic and acquired CDK4i/6i resistance. MEK and/or ERK inhibition increases CDK4i/6i efficacy in a patient-derived xenograft (PDX) model of ALM and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach to improve outcomes for patients with advanced ALM.