Caspase-8 Blocks Receptor-Interacting Protein Kinase-1 Kinase-Independent Necroptosis during Embryogenesis.

Caspase-8 (Casp8) suppresses receptor-interacting protein kinase-3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis, demonstrated by the genetic evidence that deletion of Ripk3 or Mlkl prevented embryonic lethality of Casp8-deficient mice. However, the detailed mechanisms by which Casp8 deficiency triggers necroptosis during embryonic development remain unclear. In this article, we show that Casp8 deletion caused formation of the RIPK1-RIPK3 necrosome in the yolk sac, leading to vascularization defects, prevented by MLKL and RIPK3 deficiency, or RIPK3 RHIM mutant (RIPK3 V448P), but not by the RIPK1 kinase-dead mutant (RIPK1 K45A). In addition, Ripk1K45A/K45ACasp8 -/- mice died on embryonic day 14.5, which was delayed to embryonic day 17.5 by ablation of one allele in Ripk1 and was completely rescued by ablation of Mlkl Our results revealed an in vivo role of RIPK3 RHIM and RIPK1K45A scaffold-mediated necroptosis in Casp8 deficiency embryonic development and suggested that the Casp8-deficient yolk sac might be implicated in identifying novel regulators as an in vivo necroptotic model.

Are recreational cannabis laws associated with declining medical cannabis program enrollment in the U.S.? An analysis of cardholder enrollment and demographic characteristics from 2013 to 2020.

BACKGROUND: There is speculation that enrollment in U.S. state medical cannabis programs differs depending on whether adult recreational cannabis use is legal. If true, this could have implications for public health and policy. METHODS: Using medical cannabis registry data from U.S. states with a mandatory registry between 2013 and 2020 (N = 23 states), this study examined time-trends in medical cannabis cardholder enrollment and tested whether enrollment trends differed depending on adult recreational cannabis legalization. RESULTS: Multilevel models showed that time-trends for registered active medical cardholders differed during years when adult recreational cannabis use was legal versus not legal (time*recreational cannabis law interaction: b = -0.004, p < 0.01, 95% CI = -0.005, -0.003). The population prevalence of registered active medical cardholders increased over time in years when recreational cannabis was not legal (i.e., medical-only years; b = 0.004, p < 0.001, 95% CI = 0.003, 0.004, corresponding to an increase of 380 cardholders per 100,000 people per year), and decreased in years when recreational cannabis was legal (i.e., recreational years; b = -0.001, p < 0.001, 95% CI = -0.002, -0.001, corresponding to a decrease of 100 cardholders per 100,000 people per year). Time-trends were similar for each sex (male, female) and age group (18-30/35, 30/35+), with each cardholder group showing increases in medical-only years and decreases in recreational years. In medical-only years, there were no differences in enrollment time-trends across sex, but older cardholder (30/35+) enrollment increased at a faster rate than younger cardholder enrollment (18-30/35) (F = 16.199, p < 0.001). In recreational years, male cardholder enrollment decreased at a faster rate than female cardholder enrollment (F = 7.347, p < 0.01), but there was no difference in trends across age. Three states, all with medical-only years, provided data on ethnicity/race. Results showed significant increases from 2016 to 2020 in enrollment of White, African-American, and Hispanic individuals. CONCLUSIONS: Findings suggest that recreational cannabis legalization is associated with decreasing enrollment in medical cannabis programs, particularly for males.

Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting. Therefore, the aim of this study was to identify effective combination treatments against CRLF2-rearranged Ph-like ALL, and to elucidate the underlying mechanisms of synergy. We carried out a series of high-throughput combination drug screenings and found that ruxolitinib exerted synergy with standard-of-care drugs used in the treatment of ALL. In addition, we investigated the molecular effects of ruxolitinib on Ph-like ALL by combining mass spectrometry phosphoproteomics with gene expression analysis. Based on these findings, we conducted preclinical in vivo drug testing and demonstrated that ruxolitinib enhanced the in vivo efficacy of an induction-type regimen consisting of vincristine, dexamethasone, and L-asparaginase in 2/3 CRLF2-rearranged Ph-like ALL xenografts. Overall, our findings support evaluating the addition of ruxolitinib to conventional induction regimens for the treatment of CRLF2-rearranged Ph-like ALL.

Adolescent executive cognitive functioning and trait impulsivity as predictors of young-adult risky drinking and alcohol-related problems.

Executive cognitive functioning (ECF) and trait impulsivity have long been implicated in risky drinking and alcohol-related problems. However, research on these constructs has developed independently. The present study tested whether two subdomains of adolescent ECF (updating and response inhibition) and adolescent trait impulsivity, considered separately and together, predicted young-adult risky drinking and alcohol-related problems. Data came from the Adolescent/Adult Family Development Project-a longitudinal study of the intergenerational transmission of alcohol use. Alcohol-naïve youth ages 11-17 (N = 249) completed three tasks tapping ECF subdomains of updating (letter-number sequencing, matrix span task) and inhibition (immediate memory task) and a self-reported measure of trait impulsivity (UPPS-P). Approximately 7 years later (ages 18-25), participants reported on their drinking behavior (maximum drinks in a day, heavy episodic drinking, alcohol-related problems). We tested whether adolescent ECF and trait impulsivity predicted young-adult drinking outcomes, separately and together. Results showed that poorer adolescent ECF (a latent factor) predicted more maximum drinks in a day (Incidence Rate Ratios [IRR] = 1.27, p = .001) but not young-adult heavy episodic drinking and alcohol-related problems. In contrast, adolescent trait impulsivity predicted all three outcomes: maximum drinks in a day (IRR = 1.34, p < .001), heavy episodic drinking (ß = 0.27, p < .001), and alcohol-related problems in young adulthood (IRR = 1.60, p = .001). Results were similar when adolescent ECF and trait impulsivity were considered together in the same model. Findings suggest that adolescent trait impulsivity is a robust predictor of young-adult risky drinking and alcohol-related problems. Adolescent ECF, and specifically response inhibition, may add predictive value over and above trait impulsivity for some alcohol outcomes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.

Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.

OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL.

PURPOSE: OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the in vitro cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX). RESULTS: AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; n = 264) than B-lineage ALL (B-ALL; n = 1,740; P < 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, OBI-3424 significantly prolonged the event-free survival (EFS) of nine of nine ALL PDXs by 17.1-77.8 days (treated/control values 2.5-14.0), and disease regression was observed in eight of nine PDXs. A significant reduction (P < 0.0001) in bone marrow infiltration at day 28 was observed in four of six evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in two T-ALL PDXs. CONCLUSIONS: OBI-3424 exerted profound in vivo efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.

Comparison of the locations where young adults smoke, vape, and eat/drink cannabis: Implications for harm reduction.

BACKGROUND: Cannabis vaping and edible use are increasingly popular methods of cannabis use. These discreet methods could increase risk of cannabis-related problems by facilitating cannabis use in a wider range of settings. METHODS: A sample of 1018 college students were recruited to complete a survey about their health and behavior. Participants who used cannabis in the past year (35.1%, n = 357) answered questions about their cannabis use, including where they were the last time they smoked, vaped, or ate/drank cannabis, and their experience of cannabis-related problems. RESULTS: Compared with cannabis smoking, participants were more likely to have vaped cannabis (15.8% smoked vs. 24.6% vaped; X2 = 4.59, p = .032), and were slightly, but not statistically significantly, more likely to have used cannabis edibles (17.5% smoked vs. 24.2% used edibles; X2 = 3.57, p = .059), in locations other than a private residence. For example, participants were more likely to have vaped cannabis in a car than to have smoked cannabis in a car (8.8% vaped vs. 3.5% smoked; X2 = 4.26, p = .039). More frequent cannabis vaping was associated with driving while high on cannabis, even after accounting for overall frequency of cannabis use and other covariates (OR = 1.22, p = .047). More frequent cannabis vaping and edible use were associated with various cannabis-related problems, but, in general, these associations became statistically non-significant after accounting for overall frequency of cannabis use. CONCLUSIONS: Cannabis vaporizers and edibles facilitate cannabis use in locations that require discretion. Increased availability of cannabis vaporizers and edibles could increase risk of cannabis-related problems by enabling use in more settings.

Content Analysis of Advantages and Disadvantages of Drinking Among Individuals With the Lived Experience of Homelessness and Alcohol Use Disorders.

BACKGROUND: Alcohol use disorders (AUDs) are more prevalent among people who are homeless than in the general population. Thus, homeless individuals experience disproportionately high levels of alcohol-related problems and associated publicly funded criminal justice and healthcare system utilization. Available treatment services, however, are not effective at engaging and treating this population. To better tailor treatment services to their needs, it is imperative we understand this population's perceptions of their alcohol use. OBJECTIVES: The aim of this study was to provide description and relative rankings of the advantages and disadvantages of alcohol use from this population's perspectives. METHODS: Participants were 44 individuals with lived experiences of AUDs and homelessness who received services at community-based agencies in Seattle, Washington. Open-ended prompts were used in interviews conducted in 2013-2014 to assess the perceived role of alcohol in participants' lives, including participants' perceptions of the advantages and disadvantages of their current drinking, and a conventional content analysis was conducted. RESULTS: The most frequently mentioned advantages of drinking included positively and negatively reinforcing psychological reasons, perceived control over drinking, and social benefits. Physical effects, concerns about dependence on alcohol, and health problems were the most commonly mentioned disadvantages. Conclusions/importance: By documenting the perceived advantages and disadvantages of drinking among people with the lived experience of homelessness and AUDs, this study supplies information providers may use to better tailor treatment services to this multimorbid, high service-utilizing population's needs and interests.

Prevalence and correlates of vaping cannabis in a sample of young adults.

Vaping nicotine (i.e., the use of e-cigarettes and similar devices to inhale nicotine) is becoming increasingly popular among young people. Though some vaporizers are capable of vaporizing cannabis, sparse research has investigated this method of cannabis administration. The present study examines the prevalence and correlates of vaping cannabis in a sample of 482 college students. Participants reported high lifetime rates of vaping nicotine (37%) and cannabis (29%). Men (rs = 0.09, p = .047) and individuals from higher socioeconomic status families (rs = 0.14, p = .003) vaped cannabis more frequently than women and individuals from lower SES families. In addition, those who vaped cannabis more frequently were more open to new experiences (rs = 0.17, p < .001) and showed greater approval of smoking cannabis regularly (rs = 0.35, p < .001). Among the largest correlates of cannabis vaping were frequent cannabis use (rs = 0.70, p < .001) and nicotine vaping (rs = 0.46, p < .001), suggesting that availability of cannabis and vaporizers is particularly important. Participants' top reason for vaping cannabis, endorsed by 65% of those who had vaped cannabis, was convenience and discreetness for use in public places. Several correlates distinguished cannabis users who vaped from cannabis users who did not vape, most notably more frequent cannabis use (odds ratios [OR] = 3.68, p < .001), alcohol use (OR = 2.07, p < .001), nicotine vaping (OR = 1.73, p < .001), and greater approval of smoking cannabis regularly (OR = 2.15, p < .001). Findings suggest that cannabis vaping is prevalent among young adults, particularly among those who use other substances frequently and have more favorable attitudes toward smoking cannabis. Research is needed on the antecedents and potential harms and benefits of cannabis vaping in young adulthood. (PsycINFO Database Record

Single-session dialectical behavior therapy skills training versus relaxation training for non-treatment-engaged suicidal adults: a randomized controlled trial.

BACKGROUND: Individuals who are not engaged in treatment are commonly overlooked in the design of intervention trials targeting suicidal populations as a result of recruitment methodology that requires individuals to be referred from their current provider. In fact, research suggests that the majority of individuals who die by suicide have not been in contact with mental health services in the year before their death. METHODS/DESIGN: A randomized controlled trial of two brief, one-session interventions for adults who are not engaged in mental health treatment. Inclusion criteria include 1) 18 years or older, 2) experiencing suicidal ideation in the past week, 3) have not received mental health treatment in the month prior to screening, 4) living within commuting distance to the research office, and 5) willing to consent to recording and assessment. Exclusion criteria are 1) non-English speaking and 2) significant cognitive impairment. Recruitment takes place in the community via flyers, radio, and online advertisements. Interested individuals are screened via telephone and those who are eligible attend a one-time in-person assessment and intervention appointment. During this appointment, they are randomized to a single-session intervention in which they are presented with either dialectical behavior therapy skills or supportive discussion and instruction in relaxation. Following the in-person appointment, participants complete three follow-up interviews via telephone at one-week, four-weeks, and twelve-weeks post-intervention. The primary outcomes are suicidal ideation, emotion dysregulation, and skills use. Secondary outcomes include depression, anxiety, self-efficacy, and treatment utilization. Exploratory outcomes are suicidal and intentionally self-injurious behaviors. Intent-to-treat analyses will be conducted on primary and secondary outcomes. DISCUSSION: Suicidal individuals who are not engaged in mental health treatment are an understudied and significantly at-risk group for death by suicide. A better understanding of this population, targeted efforts to recruit and engage these individuals, and developing effective interventions for this group are critical areas for investigation in the field that this trial seeks to address. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02236325 ; Date of registration: 05-Sept-2014.

In their own words: Content analysis of pathways to recovery among individuals with the lived experience of homelessness and alcohol use disorders.

BACKGROUND: Alcohol use disorders (AUDs) are more prevalent among homeless individuals than in the general population, and homeless individuals are disproportionately affected by alcohol-related morbidity and mortality. Unfortunately, abstinence-based approaches are neither desirable to nor highly effective for most members of this population. Recent research has indicated that homeless people aspire to clinically significant recovery goals beyond alcohol abstinence, including alcohol harm reduction and quality-of-life improvement. However, no research has documented this population's preferred pathways toward self-defined recovery. Considering principles of patient-centred care, a richer understanding of this population's desired pathways to recovery may help providers better engage and support them. METHODS: Participants (N=50) had lived experience of homelessness and AUDs and participated in semi-structured interviews regarding histories of homelessness, alcohol use, and abstinence-based treatment as well as suggestions for improving alcohol treatment. Conventional content analysis was used to ascertain participants' perceptions of abstinence-based treatment and mutual-help modalities, while it additionally revealed alternative pathways to recovery. RESULTS: Most participants reported involvement in abstinence-based modalities for reasons other than the goal of achieving long-term abstinence from alcohol (e.g., having shelter in winter months, "taking a break" from alcohol use, being among "like-minded people"). In contrast, most participants preferred alternative pathways to recovery, including fulfilling basic needs (e.g., obtaining housing), using harm reduction approaches (e.g., switching from higher to lower alcohol content beverages), engaging in meaningful activities (e.g., art, outings, spiritual/cultural activities), and making positive social connections. CONCLUSIONS: Most people with the lived experience of homelessness and AUDs we interviewed were uninterested in abstinence-based modalities as a means of attaining long-term alcohol abstinence. These individuals do, however, have creative ideas about alternative pathways to recovery that treatment providers may support to reduce alcohol-related harm and enhance quality of life.

Qualitatively and quantitatively evaluating harm-reduction goal setting among chronically homeless individuals with alcohol dependence.

INTRODUCTION: Most treatment programs for alcohol dependence have prioritized alcohol abstinence as the primary treatment goal. However, abstinence-based goals are not always considered desirable or attainable by more severely affected populations, such as chronically homeless people with alcohol dependence. Because these individuals comprise a multimorbid and high-utilizing population, they are in need of more focused research attention that elucidates their preferred treatment goals. The aim of this secondary study was therefore to qualitatively and quantitatively document participant-generated treatment goals METHODS: Participants were currently or formerly chronically homeless individuals (N=31) with alcohol dependence who participated in a pilot of extended-release naltrexone and harm-reduction counseling. Throughout the treatment period, study interventionists elicited participants' goals and recorded them on an open-ended grid. In subsequent weeks, progress towards and achievement of goals was obtained via self-report and recorded by study interventionists. Conventional content analysis was performed to classify participant-generated treatment goals RESULTS: Representation of the three top categories remained stable over the course of treatment. In the order of their frequency, they included drinking-related goals, quality-of-life goals and health-related goals. Within the category of drinking-related goals, participants consistently endorsed reducing drinking and alcohol-related consequences ahead of abstinence-based goals. Quantitative analyses indicated participants generated an increasing number of goals over the course of treatment. Proportions of goals achieved and progressed towards kept pace with this increase CONCLUSIONS: Findings confirmed hypotheses that chronically homeless people with alcohol dependence can independently generate and achieve treatment goals towards alcohol harm reduction and quality-of-life improvement.

Suicide-Bereaved Individuals' Attitudes Toward Therapists.

BACKGROUND: Suicide-bereaved individuals represent an important group impacted by suicide. Understanding their experiences following the suicide of a loved one is an important research domain, despite receiving limited attention. Although suicide-bereaved individuals may benefit from mental health treatment, their attitudes toward therapy and therapists are poorly understood. AIMS: The present study aimed to understand the extent to which bereaved individuals' attitudes toward therapy and therapists are impacted by whether their loved one was in therapy at the time of death. METHOD: Suicide-bereaved individuals (N = 243) from the United States were recruited to complete an online survey about their experience with and attitudes toward therapy and therapists following the suicide of a loved one. RESULTS: Bereaved individuals whose loved one was in therapy at the time of death (N = 48, 19.8%) reported more negative and less positive attitudes toward the treating therapist than those whose loved one was not in therapy at the time of death (N = 81, 33.3%) or whose loved one was never in therapy/the deceased's therapy status was unknown (N = 114, 46.9%). CONCLUSION: The deceased's involvement with a therapist appears to be an important factor impacting the experience of bereaved individuals and should be considered when attempting to engage these individuals in postvention.