Awareness of peers in recovery and of a campus collegiate recovery community at a university in the southeastern United States.

Objective: Little is known about the extent of student awareness about collegiate recovery communities (CRCs) and of peers in recovery. Participants: A convenience sample of 237 undergraduate students from a diverse major at a private university participated in an anonymous online survey in Fall 2019. Methods: Participants reported whether they knew about the local CRC, whether they knew a peer in recovery, sociodemographic characteristics, and other information. Multivariable modified Poisson regression models were fitted to estimate correlates of awareness of the CRC and of peers in recovery. Results: Overall, 34% were aware of the CRC and 39% knew a peer in recovery. The latter was associated with being a member of Greek life, a junior or senior, using substances regularly, and personally being in recovery. Conclusions: Future research should explore ways to increase awareness of CRCs and assess the role of connections between students in recovery and peers across campus.

Spotlight on New Therapeutic Opportunities for MYC-Driven Cancers.

MYC can be considered to be one of the most pressing and important targets for the development of novel anti-cancer therapies. This is due to its frequent dysregulation in tumors and due to the wide-ranging impact this dysregulation has on gene expression and cellular behavior. As a result, there have been numerous attempts to target MYC over the last few decades, both directly and indirectly, with mixed results. This article reviews the biology of MYC in the context of cancers and drug development. It discusses strategies aimed at targeting MYC directly, including those aimed at reducing its expression and blocking its function. In addition, the impact of MYC dysregulation on cellular biology is outlined, and how understanding this can underpin the development of approaches aimed at molecules and pathways regulated by MYC. In particular, the review focuses on the role that MYC plays in the regulation of metabolism, and the therapeutic avenues offered by inhibiting the metabolic pathways that are essential for the survival of MYC-transformed cells.

Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia.

Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase (COASY), induced by mutations in SF3B1, affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.

Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.

Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.

MYC sensitises cells to apoptosis by driving energetic demand.

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver- enriched mitochondrial SOP enzyme thiosulfate sulfurtransferase (Tst-/- mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia, and fatty liver. Unexpectedly, hepatic sulfide levels are normal in Tst-/- mice because of exaggerated induction of sulfide disposal, with associated suppression of global protein persulfidation and nuclear respiratory factor 2 target protein levels. Hepatic proteomic and persulfidomic profiles converge on gluconeogenesis and lipid metabolism, revealing a selective deficit in medium-chain fatty acid oxidation in Tst-/- mice. We reveal a critical role of TST in hepatic metabolism that has implications for sulfide donor strategies in the context of metabolic disease.

Defining the fetal origin of MLL-AF4 infant leukemia highlights specific fatty acid requirements.

Infant MLL-AF4-driven acute lymphoblastic leukemia (ALL) is a devastating disease with dismal prognosis. A lack of understanding of the unique biology of this disease, particularly its prenatal origin, has hindered improvement of survival. We perform multiple RNA sequencing experiments on fetal, neonatal, and adult hematopoietic stem and progenitor cells from human and mouse. This allows definition of a conserved fetal transcriptional signature characterized by a prominent proliferative and oncogenic nature that persists in infant ALL blasts. From this signature, we identify a number of genes in functional validation studies that are critical for survival of MLL-AF4+ ALL cells. Of particular interest are PLK1 because of the readily available inhibitor and ELOVL1, which highlights altered fatty acid metabolism as a feature of infant ALL. We identify which aspects of the disease are residues of its fetal origin and potential disease vulnerabilities.

Spatiofunctional Dynamics of NKX3.1 to Safeguard the Prostate from Cancer.

A novel role of NKX3.1 in the mitochondria regulating the transcription of the electron transport chain components is reported. Mechanistically, HSPA9 chaperones NKX3.1 into the mitochondria in response to oxidative stress to regulate reactive oxygen species and suppress tumor initiation.See related article by Papachristodoulou et al., p. 2316.

De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands.

The aberrant gain of DNA methylation at CpG islands is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CpG islands are targeted by de novo DNA methyltransferases in a sequence-specific manner, but this has not been tested. Using ectopically integrated CpG islands, here we find that aberrantly methylated CpG islands are subject to low levels of de novo DNA methylation activity in colorectal cancer cells. By delineating DNA methyltransferase targets, we find that instead de novo DNA methylation activity is targeted primarily to CpG islands marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CpG islands are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNA methyltransferase activity at CpG islands in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

The Biosynthesis of Enzymatically Oxidized Lipids.

Enzymatically oxidized lipids are a specific group of biomolecules that function as key signaling mediators and hormones, regulating various cellular and physiological processes from metabolism and cell death to inflammation and the immune response. They are broadly categorized as either polyunsaturated fatty acid (PUFA) containing (free acid oxygenated PUFA "oxylipins", endocannabinoids, oxidized phospholipids) or cholesterol derivatives (oxysterols, steroid hormones, and bile acids). Their biosynthesis is accomplished by families of enzymes that include lipoxygenases (LOX), cyclooxygenases (COX), cytochrome P450s (CYP), and aldo-keto reductases (AKR). In contrast, non-enzymatically oxidized lipids are produced by uncontrolled oxidation and are broadly considered to be harmful. Here, we provide an overview of the biochemistry and enzymology of LOXs, COXs, CYPs, and AKRs in humans. Next, we present biosynthetic pathways for oxylipins, oxidized phospholipids, oxysterols, bile acids and steroid hormones. Last, we address gaps in knowledge and suggest directions for future work.

Recovery and Youth: An Integrative Review.

Although rates of alcohol and other substance use disorders in adolescents have been estimated for decades, little is known about the prevalence, pathways, and predictors of remission and long-term recovery among adolescents. This article provides an integrative review of the literature on youth recovery. A final selection of 39 relevant articles was grouped into five sections: treatment outcomes, special emphasis populations, recovery-oriented systems of care, families, and non-abstinence-based approaches. The review recommends more adolescent research in three basic areas: more research about medication-assisted treatment and recovery as well as harm reduction approaches for adolescents; expansion of research on recovery practices for youth who do not receive treatment due to personal choice or societal disparities; and more life course research, which may begin with adolescent participants and extend across the life span. Additionally, the authors suggest the recovery capital model for adolescents and the neuroscience of addiction may provide additional precision and direction for the study of youth recovery.

Recovery High School Attendance Effects on Student Delinquency and Substance Use: the Moderating Role of Social Problem Solving Styles.

Recovery high schools (RHSs) provide educational programming and therapeutic support services for young people in recovery from substance use disorders (SUDs). The objectives of this study were to examine whether students with SUDs who attended RHSs report less delinquency and substance use than students with SUDs who attended non-RHSs, and how students' social problem solving styles might moderate those associations. Participants were students from a longitudinal quasi-experimental study of adolescents who enrolled in high schools after receiving treatment for SUDs. The propensity-score balanced sample included 260 adolescents (143 in RHSs, 117 in non-RHSs) enrolled in schools in Minnesota, Wisconsin, or Texas (M age = 16; 83% White; 44% female). Negative binomial regression models were used to compare delinquency and substance use outcomes for RHS and non-RHS students at 6-month and 12-month follow-ups. The results indicated that students attending RHSs after discharge from SUD treatment reported less frequent delinquent behavior while intoxicated, and fewer days of substance use relative to students attending non-RHSs. Negative problem solving styles moderated the effect of RHS attendance on substance use outcomes, with RHSs providing minimal beneficial effects for those students endorsing maladaptive problem solving styles. We conclude that RHSs offer a promising continuing care approach for adolescents in recovery from SUD problems, but may vary in their effectiveness for students with impulsive, careless, or avoidant problem solving styles.

Net Benefits of Recovery High Schools: Higher Cost but Increased Sobriety and Educational Attainment.

BACKGROUND: Recovery high schools (RHS) provide a supportive educational and therapeutic environment for students subsequent to treatment for substance use disorders (SUDs). Most students served by RHSs have concurrent mental health disorders and are at risk for school failure or dropout and substance use relapse. AIMS OF THE STUDY: The central question addressed is whether RHSs are economically efficient alternatives to other high school settings for students in recovery. The aim is to estimate the incremental cost-benefit of RHSs. METHODS: A quasi-experimental non-equivalent pretest-posttest comparison group design was used. We compared substance use and educational outcomes for adolescents who had received specialty SUD treatment; 143 who enrolled in an RHS were compared to 117 who enrolled in a non-RHS school. Groups were balanced by use of a propensity score to drop students who were not similar to those in the other group. The propensity score was also used as a covariate in multiple regression to estimate cost and outcome parameters and standard errors. To take account of uncertainties in impacts and shadow prices, we used Monte Carlo simulations to estimate the distribution of incremental benefits of RHS relative to non-RHS schooling. RESULTS: Two beneficial impacts of statistical and substantive importance were identified: increased probability of high school graduation and increased sobriety. RHS students had significantly (p<.05) less substance use during the study period -- at 12-month follow-up, 55% of RHS and 26% of comparison students reported 3 month abstinence from alcohol and drugs. Urinalysis confirmed abstinence from THC (cannabis) for 68% of RHS versus 37% of comparison students. RHS students' high school graduation rates were 21 to 25 percentage points higher than comparison students. Adopting a societal perspective, incremental benefits of RHSs were estimated by monetizing the increased probability of high school graduation and comparing it to incremental costs. Mean net benefits ranged from USD16.1 thousand to USD51.9 thousand per participant; benefit-to-cost ratios ranged from 3.0 to 7.2. DISCUSSION: Monetizing the benefits and the incremental costs of RHS relative to conventional schooling show substantial positive net benefits from RHS participation. Two factors lend credibility to the results. First, the RHS improvement in substance use indicates a mechanism through which the increased probability of high school graduation can plausibly occur. Second, the estimated increases in the probability of high school graduation were large and statistically significant. As the productivity gains from high school graduation are also large, the dominant benefit category is very plausible. Limitations include the non-randomized design; selection bias into the study conditions not fully controlled by the propensity scores; generalizability only to young people with treated behavioral health disorders; lack of estimates for direct monetization of reduced substance use among adolescents; possible attenuation of the value of education among individuals with behavioral health issues; and uncertainty in calculation of school costs. IMPLICATIONS FOR BEHAVIORAL HEALTH POLICIES: This research provides evidence that the recovery high school model provides cost beneficial support for high school students after primary SUD treatment. The students who enroll in RHSs typically have co-occurring mental health and substance use disorders, adding complexity to their continuing care. Funding policies recognizing the multiple systems of care (behavioral health, education, child and family services, juvenile justice) responsible for these young people are called for.

Adolescent recovery capital and recovery high school attendance: An exploratory data mining approach.

Recovery high schools (RHSs) provide a recovery-supportive academic environment for adolescents in recovery from a substance use disorder and are located across the United States. However, only a small proportion of the 160,000 youth in recovery each year in the United States enroll in RHSs posttreatment, indicating that many youth do not access this relapse prevention resource despite its effectiveness. Thus, this study uses the adolescent-adapted recovery capital model (RCAM) to understand individual- and community-level predictors of attendance and identify disparities leading to barriers to accessing RHSs. Data were collected as part of a multisite observational study of adolescents in recovery (N = 294). Logistic regressions and classification trees explored which different recovery capital factors predicted the odds of attending an RHS for at least 28 days during a 12-month period (n = 171) versus a non-RHS (e.g., traditional school: n = 123). The RCAM model is a useful theoretical framework for examining predictors of RHS attendance, and both analysis methods identified multiple unique predictors of RHS attendance. The strongest predictors of RHS attendance were individual-level factors, including problem-solving skills, 12-Step frequency, and financial resources. The classification trees highlighted additional interactions that should be explored in future empirical research. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype.

Cellular senescence is a stress response program characterized by a robust cell cycle arrest and the induction of a proinflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that, during oncogene-induced senescence (OIS), the Toll-like receptor 2 (TLR2) and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumor suppressors p53-p21CIP1, p16INK4a, and p15INK4b and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAAs) that, in turn, function as the damage-associated molecular patterns (DAMPs) signaling through TLR2 in OIS. Last, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAAs expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.

Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence.

Cellular senescence is triggered by diverse stimuli and is characterized by long-term growth arrest and secretion of cytokines and chemokines (termed the SASP-senescence-associated secretory phenotype). Senescence can be organismally beneficial as it can prevent the propagation of damaged or mutated clones and stimulate their clearance by immune cells. However, it has recently become clear that senescence also contributes to the pathophysiology of aging through the accumulation of damaged cells within tissues. Here, we describe that inhibition of the reaction catalysed by LSG1, a GTPase involved in the biogenesis of the 60S ribosomal subunit, leads to a robust induction of cellular senescence. Perhaps surprisingly, this was not due to ribosome depletion or translational insufficiency, but rather through perturbation of endoplasmic reticulum homeostasis and a dramatic upregulation of the cholesterol biosynthesis pathway. The underlying transcriptomic signature is shared with several other forms of senescence, and the cholesterol biosynthesis genes contribute to the cell cycle arrest in oncogene-induced senescence. Furthermore, targeting of LSG1 resulted in amplification of the cholesterol/ER signature and restoration of a robust cellular senescence response in transformed cells, suggesting potential therapeutic uses of LSG1 inhibition.

The long non-coding RNA Cerox1 is a post transcriptional regulator of mitochondrial complex I catalytic activity.

To generate energy efficiently, the cell is uniquely challenged to co-ordinate the abundance of electron transport chain protein subunits expressed from both nuclear and mitochondrial genomes. How an effective stoichiometry of this many constituent subunits is co-ordinated post-transcriptionally remains poorly understood. Here we show that Cerox1, an unusually abundant cytoplasmic long noncoding RNA (lncRNA), modulates the levels of mitochondrial complex I subunit transcripts in a manner that requires binding to microRNA-488-3p. Increased abundance of Cerox1 cooperatively elevates complex I subunit protein abundance and enzymatic activity, decreases reactive oxygen species production, and protects against the complex I inhibitor rotenone. Cerox1 function is conserved across placental mammals: human and mouse orthologues effectively modulate complex I enzymatic activity in mouse and human cells, respectively. Cerox1 is the first lncRNA demonstrated, to our knowledge, to regulate mitochondrial oxidative phosphorylation and, with miR-488-3p, represent novel targets for the modulation of complex I activity.

ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy.

Typical Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Genetic analysis of 85 unrelated "mutation negative" probands with Martsolf or Martsolf-like syndromes identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). Both probands were from multiplex families with a consistent, lethal and highly distinctive disorder; a Martsolf-like syndrome with infantile-onset dilated cardiomyopathy. Severe ITPase-deficiency has been previously reported with infantile epileptic encephalopathy (MIM 616647). ITPase acts to prevent incorporation of inosine bases (rI/dI) into RNA and DNA. In Itpa-null cells dI was undetectable in genomic DNA. dI could be identified at a low level in mtDNA without detectable mitochondrial genome instability, mtDNA depletion or biochemical dysfunction of the mitochondria. rI accumulation was detectable in proband-derived lymphoblastoid RNA. In Itpa-null mouse embryos rI was detectable in the brain and kidney with the highest level seen in the embryonic heart (rI at 1 in 385 bases). Transcriptome and proteome analysis in mutant cells revealed no major differences with controls. The rate of transcription and the total amount of cellular RNA also appeared normal. rI accumulation in RNA-and by implication rI production-correlates with the severity of organ dysfunction in ITPase deficiency but the basis of the cellulopathy remains cryptic. While we cannot exclude cumulative minor effects, there are no major anomalies in the production, processing, stability and/or translation of mRNA.

Effects of Recovery High School Attendance on Students' Mental Health Symptoms.

Recovery high schools are one form of continuing care support for adolescents with substance use or other co-occurring disorders. Using a controlled quasi-experimental design, we compared mental health symptom outcomes at 6 months for adolescents who attended recovery high schools vs. non-recovery high schools (e.g., traditional or alternative schools). The propensity score balanced sample included 194 adolescents (134 in recovery schools, 60 in non-recovery schools) enrolled in schools in MN, WI, or TX (average age = 16; 86% White; 51% female). Baseline data indicated that this is a dually diagnosed population-94% of students met criteria for at least one mental health diagnosis and 90% had received mental health treatment distinct from treatment for substance use disorders. Results from multilevel logistic regression models indicated that at the 6-month follow-up, adolescents attending both recovery and non-recovery high schools reported substantial improvements in mental health symptoms. However, there were no significant differences in mental health outcomes between the two groups. We conclude that although recovery high schools offer promise for reducing substance use and improving academic success, and while adolescents' mental health symptoms improved between baseline and follow-up, recovery high schools may have minimal differential effects on adolescents' mental health symptoms.