Age Specificity of Effects of Health Problems on Drinking Reduction: A Lifespan Developmental Analysis.

Older adult drinking poses a growing public health concern, especially given the ongoing aging of the United States population. As part of a larger lifespan developmental project contrasting predictors of drinking reductions across different periods of adulthood, we tested age differences in effects of health problems on drinking declines across young adulthood, midlife, and older adulthood. We predicted these effects to be developmentally specific to midlife and older adulthood. We also tested moderation by alcohol use disorder (AUD) symptomatology and by indices of sociodemographic disadvantage (sex and race/ethnicity). Analyses used data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), leveraging NESARC's vast age range (18-90 + ; N = 43,093) and two waves of longitudinal data. Multiple-group cross-lag models tested differences across age groups in cross-lag paths between health problems and alcohol consumption. As hypothesized, health problem effects on drinking reductions were developmentally specific to midlife and older adulthood. However, models testing moderation by AUD symptomatology showed that these adaptive effects of health problems on drinking reductions did not extend to those with one or more AUD symptoms. Little evidence was found for moderation by sex or race/ethnicity. Findings support the notion of health concerns as a pathway to drinking reduction that increases in importance across the adult lifespan. However, given the moderation by AUD symptoms, findings also highlight a need to understand barriers to health-related pathways to drinking reduction among relatively severe midlife and older adult drinkers. These findings hold implications for lifespan developmental tailoring of clinical, public health, and policy interventions.

A life span developmental investigation of marriage and problem-drinking reduction.

While prior literature has largely focused on marriage effects during young adulthood, it is less clear whether these effects are as strong in middle adulthood. Thus, we investigated age differences in marriage effects on problem-drinking reduction. We employed parallel analyses with two independent samples (analytic-sample Ns of 577 and 441, respectively). Both are high-risk samples by design, with about 50% of participants having a parent with lifetime alcohol use disorder. Both samples have been assessed longitudinally from early young adulthood to the mid-to-late 30s. Separate parallel analyses with these two samples allowed evaluation of the reproducibility of results. Growth models of problem drinking tested marriage as a time-varying predictor and thereby assessed age differences in marriage effects. For both samples, results consistently showed marriage effects to be strongest in early young adulthood and to decrease somewhat monotonically thereafter with age, reaching very small (and nonsignificant) magnitudes by the 30s. Results may reflect that role transitions like marriage have more impact on problem drinking in earlier versus later adulthood, thereby highlighting the importance of life span developmental research for understanding problem-drinking desistance. Our findings can inform intervention strategies aimed at reducing problem drinking by jumpstarting or amplifying natural processes of adult role adaptation.

Evidence for discrete profiles of children's physiological activity across three neurobiological system and their transitions over time.

The conceptualization of stress-responsive physiological systems as operating in an integrated manner is evident in several theoretical models of cross-system functioning. However, limited empirical research has modeled the complexity of multisystem activity. Moreover few studies have explored developmentally regulated changes in multisystem activity during early childhood when plasticity is particularly pronounced. The current study used latent profile analysis (LPA) to evaluate multisystem activity during fall and spring of children's transition to kindergarten in three biological systems: the parasympathetic nervous system (PNS), sympathetic nervous system (SNS), and hypothalamic pituitary adrenal (HPA) axis. Latent transition analysis (LTA) was then used to examine the stability of profile classification across time. Across both timepoints, three distinct profiles of multisystem activity emerged. One profile was characterized by heightened HPA axis activity (HPA Axis Responders), a second profile was characterized by moderate, typically adaptive patterns across the PNS, SNS, and HPA axis (Active Copers/Mobilizers), and a third profile was characterized by heightened baseline activity, particularly in the PNS and SNS (Anticipatory Arousal/ANS Responders). LTA of fall-to-spring profile classifications indicated higher probabilities that children remained in the same profile over time compared to probabilities of profile changes, suggesting stability in certain patterns of cross-system responsivity. Patterns of profile stability and change were associated with socioemotional outcomes at the end of the school year. Findings highlight the utility of LPA and LTA to detect meaningful patterns of complex multisystem physiological activity across three systems and their associations with early adjustment during an important developmental transition.

The Association Between Alcohol Consumption and Pain Interference in a Nationally Representative Sample: The Moderating Roles of Gender and Alcohol Use Disorder Symptomatology.

BACKGROUND: Prior research on alcohol consumption and pain has yielded inconsistent results regarding the directionality of effects for both consumption-to-pain and pain-to-consumption relations. The present study sought to examine directionality of these relations by testing bidirectional longitudinal associations between consumption and pain interference, a crucial aspect of pain that captures pain-related disability and has been regarded as a valuable measure of treatment outcome. In addition, this study explored possible moderation of these bidirectional longitudinal associations by gender and alcohol use disorder (AUD) symptomatology. METHODS: Analyses included 29,989 current/former drinkers who were interviewed at both waves (2001 and 2004) of the U.S. National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Analyses used self-report data from both waves on past-year average daily volume of alcohol consumed and past-month pain interference (1 item from the Medical Outcomes Study 12-item Short-Form Health Survey [MOS-SF-12]). AUDADIS-IV data from Wave 1 were used to index baseline AUD symptomatology (i.e., symptom count). Cross-lagged panel modeling and multigroup analyses were employed. RESULTS: Regarding the consumption-to-pain-interference relation, in general, higher baseline alcohol consumption was associated with lower subsequent pain interference at follow-up. However, among men with higher AUD-symptom counts, the opposite pattern emerged, with higher baseline alcohol consumption being significantly related to higher subsequent pain interference at follow-up. Regarding the pain-interference-to-consumption relation, higher baseline pain interference was significantly associated with lower subsequent alcohol consumption at follow-up, and no moderating effects were observed. CONCLUSIONS: The distinctive patterns of the consumption-to-pain-interference relation observed among men with elevated AUD symptomatology suggest that this relation might be driven by different mechanisms across different groups of individuals. Specifically, the detrimental effect of alcohol on pain interference might emerge at relatively advanced stages of AUD among men, consistent with Koob's Dark Side of Alcohol Addiction theory in human research.

Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors.

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50 values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.

Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.

One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.

Integrating Social-Contextual and Intrapersonal Mechanisms of "Maturing Out": Joint Influences of Familial-Role Transitions and Personality Maturation on Problem-Drinking Reductions.

BACKGROUND: "Maturing out" of problem drinking is associated with both role transitions (e.g., getting married) and personality development. However, little is known concerning how these 2 mechanisms jointly influence problem-drinking desistance. This study investigated whether salutary effects of role transitions and personality occur at different points in young-adult development and whether they mediate one another's effects. METHODS: Participants were initially recruited as first-year undergraduates, with family history of alcoholism overrepresented by design (N = 489). Using 4 waves of data at roughly ages 21, 25, 29, and 34, cross-lagged panel models estimated prospective relations among familial-role transitions (marriage or parenthood), personality (disinhibition, conscientiousness, and neuroticism), and problem drinking. RESULTS: Mixed support was found for the prediction of roles being more strongly associated with earlier maturing out of problem drinking and personality being more strongly associated with later maturing out. Regarding mediation, no evidence was found for the expectation that role effects would be mediated by personality. However, results did support mediation of personality effects by role transitions. Specifically, lower disinhibition and higher conscientiousness in emerging adulthood predicted role adoption, which, in turn, predicted later problem-drinking reductions. Family history of alcoholism also distally influenced these mediation processes. CONCLUSIONS: The differential timing of role and personality effects is consistent with the notion of decreasing contextual influences and increasing intrapersonal influences across development. In light of role incompatibility theory, results suggest that, over the course of development, the association of familial roles with problem drinking may increasingly reflect problem-drinking effects on role entry (i.e., role selection) and decreasingly reflect role entry effects on problem drinking (i.e., role socialization). As emerging-adult disinhibition and conscientiousness were associated with an apparent developmental cascade of both direct and indirect effects, findings highlight their potential importance as etiologic mechanisms and intervention targets.

Role transitions and young adult maturing out of heavy drinking: evidence for larger effects of marriage among more severe premarriage problem drinkers.

BACKGROUND: Research has shown a developmental process of "maturing out" of problem drinking beginning in young adulthood. Perhaps surprisingly, past studies suggest that young adult drinking reductions may be particularly pronounced among those exhibiting relatively severe forms of problem drinking earlier in emerging adulthood. This may occur because more severe problem drinkers experience stronger ameliorative effects of normative young adult role transitions like marriage. METHODS: The hypothesis of stronger marriage effects among more severe problem drinkers was tested using 3 waves of data from a large ongoing study of familial alcohol disorder (N = 844; 51% children of alcoholics). RESULTS: Longitudinal growth models characterized (i) the curvilinear trajectory of drinking quantity from ages 17 to 40, (ii) effects of marriage on altering this age-related trajectory, and (iii) moderation of this effect by premarriage problem drinking levels (alcohol consequences and dependence symptoms). Results confirmed the hypothesis that protective marriage effects on drinking quantity trajectories would be stronger among more severe premarriage problem drinkers. Supplemental analyses showed that results were robust to alternative construct operationalizations and modeling approaches. CONCLUSIONS: Consistent with role incompatibility theory, findings support the view of role conflict as a key mechanism of role-driven behavior change, as greater problem drinking likely conflicts more with demands of roles like marriage. This is also consistent with the developmental psychopathology view of transitions and turning points. Role transitions among already low-severity drinkers may merely represent developmental continuity of a low-risk trajectory, whereas role transitions among higher-severity problem drinkers may represent developmentally discontinuous "turning points" that divert individuals from a higher- to a lower-risk trajectory. Practically, findings support the clinical relevance of role-related "maturing out processes" by suggesting that they often reflect natural recovery from clinically significant problem drinking. Thus, understanding these processes could help clarify the nature of pathological drinking and inform interventions.

Discovery of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines as potent PIM inhibitors.

PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.

The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors.

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.

The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors.

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55nM and 0.28nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50=150nM). This compound had moderate clearance and bioavailability in rat (CL=2.42L/kg/h; %F=24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74µM (18µg/mL) when dosed at 10, 30, 100 and 200mg/kg po in mice.

Civic communities and urban violence.

Civic communities have a spirit of entrepreneurialism, a locally invested population and an institutional structure fostering civic engagement. Prior research, mainly confined to studying rural communities and fairly large geographic areas, has demonstrated that civic communities have lower rates of violence. The current study analyzes the associations between the components of civic communities and homicide rates for New Orleans neighborhoods (census tracts) in the years following Hurricane Katrina. Results from negative binomial regression models adjusting for spatial autocorrelation reveal that community homicide rates are lower where an entrepreneurial business climate is more pronounced and where there is more local investment. Additionally, an interaction between the availability of civic institutions and resource disadvantage reveals that the protective effects of civic institutions are only evident in disadvantaged communities.

The Interactive Effects of the Anti-Sea Lice Pesticide Azamethiphos and Temperature on Oxidative Damage and Antioxidant Responses in the Oyster Ostrea chilensis.

Azamethiphos is used in the salmon industry to treat sea lice and is subsequently discharged into the sea, which may affect non-target species (NTS). A rise in seawater temperature could enhance the sensitivity of NTS. Thus, in the present investigation, the combined effects of azamethiphos (0 µg L-1, 15 µg L-1 and 100 µg L-1) and temperature (12 °C and 15 °C) was assessed over time (7 days) in the gonads and gills of the oyster Ostrea chilensis, assessing its oxidative damage (lipid peroxidation and protein carbonyls) and total antioxidant capacity. Our results indicated that in gonads and gills, lipid peroxidation levels increased over time during exposure to both pesticide concentrations. Protein carbonyl levels in gills increased significantly in all experimental treatments; however, in gonads, only pesticide concentration and exposure time effected a significant increase in protein damage. In both, gill and gonad temperature did not influence oxidative damage levels. Total antioxidant capacity in gonads was influenced only by temperature treatment, whereas in the gills, neither temperature nor azamethiphos concentration influenced defensive responses. In conclusion, our results indicated the time of pesticide exposure (both concentrations) had a greater influence than temperature on the cellular damage in this oyster.

A phase II study of potentiation of pembrolizumab with binimetinib and bevacizumab in refractory microsatellite stable colorectal cancer.

PURPOSE: In this single-institution phase II investigator-initiated study we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite stable metastatic colorectal cancer (MSS mCRC). PATIENTS AND METHODS: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate in all patients combined (ORR, by RECIST v1.1). RESULTS: Fifty patients received study drug treatment; 54% were male with median age 55 years (range 31-79). The primary endpoint, ORR, was 12.0% (95% confidence interval [CI] 4.5-24.3%), which was not statistically different than the historical control data of 5% (p=0.038, exceeding pre-specified threshold of 0.025). The disease control rate was 70.0% (95% CI 55.4-82.1%), median progression-free survival 5.9 months (95% CI 4.2-8.7 months), and median overall survival 9.3 months (95% CI 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%). CONCLUSION: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared to historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.

Maturing out of alcohol involvement: transitions in latent drinking statuses from late adolescence to adulthood.

Research has shown a developmental process of "maturing out" of alcohol involvement beginning in young adulthood, but the precise nature of changes characterizing maturing out is unclear. We used latent transition analysis to investigate these changes in a high-risk sample from a longitudinal study of familial alcoholism (N = 844; 51% children of alcoholics; 53% male, 71% non-Hispanic Caucasian, 27% Hispanic). Analyses classified participants into latent drinking statuses during late adolescence (ages 17-22), young adulthood (ages 23-28), and adulthood (ages 29-40), and characterized transitions among these statuses over time. The resulting four statuses were abstainers, low-risk drinkers who typically drank less than weekly and rarely binged or showed drinking problems, moderate-risk drinkers who typically binged less than weekly and showed moderate risk for drinking problems, and high-risk drinkers who typically binged at least weekly and showed high risk for drinking problems. Maturing out between late adolescence and young adulthood was most common among initial high-risk drinkers, but they typically declined to moderate-risk drinking rather than to nonrisky drinking statuses. This suggests that the developmental phenomenon of maturing out pertains primarily to relatively high-risk initial drinkers and that many high-risk drinkers who mature out merely reduce rather than eliminate their risky drinking.

The interactive effect of anti-sea lice pesticide azamethiphos and temperature on the physiological performance of the filter-feeding bivalve Ostrea chilensis: A non-target species.

The pesticide azamethiphos used by the salmon industry to treat sea lice, is applied as a bath and subsequently discharged into the sea. The effects of azamethiphos concentration (0, 15 and 100 µg L-1) on the physiology of the Chilean oyster (Ostrea chilensis) at two temperatures (12 and 15 °C) was examined. In all azamethiphos treatments, oysters kept at 15 °C had clearance rates (CR) higher than oysters kept at 12 °C. The oxygen consumption rate (OCR) increased at higher temperatures, except with 100 µg L-1 of azamethiphos, where no changes were observed. Sixty days after the exposure, survival rates of 91 and 79% (15 and 100 µg L-1, respectively), were observed compared to the controls, a situation independent of the experimental temperature. The interaction between temperature and pesticide has detrimental effects on the physiological performance and survival of O. chilensis, and these effects should also be assessed for other non-target species.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

Identification of triazolopyridazinones as potent p38α inhibitors.

Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.

Quinolinone-based agonists of S1P1: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 µM, 120% efficacy; 5: EC(50)=0.070 µM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 µM; 5: EC(50)=1.5 µM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.