Identification of a synergistic combination of dimethylaminoparthenolide and shikonin alters metabolism and inhibits proliferation of pediatric precursor-B cell acute lymphoblastic leukemia

Exploiting metabolic vulnerabilities of cancer cells with nontoxic, plant derived compounds constitutes a novel strategy for both chemoprevention and treatment. A high-throughput screening approach was used to evaluate a library of natural products to determine the most synergistic combination in precursor-B cell acute lymphoblast leukemia. Dimethylaminoparthenolide and shikonin effectively inhibited proliferation resulting in cell death in primary and immortalized leukemia cells, while having negligible effects on normal cells. Dimethylaminoparthenolide and shikonin have been shown separately to inhibit cell survival and proliferative signaling and activate tumor suppressors and proapoptotic pathways. Untargeted metabolomics and metabolic flux analysis with stable isotopically labeled glucose and glutamine exhibited a global shift in metabolism following treatment. Pathway analysis indicated significant differences in amino acid, antioxidant, tricarboxylic acid cycle, and nucleotide metabolism. Together, dimethylaminoparthenolide and shikonin reduced the shunting of glycolytic intermediates into the pentose phosphate pathway for biosynthetic purposes. Similarly, the incorporation of glutamine and glutamine-derived metabolites into purine and pyrimidine synthesis was inhibited by the combination of dimethylaminoparthenolide and shikonin, effectively impeding biosynthetic pathways critical for leukemia cell survival. This approach demonstrates that a synergistic pair of compounds with malignant cell specificity can effectively target metabolic pathways crucial to leukemia cell proliferation and induce apoptosis.     

High Altitude Continues to Reduce Birth Weights in Colorado

Maternal and Child Health Journal - Objectives Colorado’s relatively high altitudes have been reported to lower birth weight but the most recent studies were conducted 20 years ago....     

The Core Components of Evidence-Based Social Emotional Learning Programs

Prevention Science - Implementing social emotional learning (SEL) programs in school settings is a promising approach to promote critical social and emotional competencies for all students....     

Breastfeeding and the origins of health: Interdisciplinary perspectives and priorities

Breastfeeding and human milk (HM) are critically important to maternal, infant and population health. This paper summarizes the proceedings of a workshop that convened a multidisciplinary panel of researchers to identify key priorities and anticipated breakthroughs in breastfeeding and HM research, discuss perceived barriers and challenges to achieving these breakthroughs and propose a constructive action plan to maximize the impact of future research in this field. Priority research areas identified were as follows: (1) addressing low breastfeeding rates and inequities using mixed methods, community partnerships and implementation science approaches; (2) improving awareness of evidence‐based benefits, challenges and complexities of breastfeeding and HM among health practitioners and the public; (3) identifying differential impacts of alternative modes of HM feeding including expressed/pumped milk, donor milk and shared milk; and (4) developing a mechanistic understanding of the health effects of breastfeeding and the contributors to HM composition and variability. Key barriers and challenges included (1) overcoming methodological limitations of epidemiological breastfeeding research and mechanistic HM research; (2) counteracting ‘breastfeeding denialism’ arising from negative personal breastfeeding experiences; (3) distinguishing and aligning research and advocacy efforts; and (4) managing real and perceived conflicts of interest. To advance research on breastfeeding and HM and maximize the reach and impact of this research, larger investments are needed, interdisciplinary collaboration is essential, and the scientific community must engage families and other stakeholders in research planning and knowledge translation.     

Impact of familial risk and mammography screening on prognostic indicators of breast disease among women from the Ontario site of the Breast Cancer Family Registry

Although several studies have found screen-detected cancers in women with familial breast cancer risk have favorable prognostic features compared with symptomatic cancers, the impact of level of familial risk is unknown. A cohort of 899 first-degree female relatives of cases of breast cancer from the Ontario site of the Breast Cancer Family Registry was followed for 2 years. Logistic regression analyses compared diagnoses of breast cancer or benign breast disease (BBD) between women at high (n = 258, 28.7 %) versus low/moderate (n = 641, 71.3 %) familial risk. Similar analyses compared prognostic features of invasive cancers and BBD by level of familial risk and mammography screening status. Among 899 women, 44 (4.9 %) were diagnosed with invasive breast cancer and/or ductal carcinoma in situ, and 56 (6.2 %) with BBD. Women with high familial risk were significantly more likely to be diagnosed with breast cancer [odds ratio (OR) = 2.84, 95 % confidence interval (CI) 1.50–5.38] than low/moderate risk women, particularly if diagnosed at age ≥50 (OR = 2.99, 95 % CI 1.37–6.56) or screened with mammography (OR = 3.33, 95 % CI 1.54–7.18). High risk women were more likely to be diagnosed with BBD (OR = 1.94, 95 % CI 1.03–3.66). Level of familial risk was not associated with prognostic features. Cancers among unscreened women were larger (OR = 9.72, 95 % CI 1.01–93.61) and diagnosed at stage II or above (OR = 7.80, 95 % CI 1.18–51.50) compared with screen-detected cancers. Screening mammography may be effective for women with a first-degree family history of breast cancer, irrespective of level of familial risk.     

Social phobia and selective mutism

Social phobia (SOP) and selective mutism (SM) are related anxiety disorders characterized by distress and dysfunction in social situations. SOP typically onsets in adolescence and affects about 8% of the general population, whereas SM onsets before age 5 and is prevalent in up to 2% of youth. Prognosis includes a chronic course that confers risk for other disorders or ongoing social disability, but more favorable outcomes may be associated with young age and low symptom severity. SOP treatments are relatively more established, whereas dissemination of promising and innovative SM-treatment strategies is needed.     

Symptoms of depression and PTSD are associated with elevated alcohol demand

BackgroundBehavioral economic demand curves measure individual differences in motivation for alcohol and have been associated with problematic patterns of alcohol use, but little is known about the variables that may contribute to elevated demand. Negative visceral states have been theorized to increase demand for alcohol and to contribute to excessive drinking patterns, but little empirical research has evaluated this possibility. The present study tested the hypothesis that symptoms of depression and PTSD would be uniquely associated with elevated alcohol demand even after taking into account differences in typical drinking levels.MethodAn Alcohol Purchase Task (APT) was used to generate a demand curve measure of alcohol reinforcement in a sample of 133 college students (50.4% male, 64.4% Caucasian, 29.5% African-American) who reported at least one heavy drinking episode (5/4 or more drinks in one occasion for a man/woman) in the past month. Participants also completed standard measures of alcohol consumption and symptoms of depression and PTSD.ResultsRegression analyses indicated that symptoms of depression were associated with higher demand intensity (alcohol consumption when price = 0; ΔR² = .05, p = .002) and lower elasticity (ΔR² = .04, p = .03), and that PTSD symptoms were associated with all five demand curve metrics (ΔR² = .04–.07, ps < .05).ConclusionsThese findings provide support for behavioral economic models of addiction that highlight the role of aversive visceral states in increasing the reward value of alcohol and provide an additional theoretical model to explain the association between negative affect and problematic drinking patterns.     

Arrest history,stigma, and self-esteem: a modified labeling theory approach to understanding how arrests impact lives

Purpose

Modified labeling theory theorizes that when people acquire a label, personally held views about that label gain relevance and exert negative effects. We assessed whether being arrested reduces self-esteem to different extents based on the degree to which individuals hold stigmatizing beliefs about people with arrest records.

Methods

Adults living in the South Bronx, New York City (N = 532, 56% of whom had ever been arrested) indicated their level of agreement with statements about people with arrest records. We used exploratory factor analysis to identify categories of stigmatizing views, and calculated scores for the two following categories: “stereotype awareness” and “stereotype agreement.” Self-esteem was assessed with the Rosenberg self-esteem scale. Using fitted linear regression models, we assessed interaction between arrest history and each stigma score, and calculated mean differences representing the association between arrest history and self-esteem score, for those with stigma scores one standard deviation (SD) below and above the mean.

Results

For each type of stigma, participants with stigma scores one SD below the mean had similar self-esteem scores, regardless of arrest history. However, among participants with stigma scores one SD above the mean, those who had experienced an arrest had lower self-esteem scores than those who had not (mean difference = − 2.07, 95% CI − 3.16, − 0.99 for “stereotype awareness”; mean difference = − 2.92, 95% CI − 4.05, − 1.79 for “stereotype agreement”).

Conclusion

Being arrested affects self-esteem to a greater degree among persons who hold stigmatizing views about people with arrest records. These findings support a modified labeling theory of arrest-related stigma.