"Dysregulated not deficit": A qualitative study on symptomatology of ADHD in young adults.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common condition that often persists into adulthood, although data suggest that the current diagnostic criteria may not represent how the condition presents in adults. We aimed to use qualitative methods to better understand ADHD symptomatology in young adults, especially regarding attentional and emotional dysregulation. METHODS: Nine focus groups involving young adults (aged 18-35 years; N = 43; 84% female; 86% US and Canada) with diagnoses of ADHD were conducted. Participants were asked about their perceptions of the current diagnostic criteria and how their symptoms have presented and changed over time. Data were analyzed using an interpretive phenomenological analysis framework. RESULTS: Most participants reported that the diagnostic criteria did not accurately capture their experiences with ADHD. They reported struggling with attention dysregulation, including hyperfocusing, and emotional dysregulation, including rejection-sensitive dysphoria. Many participants believed that their changing environments and behavioral adaptations influenced how their symptoms presented into adulthood. CONCLUSION: Current diagnostic criteria for ADHD may not capture the range of symptoms present in young adults. More research is needed to characterize attentional and emotional dysregulation in this population.

An exploratory study of problematic shopping and problematic video gaming in adolescents.

Problematic video gaming (PVG) and problematic shopping (PS) are addictive behaviors prevalent in adolescents, characterized by positive and negative reinforcement, and associated with psychosocial impairment. This study examined how PS and PVG relate in adolescents. It also examined how PS interacts with PVG in relation to health/functioning measures. Survey data from 3,657 Connecticut high-school students were evaluated. Chi-square analyses and logistic regression models were used to assess relationships between PS and measures of PVG. Interaction analyses measured effects of PS on relationships between PVG and health/functioning measures. Relative to adolescents without PS, those with PS had 8.79-fold higher odds of exhibiting PVG and were more likely to endorse gaming to relieve anxiety and impairment due to gaming. Interaction analyses revealed that in adolescents with PS, the relationships between PVG and aggressive behaviors, including fighting, serious fighting leading to physical injury, and weapon-carrying, were stronger than in adolescents without PS. PS strongly relates to PVG, and among youth reporting PS, there are stronger associations between PVG and aggressive behaviors. Prevention efforts for adolescents should consider the co-occurrence of PS and PVG. PS and PVG may be linked by negative reinforcement and propensities for aggressive and addictive behaviors, suggesting that further research should explore possible interventions targeting stress management and maladaptive coping.

Mobilization of innate and adaptive antitumor immune responses by the RNP-targeting antibody ATRC-101.

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

Difficulties in impulse control in adolescents with problematic use of the internet and self-injurious behaviors.

Problematic use of the internet (PUI) and self-injurious behaviors (SIB) associate in adolescents and both relate to impulsivity. However, studies have not examined whether difficulties in impulse control are shared in adolescents with PUI and SIB, and how PUI relates to SIB frequency and impairment. Here, exploratory factor analysis was performed on a PUI questionnaire based on the Minnesota Impulse Disorder Interview, using survey data from 2,912 Connecticut high-school students. Regression analyses evaluated relationships between PUI factor scores and correlates of SIB. Moderation analyses examined impulsivity and sensation-seeking in relationship to PUI factors and SIB. Two PUI factors were extracted. The first PUI factor was associated with lifetime SIB, frequency, severity, urges, rising tension, and self-perceived problems with SIB. The second factor was associated with lifetime SIB and attempts to reduce SIB. Impulsivity and sensation-seeking associated with PUI factors and SIB, but did not moderate relationships between PUI and SIB. Findings suggest that PUI and SIB are related by difficulties in impulse control, and poor control over internet use is associated with more impairing SIB in adolescents who self-injure. Further research should investigate possible interventions targeting impulsivity and sensation-seeking to prevent PUI and SIB in youth.

The Potential of N-acetyl Cysteine in Behavioral Addictions and Related Compulsive and Impulsive Behaviors and Disorders: a Scoping Review.

Purpose of Review: Behavioral addictions (also termed disorders due to addictive behaviors) contain impulsive and compulsive features and have been shown to involve glutamate dysregulation. N-acetylcysteine (NAC), a well-tolerated cysteine pro-drug and antioxidant, may reduce addictive behaviors by restoring glutamate homeostasis. The current review details and discusses the use of NAC in behavioral addictions and related impulsive and compulsive behaviors, including gambling disorder, problematic use of the internet, problematic video gaming, compulsive sexual behavior, problematic shopping/buying, problematic stealing, repetitive self-injurious behavior, and binge eating disorder. Recent Findings: Preliminary results have indicated the usefulness of NAC in gambling disorder, self-injurious behaviors, and compulsive sexual behaviors. Preclinical studies indicate that NAC is effective in improving binge eating behavior, but clinical trials are limited to a small open-label trial and case report. Studies are lacking on the efficacy of NAC in problematic use of the internet, problematic video gaming, problematic stealing, and problematic shopping/buying. Summary: NAC demonstrates potential for use in behavioral addictions and compulsive behaviors, particularly in gambling disorder and self-injury. However, more studies are needed to assess the effectiveness of NAC in other behavioral addictions and the mechanisms by which NAC improves these conditions.

Problematic shopping and self-injurious behaviors in adolescents.

BACKGROUND AND AIMS: Self-injurious behaviors (SIBs) and problematic shopping (PS) are both prevalent in adolescents. These behaviors have been proposed as behavioral addictions and linked to impulsivity (Imp) and sensation-seeking (SS). They are also associated with negative mental health and psychosocial measures. This study examined relationships between PS and SIB in adolescents. It also examined how PS and SIB relate to Imp and SS, and interactions between PS and SIB in relation to health/functioning measures. METHODS: Survey data from 2,624 Connecticut high-school students were evaluated using chi-square analyses. Next, logistic regression models were used to assess relationships between PS and measures of SIB. T-tests compared Imp and SS in adolescents with and without PS and SIB. Interaction analyses assessed effects of PS on relationships between SIB and health/functioning measures. RESULTS: Adolescents with PS had 3.43-fold higher odds of endorsing lifetime SIB than those without PS, and were more likely to exhibit severe SIB and disruption due to SIB. PS and SIB were associated with elevated Imp and SS. Interaction analyses revealed that in adolescents with PS, the relationships between SIB and substance use was weaker than in adolescents without PS. This suggests PS accounts for variance in relationships between SIB and substance use. DISCUSSION AND CONCLUSIONS: PS is strongly related to SIB prevalence, severity, and impairment in adolescents, and weakens associations between SIB and substance use. PS should therefore be considered for prevention efforts for SIB. Further research should investigate mechanisms connecting PS and SIB and explore possible interventions targeting associated features like Imp and SS.

Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS.

Ketones represent an important alternative fuel for the brain under glucose hypo-metabolic conditions induced by neurological diseases or aging, however their metabolic consequences in healthy brain remain unclear. Here we report that ketones can increase the redox NAD+/NADH ratio in the resting brain of healthy young adults. As NAD is an important energetic and signaling metabolic modulator, these results provide mechanistic clues on how nutritional ketosis might contribute to the preservation of brain health.

Natural Bioactive Food Components for Improving Enteral Tube Feeding Tolerance in Adult Patient Populations.

Tube feeding (TF) is the most common form of nutrition support. In recent years, TF administration has increased among patient populations within and outside hospital settings, in part due to greater insurance coverage, reduced use of parenteral nutrition, and improved formularies suitable for sole source nutrition. With increasing life expectancy and improved access to TFs, the number of adults dependent on enteral nutrition is expected to grow. However, enteral TF intolerance (ETFI) is the most common complication of TFs, typically presenting with at least 1 adverse gastrointestinal event, including nausea, diarrhea, and constipation. ETFI often leads to reductions in TF volume with associated energy and protein deficits. Potentially ensuing malnutrition is a major public health concern due its effects on increased risk of morbidity and mortality, infections, prolonged hospital length of stay, and higher healthcare costs. As such, there is a need for intervention strategies to prevent and reduce ETFI. Incorporating whole foods with bioactive properties is a promising strategy. Emerging research has elucidated bioactive properties of whole foods with specific benefits for the prevention and management of adverse gastrointestinal events commonly associated with TFs. However, lack of evidence-based recommendations and technological challenges have limited the use of such foods in commercial TF formulas. This review addresses research gaps by discussing 5 whole foods (rhubarb, banana, curcumin, peppermint oil, and ginger) with bioactive attributes identified through literature searches and clinical experience as having substantial scientific rationale to consider their application for ETFI in adult populations.

Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.

Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light.

Enzymes are ideal for use in asymmetric catalysis by the chemical industry, because their chemical compositions can be tailored to a specific substrate and selectivity pattern while providing efficiencies and selectivities that surpass those of classical synthetic methods. However, enzymes are limited to reactions that are found in nature and, as such, facilitate fewer types of transformation than do other forms of catalysis. Thus, a longstanding challenge in the field of biologically mediated catalysis has been to develop enzymes with new catalytic functions. Here we describe a method for achieving catalytic promiscuity that uses the photoexcited state of nicotinamide co-factors (molecules that assist enzyme-mediated catalysis). Under irradiation with visible light, the nicotinamide-dependent enzyme known as ketoreductase can be transformed from a carbonyl reductase into an initiator of radical species and a chiral source of hydrogen atoms. We demonstrate this new reactivity through a highly enantioselective radical dehalogenation of lactones-a challenging transformation for small-molecule catalysts. Mechanistic experiments support the theory that a radical species acts as an intermediate in this reaction, with NADH and NADPH (the reduced forms of nicotinamide adenine nucleotide and nicotinamide adenine dinucleotide phosphate, respectively) serving as both a photoreductant and the source of hydrogen atoms. To our knowledge, this method represents the first example of photo-induced enzyme promiscuity, and highlights the potential for accessing new reactivity from existing enzymes simply by using the excited states of common biological co-factors. This represents a departure from existing light-driven biocatalytic techniques, which are typically explored in the context of co-factor regeneration.

s-SHIP expression identifies a subset of murine basal prostate cells as neonatal stem cells.

Isolation of prostate stem cells (PSCs) is crucial for understanding their biology during normal development and tumorigenesis. In this aim, we used a transgenic mouse model expressing GFP from the stem cell-specific s-SHIP promoter to mark putative stem cells during postnatal prostate development. Here we show that cells identified by GFP expression are present transiently during early prostate development and localize to the basal cell layer of the epithelium. These prostate GFP+ cells are a subpopulation of the Lin- CD24+ Sca-1+ CD49f+ cells and are capable of self-renewal together with enhanced growth potential in sphere-forming assay in vitro, a phenotype consistent with that of a PSC population. Transplantation assays of prostate GFP+ cells demonstrate reconstitution of prostate ducts containing both basal and luminal cells in renal grafts. Altogether, these results demonstrate that s-SHIP promoter expression is a new marker for neonatal basal prostate cells exhibiting stem cell properties that enables PSCs in situ identification and isolation via a single consistent parameter. Transcriptional profiling of these GFP+ neonatal stem cells showed an increased expression of several components of the Wnt signaling pathway. It also identified stem cell regulators with potential applications for further analyses of normal and cancer stem cells.

Investigation of effect of nutritional drink on chemotherapy-induced mucosal injury and tumor growth in an established animal model.

Chemotherapy-induced mucositis represents a significant burden to quality of life and healthcare costs, and may be improved through enhanced nutritional status. We first determined the safety of two nutritional drinks (plus placebo), and then potential gut protection in tumor-bearing rats in a model of methotrexate-induced mucositis. In study 1, animals were fed one of two test diets (or placebo or control chow pellets) for a total of 60 days and were monitored daily. All diets were found to be safe to administer. In study 2, after seven days of receiving diets, a Dark Agouti Mammary Adenocarcinoma (DAMA) was transplanted subcutaneously. Ten days after starting diets, animals had 2 mg/kg intramuscular methotrexate administered on two consecutive days; after this time, all animals were given soaked chow. Animals were monitored daily for changes in bodyweight, tumor burden and general health. Animals were killed 10, 12 and 16 days after initially starting diets, and tissues were collected at necropsy. In study 1, animals receiving diets had gained 0.8% and 10.8% of their starting bodyweight after 60 days, placebo animals 4.4%, and animals fed on standard chow had gained 15.1%. In study 2, there was no significant influence of test diet on bodyweight, organ weight, tumor burden or biochemical parameters. Only animals treated with MTX exhibited diarrhea, although animals receiving Diet A and Diet C showed a non-significant increase in incidence of diarrhea. Administration of these nutritional drinks did not improve symptoms of mucositis.

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis.

The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligands contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of "humanized" bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in "humanized" mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cell-based cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization.

ß4 Integrin signaling induces expansion of prostate tumor progenitors.

The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the ß4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of ß4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective ß4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant ß4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that ß4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the ß4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.

Cell-intrinsic abrogation of TGF-ß signaling delays but does not prevent dysfunction of self/tumor-specific CD8 T cells in a murine model of autochthonous prostate cancer.

Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials. However, poor in vivo persistence and maintenance of antitumor activity of transferred T cells remain major problems. TGF-ß is a potent immunosuppressive cytokine that is often expressed at high levels within the tumor microenvironment, potentially limiting T cell-mediated antitumor activity. In this study, we used a model of autochthonous murine prostate cancer to evaluate the effect of cell-intrinsic abrogation of TGF-ß signaling in self/tumor-specific CD8 T cells used in ACT to target the tumor in situ. We found that persistence and antitumor activity of adoptively transferred effector T cells deficient in TGF-ß signaling were significantly improved in the cancerous prostate. However, over time, despite persistence in peripheral lymphoid organs, the numbers of transferred cells in the prostate decreased and the residual prostate-infiltrating T cells were no longer functional. These findings reveal that TGF-ß negatively regulates the accumulation and effector function of transferred self/tumor-specific CD8 T cells and highlight that, when targeting a tumor Ag that is also expressed as a self-protein, additional substantive obstacles are operative within the tumor microenvironment, potentially hampering the success of ACT for solid tumors.